Culture

Inducing strong responses from T helper (TH) cells - long seen as a desirable goal for HIV vaccines - and using multiple antigens can hamper the effectiveness of vaccine candidates for HIV, according to an analysis of macaque experiments and a multicenter, phase 1 trial. The results from both studies highlight how investigators will need to carefully account for the effects of activated TH cells in their efforts to create a workable vaccine for HIV. Many vaccine candidates for HIV aim to induce strong and durable antibody responses, often by stimulating responses from CD4 TH cells. However, recent research has called this assumption into question: some studies indicate HIV-specific CD4 T cells are more easily infected by the virus, and a previous trial showed that a vaccine candidate actually increased the risk of acquiring HIV among some individuals. Venkateswarlu Chamcha and colleagues studied immunization data from four previous studies in macaques and discovered that a vaccine for SIV only granted strong protection to animals that had a lower frequency of vaccine-specific T helper type 1 (TH1) cells. Specifically, they observed that vaccine-induced CD4 T cells migrated to mucosal tissue in the colon and cervix, where they persisted and expressed a higher amount of CCR5, a coreceptor that HIV exploits to enter immune cells. The authors theorize that the stimulated cells could be abrogating vaccine protection by providing new targets for the virus to infect.

SPOKANE, Wash. -- Wrinkles on the skin of a microscopic worm might provide the key to a longer, healthier life for humans.

Working with Caenorhabditis elegans, a transparent nematode found in soil, researchers at Washington State University's Elson S. Floyd College of Medicine were the first to find that the nervous system controls the tiny worm's cuticle, a skin-like exterior barrier, in response to bacterial infections. Their study was published today in Science Advances.

Often used in biologic research as a model organism, the C. elegans nematode has a relatively simple structure while still sharing several genetic similarities with more complex mammals including humans, so this discovery holds implications for human health as well.

"Our study challenges the traditional view that a physical barrier such as a worm's cuticle or a human's skin does not respond to infections but is part of the body's innate defense against a pathogen," said Assistant Professor Jingru Sun, the corresponding author on the paper. "We show that during infection the nematode can change its cuticle structure and that defense response is controlled by the nervous system."

Sun and her colleagues used technologies such as gene silencing and CRISPR gene editing to show that a G-protein-coupled receptor tied to a gene called npr-8 regulates collagens, proteins that are the key structural components of the nematode's cuticle. Nematodes whose NPR-8 receptor was removed survived longer when exposed to the pathogens that cause pneumonia, salmonella and staph infections. The cuticle of the nematodes without the receptor also remained smooth compared to their wild peers whose cuticle wrinkled in response to the same pathogens.

"For nematodes, it's important to maintain a healthy cuticle that acts as the first line of defense against external insults," said Durai Sellegounder, lead author on the paper and a postdoctoral researcher in Sun's Lab.  "Many pathogens produce wicked proteins that try to destroy this barrier and establish infection. Our results show that the nervous system can detect these attacks and respond by remodeling or strengthening this protective structure."

Collagens are the most abundant proteins found in mammals, and declining collagen levels are associated with aging. For humans, collagen loss can create more problems than just unsightly wrinkles. While nematodes have only one "extracellular matrix," the cuticle, humans have an extracellular matrix on every organ and if that matrix is too stiff or too loose it can be harmful.

The WSU study results indicate that collagens play an important role in defense of pathogen infection, and the researchers speculate that the neural regulation of collagens might play a role in overall longevity as well. Their next goal is to understand the underlying defense response mechanisms.

New fossils of an ancient legged snake, called Najash, shed light on the origin of the slithering reptiles.

The fossil discoveries published in Science Advances have revealed they possessed hind legs during the first 70 million years of their evolution.

They also provide details about how the flexible skull of snakes evolved from their lizard ancestors.

The evolution of the snake body has captivated researchers for a long time - representing one of the most dramatic examples of the vertebrate body's ability to adapt - but a limited fossil record has obscured our understanding of their early evolution until now.

Dr Alessandro Palci, from Flinders University, was part of the international research team that performed high-resolution (CT) scanning and light microscopy of the preserved skulls of Najash to reveal substantial new anatomical data on the early evolution of snakes.

