Page 118«..1020..117118119120..130140..»

Category Archives: Transhuman News

Seborrheic dermatitis – Symptoms and causes – Mayo Clinic

Posted: November 23, 2022 at 4:30 am

Overview Seborrheic dermatitis on the face Open pop-up dialog box

Close

Seborrheic dermatitis causes a rash of oily patches with yellow or white scales. The rash may look darker or lighter in people with brown or Black skin and redder in those with white skin.

Seborrheic (seb-o-REE-ik) dermatitis is a common skin condition that mainly affects your scalp. It causes scaly patches, inflamed skin and stubborn dandruff. It usually affects oily areas of the body, such as the face, sides of the nose, eyebrows, ears, eyelids and chest. This condition can be irritating but it's not contagious, and it doesn't cause permanent hair loss.

Seborrheic dermatitis may go away without treatment. Or you may need to use medicated shampoo or other products long term to clear up symptoms and prevent flare-ups.

Seborrheic dermatitis is also called dandruff, seborrheic eczema and seborrheic psoriasis. When it occurs in infants, it's called cradle cap.

Seborrheic dermatitis signs and symptoms may include:

The signs and symptoms of seborrheic dermatitis tend to flare with stress, fatigue or a change of season.

See your health care provider if:

Sign up for free, and stay up to date on research advancements, health tips and current health topics, like COVID-19, plus expertise on managing health.

To provide you with the most relevant and helpful information, and understand which information is beneficial, we may combine your email and website usage information with other information we have about you. If you are a Mayo Clinic patient, this could include protected health information. If we combine this information with your protected health information, we will treat all of that information as protected health information and will only use or disclose that information as set forth in our notice of privacy practices. You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail.

Subscribe!

You'll soon start receiving the latest Mayo Clinic health information you requested in your inbox.

Please, try again in a couple of minutes

Retry

The exact cause of seborrheic dermatitis isn't clear. It may be due to the yeast Malassezia, excess oil in the skin or a problem in the immune system.

Risk factors for seborrheic dermatitis include:

Sept. 27, 2022

See the original post here:
Seborrheic dermatitis - Symptoms and causes - Mayo Clinic

Posted in Eczema | Comments Off on Seborrheic dermatitis – Symptoms and causes – Mayo Clinic

Oatmeal skincare is the perfect solution for sensitive skin (+ best products to try) – Lifestyle Asia Singapore

Posted: at 4:30 am

Oatmeal skincare is the perfect solution for sensitive skin (+ best products to try)  Lifestyle Asia Singapore

Read more:
Oatmeal skincare is the perfect solution for sensitive skin (+ best products to try) - Lifestyle Asia Singapore

Posted in Eczema | Comments Off on Oatmeal skincare is the perfect solution for sensitive skin (+ best products to try) – Lifestyle Asia Singapore

Medicine MBChB – University Of Worcester

Posted: at 4:28 am

A week in the life of a medical student A week in the life of a Three Counties Medical School student - Phase One

At the start of each week you will need to read the Study Guide which sets out the learning outcomes and learning opportunities for the week. On Monday the first formal session is in a lecture format and is called Map Reading because the tutor will go through the journey planned for the week - where you will go, what you will see and what you will bring back home.

The next session is Problem Based Learning (PBL). Here you will be in a group of about eight students with a facilitator who is a doctor. The facilitator is not there to teach; indeed, he or she will spend most of the time listening.

You will be discussing two or three Presentations, realistic patient scenarios that a doctor might encounter.

The aim is to identify what you know and what you do not know in order to understand the problem or problems (there are usually several) that the patient presents. The facilitator will keep you on track. The Presentations are carefully constructed to point to the learning required in the week. You will end up with a number of learning outcomes, things you dont know or understand.

The next session is learning about the consultation, the key interaction between doctor and patient. This will be either talking to a simulated patient (usually an actor) or performing a physical examination. This will be examining each other but we have guidelines on how this is done to avoid embarrassment.

Most of the rest of the week is about finding out the answers to the questions posed in the PBL groups. Some of this is in the form of a carousel where you will learn about normal and abnormal structure and function. This might include anatomical models or images. Another is called applied physiology and procedural skills where you will learn skills and procedures such as venepuncture. These are all linked to the learning outcomes for the week and the PBL presentations.

One week in three you will be on a placement in primary care where you are likely to meet patients with similar problems to those in the PBL group and discuss your progress with the Year Long Case Studies.

At the end of the week there is a wrap up session where we all go back to the Map and see what we have learned. Then its another PBL session where you discuss what you have learned; do we all now understand the Presentations, is there anything else we dont know? We then have another session on the consultation.

Every week will be as varied as the patients but here are some of the experiences you can expect. Not all will happen each week!

Continue reading here:
Medicine MBChB - University Of Worcester

Posted in Immortality Medicine | Comments Off on Medicine MBChB – University Of Worcester

Taoist sexual practices – Wikipedia

Posted: at 4:28 am

Religious sexual practices

Taoist sexual practices (traditional Chinese: ; simplified Chinese: ; pinyin: fngzhngsh; lit. 'arts of the bedchamber') are the ways Taoists may practice sexual activity. These practices are also known as "joining energy" or "the joining of the essences". Practitioners believe that by performing these sexual arts, one can stay in good health, and attain longevity or spiritual advancement.[1][2][3]

Some Taoist sects during the Han dynasty performed sexual intercourse as a spiritual practice, called hq (, lit. "joining energy").[citation needed] The first sexual texts that survive today are those found at Mawangdui[citation needed]. While Taoism had not yet fully evolved as a philosophy at this time, these texts shared some remarkable similarities with later Tang dynasty texts, such as the Ishinp (). The sexual arts arguably reached their climax between the end of the Han dynasty and the end of the Tang dynasty[citation needed].

After AD 1000, Confucian restraining attitudes towards sexuality became stronger, so that by the beginning of the Qing dynasty in 1644, sex was a taboo topic in public life[citation needed]. These Confucians alleged that the separation of genders in most social activities existed 2,000 years ago and suppressed the sexual arts. Because of the taboo surrounding sex, there was much censoring done during the Qing in literature, and the sexual arts disappeared in public life[citation needed]. As a result, some of the texts survived only in Japan, and most scholars had no idea that such a different concept of sex existed in early China.[4]

The basis of all Taoist thinking is that qi () is part of everything in existence.[5] Qi is related to another energetic substance contained in the human body known as jing (), and once all this has been expended the body dies. Jing can be lost in many ways, but most notably through the loss of body fluids. Taoists may use practices to stimulate/increase and conserve their bodily fluids to great extents. The fluid believed to contain the most jing is semen. Therefore, Taoists believe in decreasing the frequency of, or totally avoiding, ejaculation in order to conserve life essence.[6]

Many Taoist practitioners link the loss of ejaculatory fluids to the loss of vital life force: where excessive fluid loss results in premature aging, disease, and general fatigue. While some Taoists contend that one should never ejaculate, others provide a specific formula to determine the maximum number of regular ejaculations in order to maintain health.[7][8]

The general idea is to limit the loss of fluids as much as possible to the level of your desired practice. As these sexual practices were passed down over the centuries, some practitioners have given less importance to the limiting of ejaculation. This variety has been described as "...while some declare non-ejaculation injurious, others condemn ejaculating too fast in too much haste."[8] Nevertheless, the "retention of the semen" is one of the foundational tenets of Taoist sexual practice.[9]

There are different methods to control ejaculation prescribed by the Taoists. In order to avoid ejaculation, the man could do one of several things. He could pull out immediately before orgasm, a method also more recently termed as "coitus conservatus."[10] A second method involved the man applying pressure on the perineum, thus retaining the sperm. While if done incorrectly this can cause retrograde ejaculation, the Taoists believed that the jing traveled up into the head and "nourished the brain."[11] Cunnilingus was believed to be ideal by preventing the loss of semen and vaginal liquids.

Another important concept of "the joining of the essences" was that the union of a man and a woman would result in the creation of jing, a type of sexual energy. When in the act of lovemaking, jing would form, and the man could transform some of this jing into qi, and replenish his lifeforce. By having as much sex as possible, men had the opportunity to transform more and more jing, and as a result would see many health benefits.[6]

The concept of yin and yang is important in Taoism and consequently also holds special importance in sex. Yang usually referred to the male sex, whereas yin could refer to the female sex. Man and woman were the equivalent of heaven and earth, but became disconnected. Therefore, while heaven and earth are eternal, man and woman suffer a premature death.[12] Every interaction between yin and yang had significance. Because of this significance, every position and action in lovemaking had importance. Taoist texts described a large number of special sexual positions that served to cure or prevent illness, similar to the Kama Sutra.[13]

There was the notion that men released yang during orgasm, while women shed yin during theirs. Every orgasm from the user would nourish the partner's energy.[14]

For Taoists, sex was not just about pleasing a man.[15] The woman also had to be stimulated and pleased in order to benefit from the act of sex. Sun (), female advisor to the Yellow Emperor (Huangdi), noted ten important indications of female satisfaction.[16] If sex were performed in this manner, the woman would create more jing, and the man could more easily absorb the jing to increase his own qi.[17]

According to Jolan Chang, in early Chinese history, women played a significant role in the Tao () of loving, and that the degeneration into subordinate roles came much later in Chinese history.[18] Women were also given a prominent place in the Ishinp, with the tutor being a woman. One of the reasons women had a great deal of strength in the act of sex was that they walked away undiminished from the act. The woman had the power to bring forth life, and did not have to worry about ejaculation or refractory period. To quote Laozi from the Tao Te Ching: "The Spirit of the Valley is inexhaustible... Draw on it as you will, it never runs dry."[19]

Women also helped men extend their lives. Many of the ancient texts were dedicated explanations of how a man could use sex to extend his own life but, his life was extended only through the absorption of the woman's vital energies (jing and qi). Some Taoists came to call the act of sex "the battle of stealing and strengthening".[20] These sexual methods could be correlated with Taoist military methods. Instead of storming the gates, the battle was a series of feints and maneuvers that would sap the enemy's resistance.[21] Fang described this battle as "the ideal was for a man to 'defeat' the 'enemy' in the sexual 'battle' by keeping himself under complete control so as not to emit semen, while at the same time exciting the woman until she reached orgasm and shed her Yin essence, which was then absorbed by the man."[22]

Jolan Chang points out that it was after the Tang dynasty (AD 618906) that "the Tao of Loving" was "steadily corrupted", and that it was these later corruptions that reflected battle imagery and elements of a "vampire" mindset.[23] Other research into early Taoism found more harmonious attitudes of yin-yang communion.[24]

This practice was not limited to male on female, however, as it was possible to women to do the same in turn with the male yang. The deity known as the Queen Mother of the West was described to have no husband, instead having intercourse with young virgin males to nourish her female element.[25]

Some Ming dynasty Taoist sects believed that one way for men to achieve longevity or 'towards immortality' is by having intercourse with virgins, particularly young virgins. Taoist sexual books by Liangpi[26] and Sanfeng[27] call the female partner ding () and recommend sex with premenarche virgins.

Liangpi concludes that the ideal ding is a pre-menarche virgin just under 14 years of age and women older than 18 should be avoided.[28] Sanfeng went further and divided ding partners into three ranks of descending importance: premenarche virgins aged 14-16, menstruating virgins aged 16-20 and women aged 21-25.[29][30]

According to Ge Hong, a 4th-century Taoist alchemist, "those seeking 'immortality' must perfect the absolute essentials. These consist of treasuring the jing, circulating the qi, and consuming the great medicine."[31] The sexual arts concerned the first precept, treasuring the jing. This is partially because treasuring the jing involved sending it up into the brain. In order to send the jing into the brain, the male had to refrain from ejaculation during sex. According to some Taoists, if this was done, the jing would travel up the spine and nourish the brain instead of leaving the body. Ge Hong also states, however, that it is folly to believe that performing the sexual arts only can achieve immortality and some of the ancient myths on sexual arts had been misinterpreted and exaggerated. Indeed, the sexual arts had to be practiced alongside alchemy to attain longevity. Ge Hong also warned it could be dangerous if practiced incorrectly.[31]

More here:
Taoist sexual practices - Wikipedia

Posted in Immortality Medicine | Comments Off on Taoist sexual practices – Wikipedia

Republic of Florence – Wikipedia

Posted: at 4:28 am

City-state on the Apennine Peninsula between 1115 and 1569

The Republic of Florence, officially the Florentine Republic (Italian: Repubblica Fiorentina, pronounced[repubblika fjorentina], or Repubblica di Firenze), was a medieval and early modern state that was centered on the Italian city of Florence in Tuscany.[1] The republic originated in 1115, when the Florentine people rebelled against the Margraviate of Tuscany upon the death of Matilda of Tuscany, who controlled vast territories that included Florence. The Florentines formed a commune in her successors' place.[3] The republic was ruled by a council known as the Signoria of Florence. The signoria was chosen by the gonfaloniere (titular ruler of the city), who was elected every two months by Florentine guild members.

During the Republic's history, Florence was an important cultural, economic, political and artistic force in Europe. Its coin, the florin, became a world monetary standard.[4] During the Republican period, Florence was also the birthplace of the Renaissance, which is considered a fervent period of European cultural, artistic, political and economic rebirth.[5]

The republic had a checkered history of coups and countercoups against various factions. The Medici faction gained governance of the city in 1434 under Cosimo de' Medici. The Medici kept control of Florence until 1494. Giovanni de' Medici (later Pope Leo X) reconquered the republic in 1512.

Florence repudiated Medici authority for a second time in 1527, during the War of the League of Cognac. The Medici reassumed their rule in 1531 after an 11-month siege of the city, aided by Emperor CharlesV. Pope ClementVII, himself a Medici, appointed his relative Alessandro de' Medici as the first "Duke of the Florentine Republic", thereby transforming the Republic into a hereditary monarchy.

The second Duke, CosimoI, established a strong Florentine navy and expanded his territory, conquering Siena. In 1569, the pope declared Cosimo the first grand duke of Tuscany. The Medici ruled the Grand Duchy of Tuscany until 1737.

The city of Florence was established in 59 BC by Julius Caesar. Since 846 AD, the city had been part of the Marquisate of Tuscany. After the female ruler of the marquisate, Matilda of Tuscany, died in 1115, the city did not submit readily to her successor Rabodo (r. 11161119), who was killed in a dispute with the city.

It is not known precisely when Florence formed its own republican/oligarchical government independent of the marquisate, although the death of Rabodo in 1119 should be a turning point. The first official mention of the Florentine republic was in 1138, when several cities around Tuscany formed a league against Henry X of Bavaria. The country was nominally part of the Holy Roman Empire.[3]

According to a study carried out by Enrico Faini of the University of Florence,[8] there were about fifteen old aristocratic families who moved to Florence between 1000 and 1100: Amidei; Ardinghi; Brunelleschi; Buondelmonti; Caponsacchi; Donati; Fifanti; Gherardini of Montagliari; Guidi; Nerli; Porcelli; Sacchetti; Scolari; Uberti; and Visdomini.

The newly independent Florence prospered in the 12th century through extensive trade with foreign countries. This, in turn, provided a platform for the demographic growth of the city, which mirrored the rate of construction of churches and palazzi. This prosperity was shattered when Emperor Frederick I Barbarossa invaded the Italian peninsula in 1185. As a result, the margraves of Tuscany re-acquired Florence and its townlands. The Florentines re-asserted their independence when Holy Roman Emperor Henry VI died in 1197.[3]

Florence's population continued to grow into the 13th century, reaching a level of 30,000 inhabitants. As has been said, the extra inhabitants supported the city's trade and vice versa. Several new bridges and churches were built, most prominently the cathedral of Santa Maria del Fiore, begun in 1294. The buildings from this era serve as Florence's best examples of Gothic Architecture. Politically, Florence was barely able to maintain peace between its competing factions. The precarious peace that existed at the beginning of the century was destroyed in 1216 when two factions, known as the Guelphs and the Ghibellines, began to war. The Ghibellines were supporters of the noble rulers of Florence, whereas the Guelphs were populists.

The Ghibellines, who had ruled the city under Frederick of Antioch since 1244, were deposed in 1250 by the Guelphs. The Guelphs led Florence to prosper further. Their primarily mercantile orientation soon became evident in one of their earliest achievements: the introduction of a new coin, the florin, in 1252. It was widely used beyond Florence's borders due to its reliable, fixed gold content and soon became one of the common currencies of Europe and the Near East. The same year saw the creation of the Palazzo del Popolo.[9] The Guelphs lost the reins of power after Florence suffered a catastrophic defeat at the Battle of Montaperti against Siena in 1260. The Ghibellines resumed power and undid many of the advances of the Guelphs, for example the demolition of hundreds of towers, homes, and palaces. The fragility of their rule caused the Ghibellines to seek out an arbitrator in the form of Pope Clement IV, who openly favoured the Guelphs, and restored them to power.

