Category Archives: Evolution

Today, with seven commercially approved antibody-drug conjugates (ADCs) on the market and approximately 90 programs in clinical trials, simplifying the complex supply chain to make manufacturing efficient is a necessity. With approximately 70 percent of ADC projects outsourced to contract development and manufacturing organizations (CMDOs),1 a transparent and integrated supply chain is critical for success. Now, this is more important than ever, with more clinical trials with combination therapy expected as more than 200 trials are registered and as ADCs are expected to gain prominence beyond oncology in the areas of anti-infection, anti-inflammatory, cardiovascular diseases and imaging and diagnostic agents.

The typical ADC supply chain is elaborate due to the numerous, specialized processes in their production and the logistical alignment needed between each step. The three main elements of an ADC are:

The benefits of working with established CDMOs on ADC projects are numerous: experience with a variety of constructs and ADC technologies; efficient processes in place for tech transfer and manufacturing; manufacturing expertise, particularly with GMP batches; and understanding of the regulatory pathway for ADCs.

Interspersed with the above manufacturing steps, requisite quality control measuressuch as mAb bioassays and conjugate stability testingcompound an already complicated pathway. Clearly, manufacturers that can simplify this supply chain are doing customers a great service.

Ten years ago, ADC manufacturing took place on a much smaller scale than today. Raw materials, such as mAbs, were only available in clinical rather than commercial-sized batches. Manufacturing was performed as an add-on to other procedures rather than as an optimized, stand-alone process, and few sites were capable of handling high-potency payloads.

Full-length mAbs were humanized IgGs, most often IgG1, conjugated randomly at cysteine or lysine sites, as shown in Figure 1. In these constructs, the payload could bond to the antibody in multiple locations, potentially affecting its activity. With an IgG scaffold containing over 80 lysines,2 conjugation resulted in very heterogeneous ADCs with variable drug-to-antibody ratios (DARs). High DAR species in the final product can impact stability, solubility and cause problems in manufacturing and operations.

To solve the heterogeneity problem, research moved from native IgGs toward site-specific engineered mAbs, including mAbs with engineered cysteines, non-natural amino acids and sequence tagsall of which could be reacted to perform a more homogenous product. The goal was to manipulate the antibody, so it had specific, limited locations where the toxins were to bond. For instance, monoclonal antibodies containing engineered cysteine moieties limit conjugations to positions that do not disturb immunoglobulin folding or assembly or alter antigen binding.3 The structural representation of an ADC made with such an antibody is shown in Figure 2.

Other second-generation developments included modulation of ADC hydrophobicity by using hydrophilic linkers; structure activity relationship (SAR) design relating a molecules structure to function; and enhanced analytical tools such as chromatography. Cytotoxic payloads with greater potency, such as auristatin and maytansine microtube disruptors, also came into play. All these developments helped improve the usefulness of these agents.

More sophisticated, specialized manufacturing techniques and special facilities were also required to handle these powerful toxins safely.

Second-generation linkers had slightly more functionality than earlier linkers. They were also monovalent, but some were cleavable, either enzymatically or via acid exposure inside cells or lysosomes. Examples include linkers based on proteases, hydrazine, polyethylene glycol (PEG) and disulfides. These linkers were expected to help the antibody release the toxin at the right place and the right time and also stabilize the ADC during preparation, storage and systemic circulation.

Todays researchers are exploring additional modes of action and ways to increase activity and specificity. Bi-specific MAbs, both IgG-like and non-IgG-like, contain two dissimilar binding sites. For example, a single ADC may deliver a toxin and activate natural killer cells. One recently constructed agent had four mechanisms of action. Obviously, the conjugation processes and analytics for these agents are non-trivial.

Another up-and-coming technology is utilizing Fabs (antigen-binding fragments) in place of intact mAbs. These are sections of antibodies that include sites for antigen binding and linkage. These Fabs are very stable, may be internalized more readily, are relatively easy to purify, and tend to be less immunogenic than larger ADCs.

Third-generation payloadspotent cytotoxins such as PBDs and tubulysin, which require special facilities and handlingare not that different than second-generation payloads.

The most unexpected aspect of third-generation development is the revolution in the general understanding of what linkers can do. SAR studies show that linkers change antibody properties, including changes in toxicity and pharmacokinetic profiles. It is now known that if a linker is altered, these parameters must be reevaluated.

New linker categories still include cleavable and non-cleavable, but they also encompass entities such as the Fleximer platform, a polyvalent and biodegradable molecule that can carry multiple payloads. Additionally, hydrophilic linker modulation such as pegylation can mask a larger molecule from the immune system and decrease renal clearance to increase longevity in the circulation. This is a very useful concept as PBDs are very hydrophobic and, once conjugated, are prone to aggregation.

Todays complex, multifaceted ADCs place substantial demands on drug developers and manufacturers, and these challenges are compounded by this sense of urgency in a crowded field and need for life-saving therapies:

Established CMDOs in the ADC business will need to keep pace with future technological advances in this fast-growing industry. Companies that will be successful in the bioconjugation space are providing dedicated facilities for high-potency biologicals, establishing platform operations and developing a workforce with the advanced and specialized expertise to meet the expectations of customers and regulatory agencies. Next-generation bioconjugation will not only be challenged by new and novel chemical unit operations, but will also require novel analytical technologies to provide a more granular understanding at the molecular level. Techniques and tools will need to provide answers for the control strategy of complex products and will need to evolve to support sophisticated release strategies for on-line and at-line in-process testing.

