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New gene identified in Lou Gehrig's Disease Science Daily For the first time, a variant in UBQLN4 gene has been associated with Lou Gehrig's disease or amyotrophic lateral sclerosis (ALS) -- a progressive disease resulting in the loss of nerve cells that control muscle movement, which eventually leads to ... Ann & Robert H. Lurie Children's Hospital of ChicagoEurekAlert (press release) all 2 news articles »

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New gene identified in Lou Gehrig's Disease - Science Daily

A new study suggests that people with a genetic intolerance to lactose should increase their intake of non-dairy foods rich in vitamin D, after finding that they are more likely to have low levels of the essential nutrient.

Study co-author Ahmed El-Sohemy, a professor of nutrition at the University of Toronto's Faculty of Medicine in Canada, and colleagues recently reported their findings in the Journal of Nutrition.

Lactose intolerance is defined as the body's inability to effectively digest lactose, a sugar found in dairy products, including milk, butter, and cheese.

The condition occurs when the small intestine fails to produce sufficient amounts of lactase, which is the enzyme that breaks down lactose.

If a person with lactose intolerance consumes dairy products, they may experience bloating, flatulence, diarrhea, nausea, and abdominal pain. These symptoms usually arise around 30 minutes to 2 hours after lactose consumption.

It is unclear precisely how many people are living with lactose intolerance, but estimates suggest that around 65 percent of the population experience a reduced ability to digest lactose following infancy.

One cause of lactose intolerance is mutations in the LCT gene, which is the gene responsible for lactase production.

From an analysis of 1,495 men and women who were a part of the Toronto Nutrigenomics and Health Study, El-Sohemy and colleagues found that people who possessed LCT gene mutations had a lower intake of dairy products, compared with the general population.

Individuals with LCT gene mutations also had lower blood levels of vitamin D, which the team says is likely down to reduced intake of dairy products, since these are often fortified with vitamin D.

"We were not surprised that lactose intolerant people ate less dairy," says El-Sohemy, "but we were surprised that they did not compensate by supplementing or eating other foods fortified with this crucial nutrient."

Vitamin D is considered essential for the absorption of calcium in the gut, which is important for good bone health. The vitamin also aids nerve functioning and helps the body to stave off bacteria and viruses.

Interestingly, the researchers found that people with LCT gene mutations were shorter than individuals in the general population, which indicates that reduced intake of vitamin D through lack of dairy consumption may be inhibiting bone growth.

El-Sohemy and colleagues say that their findings suggest that people with lactose intolerance should consider increasing their intake of vitamin D through non-dairy food sources.

"These findings speak to the need for greater awareness for those who limit dairy because of lactose intolerance. They need to be mindful of getting enough vitamin D from other fortified foods like certain brands of orange juice, or to consider trying lactose-free dairy products."

Ahmed El-Sohemy

Another finding of the study was that individuals with just one mutated copy of LCT demonstrated an intolerance to lactose, but to lesser degree than those with two mutated copies; it was previously thought that two mutated copies of the gene were required for lactose intolerance to arise.

According to the researchers, this finding indicates that clinical definitions and genetic classifications for lactose intolerance may need to be reviewed.

Learn how sunscreen may lead to vitamin D deficiency.

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Lactose intolerance linked to lower vitamin D levels - Medical News Today

May 16, 2017 M. leprae, one of the causative agents of leprosy: As an acid-fast bacterium, M. leprae appears red when a Ziehl-Neelsen stain is used. Credit: Public Domain

A mutation in an immune system gene rapidly rose in frequency in Southeast Asia approximately 50,000 years ago because it likely conferred protection against leprosy, which spread to the region from Africa around the same time. The findings, published May 16th in Cell Reports, show that the gene variant, called HLA-B*46:01, encodes a protein that binds to molecules derived from the bacterium that causes leprosya chronic infection of the skin and peripheral nerves. This HLS protein then presents these foreign molecules to the immune system, which destroys the infected cells.