The Florentine economy reached a zenith in the latter half of the 13th century, and its success was reflected by the building of the famed Palazzo della Signoria, designed by Arnolfo di Cambio. The Florentine townlands were divided into administrative districts in 1292. In 1293, the Ordinances of Justice were enacted, which effectively became the constitution of the republic of Florence throughout the Italian Renaissance.[10] The city's numerous luxurious palazzi were becoming surrounded by townhouses built by the ever prospering merchant class.[3] In 1298, the Bonsignori family of Siena, one of the leading banking families of Europe, went bankrupt, and the city of Siena lost its status as the most prominent banking center of Europe to Florence.

In 1304, the war between the Ghibellines and the Guelphs led to a great fire that destroyed much of the city. Napier gives the following account:

Battles first began between the Cerchi and Giugni at their houses in the Via del Garbo; they fought day and night, and with the aid of the Cavalcanti and Antellesi the former subdued all that quarter: a thousand rural adherents strengthened their bands, and that day might have seen the Neri's destruction if an unforeseen disaster had not turned the scale. A certain dissolute priest, called Neri Abati, prior of San Piero Scheraggio, false to his family and in concert with the Black chiefs, consented to set fire to the dwellings of his own kinsmen in Orto-san-Michele; the flames, assisted by faction, spread rapidly over the richest and most crowded part of Florence: shops, warehouses, towers, private dwellings and palaces, from the old to the new market-place, from Vacchereccia to Porta Santa Maria and the Ponte Vecchio, all was one broad sheet of fire: more than nineteen hundred houses were consumed; plunder and devastation revelled unchecked amongst the flames, whole races were reduced in one moment to beggary, and vast magazines of the richest merchandise were destroyed. The Cavalcanti, one of the most opulent families in Florence, beheld their whole property consumed, and lost all courage; they made no attempt to save it, and, after almost gaining possession of the city, were finally overcome by the opposite faction.

The golden florin of the Republic of Florence was the first European gold coin struck in sufficient quantities to play a significant commercial role since the 7th century. As many Florentine banks were international companies with branches across Europe, the florin quickly became the dominant trade coin of Western Europe for large scale transactions, replacing silver bars in multiples of the mark (a weight unit equal to eight ounces).

In fact, with the collapse of the Bonsignori family[it], several new banking families sprang up in Florence: the Bardis, Peruzzis and the Acciaioli. The friction between the Guelphs and the Ghibellines did not cease, authority still passed between the two frequently.

Florence's reign as the foremost banking city of Europe did not last long; the aforesaid families were bankrupt in 1340, not because of Edward III of England's refusal to pay his debts, as is often stated (the debt was just 13,000) but because of a Europe-wide economic recession. While the banks perished, Florentine literature flourished, and Florence was home to some of the greatest writers in Italian history: Dante, Petrarch and Boccaccio. They were Europe's first vernacular writers, choosing the Tuscan dialect of Italian (which, as a result, evolved into the standard Italian language) over Latin.

Florence was hit hard by the Black Death. Having originated in the Orient, the plague arrived in Messina in 1347. The plague devastated Europe, robbing it of an estimated 1/3 of its population. This, combined with the economic downturn, took its toll on the city-state. The ensuing collapse of the feudal system changed the social composition of Europe forever; it was one of the first steps out of the Middle Ages.

The war with Avignon papacy strained the regime. In 1378 discontented wool workers revolted. The Ciompi revolt, as it is known, established a revolutionary commune. In 1382 the wealthier classes crushed the seeds of rebellion.

The famous Medici bank was established by Giovanni di Bicci de' Medici in October 1397. The bank continued to exist (albeit in an extremely diminished form) until the time of Ferdinando II de'Medici in the 17th century. But, for now, Giovanni's bank flourished.

Beginning in 1389, Gian Galeazzo Visconti of Milan expanded his dominion into the Veneto, Piedmont, Emilia and Tuscany. During this period Florence, under the leadership of Maso degli Albizzi and Niccol da Uzzano was involved in three wars with Milan (139092, 139798, 140002). The Florentine army, commanded by John Hawkwood, contained the Milanese during the first war.[17] The second war started in March 1397. Milanese troops devastated the Florentine contado, but were checked in August of that year.

The war expenses exceeded one million florins and necessitated tax raises and forced loans. A peace agreement in May 1398 was brokered by Venice, but left the struggle unresolved. Over the next two years Florentine control of Tuscany and Umbria collapsed. Pisa and Siena as well as a number of smaller cities submitted to Gian Galeazzo, while Lucca withdrew from the anti-Visconti league, with Bologna remaining the only major ally. In November 1400 a conspiracy involving both exiles and internal opponents was uncovered. Two Ricci were implicated as leaders of a plot to eliminate the regime's inner circle and open the gates to the Milanese. Confessions indicated that the plan had wide support among the elites, including a Medici and several of the Alberti.

The republic bankrolled the emperor-elect Rupert. However, he was defeated by the Milanese in the fall of 1401. Visconti then turned to Bologna. On June 26, 1402, combined Bolognese-Florentine forces were routed atCasalecchio, near Bologna, which was taken on the 30th. The road to Tuscany was open. However, Florence was saved after an outbreak of plague had spread from Tuscany to Emilia and Lombardy: Gian Galeazzo died from it on 3 September 1402.[17]

The Visconti domains were divided between three heirs. Gabriele Maria Visconti sold Pisa to the Republic of Florence for 200,000 florins. Since the Pisans did not intend to voluntarily submit to their long-time rivals, the army under Maso degli Albizzi took Pisa on 9 October 1406 after a long siege, that was accompanied by numerous atrocities.[17]

The state authorities had been approached by the Duchy of Milan in 1422, with a treaty, that prohibited Florence's interference with Milan's impending war with the Republic of Genoa.Florence obliged, but Milan disregarded its own treaty and occupied a Florentine border town. The conservative government wanted war, while the people bemoaned such a stance as they would be subject to enormous tax increases. The republic went to war with Milan, and won, upon the Republic of Venice's entry on their side. The war was concluded in 1427, and the Visconti of Milan were forced to sign an unfavourable treaty.

The debt incurred during the war was gargantuan, approximately 4,200,000 florins. To pay, the state had to change the tax system. The current estimo system was replaced with the catasto. The catasto was based on a citizen's entire wealth, while the estimo was simply a form of income tax. Apart from war, Filippo Brunelleschi created the renowned dome of the Santa Maria del Fiore, which astounded contemporaries and modern observers alike.

The son of Giovanni di Bicci de' Medici, Cosimo de' Medici succeeded his father as the head of the Medici Bank. He played a prominent role in the government of Florence until his exile in 1433, after a disastrous war with Tuscany's neighbour, the Republic of Lucca. Cosimo's exile in Venice lasted for less than a year, when the people of Florence overturned Cosimo's exile in a democratic vote. Cosimo returned to the acclaim of his people and the banishment of the Albizzi family, who had exiled him.

The Renaissance began during Cosimo's de facto rule of Florence, the seeds of which had arguably been laid before the Black Death tore through Europe. Niccol Niccoli was the leading Florence humanist scholar of the time. He appointed the first Professor of Greek, Manuel Chrysoloras (the founder of Hellenic studies in Italy), at the University of Florence in 1397. Niccoli was a keen collector of ancient manuscripts, which he bequeathed to Cosimo upon his death in 1437. Poggio Bracciolini succeeded Niccoli as the principal humanist of Florence. Bracciolini was born Arezzo in 1380. He toured Europe, searching for more ancient Greco-Roman manuscripts for Niccoli. Unlike his employer, Bracciolini also authored his own works. He was made the Chancellor of Florence shortly before his death, by Cosimo, who was his best friend.

Florence hosted the Great Ecumenical Council in 1439; this council was launched in an attempt to reconcile the Byzantine Eastern Orthodox Church with Roman Catholicism. Pope Eugenius IV convened it in reply to a cry for assistance from the Emperor of the Eastern Roman Empire (also known as the Byzantine Empire) John VIII Palaiologos. John VIII's empire was slowly being devoured by the Ottoman Turks.The council was a huge boost to Florence's international prestige. The council deliberated until July 1439. Both parties had reached a compromise, and the Pope agreed to militarily aid the Byzantine Emperor. However, upon John VIII's homecoming to Constantinople, the Greeks rejected the compromise, leading to riots throughout what remained of the Byzantine Empire. John VIII was forced to repudiate the agreement with the Roman church to appease the rioters. As a result, no Western aid was forthcoming and the Byzantine Empire's fate was sealed. Fourteen years later in 1453, Constantinople fell to the Ottomans.

Cosimo's fervent patronage transformed Florence into the epitome of a Renaissance city. He employed Donatello, Brunelleschi, and Michelozzo. All these artistic commissions cost Cosimo over 600,000 florins.

Foreign relations, both as a backdrop to Cosimo's rise to power and during first twenty years of his rule, were dominated by the Wars in Lombardy. This series of conflicts between the Venetian Republic and the Duchy of Milan for hegemony in Northern Italy lasted from 1423 to 1454 and involved a number of Italian states, that occasionally switched sides according to their changing interests. Filippo Maria Visconti of Milan invaded Florence twice in the 1430s, and again in 1440, but his army was finally defeated in the battle of Anghiari. The Milanese invasions were largely instigated by the exiled Albizzi family. Death of Filippo Maria in 1447 led to a major change in the alliances. In 1450 Cosimo's current ally Francesco Sforza established himself as the Duke of Milan. Florentine trade interests made her support Sforza's Milan in the war against Venice, while the fall of Constantinople in 1453 dealt a blow to Venetian finances. Eventually, the Peace of Lodi recognized Venetian and Florentine territorial gains and the legitimacy of the Sforza rule in Milan.[28] The Milan-Florence alliance played a major role in stabilizing the peninsula for the next 40 years.

The political crisis of 1458 was the first serious challenge to the Medici rule. The cost of wars had been borne by the great families of Florence, and disproportionately so by Medici's opponents. A number of them (Serragli, Baroncelli, Mancini, Vespucci, Gianni) were practically ruined and had to sell their properties, and those were acquired by Medici's partisans at bargain prices. The opposition used partial relaxation of Medici control of the republic institutions to demand political reforms, freedom of speech in the councils and a greater share in the decision-making. Medici's party response was to use threats of force from private armies and Milanese troops and arranging a popular assembly dominated by Cosimo's supporters. It exiled the opponents of the regime and introduced the open vote in councils, "in order to unmask the anti-Medician rebels".[28]

From 1458 Cosimo withdrew from any official public role, but his control of Florence was greater than ever. In the spring of 1459 he entertained the new pope Pius II, who stopped in Florence on his way to the Council of Mantua to declare a crusade against the Ottomans, and Galeazzo Maria Sforza, Francesco's son, who was to escort the pope from Florence to Mantua. In his memoirs, Pius said that Cosimo "was considered the arbiter of war and peace, the regulator of law; less a citizen than master of his city. Political councils were held in his home; the magistrates he chose were elected; he was king in all but name and legal status. Some asserted that his tyranny was intolerable."

Piero the Gouty was the eldest son of Cosimo. Piero, as his sobriquet the gouty implies, suffered from gout and did not enjoy good health. Lorenzo the Magnificent was Piero's eldest son by his wife Lucrezia Tornabuoni. Piero's reign furthered the always fractious political divisions of Florence when he had called up huge debts owed to the Medici Bank. These debts were owed primarily by a Florentine nobleman, Luca Pitti. Lucca called for an armed insurrection against Piero, but a co-conspirator rebutted this. Duke Francesco Sforza of Milan died in 1466, and his son Galeazzo Maria Sforza became the new Milanese duke. With the death of Francesco Sforza, Florence lost a valuable ally among the other Italian states.

In August 1466, the conspirators acted. They received support from the Duke of Ferrara, who marched troops into the Florentine countryside with the intent of deposing Piero. The coup failed. The Florentines were not willing to support it, and soon after their arrival, Ferrara's troops left the city. The conspirators were exiled for life. While the internal problems were fixed, Venice took the opportunity to invade Florentine territory in 1467. Piero appointed Federigo da Montefeltro, Lord of Urbino, to command his mercenaries. An inconclusive battle ensued, with the Venetians forces retreating. In the winter of 1469 Piero died.

Lorenzo succeeded his father, Piero. Lorenzo, as heir, was accordingly groomed by his father to rule over Florence.

Lorenzo was the greatest artistic patron of the Renaissance. He patronised Leonardo da Vinci, Michelangelo and Botticelli, among others. During Lorenzo's reign, the Renaissance truly descended on Florence. Lorenzo commissioned a multitude of amazing pieces of art and also enjoyed collecting fine gems. Lorenzo had many children with his wife Clarice Orsini, including the future Pope Leo X and his eventual successor in Florence, Piero the Unfortunate.

Lorenzo's brother Giuliano was killed before his own eyes in the Pazzi conspiracy of 1478. This plot was instigated by the Pazzi family. The coup was unsuccessful, and the conspirators were executed in a very violent manner. The scheme was supported by the Archbishop of Pisa, Francesco Salviati, who was also executed in his ceremonial robes. News of this sacrilege reached Pope Sixtus IV (who had also supported the conspiracy against the Medicis). Sixtus IV was "outraged" and excommunicated everyone in Florence. Sixtus sent a papal delegation to Florence to arrest Lorenzo. The people of Florence were obviously enraged by the Pope's actions, and the local clergy too. The populace refused to resign Lorenzo to the papal delegation. A war followed, which lasted for two years until Lorenzo tactfully went about diplomatically securing a peace. Lorenzo died in 1492 and was succeeded by his son Piero.

Piero ruled Florence for a mere two years. Charles VIII of France invaded Italy in September 1494. He demanded passage through Florence to Naples, where he intended to secure the throne for himself. Piero met Charles at the fringes of Florence to try and negotiate. Piero capitulated to all Charles' demands, and upon arriving back in the city in November, he was branded as a traitor. He was forced to flee the republic with his family.

After the fall of the Medici, Girolamo Savonarola ruled the state. Savonarola was a priest from Ferrara. He came to Florence in the 1480s. By proclaiming predictions and through vigorous preaching, he won the people to his cause. Savonarola's new government ushered in democratic reforms. It allowed many exiles back into Florence, who were banished by the Medici. Savonarola's ulterior goal, however, was to transform Florence into a "city of god". Florentines stopped wearing garish colours, and many women took oaths to become nuns. Savonarola became most famous for his "Bonfire of the Vanities", where he ordered all "vanities" to be gathered and burned. These included wigs, perfume, paintings, and ancient pagan manuscripts.[45]Savonarola's rule collapsed a year later. He was excommunicated by Pope Alexander VI in late 1497. In the same year, Florence embarked on a war with Pisa, which had been de facto independent since Charles VIII's invasion three years before. The endeavour failed miserably, and this led to food shortages. That, in turn, led to a few isolated cases of the plague. The people blamed Savonarola for their woes, and he was tortured and executed in the Piazza della Signoria by being burned at the stake by Florentine authorities, in May 1498.

In 1502, the Florentines chose Piero Soderini as their first ruler for life. Soderini succeeded where Savonarola had failed, when the Secretary of War, Niccol Machiavelli, recaptured Pisa. It was at this time that Machiavelli introduced a standing army in Florence, replacing the traditional use of hired mercenaries.

Soderini was repudiated in September 1512, when Cardinal Giovanni de' Medici captured Florence with Papal troops during the War of the League of Cambrai. The Medici rule of Florence was thus restored.