Along with comprehensive laboratory services and expert assistance, the following technologies are particularly helpful for successful ADC manufacturing:

SUS technologies add simplicity and are available for all steps throughout the ADC manufacturing process. Having a complete, single-use process in place can make a big difference: no cleaning studies are needed, reducing costs. The components are designed to be scalable. Extractables and leachables documentation is available to meet regulatory requirements. Operator safety is increased, particularly when handling highly potent ingredients. Implementation of single-use reactor along with a full line of single use equipment for all unit operations is expected be the preferred platform of choice for all bioconjugation processes.

The advancement of PAT allows real-time testing during a GMP process to gather rich, real-time data about the physical and chemical parameters during active processes. It can be used to ensure the process is going as planned and it can also be used to monitor trends in process iterations.

Purification strategies have been expanded to include large-scale chromatography and an increased number of constructs have chromatography. The major reasons to integrate chromatography include: to clear lipophilic drugs that are not amenable to TFF clearance; to remove aggregates and to refine conjugated species distribution, as in removing unconjugated mAb; and to ensure the best possible ADC therapeutic index and specificity, an important function since 60% of constructs require this type of purification.

Potential customers are also evaluating services beyond preparation of the materials, such as formulation support and studies to support the regulatory filing.

Ten years ago, ADCs were a relatively simple concept: use an antibody to target a cell and precisely deliver a biologically active agent. Now, the mission is much more complicated. CDMOs with long-range plans for ADC manufacturing are setting up processes to handle challenging supply chains and investing in facilities and processes to ensure efficiency, quality and security for their customers. Companies that can help deliver multiple constructs to enable a well-designed clinical program are providing customers the opportunity to advance in the field at a fast pace. CDMOs are uniquely positioned to see a wide variety of best practices and can provide solutions based on what has been observed in the industry. In addition, as more commercial products enter the market, there is an acute need for companies that understand how to execute late-stage studies to support a filing strategy. The growth of ADCs in the clinical and commercial API space is a testament to the ability of manufacturers to evolve the technologies required to handle complex molecules.

Whether its understanding the structure-activity relationships around the antibody, linker and drug, or managing a complex supply chain, a CDMO with experience should have the skills and tools needed to help ADC developers navigate these challenges.

Sources

Jyothi Swamy is associate director, ADC/bioconjugation contract manufacturing at MilliporeSigma.

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The Evolution Of The ADC Manufacturer - Contract Pharma

Early Topanga Beach residents endured tense times during WW II but had a front row seat for the birth of Californias surf culture. Their experiences were a key chapter in Topangas creative and colorful history.

In 2005, Topanga Messenger editor Susan Chasen and I interviewed the Rusts daughter, Thais (b.1925), about growing up in Lower Topanga. Her memories, many of which we published in the newspaper and re-published in The Topanga Story, presented a vision of our hometown so unfamiliar that it astonished us.

One of Thaiss earliest memories was watching the enormous German Graf Zeppelin fly by Topanga Beach on its 1929 trip around the world. A few years later, the zeppelin would become a symbol of Nazi propaganda and carry the swastika.

Thais also remembered the gambling ships of the 1930s, which would sometimes anchor off Topanga. They had to stay three miles from the coast to avoid U.S. laws.

Holiday fun was had at the annual Webster Christmas Party for the Children of Malibu, a 20-year tradition at Judge John L. Websters Malibu Courthouse that started in 1932, and drew hundreds.

A simpler ritual was collecting honey with painter Laura Way Mathiesen, who kept her bees in a side canyon that doubled as a shooting range for the police.

Thaiss favorite memories were of spending whole summers on the beach with her cousin Marilyn Kays, and neighbors Dick Carhart and Ida Lee Carrillo. Ida Lee was the daughter of Octavio (Ottie) and Bessie Carrillo, the niece of actor Leo Carrillo, and the descendant of one of Californias oldest Spanish families.

We were at the beach probably from eight or nine in the morning til five or six at night. It didnt matter how large the waves were, we just had fun. One day, Marilyn and I went with Ida Lee and her dad to the beach. The three of us got out beyond the waves, not knowing that there was a strong riptide. When we couldnt get back to shore, Ottie called the Santa Monica lifeguards to rescue us. We were picked up just before Sunset Boulevard. We were having a great time, but Ida Lees dad was frantic.

Other swimming options were the bathhouse of Alfred T. Stewart, rebuilt after the 1926 fire, nicknamed The Plunge, and the private swimming pool of actor/Olympian Johnny Weissmuller at Tuna Beach, where the neighborhood kids liked to jump in from the balcony.

Later, actress Natalie Talmadge lived in the Weissmuller house with her sons Joseph (James) and Robert (Bob). She legally changed their surnames to Talmadge to avoid being reminded of her famous ex-husband, Buster Keaton.

In the early 1940s, actors David Niven and Errol Flynn took over the house, with Bing Crosby and Paulette Goddard living on either side. In the mid-1940s, it became the Las Tunas Isle Motel. Today its a private residence again.

After high school, Thais became engaged to Bob Talmadge, but they broke up before the wedding. During World War II, she spent Friday nights scanning the sky for enemy planes from a lookout tower that was across the street from todays Getty Villa. In the early 1950s, she was briefly married to a second beach resident, Dave Sykes (1926-2009).