"Snakes are famously legless, but then so are many lizards. What truly sets snakes apart is their highly mobile skull, which allows them to swallow large prey items. For a long time we have been lacking detailed information about the transition from the relatively rigid skull of a lizard to the super flexible skull of snakes".

"Najash has the most complete, three-dimensionally preserved skull of any ancient snake, and this is providing an amazing amount of new information on how the head of snakes evolved. It has some, but not all of the flexible joints found in the skull of modern snakes. Its middle ear is intermediate between that of lizards and living snakes, and unlike all living snakes it retains a well-developed cheekbone, which again is reminiscent of that of lizards."

Flinders University and South Australian Museum researcher Professor Mike Lee, was also part of the study, and adds "Najash shows how snakes evolved from lizards in incremental evolutionary steps, just like Darwin predicted."

The new snake family tree also reveals that snakes possessed small but perfectly formed hind legs for the first 70 million years of their evolution.

"These primitive snakes with little legs weren't just a transient evolutionary stage on the way to something better. Rather, they had a highly successful body plan that persisted across many millions of years, and diversified into a range of terrestrial, burowing and aquatic niches," says Professor Lee.

A new analysis of patients' heart data has shown that even a slight increase in a protein linked to heart attacks, called troponin, is linked to an increased risk of early death at all ages.

Clinicians use troponin testing, alongside other investigations, to determine whether a patient is having a heart attack and to inform treatment choices. It has been assumed that the higher the amount of troponin in the blood, the higher the risk of death in all age groups.

In a large new study, published in the British Medical Journal, researchers from the National Institute of Health Research Health Informatics Collaborative (NIHR-HIC) led by Imperial College Healthcare NHS Trust and Imperial College London found that a raised troponin level was associated with an increase in risk of death in all age groups. This was seen even if the troponin result was slightly raised, with the increased risk of death occurring very early.

They also showed that that regardless of age, the higher the amount of troponin in the blood, the higher the risk of death in patients with a heart attack. The results suggests that even a small rise in troponin in all age groups is clinically significant and can indicate underlying health problems.

However, the team also found that, contrary to what they expected, very high levels of troponin in the blood in patients with a heart attack was associated with a lower risk of dying. They suggest that a possible reason is that patients with very high troponin levels are more likely to have a type of heart attack which can be treated by an operation to improve blood flow to the heart and therefore reduce the risk of dying.

Amit Kaura, lead author of the research and NIHR Clinical Research Fellow at Imperial College London, said: "There have been many advances in treating heart disease yet it remains the leading cause of death in the UK and around the world. This is the first study to address the implications of raised troponin in a real world large sample of patients across a wide range of ages. Doctors will be able to use this information to help identify the risk of early death in patients who have a troponin level measured; this could lead to interventions at a much earlier stage in a wider group of patients than are currently treated."

The researchers found that in young patients (18-29 years), those whose blood showed a raised troponin had a 10-fold higher risk of death than those whose blood did not. This increased risk fell with age, reaching 1.5 times the risk in patients over the age of 90. Nevertheless, even in very elderly patients, raised troponin in the blood signifies a higher risk of dying. Over the age of 80, almost half of patients with a raised troponin level died within three years.

They also found that even when doctors do not think the primary problem is a heart attack, the presence of a raised troponin in the blood signifies an increased risk of death. Therefore, the troponin result provides meaningful information in all age groups, regardless of the underlying problem.

Troponins are a group of proteins that helps regulate the contractions of the heart and skeletal muscle. The heart releases troponin into the bloodstream following an injury to the heart such as a heart attack. High levels of troponin usually mean there is a problem with the heart.

Doctors carry out a blood test to measure the levels of troponin in the blood which enables them to assess the damage caused to the heart and how patients are responding to treatment. It has previously been assumed that higher levels of troponin, mean a higher mortality risk.

However, it has been unclear how to manage patients who have small troponin rises, particularly if they do not have other symptoms associated with heart disease or a heart attack.