Soon after retaking Florence, Cardinal Giovanni de' Medici was recalled to Rome. Pope Julius II had just died, and he needed to be present for the ensuing Papal conclave. Giovanni was elected Pope, taking the name Leo X. This effectively brought the Papal States and Florence into a political union. Leo X ruled Florence by proxy, first appointing his brother Giuliano de' Medici to rule in his stead, and then in 1513, replacing Giuliano with his cousin, Lorenzo II de' Medici.[50]

Lorenzo II's government proved unpopular in Florence.[50] According to U.S. President and historian John Adams, "at this time the citizens of the state of Florence were in secret very discontented, because the Duke Lorenzo, desiring to reduce the government to the form of a principality, appeared to disdain to consult any longer with the magistrates and his fellow-citizens as he used to do, and gave audiences very seldom, and with much impatience; he attended less to the business of the city, and caused all public affairs to be managed by Messer Goro da Pistoia, his secretary."[50] In 1519, Lorenzo died from syphilis, shortly before his wife gave birth to Catherine de' Medici, the future Queen of France.[51]

Following the death of Lorenzo II, Cardinal Giulio de' Medici governed Florence until 1523, when he was elected Pope Clement VII. U.S. President John Adams later characterized his administration of Florence as "very successful and frugal."[50] Adams chronicles Cardinal Giulio as having "reduced the business of the magistrates, elections, customs of office, and the mode of expenditure of public money, in such a manner that it produced a great and universal joy among the citizens."[50]

On the death of Pope Leo X in 1521, Adams writes there was a "ready inclination in all of the principal citizens [of Florence], and a universal desire among the people, to maintain the state in the hands of the Cardinal de' Medici; and all this felicity arose from his good government, which since the death of the Duke Lorenzo, had been universally agreeable."[50]

When Cardinal Giulio was elected Pope Clement VII, he appointed Ippolito de' Medici and Alessandro de' Medici to rule Florence, under the guardianship of Cardinal Passerini. Ippolito was the son of Giuliano de' Medici, while Alessandro was allegedly the son of Clement VII. Cardinal Passerini's regency government proved highly unpopular.[53]

In May 1527, Rome was sacked by the Holy Roman Empire. The city was destroyed, and Pope Clement VII was imprisoned. During the tumult, a faction of Republicans drove out the Medici from Florence. A new wave of Puritanism swept through the city. Many new restricting fundamentalist laws were passed.

In 1529, Clement VII signed the Treaty of Barcelona with Charles V, under which Charles would, in exchange for the Pope's blessing, invade Florence and restore the Medici. They were restored after a protracted siege.

Following the Republic's surrender in the Siege of Florence, Charles V, Holy Roman Emperor issued a proclamation explicitly stating that he and he alone could determine the government of Florence. On 12 August 1530, the Emperor created the Medici hereditary rulers (capo) of the Republic of Florence. The title "Duke of the Florentine Republic" was chosen because it would bolster Medici power in the region.

Pope Clement VII intended his relative Alessandro de' Medici[a] to be the ruler of Florence, but also wanted to give the impression that the Florentines had democratically chosen Alessandro as their ruler. Even after Alessandro's accession in 1530 (he reigned as Duke of the Florentine Republic from 1532 on), Imperial troops remained stationed in Florence. In 1535, several prominent Florentine families, including the Pazzi (who attempted to kill Lorenzo de' Medici in the Pazzi Conspiracy) dispatched a delegation under Ippolito de' Medici, asking Charles V to depose Alessandro. Much to their dismay, the Emperor rejected their appeal. Charles had no intention of deposing Alessandro, who was married to Charles' daughter Margaret of Parma.

Alessandro continued to rule Florence for another two years until he was murdered on January 1, 1537 by his distant relative Lorenzino de' Medici.

As Alessandro left no legitimate issue, the question of succession was open. Florentine authorities selected Cosimo I in 1537. At the news of this, the exiled Strozzi family invaded and tried to depose Cosimo, but were defeated at Montemurlo.[60] Cosimo completely overhauled the bureaucracy and administration of Florence. In 1542, the Imperial troops stationed in Florence by Charles V were withdrawn.

In 1548, Cosimo was given a part of the Island of Elba by Charles V, and based his new developing navy there. Cosimo founded the port city of Livorno and allowed the city's inhabitants to enjoy freedom of religion. In alliance with Spain and the Holy Roman Empire, Cosimo defeated the Republic of Siena, which was allied with France, in the Battle of Marciano on August 2, 1554. On April 17, 1555, Florence and Spain occupied the territory of Siena, which, in July 1557 Philip II of Spain bestowed on Cosimo as a hereditary fiefdom. The ducal family moved into the Palazzo Pitti in 1560. Cosimo commissioned the architect Vasari to build the Uffizi, as offices for the Medici bank, continuing the Medici tradition of patronage of the arts.

In 1569, Cosimo was elevated to the rank of the Grand Duke of Tuscany in 1569 by Pope Pius V. This marks the end of the Florence Republic, and the beginning of the Grand Duchy of Tuscany.

Medici rule continued into the Grand Duchy of Tuscany until the family became extinct in 1737.

Florence was governed by a council called the signoria, which consisted of nine men. The head of the signoria was the gonfaloniere, who was chosen every two months in a lottery, as was his signoria. To be eligible, one had to have sound finances, no arrears or bankruptcies, he had to be older than thirty, had to be a member of Florence's seven main guilds (merchant traders, bankers, two clothe guilds, and judges). The lottery was often pre-determined, and the results were usually favourable to influential families. The roster of names in the lottery were replaced every five years.

The main organs of government were known as the tre maggiori. They were: the twelve good men, the standard bearers of the gonfaloniere, and the signoria. The first two debated and ratified proposed legislation, but could not introduce it. The gonfaloniere's initial two month-term in office was expanded upon the fall of Savonarola in 1498, to life, much like that of the Venetian doge. The signoria held meetings each day in the Palazzo della Signoria. Various committees controlled particular aspects of government, e.g. the Committee of War. For administrative purposes, Florence was divided into four districts, which were divided into four sub-districts. The main purpose of these counties was to ease the gathering of local militias.

To hold an elective office, one had to be of a family that had previously held office. The Medici family effectively ruled Florence on a hereditary basis, from 1434 to 1494, and 15121527.

After Alessandro de' Medici was installed as the "Duke of the Florentine Republic" in 1530, in April 1532, Pope Clement VII convinced the Bala, Florence's ruling commission, to draw up a new constitution, which formally created a hereditary monarchy. It abolished the age-old signoria (elective government) and the office of gonfaloniere (titular head-of-state elected for a two-month term) and replaced it with three institutions:

Read more from the original source:
Republic of Florence - Wikipedia

Posted in Immortality Medicine | Comments Off on Republic of Florence – Wikipedia

Elon Musk’s Free Speech Twitter Still Censoring DDoSecrets – The Intercept

Posted: at 4:21 am

  1. Elon Musk's Free Speech Twitter Still Censoring DDoSecrets  The Intercept
  2. Schiff--Russia collusion disinformation specialist--wants more censorship.  KABC
  3. Jordan Peterson Returns To Twitter, Immediately Demands The Site Censor Anonymous Trolls  Forbes
  4. Donald Trump and the blue-tick pricks  Spiked
  5. View Full Coverage on Google News

Read more here:
Elon Musk's Free Speech Twitter Still Censoring DDoSecrets - The Intercept

Posted in Censorship | Comments Off on Elon Musk’s Free Speech Twitter Still Censoring DDoSecrets – The Intercept

Moon – Wikipedia

Posted: at 4:20 am

Natural satellite orbiting the Earth

The Moon is Earth's only natural satellite. It is the fifth largest satellite in the Solar System and the largest and most massive relative to its parent planet,[f] with a diameter about one-quarter that of Earth (comparable to the width of Australia).[16] The Moon is a planetary-mass object with a differentiated rocky body, making it a satellite planet under the geophysical definitions of the term and larger than all known dwarf planets of the Solar System.[17] It lacks any significant atmosphere, hydrosphere, or magnetic field. Its surface gravity is about one-sixth of Earth's at 0.1654g, with Jupiter's moon Io being the only satellite in the Solar System known to have a higher surface gravity and density.

Orbiting Earth at an average distance of 384,400km (238,900mi), or about 30 times Earth's diameter, its gravitational influence very slowly lengthens Earth's day and is the main driver of Earth's tides. The Moon's orbit around Earth has a sidereal period of 27.3 days. During each synodic period of 29.5 days, the amount of visible surface illuminated by the Sun varies from none up to 100%, resulting in lunar phases that form the basis for the months of a lunar calendar. The Moon is tidally locked to Earth, which means that the length of a full rotation of the Moon on its own axis causes its same side (the near side) to always face Earth, and the somewhat longer lunar day is the same as the synodic period. However, 59% of the total lunar surface can be seen from Earth through shifts in perspective due to libration.

The most widely accepted origin explanation posits that the Moon formed 4.51billion years ago, not long after Earth, out of the debris from a giant impact between the planet and a hypothesized Mars-sized body called Theia. It then receded to a wider orbit because of tidal interaction with the Earth. The near side of the Moon is marked by dark volcanic maria ("seas"), which fill the spaces between bright ancient crustal highlands and prominent impact craters. Most of the large impact basins and mare surfaces were in place by the end of the Imbrian period, some three billion years ago. The lunar surface is relatively non-reflective, with a reflectance just slightly brighter than that of worn asphalt. However, because it has a large angular diameter, the full moon is the brightest celestial object in the night sky. The Moon's apparent size is nearly the same as that of the Sun, allowing it to cover the Sun almost completely during a total solar eclipse.

Both the Moon's prominence in Earth's sky and its regular cycle of phases have provided cultural references and influences for human societies throughout history. Such influences can be found in language, calendar systems, art, and mythology.The first artificial object to reach the Moon was the Soviet Union's Luna 2 uncrewed spacecraft in 1959; this was followed by the first successful soft landing by Luna 9 in 1966. The only human lunar missions to date have been those of the United States' Apollo program, which landed twelve men on the surface between 1969 and 1972. These and later uncrewed missions returned lunar rocks that have been used to develop a detailed geological understanding of the Moon's origins, internal structure, and subsequent history.

The usual English proper name for Earth's natural satellite is simply Moon, with a capital M.[18][19] The noun moon is derived from Old English mna, which (like all its Germanic cognates) stems from Proto-Germanic *mnn,[20] which in turn comes from Proto-Indo-European *mnsis "month"[21] (from earlier *mnt, genitive *mneses) which may be related to the verb "measure" (of time).[22]

Occasionally, the name Luna is used in scientific writing[23] and especially in science fiction to distinguish the Earth's moon from others, while in poetry "Luna" has been used to denote personification of the Moon.[24] Cynthia is another poetic name, though rare, for the Moon personified as a goddess,[25] while Selene (literally "Moon") is the Greek goddess of the Moon.

The usual English adjective pertaining to the Moon is "lunar", derived from the Latin word for the Moon, lna. The adjective selenian ,[26] derived from the Greek word for the Moon, seln, and used to describe the Moon as a world rather than as an object in the sky, is rare,[27] while its cognate selenic was originally a rare synonym[28] but now nearly always refers to the chemical element selenium.[29] The Greek word for the Moon does however provide us with the prefix seleno-, as in selenography, the study of the physical features of the Moon, as well as the element name selenium.[30][31]

The Greek goddess of the wilderness and the hunt, Artemis, equated with the Roman Diana, one of whose symbols was the Moon and who was often regarded as the goddess of the Moon, was also called Cynthia, from her legendary birthplace on Mount Cynthus.[32] These names Luna, Cynthia and Selene are reflected in technical terms for lunar orbits such as apolune, pericynthion and selenocentric.

The astronomical symbol for the Moon is a crescent, , for example in M 'lunar mass' (also ML).

Millions of years before present

Isotope dating of lunar samples suggests the Moon formed around 50million years after the origin of the Solar System.[33][34] Historically, several formation mechanisms have been proposed,[35] but none satisfactorily explains the features of the EarthMoon system. A fission of the Moon from Earth's crust through centrifugal force[36] would require too great an initial rotation rate of Earth.[37] Gravitational capture of a pre-formed Moon[38] depends on an unfeasibly extended atmosphere of Earth to dissipate the energy of the passing Moon.[37] A co-formation of Earth and the Moon together in the primordial accretion disk does not explain the depletion of metals in the Moon.[37] None of these hypotheses can account for the high angular momentum of the EarthMoon system.[39]

The prevailing theory is that the EarthMoon system formed after a giant impact of a Mars-sized body (named Theia) with the proto-Earth. The impact blasted material into orbit about the Earth and the material accreted and formed the Moon[40][41] just beyond the Earth's Roche limit of ~2.56R.[42]

Giant impacts are thought to have been common in the early Solar System. Computer simulations of giant impacts have produced results that are consistent with the mass of the lunar core and the angular momentum of the EarthMoon system. These simulations show that most of the Moon derived from the impactor, rather than the proto-Earth.[43] However, more recent simulations suggest a larger fraction of the Moon derived from the proto-Earth.[44][45][46][47] Other bodies of the inner Solar System such as Mars and Vesta have, according to meteorites from them, very different oxygen and tungsten isotopic compositions compared to Earth. However, Earth and the Moon have nearly identical isotopic compositions. The isotopic equalization of the Earth-Moon system might be explained by the post-impact mixing of the vaporized material that formed the two,[48] although this is debated.[49]

The impact would have released enough energy to liquefy both the ejecta and the Earth's crust, forming a magma ocean. The liquefied ejecta could have then re-accreted into the EarthMoon system.[50][51] Similarly, the newly formed Moon would have had its own lunar magma ocean; its depth is estimated from about 500km (300 miles) to 1,737km (1,079 miles).[50]

While the giant-impact theory explains many lines of evidence, some questions are still unresolved, most of which involve the Moon's composition.[52][example needed]Above a high resolution threshold for simulations, a study published in 2022 finds that giant impacts can immediately place a satellite with similar mass and iron content to the Moon into orbit far outside Earth's Roche limit. Even satellites that initially pass within the Roche limit can reliably and predictably survive, by being partially stripped and then torqued onto wider, stable orbits.[53]

After the Moon's formation the Moon settled in orbit around Earth much closer than today, making both bodies appear much larger in each's sky and causing on both more frequent and stronger eclipses and tidal effects.[54]Since then, due to tidal acceleration, the Moon's orbit around Earth has become significantly larger as well as longer, tidally locking the so-called lunar near side, always facing Earth with this same side.

The post formation cooled lunar surface has been shaped by large and many small impact events, retaining a broadly cratered landscape of all ages, as well as by volcanic activity, producing the prominent lunar maria. Volcanically active until 1.2billion years ago, most of the Moon's mare basalts erupted during the Imbrian period, 3.33.7billion years ago, though some being as young as 1.2billion years[55] and some as old as 4.2billion years.[56] The causes for the eruption of mare basalts, particularly their uneven occurrence on mainly the near-side, like the lunar highlands on the far side, has been an unresolved issue due to differing explanations. One explanation suggests that large meteorites were hitting the Moon in its early history leaving large craters which then were filled with lava. Other explanations suggest processes of lunar volcanism.[57]

The Moon is a very slightly scalene ellipsoid due to tidal stretching, with its long axis displaced 30 from facing the Earth, due to gravitational anomalies from impact basins. Its shape is more elongated than current tidal forces can account for. This 'fossil bulge' indicates that the Moon solidified when it orbited at half its current distance to the Earth, and that it is now too cold for its shape to adjust to its orbit.[58]

The Moon is by size and mass the fifth largest natural satellite of the Solar System, categorizeable as one of its planetary-mass moons, making it a satellite planet under the geophysical definitions of the term.[17] It is smaller than Mercury and considerably larger than the largest dwarf planet of the Solar System, Pluto. While the minor-planet moon Charon of the Pluto-Charon system is larger relative to Pluto,[f][59] the Moon is the largest natural satellite of the Solar System relative to their primary planets.[g]

The Moon's diameter is about 3,500km, more than a quarter of Earth's, with the face of the Moon comparable to the width of Australia.[16] The whole surface area of the Moon is about 38 million square kilometers, slightly less than the area of the Americas (North and South America).

The Moon's mass is 1/81 of Earth's,[60] being the second densest among the planetary moons, and having the second highest surface gravity, after Io, at 0.1654g and an escape velocity of 2.38km/s (8600km/h; 5300mph).