However, a third man from the beach was destined to become her life partner, and surprisingly it was Daves younger brother, John (Jack) Sykes (1935-2017), whom she married in 1956.

Jack, Dave, and their sister Beverly were the children of Sherman and Gladys Sykes, who owned a bar called The Glen, in Beverly Glen. It had a reputation for being tough, and Sherman carried a gun that he would sometimes leave out on the table. Their house had a gangplank that led onto the sand. When it was pulled up, it covered the door to keep big waves from splashing in.

Chasen and I simultaneously interviewed Jack, and he shared vivid memories of what Topanga Beach was like during World War II.

By then, the gambling ships had been outlawed, but the Air Force kept an abandoned ship moored off Topanga for target practice. The hills along the coast were full of artillery. It was a common sight to see 100 army vehicles at a time driving down the highway in convoy. At night, drivers kept their headlights off, and a Blackout Warden fined houses where light was visible.

The Coast Guard had a headquarters at Sunset Blvd., and patrolled the coast on foot every evening, passing by Topanga Beach with bayonets and German Shepherds. Sometimes the army closed the beach to play war games.

On either side of the lagoon, machine gun nests were placed on dirt mounds. One was in front of Jacks house.

They dug a big hole in the sand, and had soldiers in there. I would bring them cookies from our house, and my dad got so mad at me. I was taking all our stuff out for these guys to eat.

Contrasting with the wartime grittiness was the glamour of Jacks celebrity neighbors, like actresses Greta Garbo, with whom he took walks, and Shirley Temple, who occasionally asked his dad for a ride to town.

Jack was also surrounded by icons of early California surfing, which included his brother.

[Dave] Sykes was the best surfer I had seen at that time because he lived there and surfed all day, every day. He could just glide and glide. (Joe Quigg, The Archivist: Turning Points, The Surfers Journal, September 19, 2017)

Topanga dweller Sykes finely honed speed lines and turning were years in advance of others. Sykes delighted in [perfectly] planing surfaces and placed 15 layers of hand-rubbed lacquer over his boards creating a hard-shelled outer surface many years before the discovery of fiberglass and resin. (Craig Stecyk, The Surfers Journal)

The Malibu Point was first surfed in September 1927, when it was still a private ranch, by Tom Blake and Sam Reid. We dont know who first surfed Topanga, but it would make sense for Tom and Sam to have tried it before Malibu. Reid is often quoted as saying that there were only six surfboards in the entire United States when he graduated from Santa Monica High School in the early 1920s.

Although Reids count was meant more to give an impression, two of those six surfboards belonged to brothers John E. O. (1915-1990) and Jim Larronde (1917-1989), who had them engraved with their initials in Hawaii and shipped to their parents Topanga Beach vacation house (Johns redwood surfboard is now in the Museum of Ventura County). In the late 1930s, a transition balsa-redwood surfboard was called the Larronde Model. In the late 1940s, John made a 16-minute home surf movie, popularly known as Sweet Sixteen, of trips he took between Malibu and Santa Barbara.

Their father, Pedro Larronde, supposedly built their beach house in 1917, just after the prison camp closed. He may have been given this privilege because his brother John M. Larronde was an executive of the Title Insurance and Trust Company, who owned the land before the Los Angeles Athletic Club (LAAC). Or it may have happened because their grandfather, Pierre, had been the legal guardian of future-Sheriff Eugene Biscailuzs Uncle William, who was also of Basque ancestry.

Pedro was an executive of the Franco-American Baking Company, and a member of the Los Angeles Athletic Club. For some reason, his wife, another Gladys, was forced to move their beach house across the street to Old Malibu Road when the LAAC took ownership in the mid-1920s.

The Larronde house was bulldozed, along with the Rust house and the rest of the neighborhood, when State Parks took ownership in the mid-2000s.

Other early Topanga Beach surfers that Thais and Jack remembered were Don James, Bob Simmons, Ed Fearon, Jack Quigg, Bob Talmadge, Warren Miller, half-brothers Jerry Hanes and Bobby Jacks, Dave Sweet, Matt Kivlin, and twin brothers Corny and Peter Cole.

More than just a random surf pack, this group is actually noted for evolving the sport with their skill, precociousness, and other contributions. James was Californias first dedicated surf photographer; Simmons and Sweet were influential shapers; Miller was an early surf filmmaker who transitioned to ski filming, a passion which he traced back to a freak snowstorm at Topanga Beach.

Many people and businesses change forever because of a simple event. Mine changed on the beach at Topanga Canyon in 1929. It had snowed about an inch the night before and as I walked barefooted in ankle-deep warm ocean water, I stepped out onto the snow and a kind of visceral feeling happened that to this day is impossible for me to explain. (Nostalgia, Idaho Mountain Express, January 22, 2010)

Kivlin was considered to be the best California surfer of his generation, and Kathy (Gidget) Kohner caught her first wave on his board, which led to an explosion in surfings popularity.

The Cole brothers opened a primitive surf shop at the gas station. Peter later moved to Hawaii to become a big-wave rider, and Corny became the art director of Topanga Beachs own Surf Guide magazine.

World War II interrupted the lives of many of these young surfers but offered unexpected opportunities for the Rust women. Thais followed her mom into the aerospace field, getting her first job at Douglas Aircraft. She went on to work at the RAND Corporation and the Planning Research Corporation.

Jack was too young to fight in World War II but embarked on a military career anyway when he came of age. He then worked as a plumber and eventually started his own company. Jack and Thais raised two daughters, Lisa and Lori, and retired in Orange, CA.