"Our study suggests that HLA-B*46:01 may provide protection against severe leprosy because it is better adapted to present pathogen-derived peptide antigens for immunosurveillance by the immune system," says lead author Hugo Hilton of Stanford University School of Medicine. "The findings may explain why HLA-B*46:01 evolved 50,000 years ago and spread to become one of the most prevalent immunity gene variants in Southeast Asia."

Population expansion, cultural changes, and migration during the last 100,000 years exposed humans to pathogens against which they had not evolved effective resistance. Due to strong selective pressure, human leukocyte antigen (HLA) genes have evolved to provide immunity against diverse and rapidly evolving pathogens. "New HLA gene variants, or alleles, are thought to arise in human populations during episodes of Darwinian selection, but there is little direct evidence for the nature of this process," says senior study author Peter Parham of Stanford University School of Medicine.

One compelling example of such an episode is the HLA-B*46:01 allele, which is now carried by approximately 110 million individuals of Southeast Asian descent. This HLA-B gene variant formed through genetic recombination between its two parent alleles: HLA-B*15:01 and HLA-C*01:02. "HLA-B*46:01 has since become the most common HLA-B allele in Southeast Asia, suggesting that it fills an immunological niche not afforded by either parent or any other HLA variant found in the region," Hilton says.

In the new study, Hilton and Parham set out to determine why HLA-B*46:01 rapidly rose in frequency in Southeast Asia over a relatively short period. To do so, the researchers used high-resolution mass spectrometry to compare the peptide sequences presented by the HLA-B*46:01 protein with those presented by its parent alleles. They found that HLA-B*46:01 binds a small, distinct, and less diverse set of peptides compared with its most closely related parent, suggesting that the HLA molecule is specialized to protect against one or a small number of closely related pathogens. Moreover, 21% of HLA-B*46:01 peptides strongly bind to a natural killer cell receptor called KIR2DL3, allowing the HLA molecule to trigger an effective immune response.

Using an algorithm that predicts binding affinities of HLA molecules to peptides, the researchers found that HLA-B*46:01 is predicted to bind a significantly higher number of peptides derived from Mycobacterium lepraethe pathogen that causes leprosycompared with its most closely related parent. But surprisingly, HLA-B*46:01 is predicted to bind equal or lower numbers of peptides derived from Salmonella Enteritidis, HIV-1, or H1N1-influenza as compared to its parents.

The new findings are consistent with epidemiological studies showing that HLA-B*46:01 carriers are protected against a severe, life-threatening form of leprosy but are more susceptible to other infectious diseases, such as malaria, HIV, and SARS coronavirus. Moreover, this gene variant predisposes individuals to autoimmune disorders such as myasthenia gravis and Grave's disease, in addition to a rare type of head and neck cancer.

"Taken together, these observations support the notion that HLA-B*46:01 poses an immunological trade-off between protection against leprosy and protection against other diseases," Hilton says. "This suggests that the selective pressure exerted by leprosy in Southeast Asia must have been a stronger force over the past tens of thousands of years compared with the collective fitness detriment imposed by many other serious diseases in the region."

Explore further: Immune suppressant ineffective in treating leprosy inflammation

More information: Cell Reports, Hilton et al.: "The Intergenic Recombinant HLA-B*46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands" http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30570-3 , DOI: 10.1016/j.celrep.2017.04.059

Journal reference: Cell Reports

Provided by: Cell Press

Throughout the course of a leprosy infection, patients often have episodes of painful inflammation affecting their skin and nerves. Researchers have continuously struggled with finding effective drugs to treat these so-called ...

In many parts of the world, leprosy and tuberculosis live side-by-side. Worldwide there are approximately 233,000 new cases of leprosy per year, with nearly all of them occurring where tuberculosis is endemic.

The avian influenza A (H7N9) virus has been a major concern since the first outbreak in China in 2013. Due to its high rate of lethality and pandemic potential, H7N9 vaccine development has become a priority for public health ...