The Moon is a differentiated body that was initially in hydrostatic equilibrium but has since departed from this condition.[61] It has a geochemically distinct crust, mantle, and core. The Moon has a solid iron-rich inner core with a radius possibly as small as 240 kilometres (150mi) and a fluid outer core primarily made of liquid iron with a radius of roughly 300 kilometres (190mi). Around the core is a partially molten boundary layer with a radius of about 500 kilometres (310mi).[62][63] This structure is thought to have developed through the fractional crystallization of a global magma ocean shortly after the Moon's formation 4.5billion years ago.[64]

Crystallization of this magma ocean would have created a mafic mantle from the precipitation and sinking of the minerals olivine, clinopyroxene, and orthopyroxene; after about three-quarters of the magma ocean had crystallised, lower-density plagioclase minerals could form and float into a crust atop.[65] The final liquids to crystallise would have been initially sandwiched between the crust and mantle, with a high abundance of incompatible and heat-producing elements.[1] Consistent with this perspective, geochemical mapping made from orbit suggests a crust of mostly anorthosite.[15] The Moon rock samples of the flood lavas that erupted onto the surface from partial melting in the mantle confirm the mafic mantle composition, which is more iron-rich than that of Earth.[1] The crust is on average about 50 kilometres (31mi) thick.[1]

The Moon is the second-densest satellite in the Solar System, after Io.[66] However, the inner core of the Moon is small, with a radius of about 350 kilometres (220mi) or less,[1] around 20% of the radius of the Moon. Its composition is not well understood, but is probably metallic iron alloyed with a small amount of sulfur and nickel; analyses of the Moon's time-variable rotation suggest that it is at least partly molten.[67] The pressure at the lunar core is estimated to be 5GPa (49,000atm).[68]

The Moon has an external magnetic field of less than 0.2 nanoteslas,[69] or less than one hundred thousandth that of Earth. The Moon does not currently have a global dipolar magnetic field and only has crustal magnetization likely acquired early in its history when a dynamo was still operating.[70][71] However, early in its history, 4 billion years ago, its magnetic field strength was likely close to that of Earth today.[69] This early dynamo field apparently expired by about one billion years ago, after the lunar core had completely crystallized.[69] Theoretically, some of the remnant magnetization may originate from transient magnetic fields generated during large impacts through the expansion of plasma clouds. These clouds are generated during large impacts in an ambient magnetic field. This is supported by the location of the largest crustal magnetizations situated near the antipodes of the giant impact basins.[72]

The Moon's gravitational field is not uniform. The details of the gravitational field have been measured through tracking the Doppler shift of radio signals emitted by orbiting spacecraft. The main lunar gravity features are mascons, large positive gravitational anomalies associated with some of the giant impact basins, partly caused by the dense mare basaltic lava flows that fill those basins.[73][74] The anomalies greatly influence the orbit of spacecraft about the Moon. There are some puzzles: lava flows by themselves cannot explain all of the gravitational signature, and some mascons exist that are not linked to mare volcanism.[75]

On average the Moon's surface gravity is 1.62m/s2[4] (0.1654g; 5.318ft/s2), about half of the surface gravity of Mars and about a sixth of Earth's. The surface of the Moon, having a surface pressure of 1010Pa, lacks any significant atmosphere to moderate the extreme conditions of the surface.

Ionizing radiation from cosmic rays, the Sun and the resulting neutron radiation[76] produce radiation levels on average of 1,369 microsieverts per day, which is about 2-3 times more than on the International Space Station at about 400 km above Earth in orbit,[77] 5-10 times more than during a trans-Atlantic flight,[78] 200 times more than on Earth's surface.[77] For further comparison radiation on a flight to Mars is about 1.84 millisieverts per day and on Mars 0.64 millisieverts per day.[79]

The Moon's axial tilt with respect to the ecliptic is only 1.5427,[8][80] much less than the 23.44 of Earth. Because of this small tilt, the Moon's solar illumination varies much less with season than on Earth and it allows for the existence of some peaks of eternal light at the Moon's north pole, at the rim of the crater Peary.

The surface is exposed to drastic temperature differences ranging from 140C to 171C depending on the solar irradiance.Because of the lack of atmosphere, temperatures of different areas vary particularly upon whether they are in sunlight or shadow,[81] making topographical details play a decisive role on local surface temperatures.[82]Parts of many craters, particularly the bottoms of many polar craters,[83] are permanently shadowed, these "craters of eternal darkness" have extremely low temperatures. The Lunar Reconnaissance Orbiter measured the lowest summer temperatures in craters at the southern pole at 35K (238C; 397F)[84] and just 26K (247C; 413F) close to the winter solstice in the north polar crater Hermite. This is the coldest temperature in the Solar System ever measured by a spacecraft, colder even than the surface of Pluto.[82]

These extreme conditions for example are considered making it unlikely for spacecrafts to harbor bacterial spores at the Moon longer than just one lunar orbit.[85]

The Moon has an atmosphere so tenuous as to be nearly vacuum, with a total mass of less than 10 tonnes (9.8 long tons; 11 short tons).[90] The surface pressure of this small mass is around 3 1015atm (0.3nPa); it varies with the lunar day. Its sources include outgassing and sputtering, a product of the bombardment of lunar soil by solar wind ions.[15][91] Elements that have been detected include sodium and potassium, produced by sputtering (also found in the atmospheres of Mercury and Io); helium-4 and neon[92] from the solar wind; and argon-40, radon-222, and polonium-210, outgassed after their creation by radioactive decay within the crust and mantle.[93][94] The absence of such neutral species (atoms or molecules) as oxygen, nitrogen, carbon, hydrogen and magnesium, which are present in the regolith, is not understood.[93] Water vapor has been detected by Chandrayaan-1 and found to vary with latitude, with a maximum at ~6070degrees; it is possibly generated from the sublimation of water ice in the regolith.[95] These gases either return into the regolith because of the Moon's gravity or are lost to space, either through solar radiation pressure or, if they are ionized, by being swept away by the solar wind's magnetic field.[93]

Studies of Moon magma samples retrieved by the Apollo missions demonstrate that the Moon had once possessed a relatively thick atmosphere for a period of 70 million years between 3 and 4 billion years ago. This atmosphere, sourced from gases ejected from lunar volcanic eruptions, was twice the thickness of that of present-day Mars. The ancient lunar atmosphere was eventually stripped away by solar winds and dissipated into space.[96]

A permanent Moon dust cloud exists around the Moon, generated by small particles from comets. Estimates are 5 tons of comet particles strike the Moon's surface every 24 hours, resulting in the ejection of dust particles. The dust stays above the Moon approximately 10 minutes, taking 5 minutes to rise, and 5 minutes to fall. On average, 120 kilograms of dust are present above the Moon, rising up to 100 kilometers above the surface. Dust counts made by LADEE's Lunar Dust EXperiment (LDEX) found particle counts peaked during the Geminid, Quadrantid, Northern Taurid, and Omicron Centaurid meteor showers, when the Earth, and Moon pass through comet debris. The lunar dust cloud is asymmetric, being more dense near the boundary between the Moon's dayside and nightside.[97][98]

The topography of the Moon has been measured with laser altimetry and stereo image analysis.[99] Its most extensive topographic feature is the giant far-side South PoleAitken basin, some 2,240km (1,390mi) in diameter, the largest crater on the Moon and the second-largest confirmed impact crater in the Solar System.[100][101] At 13km (8.1mi) deep, its floor is the lowest point on the surface of the Moon.[100][102] The highest elevations of the Moon's surface are located directly to the northeast, which might have been thickened by the oblique formation impact of the South PoleAitken basin.[103] Other large impact basins such as Imbrium, Serenitatis, Crisium, Smythii, and Orientale possess regionally low elevations and elevated rims.[100] The far side of the lunar surface is on average about 1.9km (1.2mi) higher than that of the near side.[1]

The discovery of fault scarp cliffs suggest that the Moon has shrunk by about 90 metres (300ft) within the past billion years.[104] Similar shrinkage features exist on Mercury. Mare Frigoris, a basin near the north pole long assumed to be geologically dead, has cracked and shifted. Since the Moon doesn't have tectonic plates, its tectonic activity is slow and cracks develop as it loses heat.[105]

The main features visible from Earth by the naked eye are dark and relatively featureless lunar plains called maria (singular mare; Latin for "seas", as they were once believed to be filled with water)[106] are vast solidified pools of ancient basaltic lava. Although similar to terrestrial basalts, lunar basalts have more iron and no minerals altered by water.[107] The majority of these lava deposits erupted or flowed into the depressions associated with impact basins. Several geologic provinces containing shield volcanoes and volcanic domes are found within the near side "maria".[108]

Almost all maria are on the near side of the Moon, and cover 31% of the surface of the near side[60] compared with 2% of the far side.[109] This is likely due to a concentration of heat-producing elements under the crust on the near side, which would have caused the underlying mantle to heat up, partially melt, rise to the surface and erupt.[65][110][111] Most of the Moon's mare basalts erupted during the Imbrian period, 3.33.7billion years ago, though some being as young as 1.2billion years[55] and as old as 4.2billion years.[56]

In 2006, a study of Ina, a tiny depression in Lacus Felicitatis, found jagged, relatively dust-free features that, because of the lack of erosion by infalling debris, appeared to be only 2 million years old.[112] Moonquakes and releases of gas indicate continued lunar activity.[112] Evidence of recent lunar volcanism has been identified at 70 irregular mare patches, some less than 50 million years old. This raises the possibility of a much warmer lunar mantle than previously believed, at least on the near side where the deep crust is substantially warmer because of the greater concentration of radioactive elements.[113][114][115][116] Evidence has been found for 210 million years old basaltic volcanism within the crater Lowell,[117][118] inside the Orientale basin. Some combination of an initially hotter mantle and local enrichment of heat-producing elements in the mantle could be responsible for prolonged activities on the far side in the Orientale basin.[119][120]

The lighter-colored regions of the Moon are called terrae, or more commonly highlands, because they are higher than most maria. They have been radiometrically dated to having formed 4.4billion years ago, and may represent plagioclase cumulates of the lunar magma ocean.[56][55] In contrast to Earth, no major lunar mountains are believed to have formed as a result of tectonic events.[121]

The concentration of maria on the near side likely reflects the substantially thicker crust of the highlands of the Far Side, which may have formed in a slow-velocity impact of a second moon of Earth a few tens of millions of years after the Moon's formation.[122][123] Alternatively, it may be a consequence of asymmetrical tidal heating when the Moon was much closer to the Earth.[124]

A major geologic process that has affected the Moon's surface is impact cratering,[125] with craters formed when asteroids and comets collide with the lunar surface. There are estimated to be roughly 300,000 craters wider than 1km (0.6mi) on the Moon's near side.[126] The lunar geologic timescale is based on the most prominent impact events, including Nectaris, Imbrium, and Orientale; structures characterized by multiple rings of uplifted material, between hundreds and thousands of kilometers in diameter and associated with a broad apron of ejecta deposits that form a regional stratigraphic horizon.[127] The lack of an atmosphere, weather, and recent geological processes mean that many of these craters are well-preserved. Although only a few multi-ring basins have been definitively dated, they are useful for assigning relative ages. Because impact craters accumulate at a nearly constant rate, counting the number of craters per unit area can be used to estimate the age of the surface.[127] The radiometric ages of impact-melted rocks collected during the Apollo missions cluster between 3.8 and 4.1billion years old: this has been used to propose a Late Heavy Bombardment period of increased impacts.[128]

High-resolution images from the Lunar Reconnaissance Orbiter in the 2010s show a contemporary crater-production rate significantly higher than was previously estimated. A secondary cratering process caused by distal ejecta is thought to churn the top two centimeters of regolith on a timescale of 81,000 years.[129][130] This rate is 100 times faster than the rate computed from models based solely on direct micrometeorite impacts.[131]

Lunar swirls are enigmatic features found across the Moon's surface. They are characterized by a high albedo, appear optically immature (i.e. the optical characteristics of a relatively young regolith), and often have a sinuous shape. Their shape is often accentuated by low albedo regions that wind between the bright swirls. They are located in places with enhanced surface magnetic fields and many are located at the antipodal point of major impacts. Well known swirls include the Reiner Gamma feature and Mare Ingenii. They are hypothesized to be areas that have been partially shielded from the solar wind, resulting in slower space weathering.[132]

Blanketed on top of the Moon's crust is a highly comminuted (broken into ever smaller particles) and impact gardened mostly gray surface layer called regolith, formed by impact processes. The finer regolith, the lunar soil of silicon dioxide glass, has a texture resembling snow and a scent resembling spent gunpowder.[133] The regolith of older surfaces is generally thicker than for younger surfaces: it varies in thickness from 1015m (3349ft) in the highlands and 45m (1316ft) in the maria.[134]

Beneath the finely comminuted regolith layer is the megaregolith, a layer of highly fractured bedrock many kilometers thick.[135]

Liquid water cannot persist on the lunar surface. When exposed to solar radiation, water quickly decomposes through a process known as photodissociation and is lost to space. However, since the 1960s, scientists have hypothesized that water ice may be deposited by impacting comets or possibly produced by the reaction of oxygen-rich lunar rocks, and hydrogen from solar wind, leaving traces of water which could possibly persist in cold, permanently shadowed craters at either pole on the Moon.[136][137] Computer simulations suggest that up to 14,000km2 (5,400sqmi) of the surface may be in permanent shadow.[83] The presence of usable quantities of water on the Moon is an important factor in rendering lunar habitation as a cost-effective plan; the alternative of transporting water from Earth would be prohibitively expensive.[138]

In years since, signatures of water have been found to exist on the lunar surface.[139] In 1994, the bistatic radar experiment located on the Clementine spacecraft, indicated the existence of small, frozen pockets of water close to the surface. However, later radar observations by Arecibo, suggest these findings may rather be rocks ejected from young impact craters.[140] In 1998, the neutron spectrometer on the Lunar Prospector spacecraft showed that high concentrations of hydrogen are present in the first meter of depth in the regolith near the polar regions.[141] Volcanic lava beads, brought back to Earth aboard Apollo 15, showed small amounts of water in their interior.[142]

The 2008 Chandrayaan-1 spacecraft has since confirmed the existence of surface water ice, using the on-board Moon Mineralogy Mapper. The spectrometer observed absorption lines common to hydroxyl, in reflected sunlight, providing evidence of large quantities of water ice, on the lunar surface. The spacecraft showed that concentrations may possibly be as high as 1,000ppm.[143] Using the mapper's reflectance spectra, indirect lighting of areas in shadow confirmed water ice within 20 latitude of both poles in 2018.[144] In 2009, LCROSS sent a 2,300kg (5,100lb) impactor into a permanently shadowed polar crater, and detected at least 100kg (220lb) of water in a plume of ejected material.[145][146] Another examination of the LCROSS data showed the amount of detected water to be closer to 15512kg (34226lb).[147]

In May 2011, 6151410 ppm water in melt inclusions in lunar sample 74220 was reported,[148] the famous high-titanium "orange glass soil" of volcanic origin collected during the Apollo 17 mission in 1972. The inclusions were formed during explosive eruptions on the Moon approximately 3.7 billion years ago. This concentration is comparable with that of magma in Earth's upper mantle. Although of considerable selenological interest, this insight does not mean that water is easily available since the sample originated many kilometers below the surface, and the inclusions are so difficult to access that it took 39 years to find them with a state-of-the-art ion microprobe instrument.

Analysis of the findings of the Moon Mineralogy Mapper (M3) revealed in August 2018 for the first time "definitive evidence" for water-ice on the lunar surface.[149][150] The data revealed the distinct reflective signatures of water-ice, as opposed to dust and other reflective substances.[151] The ice deposits were found on the North and South poles, although it is more abundant in the South, where water is trapped in permanently shadowed craters and crevices, allowing it to persist as ice on the surface since they are shielded from the sun.[149][151]

In October 2020, astronomers reported detecting molecular water on the sunlit surface of the Moon by several independent spacecraft, including the Stratospheric Observatory for Infrared Astronomy (SOFIA).[152][153][154][155]

The Earth and the Moon form the Earth-Moon satellite system with a shared center of mass, or barycentre. This barycentre stays located at all times 1,700km (1,100mi) (about a quarter of Earth's radius) beneath the Earth's surface, making the Moon seemingly orbit the Earth.

The orbital eccentricity, giving ovalness of the orbit, is 0.055.[1]The Lunar distance, or the semi-major axis of the geocentric lunar orbit, is approximately 400,000km, which is a quarter of a million miles or 1.28 light-seconds, and a unit of measure in astronomy. This is not to be confused with the instantaneous EarthMoon distance, or distance to the Moon, the momentanous distance from the center of Earth to the center of the Moon.

The Moon makes a complete orbit around Earth with respect to the fixed stars, its sidereal period, about once every 27.3days,[h]. However, because the Earth-Moon system moves at the same time in its orbit around the Sun, it takes slightly longer, 29.5days;[i],[60] to return at the same lunar phase, completing a full cycle, as seen from Earth. This synodic period or synodic month is commonly known as the lunar month and is equal to the length of the solar day on the Moon.[156]

Due to tidal locking, the Moon has a 1:1 spinorbit resonance. This rotationorbit ratio makes the Moon's orbital periods around Earth equal to its corresponding rotation periods. This is the reason for only one side of the Moon, its so-called near side, being visible from Earth. That said, while the movement of the Moon is in resonance, it still is not without nuances such as libration, resulting in slightly changing perspectives, making over time and location on Earth about 59% of the Moon's surface visible from Earth.[157]

Unlike most satellites of other planets, the Moon's orbital plane is closer to the ecliptic plane than to the planet's equatorial plane. The Moon's orbit is subtly perturbed by the Sun and Earth in many small, complex and interacting ways. For example, the plane of the Moon's orbit gradually rotates once every 18.61years,[158] which affects other aspects of lunar motion. These follow-on effects are mathematically described by Cassini's laws.[159]

The gravitational attraction that Earth and the Moon (as well as the Sun) exert on each other manifests in a slightly greater attraction on the sides of closest to each other, resulting in tidal forces. Ocean tides are the most widely experienced result of this, but tidal forces considerably affect also other mechanics of Earth, as well as the Moon and their system.