Thais will be 95 on April 5, 2020.

Pablo Capra is a former Lower Topanga resident, and continues to preserve the history of that neighborhood on his website, http://www.brasstackspress.com, and as a board member of the Topanga Historical Society, http://www.topangahistoricalsociety.org.

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The Original Topanga Beach Generation Helped Shape the Evolution of Southern California Surf Culture - M'Online

Personal and social hygiene awareness has increased exponentially, with a growing scepticism of what and what is not clean.

Whether we are at our workplace, attending leisure facilities or travelling for business or pleasure, we all now have a heightened awareness of how we interact and will now expect and demand a higher level of service from providers that takes cognisance of the perceived risks as a result of this. Put simply, COVID19 will change the way we work, how we live and how and where we travel.

Image credit: Room to Breathe

Few markets have felt the full force of this pandemic more than the hospitality sector. It has decimated trade, scattered the labour force and threatened the very existence of the supply chain. Travellers, holiday makers and businesspeople alike will now become even more difficult to satisfy and will seek to be given as much reassurance as possible.

A single night stay becomes your biggest issue as each and every night your new customer requires that peace of mind that your room is as safe as possible for them to stay in. Failure to address these new concerns could result in the long-term repeat visitor more likely to go somewhere else next time.

By taking steps to show your commitment to your customers health and wellbeing is now, more than ever, of paramount importance.

Image credit: Room to Breathe

Capturing this feeling of assured safety every time must be seen as the focal point for Customer Satisfaction.

What can be done?

So what can the hospitality sector do to insulate itself from the aftershock of COVID19 and prepare for the inevitable increase in customer demands? What can be done to provide that peace of mind that is desired?

Is carrying out the same cleaning protocols more frequently by an already stretched housekeeping department going to provide the reassurance required? In a word, no.

By taking steps to show your commitment to your customers health and wellbeing is now, more than ever, of paramount importance.

Image credit: Room to Breathe

A cleaner solution

A new approach to a new problem must be the way forward. It needs to address the worries and concerns of your customers but must, just as importantly, be cost effective. Imagine the cost of a deep clean between every guest. This is neither practical nor affordable.

This is where Room to Breathe comes into its own. By providing a room that can demonstrate continuous and permanent self-cleaning provision, you can provide customers with an unrivalled level of service and commitment to their needs and concerns.

Room to Breathe also kills 99.99 per cent of viruses and bacteria, including coronaviruses.

Originally developed to provide safe, clean accommodation for the millions of travellers who have a hypersensitivity to various toxins, pathogens and allergens, Room to Breathe also kills 99.99 per cent of viruses and bacteria, including coronaviruses (incl. influenza, SARS, MERS).

Step One deep clean

An initial industrial air purge followed by a combination of steam cleaning above 40, ultra-low-penetration air (UPLA) vacuuming and the application of our unique decontamination fluid which is deadly to pathogens (but is safe to all higher living organisms) is fogged into the area ensuring every surface coated.

Additionally, by using innovative UV technology we can rid mattresses, pillows and soft furnishings of undesirable micro-organisms within seconds.

Image credit: Room to Breathe

Step Two Anti-microbial coating

Once the area has been decontaminated, our antimicrobial coating BioTouch, will be is applied. The BioTouch formula bonds to a clean surface and when viruses and bacteria land on the protected surface, the cellular structure is ruptured (not poisoned) and becomes defunct.

The only way BioTouch can be removed is by it being chipped off. Where there is a risk of this, on door handles, light switches for example, we can easily reapply to maintain the coatings efficiency.

Step three Bedding and soft furnishings

Using our own unique formula, Protextsolution provides a layer of invisible protection which permanently interrupts the life cycle of dust mites and bed bugs.

Our method avoids the use of toxins so whilst lethal to bugs and mites does not pose a risk to the client.This is also applied to all fabrics and soft furnishings.

Step Four continuous air sanification.

Installing filterless air sanifiers provides the final level of protection. Using technology originally developed by NASA, our sanifiers seek out contaminants and pathogens within the air and on surfaces and neutralise them.

By applying this four step process, we not only eradicate 99.99 per cent of viruses and bacteria, we also provide a continuous level of protection in between our Deep Clean processes.

Certification

On completion certification is provided and displayed either outside or within the room to provide that peace of mind to Customers and employees alike.

A Room Information Pack is provided for guests to simply explain the RTB system, providing that peace of mind. In order to maintain the certification, Steps One and Two are carried out every four months in accordance with our terms and conditions.

On-site training is also provided to Housekeeping staff in order to ensure the efficacy of the RTB system is maintained. This is no more onerous to staff and in fact will simplify their cleaning protocols.

Cost

Based on an occupancy of 72 per cent, our cost model demonstrates that a ROI of 100 per centcan be achieved in the first year with a surcharge of just 15 per night per room.

We truly believe Room to Breathe is the next step in the evolution of the hospitality market. Our processes not only provide protection from unseen pathogens but are also proven to improve cognitive function, enable better quality of sleep and promote overall wellbeing.

So whether you are wanting ensure the highest level of protection for your customers or are looking to capture the untapped market for those travellers with intolerances or allergies then Room to Breathe could well be the answer.

Room to Breathe is one of our recommended suppliers. To keep up to date with their news, click here. And, if you are interested in becoming one of our recommended suppliers, please email Katy Phillips byclicking here.