The researchers behind today's study wanted to examine the impact of raised troponin across different ages, specifically the very elderly. They also wanted to investigate the significance of very small troponin levels, compared with larger levels, on patients' prognosis.

The team analysed the anonymised cardiovascular data of more than 250,000 patients who had troponin tests at National Institute for Health Research Health Informatics Collaborative sites including: Imperial College Healthcare NHS Trust, University College London Hospitals NHS Foundation Trust, Oxford University Hospitals NHS Foundation Trust, King's College Hospital NHS Foundation Trust and Guy's and St Thomas' NHS Foundation Trust from 2010-2017. The team grouped the patients by age and compared their troponin results with their outcomes over a period of three years.

The team are currently designing a trial to see if patients with a raised troponin, without a heart attack, may benefit from cardiac treatments including cholesterol lowering medication, such as a statin.

The work is part of the NIHR Health Informatics Collaborative (NIHR-HIC) which Imperial College London and Imperial College Healthcare NHS Trust is part of. The NIHR-HIC was established to improve the quality and availability of patient data for research purposes. This will enable researchers to gain new insights into areas such as the effectiveness of different treatments and what factors influence patient outcomes and recovery.

The collaboration is between five leading NHS trusts, each of which has a strong relationship with a partner university.

The ultimate aim of all this work is to find ways to improve the experience and outcomes of patients in the NHS.

The study was funded by NIHR Imperial Biomedical Centre (BRC) and was conducted using National Institute for Health Research Health Informatics Collaborative (NIHR HIC) data resources.

This research is an example of the work carried out by Imperial College Academic Health Science Centre, a joint initiative between Imperial College London and three NHS hospital trusts. It aims to transform healthcare by turning scientific discoveries into medical advances to benefit local, national and global populations in as fast a timeframe as possible.

New research led by the University of Bristol has found that over half of people would be willing to donate their personal data for research to benefit the wider general public.

The study published in PLOS ONE today [Wednesday 20 November] investigated whether the donation of personal data could be a publicly acceptable act to support the use of consumer personal data for academic research.

The researchers developed a new questionnaire that measured individuals' motivations for donating data, which could be used in future research on data donation in different contexts, such as medical data. The questionnaire explored the intentions and reasons of 1,300 people to donate personal data.

The newly developed questionnaire contained three distinct reasons to donate personal data: an opportunity to achieve self-benefit, prosocial motive to serve society, and the need to understand the purpose of data donation.

Social Duty considered the desire to serve society and give back to community. Self-interest reflected the need to gain personal benefits as a results of data donation, such as reputation and avoiding feeling guilty. Purpose showed the need to understand the consequences of data donation as well as the importance of understanding what will be done with the data after donation.

The research found that the strongest predictor of the decision to donate personal data was the desire to serve society, while the strongest predictor of the decision not to donate personal data was the need to gain direct benefits as a result of data donation.

The study also identified that in the context of personal data, the need to know the consequences of donating personal data was an important third factor influencing the decision whether to donate.

Dr Anya Skatova, Turing and Vice-Chancellor's Fellow in Digital Innovation and Wellbeing in the School of Psychological Science, said: "Digital technology opens up a new era in the understanding of human behaviour and lifestyle choices, with people's daily activities and habits leaving 'footprints' in their digital records.

"Our results demonstrate that these motivations predict people's intentions to donate personal data over and above generic altruistic motives and relevant personality traits."

The study is the first step in opening up the possibilities of a new method that could enable the use commercial data for research that benefits the public good.

Dr Skatova added: "The creation and use of data generated by each and every one of us for industry is here to stay, along with all the good and bad that can entail. In these times where consumer data is mined by companies, data donation can redress this power imbalance by providing a safe and ethical route that allows individuals to explicitly consent to what research organisation they share their data with, and for what purpose."

The study's findings could be used to support how the opportunities created by the use of commercial data in academic research more broadly, and health research specifically, are communicated.

The research has also shown that different forms of empathy play a role in defining various forms of prosocial motivation, which should make a difference in the context of data donation. Future research could investigate what personality differences or contextual factors can explain differences in motivations to donate personal data.