The lunar solid crust experiences tides of around 10cm (4in) amplitude over 27days, with three components: a fixed one due to Earth, because they are in synchronous rotation, a variable tide due to orbital eccentricity and inclination, and a small varying component from the Sun.[160] The Earth-induced variable component arises from changing distance and libration, a result of the Moon's orbital eccentricity and inclination (if the Moon's orbit were perfectly circular and un-inclined, there would only be solar tides).[160] According to recent research, scientists suggest that the Moon's influence on the Earth may contribute to maintaining Earth's magnetic field.[161]

The cumulative effects of stress built up by these tidal forces produces moonquakes. Moonquakes are much less common and weaker than are earthquakes, although moonquakes can last for up to an hour significantly longer than terrestrial quakes because of scattering of the seismic vibrations in the dry fragmented upper crust. The existence of moonquakes was an unexpected discovery from seismometers placed on the Moon by Apollo astronauts from 1969 through 1972.[162]

The most commonly known effect of tidal forces are elevated sea levels called ocean tides.[163] While the Moon exerts most of the tidal forces, the Sun also exerts tidal forces and therefore contributes to the tides as much as 40% of the Moon's tidal force; producing in interplay the spring and neap tides.[163]

The tides are two bulges in the Earth's oceans, one on the side facing the Moon and the other on the side opposite. As the Earth rotates on its axis, one of the ocean bulges (high tide) is held in place "under" the Moon, while another such tide is opposite. As a result, there are two high tides, and two low tides in about 24 hours.[163] Since the Moon is orbiting the Earth in the same direction of the Earth's rotation, the high tides occur about every 12 hours and 25 minutes; the 25 minutes is due to the Moon's time to orbit the Earth.

If the Earth were a water world (one with no continents) it would produce a tide of only one meter, and that tide would be very predictable, but the ocean tides are greatly modified by other effects:

As a result, the timing of the tides at most points on the Earth is a product of observations that are explained, incidentally, by theory.

Delays in the tidal peaks of both ocean and solid-body tides cause torque in opposition to the Earth's rotation. This "drains" angular momentum and rotational kinetic energy from Earth's rotation, slowing the Earth's rotation.[163][160] That angular momentum, lost from the Earth, is transferred to the Moon in a process known as tidal acceleration, which lifts the Moon into a higher orbit while lowering orbital speed around the Earth.

Thus the distance between Earth and Moon is increasing, and the Earth's rotation is slowing in reaction.[160] Measurements from laser reflectors left during the Apollo missions (lunar ranging experiments) have found that the Moon's distance increases by 38mm (1.5in) per year (roughly the rate at which human fingernails grow).[165][166][167]Atomic clocks show that Earth's day lengthens by about 17microseconds every year,[168][169][170] slowly increasing the rate at which UTC is adjusted by leap seconds.

This tidal drag makes the rotation of Earth and the orbital period of the Moon very slowly match. This matching first results in tidally locking the lighter body of the orbital system, as already the case with the Moon. Eventually, after 50 billion years,[171] also the Earth would be made to always face the Moon with the same side. This would complete the mutual tidal locking of Earth and the Moon, matching the length of Earth's day to the then also significantly increased lunar month and the Moon's day, and suspending the Moon over one meridian (comparable to the Pluto-Charon system). However, the Sun will become a red giant engulfing the Earth-Moon system long before the latter occurs.[172][173]

The tidally locked synchronous rotation of the Moon as it orbits the Earth results in it always keeping nearly the same face turned towards the planet. The side of the Moon that faces Earth is called the near side, and the opposite the far side. The far side is often inaccurately called the "dark side", but it is in fact illuminated as often as the near side: once every 29.5 Earth days. During dark moon to new moon, the near side is dark.[174]

The Moon originally rotated at a faster rate, but early in its history its rotation slowed and became tidally locked in this orientation as a result of frictional effects associated with tidal deformations caused by Earth.[175] With time, the energy of rotation of the Moon on its axis was dissipated as heat, until there was no rotation of the Moon relative to Earth. In 2016, planetary scientists using data collected on the 1998-99 NASA Lunar Prospector mission, found two hydrogen-rich areas (most likely former water ice) on opposite sides of the Moon. It is speculated that these patches were the poles of the Moon billions of years ago before it was tidally locked to Earth.[176]

The Moon's highest altitude at culmination varies by its lunar phase, or more correctly its orbital position, and time of the year, or more correctly the position of the Earth's axis. The full moon is highest in the sky during winter and lowest during summer (for each hemisphere respectively), with its altitude changing towards dark moon to the opposite.

At the North and South Poles the Moon is 24 hours above the horizon for two weeks every tropical month (about 27.3 days), comparable to the polar day of the tropical year. Zooplankton in the Arctic use moonlight when the Sun is below the horizon for months on end.[177]

The apparent orientation of the Moon depends on its position in the sky and the hemisphere of the Earth from which it is being viewed. In the northern hemisphere it is seen upside down compared to the view in the southern hemisphere.[178] Sometimes the "horns" of a crescent moon appear to be pointing more upwards than sideways. This phenomenon is called a wet moon and occurs more frequently in the tropics.[179]

The distance between the Moon and Earth varies from around 356,400km (221,500mi) to 406,700km (252,700mi) at perigee (closest) and apogee (farthest), respectively, making the Moon's apparent size fluctuate. On sverage the Moon's angular diameter is about 0.52 (on average) in the sky, roughly the same apparent size as the Sun (see Eclipses). Additionally when close to the horizon a purely psychological effect, known as the Moon illusion, makes the Moon appear larger.[180]

Despite the Moon's tidal locking, the effect of libration makes about 59% of the Moon's surface visible from Earth over the course of one month.[157][60]

The Moon has an exceptionally low albedo, giving it a reflectance that is slightly brighter than that of worn asphalt. Despite this, it is the brightest object in the sky after the Sun.[60][j] This is due partly to the brightness enhancement of the opposition surge; the Moon at quarter phase is only one-tenth as bright, rather than half as bright, as at full moon.[181] Additionally, color constancy in the visual system recalibrates the relations between the colors of an object and its surroundings, and because the surrounding sky is comparatively dark, the sunlit Moon is perceived as a bright object. The edges of the full moon seem as bright as the center, without limb darkening, because of the reflective properties of lunar soil, which retroreflects light more towards the Sun than in other directions. The Moon's color depends on the light the Moon reflects, which in turn depends on the Moon's surface and its features, having for example large darker regions. In general the lunar surface reflects a brown-tinged gray light.[182]

Viewed from Earth the air filters the reflected light, at times giving it a red colour depending on the angle of the Moon in the sky and thickness of the atmosphere, or a blue tinge depending on the particles in the air,[182] as in cases of volcanic particles.[183] The terms blood moon and blue moon do not necessarily refer to circumstances of red or blue moonlight, but are rather particular cultural references such as particular full moons of a year.

There has been historical controversy over whether observed features on the Moon's surface change over time. Today, many of these claims are thought to be illusory, resulting from observation under different lighting conditions, poor astronomical seeing, or inadequate drawings. However, outgassing does occasionally occur and could be responsible for a minor percentage of the reported lunar transient phenomena. Recently, it has been suggested that a roughly 3km (1.9mi) diameter region of the lunar surface was modified by a gas release event about a million years ago.[184][185]

Half of the Moon's surface is always illuminated by the Sun (except during a lunar eclipse). Earth also reflects light onto the Moon, observable at times as Earthlight when it is again reflected back to Earth from areas of the near side of the Moon that are not illuminated by the Sun.

With the different positions of the Moon, different areas of it are illuminated by the Sun. This illumination of different lunar areas, as viewed from Earth, produces the different lunar phases during the synodic month. A phase is equal to the area of the visible lunar sphere that is illuminated by the Sun. This area or degree of illumination is given by ( 1 cos e ) / 2 = sin 2 ( e / 2 ) {displaystyle (1-cos e)/2=sin ^{2}(e/2)} , where e {displaystyle e} is the elongation (i.e., the angle between Moon, the observer on Earth, and the Sun).

On 14 November 2016, the Moon was at full phase closer to Earth than it had been since 1948. It was 14% closer and larger than its farthest position in apogee.[187] This closest point coincided within an hour of a full moon, and it was 30% more luminous than when at its greatest distance because of its increased apparent diameter, which made it a particularly notable example of a "supermoon".[188][189][190]

At lower levels, the human perception of reduced brightness as a percentage is provided by the following formula:[191][192]

When the actual reduction is 1.00 / 1.30, or about 0.770, the perceived reduction is about 0.877, or 1.00 / 1.14. This gives a maximum perceived increase of 14% between apogee and perigee moons of the same phase.[193]

Eclipses only occur when the Sun, Earth, and Moon are all in a straight line (termed "syzygy"). Solar eclipses occur at new moon, when the Moon is between the Sun and Earth. In contrast, lunar eclipses occur at full moon, when Earth is between the Sun and Moon. The apparent size of the Moon is roughly the same as that of the Sun, with both being viewed at close to one-half a degree wide. The Sun is much larger than the Moon but it is the vastly greater distance that gives it the same apparent size as the much closer and much smaller Moon from the perspective of Earth. The variations in apparent size, due to the non-circular orbits, are nearly the same as well, though occurring in different cycles. This makes possible both total (with the Moon appearing larger than the Sun) and annular (with the Moon appearing smaller than the Sun) solar eclipses.[194] In a total eclipse, the Moon completely covers the disc of the Sun and the solar corona becomes visible to the naked eye. Because the distance between the Moon and Earth is very slowly increasing over time,[163] the angular diameter of the Moon is decreasing. As it evolves toward becoming a red giant, the size of the Sun, and its apparent diameter in the sky, are slowly increasing.[k] The combination of these two changes means that hundreds of millions of years ago, the Moon would always completely cover the Sun on solar eclipses, and no annular eclipses were possible. Likewise, hundreds of millions of years in the future, the Moon will no longer cover the Sun completely, and total solar eclipses will not occur.[195]

Because the Moon's orbit around Earth is inclined by about 5.145 (5 9') to the orbit of Earth around the Sun, eclipses do not occur at every full and new moon. For an eclipse to occur, the Moon must be near the intersection of the two orbital planes.[196] The periodicity and recurrence of eclipses of the Sun by the Moon, and of the Moon by Earth, is described by the saros, which has a period of approximately 18years.[197]

Because the Moon continuously blocks the view of a half-degree-wide circular area of the sky,[l][198] the related phenomenon of occultation occurs when a bright star or planet passes behind the Moon and is occulted: hidden from view. In this way, a solar eclipse is an occultation of the Sun. Because the Moon is comparatively close to Earth, occultations of individual stars are not visible everywhere on the planet, nor at the same time. Because of the precession of the lunar orbit, each year different stars are occulted.[199]

It is believed by some that 2030,000 year old tally sticks, were used to observe the phases of the Moon, keeping time using the waxing and waning of the Moon's phases.[200]One of the earliest-discovered possible depictions of the Moon is a 5000-year-old rock carving Orthostat 47 at Knowth, Ireland.[201][202]

The ancient Greek philosopher Anaxagoras (d.428 BC) reasoned that the Sun and Moon were both giant spherical rocks, and that the latter reflected the light of the former.[203][204]:227 Elsewhere in the 5th century BC to 4th century BC, Babylonian astronomers had recorded the 18-year Saros cycle of lunar eclipses,[205] and Indian astronomers had described the Moon's monthly elongation.[206] The Chinese astronomer Shi Shen (fl. 4th century BC) gave instructions for predicting solar and lunar eclipses.[204]:411

In Aristotle's (384322BC) description of the universe, the Moon marked the boundary between the spheres of the mutable elements (earth, water, air and fire), and the imperishable stars of aether, an influential philosophy that would dominate for centuries.[207] Archimedes (287212 BC) designed a planetarium that could calculate the motions of the Moon and other objects in the Solar System.[208] In the 2nd century BC, Seleucus of Seleucia correctly theorized that tides were due to the attraction of the Moon, and that their height depends on the Moon's position relative to the Sun.[209] In the same century, Aristarchus computed the size and distance of the Moon from Earth, obtaining a value of about twenty times the radius of Earth for the distance.

Although the Chinese of the Han Dynasty believed the Moon to be energy equated to qi, their 'radiating influence' theory recognized that the light of the Moon was merely a reflection of the Sun, and Jing Fang (7837BC) noted the sphericity of the Moon.[204]:413414 Ptolemy (90168AD) greatly improved on the numbers of Aristarchus, calculating the values of a mean distance of 59times Earth's radius and a diameter of 0.292Earth diameters were close to the correct values of about 60 and 0.273 respectively.[210] In the 2nd century AD, Lucian wrote the novel A True Story, in which the heroes travel to the Moon and meet its inhabitants. In 499AD, the Indian astronomer Aryabhata mentioned in his Aryabhatiya that reflected sunlight is the cause of the shining of the Moon.[211] The astronomer and physicist Alhazen (9651039) found that sunlight was not reflected from the Moon like a mirror, but that light was emitted from every part of the Moon's sunlit surface in all directions.[212] Shen Kuo (10311095) of the Song dynasty created an allegory equating the waxing and waning of the Moon to a round ball of reflective silver that, when doused with white powder and viewed from the side, would appear to be a crescent.[204]:415416

During the Middle Ages, before the invention of the telescope, the Moon was increasingly recognised as a sphere, though many believed that it was "perfectly smooth".[213]

In 1609, Galileo Galilei used an early telescope to make drawings of the Moon for his book Sidereus Nuncius, and deduced that it was not smooth but had mountains and craters. Thomas Harriot had made, but not published such drawings a few months earlier.

Telescopic mapping of the Moon followed: later in the 17th century, the efforts of Giovanni Battista Riccioli and Francesco Maria Grimaldi led to the system of naming of lunar features in use today. The more exact 18341836 Mappa Selenographica of Wilhelm Beer and Johann Heinrich Mdler, and their associated 1837 book Der Mond, the first trigonometrically accurate study of lunar features, included the heights of more than a thousand mountains, and introduced the study of the Moon at accuracies possible in earthly geography.[214] Lunar craters, first noted by Galileo, were thought to be volcanic until the 1870s proposal of Richard Proctor that they were formed by collisions.[60] This view gained support in 1892 from the experimentation of geologist Grove Karl Gilbert, and from comparative studies from 1920 to the 1940s,[215] leading to the development of lunar stratigraphy, which by the 1950s was becoming a new and growing branch of astrogeology.[60]

After World War II the first launch systems were developed and by the end of the 1950s they reached capabilities that allowed the Soviet Union and the United States to launch spacecrafts into space. The Cold War fueled a closely followed development of launch systems by the two states, resulting in the so-called Space Race and its later phase the Moon Race, accelerating efforts and interest in exploration of the Moon.

After the first spaceflight of Sputnik 1 in 1957 during International Geophysical Year the spacecrafts of the Soviet Union's Luna program were the first to accomplish a number of goals. Following three unnamed failed missions in 1958,[216] the first human-made object Luna 1 escaped Earth's gravity and passed near the Moon in 1959. Later that year the first human-made object Luna 2 reached the Moon's surface by intentionally impacting. By the end of the year Luna 3 reached as the first human-made object the normally occluded far side of the Moon, taking the first photographs of it.The first spacecraft to perform a successful lunar soft landing was Luna 9 and the first vehicle to orbit the Moon was Luna 10, both in 1966.[60]

Following President John F. Kennedy's 1961 commitment to a manned Moon landing before the end of the decade, the United States, under NASA leadership, launched a series of uncrewed probes to develop an understanding of the lunar surface in preparation for human missions: the Jet Propulsion Laboratory's Ranger program, the Lunar Orbiter program and the Surveyor program. The crewed Apollo program was developed in parallel; after a series of uncrewed and crewed tests of the Apollo spacecraft in Earth orbit, and spurred on by a potential Soviet lunar human landing, in 1968 Apollo 8 made the first human mission to lunar orbit. The subsequent landing of the first humans on the Moon in 1969 is seen by many as the culmination of the Space Race.[217]

Neil Armstrong became the first person to walk on the Moon as the commander of the American mission Apollo 11 by first setting foot on the Moon at 02:56UTC on 21 July 1969.[218] An estimated 500million people worldwide watched the transmission by the Apollo TV camera, the largest television audience for a live broadcast at that time.[219][220] The Apollo missions 11 to 17 (except Apollo 13, which aborted its planned lunar landing) removed 380.05 kilograms (837.87lb) of lunar rock and soil in 2,196 separate samples.[221]

Scientific instrument packages were installed on the lunar surface during all the Apollo landings. Long-lived instrument stations, including heat flow probes, seismometers, and magnetometers, were installed at the Apollo 12, 14, 15, 16, and 17 landing sites. Direct transmission of data to Earth concluded in late 1977 because of budgetary considerations,[222][223] but as the stations' lunar laser ranging corner-cube retroreflector arrays are passive instruments, they are still being used.[224]Apollo 17 in 1972 remains the last crewed mission to the Moon. Explorer 49 in 1973 was the last dedicated U.S. probe to the Moon until the 1990s.