Leprosy is a bacterial infection caused by Mycobacterium leprae or Mycobacterium lepromatosis. It has afflicted humans for thousands of years, reaching epidemic levels during the Middle Ages, and people continue to be affected ...

A mutation in an immune system gene rapidly rose in frequency in Southeast Asia approximately 50,000 years ago because it likely conferred protection against leprosy, which spread to the region from Africa around the same ...

The blood-brain barrier is biology's proverbial double-edged sword.

A study in mice finds that development of age-related macular degeneration (AMD) could be arrested by switching from a high-glycemic diet (starches as are found in white bread) to a low-glycemic (starches found in whole grains). ...

A team of University of Kentucky researchers has discovered that macrophages, a type of immune cell that clears debris at injury sites during normal wound healing and helps produce scar tissue, are required for complex tissue ...

Stem cells that seem key for maintaining and repairing the body's knee joints have been identified by scientists.

Two chemicals found in anti-fertility folk medicines block a key step in fertilizationthe meeting of egg and spermand may make effective alternatives to today's hormone-based contraceptives, which sometimes cause side ...

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An immunity gene evolved in Southeast Asia to protect against leprosy - Medical Xpress

Employing a zebrafish model, the investigators were able to reverse the defects caused by the UBQLN4 gene variant by inhibiting the beta-catenin signaling pathway with the drug quercetin. Importantly, these findings suggest that this pathway could be targeted for treatment. More research will be needed before a similar drug could be shown to work in people with ALS.

"At this stage, it is unclear how many people with ALS have the UBQLN4 gene variant, and this will be important to determine," noted senior study investigator Yongchao Ma, Ph.D., assistant professor of developmental-behavioral pediatrics at Northwestern University Feinberg School of Medicine. "Another important next step will be to assess whether the disease mechanism we describe is common to other forms of ALS."

As it is estimated that ALS occurs in 20,000 Americans at any given time, with over 6000 new cases diagnosed each year, these new insights open the door to potential treatment targets for ALS.

"Another intriguing aspect of our study is the molecular link we have established between ALS and spinal muscular atrophy, or SMA, which is a pediatric motor neuron disease," Ms. Edens concluded. "We see a similarity in the increase of beta-catenin, which causes defective motor neuron development. So even though the genes that cause ALS and SMA are different, they might share a common pathway that affects motor neuron structure and function."

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New ALS Gene Variant Identified - Genetic Engineering & Biotechnology News (press release)

Using gene sequencing tools, scientists from Johns Hopkins Medicine and the University of British Columbia have found a set of genetic mutations in samples from 24 women with benign endometriosis, a painful disorder marked by the growth of uterine tissue outside of the womb. The findings, described in the May 11 issue of The New England Journal of Medicine, may eventually help scientists develop molecular tests to distinguish between aggressive and clinically indolent, or non-aggressive, types of endometriosis.

Our discovery of these mutations is a first step in developing a genetics-based system for classifying endometriosis so that clinicians can sort out which forms of the disorder may need more aggressive treatment and which may not, said Ie-Ming Shih, M.D., Ph.D., the Richard W. TeLinde Distinguished Professor in the Department of Gynecology & Obstetrics at the Johns Hopkins University School of Medicine and co-director of the Breast and Ovarian Cancer Program at the Johns Hopkins Kimmel Cancer Center.

Endometriosis occurs when tissue lining the uterus forms and grows outside of the organ, most often into the abdomen. The disease occurs in up to 10 percent of women before menopause and half of those with abdominal pain and infertility problems. In the 1920s, Johns Hopkins graduate and trained gynecologist John Sampson first coined the term endometriosis and proposed the idea that endometriosis resulted when normal endometrial tissue spilled out through the fallopian tubes into the abdominal cavity during menstruation.

The new study, Shih said, challenges that view. The presence of the unusual set of mutations they found in their tissue samples, he says, suggests that while the origins of endometriosis are rooted in normal endometrial cells, acquired mutations changed their fate.