Main image credit: Room to Breathe

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FEATURE: COVID19 pandemic is forcing an evolution in wellness Hotel Designs - Hotel Designs

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The latest study conducted by the team of international scientistsrevealed that the novel coronavirus could have transmitted from animals to humans years before the first case was detected in Wuhan, China.

The novel coronavirus, officially named SARS-CoV-2, has spread across more than 200 countries and territories across the globe. The infection COVID-19 has already claimed more than 43,000 lives since its outbreak back in December 2019 in Wuhan. Ever since the outbreak was reported, researchers have been trying to decode the origin of the novel coronavirus strain.

Origin of novel coronavirus

Using a comparative analysis of genomic datacollected from various genetic studies of the coronavirusan international team of researchers propose two possible hypotheses about the origin of this deadly virus.

Among the origin hypothesis, one theory suggests that novel coronavirus may have crossed from the animal barrier to settle in humansbefore it evolved into an active strain and started to induce the disease. It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the genomic features through adaptation during undetected human-to-human transmission, says the paper.

Another, far scarier scenario is that it evolved into the current strain in an animal host before transmission to humans. In this scenario, there is the risk of future re-emergence similar outbreaks, the study highlights.

The correspondence was published in Nature Medicine. The researchers compared the genetic code of the novel coronavirus from its ancestral strains, found in bats and pangolin, to understand the evolutionary history of the virus. The researchers from different institutes in the United States, Britain and Australia, also explain the notable features of the SARS-CoV-2 genome in this paper.

A bat or a pangolin?

In December end, when the suspicious cases of pneumonia emerged in Wuhan, it was linked to the Huanan Market in the province, which indicated the presence of an animal source for the spread of the virus.

Soon, an unknown strain of the virus was isolated by the team of researchers from the Wuhan Institute of Virology. The origin of the strain was traced to a bat virus found close to the China-Myanmar border. However, the bat coronavirus and the novel coronavirus strains were only 96 percent similarnot sufficient to attribute as the definite source. The bat virus did not showcase the presence of spike proteinrequired for the virus to bind in human cells.

The study also highlights the presence of the SARS-CoV-2-related coronavirus in the illegally imported Malayan pangolins. Further, the analyses showcased the presence of spike protein required to optimise the virus for transmission in humans among the coronaviruses found in pangolins.

However, the present study reveals that the novel coronavirus found responsible for the current outbreak had a mutation in its genes at the polybasic cleavage site, which was not found in both coronaviruses identified in bats and pangolins.

Evolution of coronavirus by natural selection

Analysing the research so far, the scientists say that the novel coronavirus had acquired both the polybasic cleavage site and mutations in the spike protein suitable for binding to humans naturally. The question, however, remains whether this natural selection occurred in humans or animals.

The spike protein interacts with furin, a widely distributed enzyme in the human body. This interaction mediates the fusion of virus and human cell membranes, which triggers the symptoms and makes it contagious. Some of the virus diseases like HIV and Ebola also have the furin-like cleavage site, which makes them contagious.

Moreover, the study also says an animal host to allow natural selection efficiently, there has to be a high population density. The dwindling population of pangolins is, therefore, may not be an ideal host for such a mutation to occur.

The study concludes that it is important to understand the properties of a virus to trace the origins of the pandemic. Scientists hope that a detailed understanding of how an animal virus-infected humans will help in the prevention of future zoonotic events.

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Novel Coronavirus Could Have Entered and Evolved in Humans Much Before Outbreak in Wuhan: Study - The Weather Channel

Human evolution is characterized by several human species living on the same surface and interbreeding at the same time. This process has eventually led to our formation or at least that is the theory that anthropology presented. New research has been performed, and it is demonstrating that this common belief is an error.

Anthropology and archeology students were taught to follow the this evolutionary line of Homo sapiens, tracing their origins back in time through ancestral species and some other biases from biology. Nowadays, the scientists studying human evolution do not think that this is applicable anymore. They are stating that our origin is way more complicated than this narrative.

Today evidence that combats the theory has been released. Scientists are providing analysis that shows the existence of different other species that bear a resemblance to the human of todays society.

The research is militating for the importance of the exchange of fortuitous genetic material between these groups while finding the one species from which humans evolved is still challenging the researchers.

A skull that was initially assigned to the Homo rhodesiensis, and then to Homo heidelbergensis, was found in 1921 and reanalyzed during modern times by researchers. Homo heidelbergensis is a species that evolved 600.000 years ago and dating the skulls origin has been a significant burden for the scientists. Additionally, the revealed dating coincides with the debut of humans, which happened 300.000 years ago in the Middle Stone Age.

However, some researchers contradict the relevance of the Broken Hill skull in this study. Katerina Harvati is a paleoanthropologist at the Eberhard Harls University of Tubingen. She is stating that the skull does not deliver any particular feature that could link it to the evolution of modern humans. In addition to this, she believes that the Homo rhodesiensis and heidelbergensis are likely to be a late survival stage of the Homo sapiens.

Ethelene is the main editor on DualDove, she likes to write on the latest science news.

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Researchers Elaborated New Theories On The Human Evolution - Dual Dove

Lets start up with the current stock price of Sangamo Therapeutics, Inc. (SGMO), which is $6.77 to be very precise. The Stock rose vividly during the last session to $6.77 after opening rate of $6.08 while the lowest price it went was recorded $6.08 before closing at $6.21.