The Soviet Union continued sending robotic missions to the Moon until 1976, deploying in 1970 with Luna 17 the first remote controlled rover Lunokhod 1 on an extraterrestrial surface, and collecting and returning 0.3kg of rock and soil samples with three Luna sample return missions (Luna 16 in 1970, Luna 20 in 1972, and Luna 24 in 1976).[225]

A near lunar quietude of fourteen years followed the last Soviet mission to the Moon of 1976. Astronautics had shifted its focus towards the exploration of the inner (e.g. Venera program) and outer (e.g. Pioneer 10, 1972) Solar System planets, but also towards Earth orbit, developing and continuously operating, beside communication satellites, Earth observation satellites (e.g. Landsat program, 1972) space telescopes and particularly space stations (e.g. Salyut program, 1971).

Continued here:
Moon - Wikipedia

Posted in Moon Colonization | Comments Off on Moon – Wikipedia

Will Ferrell, Maya Rudolph, Nick Kroll and More Take The Hollywood Reporters Annual Comedy Survey – Hollywood Reporter

Posted: at 4:16 am

Will Ferrell, Maya Rudolph, Nick Kroll and More Take The Hollywood Reporters Annual Comedy Survey  Hollywood Reporter

More:
Will Ferrell, Maya Rudolph, Nick Kroll and More Take The Hollywood Reporters Annual Comedy Survey - Hollywood Reporter

Posted in Politically Incorrect | Comments Off on Will Ferrell, Maya Rudolph, Nick Kroll and More Take The Hollywood Reporters Annual Comedy Survey – Hollywood Reporter

Dr. Carrie Madej: why vaccines alter the human DNA – Stop World Control

Posted: at 4:13 am

This list is a mere starting point for you, to do your own research. Dr. Madej studied this for twenty years, so the actual basis of her knowledge is much larger than this list.

https://pubs.rsc.org/--/content/articlelanding/2015/ra/c5ra01508a#!divAbstract

Why “Operation Warp Speed” Could Be Deadly

https://www.facebook.com/1780584826/posts/10213711458378968/?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/

https://kenfm.de/bill-gates-predicts-700000-victims-from-corona-vaccination/

https://www.national-geographic.com/science/2020/05/moderna-coronavirus-vaccine-how-it-works-cvd/?fbclid=IwAR1EFM74n4ulVp8pEufYOA9vN13CCyYeKoXdnWpk-R_0gZoDgflr3w5N0T4#close

https://www.forbes.com/sites/nathanvardi/2020/07/29/modernas-mysterious-coronavirus-vaccine-delivery-system/#2226d81562d9

Gene Drive Files Expose Leading Role of US Military in Gene Drive Development.

https://www.washingtonpost.com/science/2018/11/30/gene-drive-research-fight-diseases-can-proceed-cautiously-un-group-decides/

https://youtu.be/iMl0ty6evhU https://steemit.com/life/@pranavsinha/bill-and-melinda-gates-foundation-kicked-out-of-india

https://m.youtube.com/watch?feature=share&v=ksEVaO806Oo

https://youtu.be/Ofdd4ILdpVY https://scialert.net/fulltext/?doi=biotech.2011.136.148

http://ir.inovio.com/news-releases/news-releases-details/2020/INOVIOs-COVID-19-DNA-Vaccine-INO-4800-Demonstrates-Robust-Neutralizing-Antibody-and-T-Cell-Immune-Responses-in-Preclinical-Models/default.aspx

https://www.researchgate.net/publication/232740966_What_you_always_needed_to_know_about_electroporation_based_DNA_vaccines

https://www.theglobeandmail.com/business/international-business/article-astrazeneca-to-be-exempt-from-coronavirus-vaccine-liability-claims-in/

https://www.discovermagazine.com/the-sciences/20-things-you-didn't-know-about-dna

https://blogs.timesofisrael.com/gene-editing-moderna-and-transhumanism/

https://www.sciencedaily.com/releases/2020/07/200715095500.htm

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC33911/

https://www.marketwatch.com/story/this-potential-coronavirus-vaccine-could-be-as-easy-as-sticking-on-a-bandage-2020-04-08

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675524/#!po=0.446429

Quantum Dots Deliver Vaccines and Invisibly Encode Vaccination History in Skin

https://newatlas.com/snake-fang-microneedle-patch/60868/

Scientists Propose ‘Tattoos’ To Solve Vaccination Issues

https://www.thermofisher.com/us/en/home/references/gibco-cell-culture-basics/transfection-basics/introduction-to-transfection.html

Injectable Body Sensors Take Personal Chemistry to a Cell Phone Closer to Reality

https://www.forbes.com/sites/sarwantsingh/2017/11/20/transhumanism-and-the-future-of-humanity-seven-ways-the-world-will-change-by-2030/

https://www.sciencedaily.com/releases/2020/07/200715095500.htm

https://www.scientificamerican.com/article/invisible-ink-could-reveal-whether-kids-have-been-vaccinated/

https://www.researchgate.net/publication/338044557_Biocompatible_near-infrared_quantum_dots_delivered_to_the_skin_by_microneedle_patches_record_vaccination

https://sciencebusiness.technewslit.com/?p=36802

See more here:
Dr. Carrie Madej: why vaccines alter the human DNA - Stop World Control

Posted in Transhuman | Comments Off on Dr. Carrie Madej: why vaccines alter the human DNA – Stop World Control

Psoriasis Pathogenesis and Treatment – PMC – PubMed Central (PMC)

Posted: at 4:06 am

Abstract

Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.

Keywords: psoriasis, inflammation, chronic skin disease

Psoriasis is a chronic inflammatory skin disease with a strong genetic predisposition and autoimmune pathogenic traits. The worldwide prevalence is about 2%, but varies according to regions [1]. It shows a lower prevalence in Asian and some African populations, and up to 11% in Caucasian and Scandinavian populations [2,3,4,5].

The dermatologic manifestations of psoriasis are varied; psoriasis vulgaris is also called plaque-type psoriasis, and is the most prevalent type. The terms psoriasis and psoriasis vulgaris are used interchangeably in the scientific literature; nonetheless, there are important distinctions among the different clinical subtypes (See ).

Clinical manifestations of psoriasis. (A,B) Psoriasis vulgaris presents with erythematous scaly plaques on the trunk and extensor surfaces of the limbs. (C) Generalized pustular psoriasis. (D) Pustular psoriasis localized to the soles of the feet. This variant typically affects the palms of the hands as well; hence, psoriasis pustulosa palmoplantaris. (E,F) Inverse psoriasis affects the folds of the skin (i.e., axillary, intergluteal, inframammary, and genital involvement).

About 90% of psoriasis cases correspond to chronic plaque-type psoriasis. The classical clinical manifestations are sharply demarcated, erythematous, pruritic plaques covered in silvery scales. The plaques can coalesce and cover large areas of skin. Common locations include the trunk, the extensor surfaces of the limbs, and the scalp [6,7].

Also called flexural psoriasis, inverse psoriasis affects intertriginous locations, and is characterized clinically by slightly erosive erythematous plaques and patches.

Guttate psoriasis is a variant with an acute onset of small erythematous plaques. It usually affects children or adolescents, and is often triggered by group-A streptococcal infections of tonsils. About one-third of patients with guttate psoriasis will develop plaque psoriasis throughout their adult life [8,9].

Pustular psoriasis is characterized by multiple, coalescing sterile pustules. Pustular psoriasis can be localized or generalized. Two distinct localized phenotypes have been described: psoriasis pustulosa palmoplantaris (PPP) and acrodermatitis continua of Hallopeau. Both of them affect the hands and feet; PPP is restricted to the palms and soles, and ACS is more distally located at the tips of fingers and toes, and affects the nail apparatus. Generalized pustular psoriasis presents with an acute and rapidly progressive course characterized by diffuse redness and subcorneal pustules, and is often accompanied by systemic symptoms [10].

Erythrodermic psoriasis is an acute condition in which over 90% of the total body surface is erythematous and inflamed. Erythroderma can develop on any kind of psoriasis type, and requires emergency treatment ().

Psoriasis typically affects the skin, but may also affect the joints, and has been associated with a number of diseases. Inflammation is not limited to the psoriatic skin, and has been shown to affect different organ systems. Thus, it has been postulated that psoriasis is a systemic entity rather than a solely dermatological disease. When compared to control subjects, psoriasis patients exhibit increased hyperlipidemia, hypertension, coronary artery disease, type 2 diabetes, and increased body mass index. The metabolic syndrome, which comprises the aforementioned conditions in a single patient, was two times more frequent in psoriasis patients [11,12]. Coronary plaques are also twice as common in psoriasis patients when compared to control subjects [13]. Several large studies have shown a higher prevalence of diabetes and cardiovascular disease correlating with the severity of psoriasis [14,15,16,17,18]. There are divided opinions regarding the contribution of psoriasis as an independent cardiovascular risk factor [19,20]; however, the collective evidence supports that psoriasis independently increases risk for myocardial infarction, stroke, and death due to cardiovascular disease (CVD) [21,22,23,24,25,26,27,28]. In addition, the risk was found to apply also to patients with mild psoriasis to a lower extent [21,27].

Vascular inflammation assessed via 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) found psoriasis duration to be a negative predicting factor. It was suggested that the cumulative effects of low-grade chronic inflammation might accelerate vascular disease development [29]. In a study by Metha et al., systemic and vascular inflammation in six patients with moderate to severe psoriasis was quantified by FDG-PET/CT. Inflammation foci were registered as expected in the skin, joints, and tendons. In addition, FDG uptake in the liver and aorta revealed subclinical systemic inflammation [30]. Furthermore, standardized uptake values were reduced in the liver, spleen, and aorta following treatment with ustekinumab {Kim, 2018 #359}. A new biomarker to assess CVD risk in psoriasis patients was proposed by nuclear magnetic resonance spectroscopy [31]. The signal originating from glycan N-acetylglucosamine residues called GlycA in psoriasis patients was associated with psoriasis severity and subclinical CVD, and was shown to be reduced in response to the effective treatment of psoriasis.

Psoriatic inflammation of the joints results in psoriatic arthritis (PsA). The skin manifestations generally precede PsA, which shares the inflammatory chronicity of psoriasis and requires systemic therapies due to a potential destructive progression. Psoriatic arthritis develops in up to 40% of psoriasis patients [32,33,34,35,36,37,38]; around 15% of psoriasis patients are thought to have undiagnosed PsA [39]. It presents clinically with dactylitis and enthesitis in oligoarticular or polyarticular patterns. The polyarticular variant is frequently associated with nail involvement [40]. Nails are specialized dermal appendages that can also be affected by psoriatic inflammation. Nail psoriasis is reported to affect more than half of psoriasis patients, and can present as the only psoriasis manifestation in 510% of patients [41]. The clinical presentation of nail psoriasis depends on the structure affected by the inflammatory process. Nail matrix involvement presents as pitting, leukonychia, and onychodystrophy, whereas inflammation of the nail bed presents as oil-drop discoloration, splinter hemorrhages, and onycholysis () [42]. Psoriatic nail involvement is associated with joint involvement, and up to 80% of patients with PsA have nail manifestations [43,44].

Onycholysis and oil drop changes on psoriatic nail involvement.

In addition to an increased risk for cardiometabolic disease, psoriasis has been associated with a higher prevalence of gastrointestinal and chronic kidney disease. Susceptibility loci shared between psoriasis and inflammatory bowel disease support this association in particular with regard to Crohns disease [45,46]. An association with mild liver disease, which correlates with imaging studies, has been reported [30,47]. Psoriasis might be a risk factor for chronic kidney disease and end-stage renal disease, independent of traditional risk factors (demographic, cardiovascular, or drug-related) [48].

Taken together, the different factors contributing to psoriasis as a systemic disease can have a dramatic effect on the quality of life of patients and their burden of disease. Psoriasis impairment to psychological quality of life is comparable to cancer, myocardial infarction, and depression [49]. The high burden of disease is thought to be owed to the symptoms of the disease, which include pain, pruritus, and bleeding, in addition to the aforementioned associated diseases [50]. The impact of psoriasis on psychological and mental health is currently an important consideration due to the implications of the disease on social well-being and treatment. Patients with psoriasis have an increased prevalence of depression and anxiety and suicidal ideation. Interestingly, psoriasis treatment leads to improvement in anxiety symptoms [51,52].

The hallmark of psoriasis is sustained inflammation that leads to uncontrolled keratinocyte proliferation and dysfunctional differentiation. The histology of the psoriatic plaque shows acanthosis (epidermal hyperplasia), which overlies inflammatory infiltrates composed of dermal dendritic cells, macrophages, T cells, and neutrophils (). Neovascularization is also a prominent feature. The inflammatory pathways active in plaque psoriasis and the rest of the clinical variants overlap, but also display discrete differences that account for the different phenotype and treatment outcomes.

Histopathology of psoriasis. (A) Psoriasis vulgaris characteristically shows acanthosis, parakeratosis, and dermal inflammatory infiltrates. (B) In pustular psoriasis, acanthotic changes are accompanied by epidermal predominantly neutrophilic infiltrates, which cause pustule formation.

Disturbances in the innate and adaptive cutaneous immune responses are responsible for the development and sustainment of psoriatic inflammation [53,54]. An activation of the innate immune system driven by endogenous danger signals and cytokines characteristically coexists with an autoinflammatory perpetuation in some patients, and T cell-driven autoimmune reactions in others. Thus, psoriasis shows traits of an autoimmune disease on an (auto)inflammatory background [55], with both mechanisms overlapping and even potentiating one another.

The main clinical findings in psoriasis are evident at the outermost layer of the skin, which is made up of keratinocytes. However, the development of the psoriatic plaque is not restricted to inflammation in the epidermal layer, but rather is shaped by the interaction of keratinocytes with many different cell types (innate and adaptive immune cells, vasculature) spanning the dermal layer of the skin. The pathogenesis of psoriasis can be conceptualized into an initiation phase possibly triggered by trauma (Koebner phenomenon), infection, or drugs [53] and a maintenance phase characterized by a chronic clinical progression (see ).

The pathogenesis of psoriasis.

It is well known that dendritic cells play a major role in the initial stages of disease. Dendritic cells are professional antigen-presenting cells. However, their activation in psoriasis is not entirely clear. One of the proposed mechanisms involves the recognition of antimicrobial peptides (AMPs), which are secreted by keratinocytes in response to injury and are characteristically overexpressed in psoriatic skin. Among the most studied psoriasis-associated AMPs are LL37, -defensins, and S100 proteins [56]. LL37 or cathelicidin has been attributed a pathogenic role in psoriasis. It is released by damaged keratinocytes, and subsequently forms complexes with self-genetic material from other damaged cells. LL37 bound to DNA stimulates toll-like receptor (TLR) 9 in plasmacytoid dendritic cells (pDCs) [57]. The activation of pDC is key in starting the development of the psoriatic plaque, and is characterized by the production of type I IFN (IFN- and IFN-). Type I IFN signaling promotes myeloid dendritic cells (mDC) phenotypic maturation, and has been implicated in Th1 and Th17 differentiation and function, including IFN- and interleukin (IL)-17 production, respectively [58,59,60].

Whilst LL37DNA complexes stimulate pDCs through TLR9, LL37 bound to RNA stimulates pDCs through TLR7. In addition, LL37RNA complexes act on mDCs via TLR8 [56,57]. Activated mDCs migrate into draining lymph nodes and secrete tumor necrosis factor (TNF)-, IL-23, and IL-12, with the latter two modulating the differentiation and proliferation of Th17 and Th1 cell subsets, respectively. Furthermore, slan+ monocytes, which are important pro-inflammatory cells found in psoriasis skin lesions, respond to LL37RNA activation by secreting high amounts of TNF-, IL-12, and IL-23 [61].