For reasons the researchers say are not yet clear, the mutations they identified have some links to genetic mutations found in some forms of cancer. They emphasize that although abnormal tissue growth in endometriosis often spreads throughout the abdominal cavity, the tissue rarely becomes cancerous except in a few cases when ovaries are involved.

For the study, Shih and his colleagues sequenced or figured out the genetic alphabet a part of the genome known as the exome, which contains all of the genes that can be expressed and make proteins. Specifically, they sequenced the exome of both normal tissue and endometriosis tissue removed during laparoscopic biopsies on 24 women, some with more than one abnormal endometrial growth. All had deep infiltrating endometriosis, the type that typically causes pain and infertility.

Seven of the 24 women were from Japan; the rest were patients at Lenox Hill Hospital-Northwell Health in New York City. The use of samples from Japanese women was selected because endometriosis before menopause occurs more often in Asian women (1318 percent) than in Caucasian women (6-10 percent), Shih says.

The scientists looked for mutations, or abnormal changes in the DNA, and filtered out normal variations in genes that commonly occur among humans. Of the 24 women, 19 had one or more mutations in their endometriosis tissue that were not present in their normal tissue.

The type and number of mutations varied per endometriosis lesion and between each of the women. The most common mutations, occurring in five of the women, occurred in genes including ARID1A, PIK3CA, KRAS and PPP2R1A, all known for controlling cell growth, cell invasion and DNA damage repair.

Mutations in these genes have been associated with one of the deadliest types of ovarian cancer, called clear cell carcinoma. Nickolas Papadopoulos, Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led the team that completed the first sequencing of the clear cell ovarian cancer genome in 2010.

We were surprised to find cancer-linked genes in these benign endometriosis samples because these lesions do not typically become cancer, said Papadopoulos, whose Ludwig Center laboratories performed the sequencing. We don't yet understand why these mutations occur in these tissues, but one possibility is that they could be giving the cells an advantage for growth and spread.

In an additional group of endometriosis samples biopsied from 15 women at the University of British Columbia, the scientists looked specifically for mutations in the KRAS gene, whose expression signals proteins that spur cell growth and replication. They found KRAS mutations in five of the 15 patients.

The scientists make clear that their sequencing studies may have missed mutations in some of the samples. Their data do not at this point reveal the aggressiveness of the lesions.

However, Shih said, he and his team are working on additional studies to determine if the mutations correlate with patients outcomes. He says a molecular test that sorts lesions as more or less aggressive has the potential to help doctors and patients decide how to treat and monitor the progression and control of the disease. We may also be able to develop new treatments for endometriosis that use agents that block a gene-related pathway specific to a persons disease, said Shih.

Women with endometriosis are typically prescribed anti-hormonal treatments that block estrogen to shrink lesions. When the disease occurs in the ovaries and forms a large cyst, which increases the risk of developing ovarian cancer, the lesion is usually surgically removed.

Image: Endometriosis in the peritoneal tissue (left) forming a scar. Under microscopy, it is composed of glands and surrounding stroma with chronic inflammation and fibrosis.

Credit: Ie-Ming Shih

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Gene Sequencing Study Reveals Unusual Mutations in Endometriosis - Bioscience Technology

May 16, 2017 A fundus photo showing intermediate age-related macular degeneration. Credit: National Eye Institute, National Institutes of Health

In a small and preliminary clinical trial, Johns Hopkins researchers and their collaborators have shown that an experimental gene therapy that uses viruses to introduce a therapeutic gene into the eye is safe and that it may be effective in preserving the vision of people with wet age-related macular degeneration (AMD). AMD is a leading cause of vision loss in the U.S., affecting an estimated 1.6 million Americans. The disease is marked by growth of abnormal blood vessels that leak fluid into the central portion of the retina called the macula, which we use for reading, driving and recognizing faces.