Sangamo Therapeutics, Inc. had a pretty Dodgy run when it comes to the market performance. The 1-year high price for the companys stock is recorded $13.91 on 04/03/19, with the lowest value was $4.81 for the same time period, recorded on 03/17/20.

Price records that include history of low and high prices in the period of 52 weeks can tell a lot about the stocks existing status and the future performance. Presently, Sangamo Therapeutics, Inc. shares are logging -51.33% during the 52-week period from high price, and 40.75% higher than the lowest price point for the same timeframe. The stocks price range for the 52-week period managed to maintain the performance between $4.81 and $13.91.

The companys shares, operating in the sector of healthcare managed to top a trading volume set approximately around 1.91 million for the day, which was evidently lower, when compared to the average daily volumes of the shares.

When it comes to the year-to-date metrics, the Sangamo Therapeutics, Inc. (SGMO) recorded performance in the market was -19.12%, having the revenues showcasing -17.54% on a quarterly basis in comparison with the same period year before. At the time of this writing, the total market value of the company is set at 825.13M, as it employees total of 354 workers.

During the last month, 5 analysts gave the Sangamo Therapeutics, Inc. a BUY rating, 0 of the polled analysts branded the stock as an OVERWEIGHT, 2 analysts were recommending to HOLD this stock, 0 of them gave the stock UNDERWEIGHT rating, and 0 of the polled analysts provided SELL rating.

According to the data provided on Barchart.com, the moving average of the company in the 100-day period was set at 8.17, with a change in the price was noted -2.57. In a similar fashion, Sangamo Therapeutics, Inc. posted a movement of -27.52% for the period of last 100 days, recording 2,166,324 in trading volumes.

Total Debt to Equity Ratio (D/E) can also provide valuable insight into the companys financial health and market status. The debt to equity ratio can be calculated by dividing the present total liabilities of a company by shareholders equity. Debt to Equity thus makes a valuable metrics that describes the debt, company is using in order to support assets, correlating with the value of shareholders equity. The total Debt to Equity ratio for SGMO is recording 0.00 at the time of this writing. In addition, long term Debt to Equity ratio is set at 0.00.

Raw Stochastic average of Sangamo Therapeutics, Inc. in the period of last 50 days is set at 44.75%. The result represents downgrade in oppose to Raw Stochastic average for the period of the last 20 days, recording 48.16%. In the last 20 days, the companys Stochastic %K was 40.30% and its Stochastic %D was recorded 38.91%.

Bearing in mind the latest performance of Sangamo Therapeutics, Inc., several moving trends are noted. Year-to-date Price performance of the companys stock appears to be encouraging, given the fact the metric is recording -19.12%. Additionally, trading for the stock in the period of the last six months notably deteriorated by -21.73%, alongside a downfall of -48.04% for the period of the last 12 months. The shares increased approximately by 14.41% in the 7-day charts and went up by 1.65% in the period of the last 30 days. Common stock shares were lifted by -17.54% during last recorded quarter.

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Sangamo Therapeutics, Inc. (SGMO) is primed for evolution with the beta value of 2.12 - The InvestChronicle

When Roselia was introduced in Generation III of Pokmon, it wouldn't have been known that it would eventually receive a pre-evolution Baby Pokmon and evolution in the following generation. But, Budew, the Baby form for Roselia, and new evolution, Roserade, both came on the scene in Generation IV.

RELATED:Pokmon: Every Grass Gym-Leader So Far, Ranked

Budew itself is a great Pokmon. It's cute, loveable, and has some interesting lore and facts attached to it. The Grass/Poison-type is modeled after a small rosebud, which will eventually grow into the rose-bearing Roselia. Here's an explanation on how to evolve this Baby Pokmon, and some other interesting things about it.

After catching Budew in the wild (in many different places across the games) or hatching it from an egg, it will need to evolve into Roselia before it's of any use in battle. In order to do this, you'll need to be nice to it and treat it well. This is because Budew evolves with a high friendship level.

Once it's friendly toward you, level it up in the daytime, and it will evolve into Roselia. From there, if you want to make this Pokmon even more powerful, you can evolve the Roselia into Roserade by exposing it to a Shiny Stone.

If you're already in possession of a Roselia or Roserade and want to fill Budew's Pokdex entry, you'll need to breed a female of one of them with either a Ditto or another compatible Pokmon. Eggs will hatch into the species that matches the mother (or non-Ditto Pokmon). However, there's a catch.

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If you breed a Roselia or Roserade, the egg will hatch into a Roselia. In order to make it hatch into a Budew, one of the parents will need to hold a Rose Incense.

Like many Baby Pokmon, Budew is virtually useless in most battle scenarios. Its stats are a joke and its movepool is very bad. Interestingly, Budew will learn zero moves by leveling up.

It can have Absorb, Growth, Stun Spore, and Worry Seed at Level 1 or when hatched, but it will not learn any other moves if leveled all the way to 100. It can learn a fair few Egg moves or TM moves, but it will need to evolve to learn anything else.

According to the Pokdex, Budew can be very poisonous to humans if they get too close at the wrong time. Per its Pokdex entries, Budew likes to live near water and dispense pollen that causes sneezing and runny noses. Its pollen is described as "toxic" in some entries, and it can release poison into the air via this pollen.

You'll need to get friendly with your Budew to evolve it, but watch out for its toxic pollen release, because it won't be fun to deal with those sinus issues.