The activation of the adaptive immune response via the distinct T cell subsets drives the maintenance phase of psoriatic inflammation [62]. Th17 cytokines, namely IL-17, IL-21, and IL-22 activate keratinocyte proliferation in the epidermis.

The inflammatory milieu activates keratinocyte proliferation via TNF-, IL-17, and IFN-. Keratinocytes are also activated by LL37 and DNA, and greatly increase the production of type I IFNs [57]. Furthermore, they participate actively in the inflammatory cascade through cytokine (IL-1, IL-6, and TNF-), chemokine, and AMP secretion.

A widely used psoriasis-like inflammation mouse model relies on the effect of the TLR7/8 agonist imiquimod, and is thus in support of the TLR7/8 disease initiation model. In addition, the response to imiquimod was blocked in mice deficient of IL-23 or IL-17R, which highlights the involvement of the IL-23/IL-17 axis in skin inflammation and psoriasis-like pathology [63].

The TNFIL-23Th17 inflammatory pathway characterizes plaque-type psoriasis. The IL-17 cytokine family is composed of six members: IL-17AF. They are produced by different cell types, and are important regulators of inflammatory responses [64]. So far, the clinically relevant signaling in psoriasis is mediated mostly by IL-17A and IL-17F; both act through the same receptor, but have different potencies. IL-17A exerts a stronger effect than IL-17F, and the IL-17A/IL-17F heterodimer has an intermediate effect. IL-17A binds to its trimeric receptor complex composed of two IL-17RA subunits and one IL-17RC subunit, resulting in the recruitment of the ACT1 adaptor protein. The interaction between ACT1 and the IL-17 receptor complex leads to the activation of a series of intracellular kinases including: extracellular signal-regulated kinase (ERK), p38 MAPK, TGF-beta-activated Kinase 1 (TAK1), I-kappa B kinase (IKK), and glycogen synthase kinase 3 beta (GSK-3 beta). These kinases enable NFB, AP-1, and C/EBP transcription of pro-inflammatory cytokines, chemokines, and antimicrobial peptides. Th1 and Th2 cytokines act through Janus kinase (JAK)-STAT signaling pathways, whereas Th17 responses are mediated by ACT1 and NFB [65]. Alternatively, T cells are able to produce IL-17A independently of the IL-23 stimulus [66].

Drugs targeting TNF, IL-23, and IL-17 and signaling pathways such as JAK/STAT are effective in the clinical management of plaque psoriasis. However, alternate inflammatory pathways may be valid for distinct psoriatic variants.

Whereas the TNFIL23Th17 axis plays a central role in T cell-mediated plaque psoriasis, the innate immune system appears to play a more prominent role in the pustular variants of psoriasis [55]. Different pathomechanisms are associated with distinct psoriasis subtypes.

In guttate psoriasis, streptococcal superantigens are thought to stimulate the expansion of T cells in the skin [67]. It was shown that there is a considerable sequence homology between streptococcal M proteins and human keratin 17 proteins. Molecular mimicry may play a role in patients with the major histocompatibility HLA-Cw6 allele, since CD8(+) T cell IFN- responses were elicited by K17 and M6 peptides in said patients [68,69].

Pustular psoriasis is characterized by the increased expression of IL-1, IL-36, and IL-36 transcripts, which have been found in pustular psoriasis compared to psoriasis vulgaris [70]. Nevertheless, IL-17 signaling is also involved in pustular psoriasis and patients with generalized pustular psoriasis without IL-36R mutations responded to anti-IL-17 treatments [71,72].

In nail psoriasis and psoriatic arthritis (PsA), an increased expression of TNF-, NFB, IL-6, and IL-8 in psoriasis-affected nails is consistent with the inflammatory markers found on lesional psoriatic skin [73]. The pathophysiology of PsA and psoriasis is shared as synovial tissue in psoriatic arthritis expresses pro-inflammatory cytokines: IL-1, IFN-, and TNF [74,75]. Infiltrating cells in psoriasis arthritis, tissues, and synovial fluid revealed large clonal expansions of CD8+ T cells. Joint pathology, specifically bone destruction, is partly mediated via IL-17A signaling, which induces the receptor activator of nuclear factor kappa b ligand (RANKL), and in turn activating osteoclasts. Pro-inflammatory cytokines IL-1 and TNF- act in synergy with the local milleu [76].

Psoriasis shows clear autoimmune-related pathomechanisms. This very important area of research will allow for a deeper understanding of to which extent autoantigen-specific T cells contribute to the development, chronification, and overall course of the disease.

LL37 is one of two well-studied T cell autoantigens in psoriasis. CD4+ and CD8+ T cells specific for LL37 were found in two-thirds of patients with moderate to severe plaque psoriasis in a study. LL37-specific T cells produce IFN-, and CD4+ T cells produce IL-17, IL-21, and IL-22 as well. LL37-specific T cells can be found in lesional skin or in the blood, where they correlate with disease activity [77]. CD8+ T cells activated through LL37 engage in epidermotropism, autoantigen recognition, and the further secretion of Th17 cytokines. The melanocytic protein ADAMTSL5 was found to be an HLA-C*06:02-restricted autoantigen recognized by an autoreactive CD8+ T cell TCR. This finding establishes melanocytes as autoimmune target cells, but does not exclude other cellular targets [78].

Other autoantigen candidates include lipid antigens generated by phospholipase A2 (PLA2) group IVD (PLA2G4D) and hair follicle-derived keratin 17 [79,80]. Interestingly, keratin 17 exposure only lead to CD8+ T cell proliferation in patients with the HLA-Cw*0602 allele (see above) [81].

Psoriasis has a genetic component that is supported by patterns of familial aggregation. First and second-degree relatives of psoriasis patients have an increased incidence of developing psoriasis, while monozygotic twins have a two to threefold increased risk compared to dizygotic twins [82,83]. Determining the precise effect of genetics in shaping innate and adaptive immune responses has proven problematic for psoriasis and other numerous immune-mediated diseases [84,85]. The genetic variants associated with psoriasis are involved in different biological processes, including immune functions such as antigen presentation, inflammation, and keratinocyte biology [55].

Genome-wide linkage studies of psoriasis-affected families have so far detected at least 60 chromosomal loci linked to psoriatic susceptibility [86,87,88]; the most prominent locus is PSORS1, which has been attributed up to 50% of the heritability of the disease [89]. PSORS1 is located on chromosome 6p21 within the major histocompatibility complex (MHC), which is specifically in the class I telomeric region of HLA-B, and spans an approximately 220 kb-long segment and corresponds to HLA-Cw6 (C*06:02). HLA-Cw6 is strongly linked to early and acute onset psoriasis [90,91]. The HLA-C*06:02 allele is present in more than 60% of patients, and increases the risk for psoriasis nine to 23-fold [92]. Nevertheless, no link between late-onset psoriasis or pustular psoriasis and PSORS1 could be established, possibly reflecting a genetically heterogenic background associated with different clinical phenotypes [93]. PSORS2 spans the CARD14 gene, while PSORS4 is located in the epidermal differentiation complex [94,95,96,97,98,99,100,101].

The results of numerous genome-wide association studies (GWAS) in psoriasis are consistent with the prominent role of PSORS1 as a risk factor, but have also revealed over 50 single-nucleotide polymorphisms (SNPs) to be associated to psoriasis [102,103,104]. Variants involving the adaptive and immune system are a constant result in these studies [53,103,105].

The immunogenetics of IL-23 are strongly associated with psoriasis. IL-23 is a dimer composed of a specific subunit, p19, and a p40 subunit, which is shared with IL-12. IL-23 signals through a heterodimeric receptor expressed by both innate and adaptive immune cells, which include Th17, natural killer T, T cells, and RORt+ innate lymphoid cells. The IL-23R signals through JAK2/TYK2 and STAT3 [106]. SNPs in the regions coding for the IL-23 cytokine (both the p40 and p19 subunit) as well as the IL-23R have been identified to convey psoriasis risk [107,108,109]. Furthermore, these variants have been found to be associated with Crohns disease, psoriatic arthritis, and ankylosing spondylitis [110] [74,75]. IL-23 drives the expansion of Th17 T cells that produce IL-17A/F, which is another set of cytokines whose role is pivotal in the pathogenesis of psoriasis. Monoclonal antibodies targeting both the common p40 and the specific p19 subunit of IL-23 have proven to have high clinical efficacy [109].

As mentioned above, STAT3 is found in downstream signaling by IL-23, and is therefore essential in T cell development and Th17 polarization. STAT3 has also been detected in psoriasis GWAS, and its variants are associated with psoriasis risk [107,111]. Furthermore, transcription factor Runx1 induces Th17 differentiation by interacting with RORt. Interestingly, the interaction of Runx1 with Foxp3 results in reduced IL-17 expression [112].

CARD14 mapping was shown to correspond to PSORS2. The CARD family encompasses scaffolding proteins that activate NF-kB. It was suggested that in psoriasis patients with respective CARD14 mutations, a triggering event can result in an aberrant NF-kB over activation [96]. CARD14 is expressed in keratinocytes and in psoriatic skin; it is upregulated in the suprabasal epidermal layers and downregulated in the basal layers. In healthy skin, CARD14 is mainly localized in the basal layer. Mutations in CARD14 have been shown to be associated with psoriasis, as well as with familial pityriasis rubra pilaris (PRP) [113].

The NF-kB signaling pathway is involved in the production of both IL-17 and TNF-, and thus participates in adaptive and innate immune responses [73]; it is upregulated in psoriatic lesions and is responsive to treatment [114]. Gene variations in NFKBIA, TNIP1, and TRAF3PI2 affecting NF-kB regulatory proteins have been linked to psoriasis via GWAS [102,115,116,117]. TRAF3PI2 codes for the ACT1 adaptor protein and the specific variant TRAF3IP2 p. Asp10Asn was associated to both psoriasis and psoriatic arthritis [117].

The different clinical psoriasis variants may have additional genetic modifiers. For instance, mutations in the antagonist to the IL-36 receptor (IL-36RN), belonging to the IL-1 pro-inflammatory cytokine family, have been linked to pustular psoriasis [118,119]. Recessive mutations in IL36RN, coding for the IL-36 receptor antagonist, have been associated with generalized pustular psoriasis (GPP). This mutation is also found in palmar plantar pustulosis and acrodermatitis continua of Hallopeau. Furthermore, in patients with pre-existing plaque-type psoriasis, the gain of function mutation in CARD14, p.Asp176His, was found to be a predisposing factor for developing GPP [120].

In addition to studies of genetic variants, the profiling of gene expression in psoriasis has aided in the understanding of the relevant pathophysiological pathways. Transcriptomic studies of psoriatic skin have revealed differentially expressed genes (DEGs) when compared to healthy skin, and also between lesional and nonlesional psoriatic skin [121,122]. Further underscoring their relevance in psoriasis pathogenesis, IL-17A genes were found to be upregulated in nonlesional psoriatic skin compared to healthy skin. This finding suggests that nonlesional psoriatic skin is also subclinically affected, and supports the concept of the widespread inflammation that is present in psoriasis [123]. In addition, data showing the upregulation of Th2 genes in nonlesional psoriatic skin may reflect the activation of T cell regulatory compensation mechanisms in an effort to override the inflammatory cascade [123]. Cross-disease transcriptomics have aided in differentiating nonspecific DEGs present in inflammatory skin conditions (such as atopic dermatitis and squamous cell carcinoma) from DEGs specific to psoriasis. The latter are induced by IL-17A and are expressed by keratinocytes [124].

Despite solid evidence of genetic relevance in the pathogenesis of psoriasis, no single genetic variant seems to be sufficient to account on its own for the development of disease. Hence, a multifactorial setting including multiple genetic mutations and environmental factors, which have been attributed up to 30% of disease risk, ought to be considered [125].

The quest for the missing heritability associated with psoriasis candidate genes has fueled the search for epigenetic modifications. Epigenetic mechanisms modify gene expression without changing the genomic sequence; some examples include: long noncoding RNA (lncRNA), microRNA (miRNA) silencing, and cytosine and guanine (CpG) methylation.

lncRNA are at least 200 nucleotides long, and are not transcribed to protein. At least 971 lncRNAs have been found to be differentially expressed in psoriatic plaques compared to normal skin [126,127,128,129,130,131]. Thereof, three differentially expressed lncRNAs in proximity to known psoriasis susceptibility loci at CARD14, LCE3B/LCE3C, and IL-23R, and are thought to modulate their function [127].

miRNAs are small, evolutionarily conserved, noncoding RNAs that base pair with complementary sequences within mRNA molecules, and regulate gene expression at the posttranscriptional level, usually downregulating expression. Most of the studies of miRNAs in association with psoriasis address the plaque-type variant (see ), and so far, more than 250 miRNAs are aberrantly expressed in psoriatic skin [132,133,134,135]. A prominent role has been attributed to miR-31, which is upregulated in psoriatic skin and regulates NF-B signaling as well as the leukocyte-attracting and endothelial cell-activating signals produced by keratinocytes [135]. miR-21 is an oncomiR with a role in inflammation, and has been found to be elevated in psoriatic skin. Increased miR-21 has been localized not only to the epidermis, but is also found in the dermal inflammatory infiltrates, and correlates with elevated TNF- mRNA expression [136]. miR-221 and miR-222 are among other upregulated miRNAs in psoriatic skin [132]. The aberrant expression of miR-21, miR-221, and miR-222 correlates with a downregulation of the tissue inhibitor of metalloprotease 3 (TIMP3) [137,138]. TIMP3 is a member of the matrix metalloprotease family with a wide range of functions. Increased levels of said miRs are thought to result in unopposed matrix metalloprotease activity, leading to inflammation (partly via TNF--mediated signaling) and epidermal proliferation [138]. miR-210 was found to be highly expressed in psoriasis patients, and induced Th17 and Th1 differentiation while inhibiting Th2 differentiation through STAT6 and LYN repression [139].

MicroRNAs (miRNAs) increased in psoriasis.

Serum levels of miR-33, miR-126, and miR-143, among others, have been proposed as potential biomarkers of disease [140,141]. However, the studies have so far failed to consistently present elevations of a single miRNA in psoriatic patients. Thus, alterations of miRNA expression are better interpreted in the context of miRNA profiles, which have been reported to shift following psoriasis treatments [132]. Thus, miRNA expression profiles could potentially be used to predict response to treatment and personalize therapies.

DNA methylation is another epigenetic mechanism that can alter gene expression in a transient or heritable fashion, and primarily involves the covalent modification of cytosine and guanine (CpG) sequences. CpG methylation is usually repressive unless it inhibits transcriptional repressors, in which case it results in gene activation. Around 1100 differentially methylated CpG sites were detected between psoriatic and control skin. Of these sites, 12 corresponded to genes regulating epidermal differentiation, and were upregulated due to a lower methylation pattern. Said changes in DNA methylation reverted to baseline under anti-TNF- treatment, indicating that CpG methylation in psoriasis is dynamic [148,149]. Further research will shed light on the functional relevance of epigenetic regulation in psoriasis.

The skin microbiome exerts an active role in immune regulation and pathogen defense by stimulating the production of antibacterial peptides and through biofilm formation. A differential colonizing microbiota in comparison to healthy skin has been found in several dermatologic diseases, including atopic dermatitis, psoriasis, and acne vulgaris [150,151]. It is hypothesized that an aberrant immune activation triggered by skin microbiota is involved in the pathogenesis of autoimmune diseases. For instance, there is growing evidence that the steady-state microbiome plays a role in autoimmune diseases such as in inflammatory bowel disease [152].

The overall microbial diversity is increased in the psoriatic plaque [151]. However, an increase in Firmicutes and Actinobacteria phyla were found in psoriatic plaques () [153]. Proteobacteria were found to be higher in healthy skin when compared to psoriatic patients [153,154]. Nevertheless, Proteobacteria were found to be increased in the trunk skin biopsies of psoriatic lesions [151]. A combined increase in Corynebacterium, Propionibacterium, Staphylococcus, and Streptococcus was found in psoriatic skin; however, in another study, Staphylococci were significantly lower in psoriatic skin compared to healthy controls [151,154].

Psoriasis microbiome. increased. > higher than.

Certain fungi such as Malassezia and Candida albicans, and viruses such as the human papilloma virus have been associated with psoriasis [155]. So far, Malassezia proved to be the most abundant fungus in psoriatic and healthy skin. Nevertheless, the colonization level of Malassezia in psoriasis patients was lower than that in healthy controls [156]. Further studies are required to explain the role of the microbiome signature and the dynamics among different commensal and pathogenic phyla [157].