The study published on May 16 in The Lancet, reports an exciting new approach in which a virus, similar to the common cold, but altered in the lab so that it is unable to cause disease, is used as a carrier for a gene and is injected into the eye. The virus penetrates retinal cells and deposits a gene, which turns the cells into factories for productions of a therapeutic protein, called sFLT01.

The abnormal blood vessels that cause wet AMD grow because patients have increased production of vascular endothelial growth factor (VEGF) in their retinas. Current treatments require injections of proteins directly into the eye that bind and inactivate VEGF, reducing fluid in the macula and improving vision. However, the therapeutic proteins exit the eye over the course of a month, so patients with wet AMD usually need to return to the clinic for more injections every six to eight weeks in order to stave off vision loss. Eye specialists say the burden and discomfort of the regimen is responsible for many patients not getting injections as frequently as they need, causing vision loss.

Because viruses naturally penetrate cells and leave behind genetic material, the investigators designed their virus to target retinal cells and provide them with a gene that produces sFLT01. Thus, retinal cells become factories that produce the therapeutic proteinpotentially eliminating the need to repeatedly inject it.

"This preliminary study is a small but promising step towards a new approach that will not only reduce doctor visits and the anxiety and discomfort associated with repeated injections in the eye, but may improve long-term outcomes because prolonged suppression of VEGF is needed to preserve vision, and that is difficult to achieve with repeated injections because life often gets in the way," says Peter Campochiaro, M.D., the George S. and Dolores D. Eccles Professor of Ophthalmology at the Johns Hopkins University School of Medicine.

The phase 1 clinical trial involved 19 men and women, 50 years old or older with advanced wet AMD.

Participants were divided into five different groups that received increasing doses from 2X10^8 to 2X10^10 viral particles containing the therapeutic gene in 0.05 mL of fluid. Each group was examined by investigators for signs of adverse reactions for at least 4 weeks before administering a higher dose to the next group.

After the virus deposited the gene, the cells began secreting sFLT01 which bound to VEGF and prevented it from stimulating leakage and growth of abnormal blood vessels. The goal is for the retinal cells infected by the virus to produce enough sFLT01 to permanently stop the progression of AMD.

After monitoring the first three groups and finding no dose-limiting toxicity, the researchers administered the maximum dose to a group of ten participants and observed no serious side effects. "Even at the highest dose, the treatment was quite safe. We found there were almost no adverse reactions in our patients," Campochiaro says.

For safety and ethical reasons, the study group was composed of people for whom standard approved treatments were highly unlikely to regain vision, meaning in part that only 11 of the 19 had the potential for fluid reduction. Of those eleven patients, four showed dramatic improvements. The amount of fluid in their eyes dropped from severe to almost nothing, just like what is observed with optimal standard treatment, Campochiaro says. In addition, two other participants showed a partial reduction in the amount of fluid in their eyes.

Five participants showed no reduction in fluid levels. Surprisingly, the researchers say, they found that all of the patients who did not show improvement had pre-existing antibodies to the AAV2 virus.

From that result, the researchers conclude that even if further studies affirm the safety and value of their gene therapy, it may have limitations for broad use. That's because an estimated sixty percent of the U.S. population has been infection with adeno-associated virus, the family of viruses that AAV2 belongs to, and have built an immunity to it. The researchers believe that in these patients, the immune system destroyed the virus before it could insert the therapeutic gene. Campochiaro explains, "The numbers are small and simply show a correlation, so we don't know if serum antibodies are definitely an impediment, but more work is needed to determine this."

Explore further: Experimental drug shows promise for sight-stealing eye condition

More information: The Lancet (2017). http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30979-0/fulltext

An experimental drug may one day make treatment simpler for patients suffering from vision-threatening age-related macular degeneration, researchers say.

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In a small and preliminary clinical trial, Johns Hopkins researchers and their collaborators have shown that an experimental gene therapy that uses viruses to introduce a therapeutic gene into the eye is safe and that it ...

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New gene therapy for vision loss proven safe in humans - Medical Xpress