While you're doing your best to avoid Budew's poisonous pollen clouds, you'll want to make sure to stay very far away if it is consuming very clean water. This is because, according to the Pokdex, clean water makes it much more toxic and poisonous.

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Considering wild Budew like to live near clean pools of water, chances are that most of them would be pretty poisonous if you get too close. As it evolves, it learns to harness this poisonous nature as well. Roserade is said to contain two deadly toxins, one in each hand, and it can jab powerfully with fatal results.

Most Pokmon have two or more abilities two regular abilities, and often a hidden ability. Budew, despite its uselessness in battle, has three abilities that are all really good. Its first ability, Natural Cure, heals all status conditions on the Pokmon when it is switched out. It will also heal any status condition when the battle finishes.

Its secondary ability, Poison Point, allows Budew a 30 percent chance to poison any Pokmon that makes contact with it. Its hidden ability, Leaf Guard, prevents Budew from being afflicted with non-volatile status conditions during harsh sunlight.

Like its evolutions, Budew has a really fantastic shiny form. It will swap its shade of green for a more yellow shade of it. The small foliage under its face will also change to a nice purple, which matches perfectly with its Poison-typing.

The two seeds inside its vines, which are normally red and blue to match its evolutions, will become purple and black, again, like its evolutions' roses. Overall, shiny Budew matches its typing and evolutionary family much better than regular Budew.

Speaking of the seeds inside its vines, it's a really great touch that they match Roselia and Roserade. These two beautiful Grass/Poison-types are adorned with two floral hands. Roselia has a blue rose and a red rose, one on each hand. Roserade's are the same shade of red and blue, but expanded to contain three flowers per hand.

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Budew's seeds, which are rarely seen as they're enclosed in its vines, are the same shades of red and blue. It's a perfect match and a subtle detail, but a great one.

It's rare, but there are occasionally Pokmon that are seen in the anime before the games. Some prominent examples are Misty's Togepi, Ho-oh, and Munchlax. Interestingly, Budew confused many when it was revealed in the anime, as it hadn't yet been seen anywhere before that.

In the episode, Dawn of a New Era!, Pochama VS Subomie! Hikari's First Battle!!, the fourth episode of the Diamond & Pearl arc, Ash and Dawn run into a trainer named Nando, who has a Budew. The Grass/Poison-type had not yet been revealed to the public, so Japanese viewers were very confused at the time.

Most Baby Pokmon (with very few exceptions) are introduced in a later generation than their evolved forms. This is true for Roselia, too, who was introduced the generation before Budew. Some Pokmon, like Magmar and Electabuzz, received Baby forms in one generation and then further evolutions later down the road.

Roselia is unique in this sense. The Baby form and evolution were both introduced in the same generation. This means that Budew and Roserade are the only Pokmon to be listed next to each other in the National Dex without their middle stage between them.

NEXT:The 5 Best Shiny Pokmon from Generation III (& The 5 Worst)

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Michael is a journalist with several years of experience writing about video games, television, and social issues. He loves playing indie platformers, old games he's already finished ten times, and Pokemon. Michael also enjoys cold weather and drinking too much coffee.

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How To Evolve Budew (& 9 Other Facts About The Pokmon) - TheGamer

In a few short weeks, COVID-19 has spread on an unprecedented scale, touching every corner of the globe and impacting all walks of life. In our industry we have seen automotive supply chains ground to a halt as manufacturers shut down plants in order to prevent the spread. Of course, we see annual shutdowns and even unplanned shutdowns in normal business, but we are now in unprecedented territory with factories shutting without notice and without any real knowledge of how long for. This means that when things return to normal we will be facing one of the biggest threats to supply chain resilience confusion.

Before a planned shutdown starts, the return to production and the increase back to full capacity is carefully considered before the plant closes. But with this shutdown initiated so quickly, businesses will need to be flexible and reactive when it comes to decisions on shift patterns and speed of return to capacity when production does recommence. The situation is so fluid that we dont know which markets will recover from a consumer demand point of view, and therefore which models vehicle manufacturers will need to make. We also have no idea, from a supply perspective, which countries will be able to restart production first. The supply chain will continue to shift and evolve as time passes and restrictions are lifted in each country. Evolution is constantly consulting with key customers to assess the impact of the sudden stop, identify existing gaps in supply and put in place plans to react quickly as customer demands change when production resumes.

The question will not only be are there enough parts to produce cars, but also will there be an availability of labour to fit those parts? Car dealerships are also seeing a substantial decline in demand, with reports of a drop of 22% in some areas hardest hit in the first half of March. While the shutdown is ongoing, manufacturers are having to review their order banks and forecasts, which will have implications deep in the supply chain. Focus will be on which areas are recovering quickest and capacity will be focused on supplying these regions.

Please click here to view the full press release.

SOURCE: Evolution Time Critical

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Evolution Time Critical: What does the next 3 months hold for automotive supply chains? - Automotive World

Freeport-McMoRan Inc. (FCX) is priced at $6.39 after the most recent trading session. At the very opening of the session, the stock price was $6.54 and reached a high price of $6.74, prior to closing the session it reached the value of $6.31. The stock touched a low price of $6.14.

Freeport-McMoRan Inc. had a pretty Dodgy run when it comes to the market performance. The 1-year high price for the companys stock is recorded $14.68 on 04/17/19, with the lowest value was $4.82 for the same time period, recorded on 03/19/20.