Psoriasis is a chronic relapsing disease, which often necessitates a long-term therapy. The choice of therapy for psoriasis is determined by disease severity, comorbidities, and access to health care. Psoriatic patients are frequently categorized into two groups: mild or moderate to severe psoriasis, depending on the clinical severity of the lesions, the percentage of affected body surface area, and patient quality of life [159]. Clinical disease severity and response to treatment can be graded through a number of different scores. The PASI score has been extensively used in clinical trials, especially those pertaining to the development of the biologic drugs, and will be used throughout this review.

Mild to moderate psoriasis can be treated topically with a combination of glucocorticoids, vitamin D analogues, and phototherapy. Moderate to severe psoriasis often requires systemic treatment. The presence of comorbidities such as psoriasis arthritis is also highly relevant in treatment selection. In this review, we will address the systemic therapies as small-molecule (traditional and new) and biologic drugs.

A number of case reports and case series have suggested that tonsillectomy has a therapeutic effect in patients with guttate psoriasis and plaque psoriasis [69,160,161]. A systematic review concluded that the evidence is insufficient to make general therapeutic recommendations for tonsillectomy, except for selected patients with recalcitrant psoriasis, which is clearly associated to tonsillitis [162]. A recent study stated that HLA-Cw*0602 homozygosity in patients with plaque psoriasis may predict a favorable outcome to tonsillectomy [163]. To date, a single randomized, controlled clinical trial showed that tonsillectomy produced a significant improvement in patients with plaque psoriasis in a two-year follow-up timespan [164]. Furthermore, the same cohort was evaluated to assess the impact of the clinical improvement after tonsillectomy on quality of life. The study reported a 50% improvement in health-related quality of life, and a mean 59% improvement in psoriasis-induced stress. Tonsillectomy was considered worthwhile by 87% of patients who underwent the procedure [165].

In the past years, an accelerated development in psoriasis therapies has resulted in advanced targeted biological drugs. Methotrexate (MTX), cyclosporin A, and retinoids are traditional systemic treatment options for psoriasis. All of the former are oral drugs with the exception of MTX, which is also available for subcutaneous administration. They will be briefly discussed in this review (see ). The section ends with an overview on dimethyl fumarate and apremilast, which are newer drugs that have been approved for psoriasis.

Drugs available for psoriasis therapy.

MTX is a folic acid analogue that inhibits DNA synthesis by blocking thymidine and purine biosynthesis. The initial recommended dose of 7.510 mg/weekly may be increased to a maximum of 25 mg/weekly [166,167]. A recent retrospective study reported successful treatment response (defined by PASI decrease of 50% to 75% and absolute DLQI value) was reached by 33%, 47%, and 64% of patients at three, six, and 12 months, respectively [168]. There is conflicting evidence regarding MTX effectiveness on psoriatic arthritis. A recent publication reported 22.4% of patients achieved minimal arthritic disease activity, and 27.2% reached a PASI 75 at week 12 [169]. Furthermore, HLA-Cw6 has been suggested as a potential marker for patients who may benefit from MTX treatment [170]. The most common side effects include nausea, leucopenia, and liver transaminase elevation. Despite the potential side effects and its teratotoxicity, it remains a frequently used cost-effective first-line drug, and the close monitoring of liver function and full blood count make a long-term administration feasible.

Cyclosporine is a T cell-inhibiting immunosuppressant from the group of the calcineurin inhibitors. Cyclosporine is effective as a remission inducer in psoriasis and as maintenance therapy for up to two years [171]. Hypertension, renal toxicity, and non-melanoma skin cancer are significant potential side effects. Nephrotoxicity is related to the duration of treatment and the dose. Cyclosporine is employed as an intermittent short-term therapy. The dosage is 2.5 to 5.0 mg/kg of body weight for up to 10 to 16 weeks. Tapering of the drug is recommended to prevent relapse [171].

Retinoids are natural or synthetic vitamin A-related molecules. Acitretin is the retinoid used in the treatment of psoriasis. It affects transcriptional processes by acting through nuclear receptors and normalizes keratinocyte proliferation and differentiation [172,173]. A multicenter, randomized study reported 22.2% and 44.4% of patients reaching PASI 75 and PASI 50 at 24 weeks [174]. Acitretin is initially administered at 0.30.5 mg/kg of body weight per day. The maximum dosage is 1 mg/kg body weight/daily. Cheilitis is the most common side effect appearing dose dependently in all patients. Other adverse effects include conjunctivitis, effluvium, hepatitis, and teratogenicity.

Fumaric acid esters (FAEs) are small molecules with immunomodulatory and anti-inflammatory properties [175,176]. The exact mechanism of action has not been cleared, but is thought to involve an interaction with glutathione, which among other mechanisms, inhibits the transcriptional activity of NF-B [177,178]. FAEs were initially available as a mix of dimethyl fumarate and monoethyl fumarate (DMF/MEF), the former being the main active compound in the formulation. DMF has been reported to decrease the migratory capacity of slan+ monocytes, and also inhibited the induction of Th1/Th17 responses [178]. DMF/MEF was approved in 1994 in Germany for the treatment of severe plaque psoriasis, and in 2008, the indication was expanded for moderate psoriasis [179]. This licensing was exclusive to Germany, where it remains a first-line drug; nevertheless, DMF/MEF was used as off-label treatment in other European countries [180,181,182,183]. A new FAE formulation containing exclusively the main active metabolite DMF became available in 2017, and was approved for psoriasis treatment in the European Union, Iceland, and Norway [184]. Although there are no studies comparing DMF/MEF directly to biologics, several studies document its efficacy [185,186,187,188,189]. A marked improvement is also seen in patients with psoriatic arthritis and nail psoriasis. The most common side effects are gastrointestinal symptoms and flushing, which are generally mild in severity, resolve over time, and are dose related [184]. In addition, FAEs may decrease lymphocyte and leukocyte counts. Therefore, it is recommended to perform a complete blood count before treatment initiation and monthly for DMF/MEF or every three months for DMF [184].

Apremilast, a phosphodiesterase-4 inhibitor, inhibits the hydrolyzation of the second messenger cAMP. This leads to the reduced expression of pro-inflammatory cytokines TNF-, IFN0, and IL-12, and increased levels of IL-10. Apremilast was shown to have broad anti-inflammatory effects on keratinocytes, fibroblasts, and endothelial cells [190]. We studied apremilast in the context of slan+ cells, which is a frequent dermal inflammatory dendritic cell type derived from blood circulating slan+ nonclassical monocytes. Here, apremilast strongly reduced TNF- and IL-12 production, but increased IL-23 secretion and IL-17 production in T cells stimulated by apremilast-treated slan+ monocytes [191]. These dual effects on slan+ antigen-presenting cells may constrain therapeutic responses. No routine monitoring of hematologic parameters is required for apremilast, which is a major advantage compared to the other small molecule drugs. Apremilast showed a 33.1% PASI 75 response at week 16. It is also effective for palmoplantar, scalp psoriasis, and nail psoriasis in addition to psoriatic arthritis [192,193,194]. The most common adverse events affected the gastrointestinal tract (nausea and diarrhea) and the upper respiratory tract (infections and nasopharyngitis). These effects were mild in nature and self-resolving over time.

The traditional systemic drugs are immunomodulators, which except for apremilast require close clinical monitoring due to the common side effects involving mainly the kidney and the liver. Methotrexate and cyclosporine are the only systemic therapies for psoriasis included in the World Health Organization (WHO) Model List of Essential Medicines, albeit for the indications of joint disease for the former and immunosuppression for the latter. The potential side effects of FAE and apremilast are usually not life-threatening, but might be sufficient to warrant discontinuation.

In the context of psoriasis treatment, current use of the term biologics refers to complex engineered molecules including monoclonal antibodies and receptor fusion proteins. Biologics are different from the above-described systemic therapies in that they target specific inflammatory pathways and are administered subcutaneously (s.c.) (or intravenously i.e., infliximab) on different weekly schedules. Biologics presently target two pathways crucial in the development and chronicity of the psoriatic plaque: the IL-23/Th17 axis and TNF--signaling (see ).

TNF- inhibitors have been available for over a decade. They are considered the first-generation biologics, and are effective for plaque psoriasis and psoriatic arthritis. TNF- inhibitors are still the standard used to evaluate drug efficacy in psoriasis clinical research. There are currently four drugs in this category: etanercept, infliximab, adalimumab, and certolizumab.

Etanercept is unique in the biologics category in that it is not a monoclonal antibody, but rather a recombinant human fusion protein. The receptor portion for the TNF- ligand is fused to the Fc portion of an IgG1 antibody. It was the first TNF- inhibitor approved by the United States Food and Drug Administration (FDA) for psoriasis. Infliximab is a chimeric monoclonal IgG1 antibody, and adalimumab is a fully human monoclonal IgG1 antibody. They neutralize TNF- activity by binding to its soluble and membrane-bound form. These drugs are particularly employed to treat psoriatic arthritis, and show a similar efficacy. In the treatment of psoriasis, they show different PASI 75 response rates: 52% for etanercept, 59% for adalimumab, and 80% for infliximab. Infliximab shows superiority in terms of efficacy when compared to the other TNF- inhibitors, and when compared with ustekinumab, it showed a similar performance [195]. The chimeric nature of infliximab might contribute to a higher immunogenic potential of the drug, which in turn might influence drug survival. Certolizumab pegol is a pegylated Fab fragment of a humanized monoclonal antibody against TNF-. PEGylation is the covalent conjugation of proteins with polyethylene glycol (PEG), and is attributed a number of biopharmaceutical improvements, including increased half-life and reduced immunogenicity [196]. The initial indication for treating Crohns disease was extended to psoriatic arthritis and recently to plaque psoriasis. Certolizumab has shown an 83% PASI 75 response. Unlike other anti-TNF- agents, it has no Fc domain, and is thus not actively transported across the placenta. Thus, certolizumab pegol is approved for use during pregnancy and breastfeeding.

As previously mentioned, IL-23 drives the expansion of Th17 cells whose inflammatory effects are in turn mediated by IL-17A, IL-17F, and IL-22.

IL-23 is a dimer composed of p40 and p19. The first biologic to be approved for psoriasis vulgaris after the TNF- inhibitors was ustekinumab, which is a monoclonal antibody directed against the p40 subunit. P40 is not exclusive to IL-23, but rather is shared with IL-12. IL-12 is a dimer consisting of p40 and p35, and is involved in the differentiation of nave T cells into Th1 cells. By targeting p40, ustekinumab blocks two different T-cell activating mechanisms, namely Th1 and Th17 selection. Ustekinumab is also effective for the treatment of PsA and Chrons disease. It is available in two dosages, 45 mg and 90 mg, depending on a threshold body weight of 100 kg. Ustekinumab has extensive safety data, few side effects, good clinical efficacy, and long treatment drug survival was reported. At 90 mg, ustekinumab showed a PASI 75 response in 72.4% and in 61.2% at 45 mg [197]. Studies using real-life data compared ustekinumab with the anti-TNF- drugs, and ustekinumab was found to have a significant longer drug survival [198,199,200]. Frequent adverse events include nasopharyngitis, upper respiratory tract infections, fatigue, and headache. Among the serious adverse events listed in the label of ustekinumab are infections. Tuberculosis (TB) has only been reported in two psoriasis patients receiving ustekinumab [201,202]. The clinical efficacy of ustekinumab and the further clarification of its mechanism of action highlighted the crucial role of IL-23 in shaping the Th17 response. On the other hand, Th1 signaling is important for the response against bacterial and viral pathogens, and a study showed IL-12 signaling to have a protective effect in a model of imiquimod psoriasis-like inflammation [203]. This rationale fueled the development of drugs targeting p19, which is the IL-23-exclusive subunit. This more specific molecular targeting approach has also achieved successful clinical outcomes. Three fully human monoclonal antibodies with p19 specificity are available: guselkumab, tildrakizumab, and risankizumab. Guselkumab is licensed for psoriasis, and showed clinical superiority when compared to adalimumab, with 85.1% of patients reaching a PASI 75, and 73.3% receiving a PASI 90 response at week 16 [204,205]. Patients receiving tildrakizumab showed a 74% PASI 75, and 52% PASI 90 at week 16. Tildrakizumab was compared to etanercept, and was more likely to reach PASI 75 at weeks 16 and 28 [206,207]. Risankizumab showed the following PASI responses at week 12: 88% PASI 75, 81% PASI 90, and 48% PASI 100. Patients were followed for 48 weeks after the last injection at week 16, and one-fourth of them showed a maintained PASI 100 [208]. Whether IL-23 inhibition has the potential to modify the course of the disease after subsequent drug retrieval is currently under study.

So far, three human monoclonal antibodies targeting IL-17 are available. Secukinumab and ixekizumab block IL-17A; whereas brodalumab is directed against the IL-17 receptor A. IL-17-targeted biologics are fast acting, showing significant differences from placebo within the first week of treatment. Secukinumab was the first IL-17A inhibitor approved for psoriasis in 2015. A year later, the approval extended to include PsA and ankylosing spondylitis. At week 12, 81.6% of patients on secukinumab reached a PASI 75 response, and 28.6% reached a PASI 100 response [209]. At week 52, over 80% maintained PASI 75. Secukinumab showed a rapid onset of action, reflecting a significant likelihood of achieving PASI 75 as early as the first week of treatment when compared to ustekinumab, and surpassed the latter in clinical superiority at week 16 and 52 [210,211].

Ixekizumab also showed a significantly rapid onset of action in the first week when compared to placebo: a 50% PASI 75 response at week four, and 50% PASI 90 by week eight. At week 12, response rates were 89.1% for PASI 75 and 35.3% for PASI 100 [212]. Secukinumab and ixekizumab have proven effective for scalp and nail psoriasis, which are two clinical variants that are resistant to conventional topical therapies.

Brodalumab is a human monoclonal antibody that targets the IL-17 receptor type A, thus inhibiting the biological activity of IL-17A, IL-17F, interleukin-17A/F, and interleukin-17E (also called interleukin-25). Brodalumab showed an 83.3% PASI 75, 70.3% PASI 90, and 41.9% PASI 100 response rate at week 12, and a satisfactory safety profile [213,214]. After the discontinuation of treatment with secukinumab, 21% of patients maintained their response after one year and 10% after two years [215]. This finding suggests that targeting IL-17 signaling exerts some disease-modifying effect that might reestablish the homeostasis of the inflammatory pathways in a subset of psoriasis patients. Frequent adverse effects under IL-17 blockade include nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Furthermore, IL-17 signaling is critical for the acute defense against extracellular bacterial and fungal infections. Candida infections are more frequent in patients receiving anti-IL17 biologics secukinumab and ixekizumab compared to etanercept [209]. Nonetheless, candida infections were not severe, and did not warrant treatment interruption. The risk of tuberculosis reactivation is considered small under biologic therapies other than anti-TNF- [216]. Anti-IL-17 biologics should not be used in psoriasis patients also suffering from Chrons disease.

The introduction of biosimilars for different diseases is revolutionizing the pharmaceutical arsenal at hand. As patents for many biologics face expiration, biosimilar versions of these drugs are being developed, or are already entering the market. A biosimilar is a biological product that must fulfill two requirements: it must be highly similar to an approved biologic product and have no clinically meaningful differences in safety, purity, or potency when compared with the reference product. Guidelines for the development and approval of biosimilars have been issued by the European Medicines Agency, the FDA, and the World Health Organization. There are currently eight adalimumab biosimilars, four infliximab biosimilars, and two etanercept biosimilars approved in Europe. By lowering the costs of systemic treatment for psoriasis patients, biosimilars may also increase access to biologics.

Tofacitinib is an oral Janus kinase (JAK) inhibitor currently approved for the treatment of rheumatoid arthritis (RA) and PsA. Tofacitinib showed a 59% PASI 75 and 39% PASI 90 response rate at week 16, and was also effective for nail psoriasis; however, its development for psoriasis was halted for reasons unrelated to safety. Upadacitinib is another JAK inhibitor currently undergoing phase III clinical trials for the treatment of psoriatic arthritis. Piclidenoson, an adenosine A3 receptor inhibitor, serlopitant, a neurokinin-1 receptor antagonist, and RORt inhibitors are each being tested as oral treatments for psoriasis [217]. Two different biologics targeting IL-17 and one targeting IL-23 are being currently tested. In addition, there are currently 13 registered phase III clinical trials testing biosimilars for adalimumab (eight), infliximab (three), and etanercept (two).

See original here:
Psoriasis Pathogenesis and Treatment - PMC - PubMed Central (PMC)

Posted in Psoriasis | Comments Off on Psoriasis Pathogenesis and Treatment – PMC – PubMed Central (PMC)

Page 118«..1020..117118119120..130140..»