Price records that include history of low and high prices in the period of 52 weeks can tell a lot about the stocks existing status and the future performance. Presently, Freeport-McMoRan Inc. shares are logging -56.46% during the 52-week period from high price, and 32.57% higher than the lowest price point for the same timeframe. The stocks price range for the 52-week period managed to maintain the performance between $4.82 and $14.68.

The companys shares, operating in the sector of basic materials managed to top a trading volume set approximately around 31.28 million for the day, which was evidently higher, when compared to the average daily volumes of the shares.

When it comes to the year-to-date metrics, the Freeport-McMoRan Inc. (FCX) recorded performance in the market was -51.30%, having the revenues showcasing -51.59% on a quarterly basis in comparison with the same period year before. At the time of this writing, the total market value of the company is set at 10.45B, as it employees total of 27500 workers.

According to the data provided on Barchart.com, the moving average of the company in the 100-day period was set at 10.92, with a change in the price was noted -4.88. In a similar fashion, Freeport-McMoRan Inc. posted a movement of -43.30% for the period of last 100 days, recording 26,881,076 in trading volumes.

Total Debt to Equity Ratio (D/E) can also provide valuable insight into the companys financial health and market status. The debt to equity ratio can be calculated by dividing the present total liabilities of a company by shareholders equity. Debt to Equity thus makes a valuable metrics that describes the debt, company is using in order to support assets, correlating with the value of shareholders equity. The total Debt to Equity ratio for FCX is recording 1.06 at the time of this writing. In addition, long term Debt to Equity ratio is set at 1.06.

Raw Stochastic average of Freeport-McMoRan Inc. in the period of last 50 days is set at 19.53%. The result represents downgrade in oppose to Raw Stochastic average for the period of the last 20 days, recording 31.46%. In the last 20 days, the companys Stochastic %K was 30.86% and its Stochastic %D was recorded 28.72%.

If we look into the earlier routines of Freeport-McMoRan Inc., multiple moving trends are noted. Year-to-date Price performance of the companys stock appears to be encouraging, given the fact the metric is recording -51.30%. Additionally, trading for the stock in the period of the last six months notably deteriorated by -27.96%, alongside a downfall of -51.44% for the period of the last 12 months. The shares increased approximately by 2.43% in the 7-day charts and went up by -8.58% in the period of the last 30 days. Common stock shares were lifted by -51.59% during last recorded quarter.

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Freeport-McMoRan Inc. (FCX) is primed for evolution with the beta value of 2.22 - The InvestChronicle

Colony Capital, Inc. (CLNY) is priced at $1.56 after the most recent trading session. At the very opening of the session, the stock price was $1.57 and reached a high price of $1.72, prior to closing the session it reached the value of $1.56. The stock touched a low price of $1.52.

Colony Capital, Inc. had a pretty Dodgy run when it comes to the market performance. The 1-year high price for the companys stock is recorded $6.14 on 09/30/19, with the lowest value was $1.33 for the same time period, recorded on 03/19/20.

Price records that include history of low and high prices in the period of 52 weeks can tell a lot about the stocks existing status and the future performance. Presently, Colony Capital, Inc. shares are logging -74.59% during the 52-week period from high price, and 17.29% higher than the lowest price point for the same timeframe. The stocks price range for the 52-week period managed to maintain the performance between $1.33 and $6.14.

The companys shares, operating in the sector of financial managed to top a trading volume set approximately around 4.02 million for the day, which was evidently lower, when compared to the average daily volumes of the shares.

When it comes to the year-to-date metrics, the Colony Capital, Inc. (CLNY) recorded performance in the market was -67.16%, having the revenues showcasing -66.74% on a quarterly basis in comparison with the same period year before. At the time of this writing, the total market value of the company is set at 821.95M, as it employees total of 400 workers.

According to the data provided on Barchart.com, the moving average of the company in the 100-day period was set at 4.2178, with a change in the price was noted -3.9200. In a similar fashion, Colony Capital, Inc. posted a movement of -71.53% for the period of last 100 days, recording 3,689,219 in trading volumes.

Total Debt to Equity Ratio (D/E) can also provide valuable insight into the companys financial health and market status. The debt to equity ratio can be calculated by dividing the present total liabilities of a company by shareholders equity. Debt to Equity thus makes a valuable metrics that describes the debt, company is using in order to support assets, correlating with the value of shareholders equity. The total Debt to Equity ratio for CLNY is recording 2.23 at the time of this writing. In addition, long term Debt to Equity ratio is set at 2.23.

Raw Stochastic average of Colony Capital, Inc. in the period of last 50 days is set at 5.99%. The result represents downgrade in oppose to Raw Stochastic average for the period of the last 20 days, recording 8.61%. In the last 20 days, the companys Stochastic %K was 10.45% and its Stochastic %D was recorded 14.40%.

Lets take a glance in the erstwhile performances of Colony Capital, Inc., multiple moving trends are noted. Year-to-date Price performance of the companys stock appears to be encouraging, given the fact the metric is recording -67.16%. Additionally, trading for the stock in the period of the last six months notably deteriorated by -72.63%, alongside a downfall of -71.84% for the period of the last 12 months. The shares increased approximately by 1.43% in the 7-day charts and went up by -35.00% in the period of the last 30 days. Common stock shares were lifted by -66.74% during last recorded quarter.

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Colony Capital, Inc. (CLNY) is primed for evolution with the beta value of 1.59 - The InvestChronicle