Inflammation drives the progression of neurodegenerative brain diseases and plays a major role in the accumulation of tau proteins within neurons. An international research team led by the German Center for Neurodegenerative Diseases (DZNE) and the University of Bonn comes to this conclusion in the journal Nature. The findings are based on the analyses of human brain tissue and further lab studies. In the particular case of Alzheimer's the results reveal a hitherto unknown connection between Abeta and tau pathology. Furthermore, the results indicate that inflammatory processes represent a potential target for future therapies.

Tau proteins usually stabilize a neuron's skeleton. However, in Alzheimer's disease, frontotemporal dementia (FTD), and other "tauopathies" these proteins are chemically altered, they detach from the cytoskeleton and stick together. As a consequence, the cell's mechanical stability is compromised to such an extent that it dies off. In essence, "tau pathology" gives neurons the deathblow. The current study led by Prof. Michael Heneka, director of the Department of Neurodegenerative Diseases and Gerontopsychiatry at the University of Bonn and a senior researcher at the DZNE, provides new insights into why tau proteins are transformed. As it turns out, inflammatory processes triggered by the brain's immune system are a driving force.

A Molecular Switch

A particular protein complex, the "NLRP3 inflammasome", plays a central role for these processes, the researchers report in Nature. Heneka and colleagues already studied this macromolecule, which is located inside the brain's immune cells, in previous studies. It is a molecular switch that can trigger the release of inflammatory substances. For the current study, the researchers examined tissue samples from the brains of deceased FTD patients, cultured brain cells, and mice that exhibited hallmarks of Alzheimer's and FTD.

"Our results indicate that the inflammasome and the inflammatory reactions it triggers, play an important role in the emergence of tau pathology", Heneka said. In particular, the researchers discovered that the inflammasome influences enzymes that induce a "hyperphosphorylation" of tau proteins. This chemical change ultimately causes them to separate from the scaffold of neurons and clump together. "It appears that inflammatory processes mediated by the inflammasome are of central importance for most, if not all, neurodegenerative diseases with tau pathology."

A Link between Abeta and Tau

This especially applies to Alzheimer's disease. Here another molecule comes into play: "amyloid beta" (Abeta). In Alzheimer's, this protein also accumulates in the brain. In contrast to tau proteins, this does not happen within the neurons but between them. In addition, deposition of Abeta starts in early phases of the disease, while aggregation of tau proteins occurs later.

In previous studies, Heneka and colleagues were able to show that the inflammasome can promote the aggregation of Abeta. Here is where the connection to the recent findings comes in. "Our results support the amyloid cascade hypothesis for the development of Alzheimer's. According to this hypothesis, deposits of Abeta ultimately lead to the development of tau pathology and thus to cell death," said Heneka. "Our current study shows that the inflammasome is the decisive and hitherto missing link in this chain of events, because it bridges the development from Abeta pathology to tau pathology. It passes the baton, so to speak." Thus, deposits of Abeta activate the inflammasome. As a result, formation of further deposits of Abeta is promoted. On the other hand, chemical changes occur to the tau proteins resulting into their aggregation.

A Possible Starting Point for Therapies

"Inflammatory processes promote the development of Abeta pathology, and as we have now been able to show, of tau pathology as well. Thus, the inflammasome plays a key role in Alzheimer's and other brain diseases," said Heneka, who is involved in the Bonn-based "ImmunoSensation" cluster of excellence and who also teaches at the University of Massachusetts Medical School. With these findings, the neuroscientist sees opportunities for new treatment methods. "The idea of influencing tau pathology is obvious. Future drugs could tackle exactly this aspect by modulating the immune response. With the development of tau pathology, mental abilities decline more and more. Therefore, if tau pathology could be contained, this would be an important step towards a better therapy."

LEXINGTON, Ky. (Nov. 20, 2019) -- It is estimated that nearly 40 percent of women diagnosed with breast cancer will require a mastectomy. For those patients, breast reconstruction surgery is a valuable part of comprehensive breast cancer care as studies show it improves quality of life, self-esteem and sexuality.

Despite the benefits of breast reconstruction, women from Appalachia are less likely to have the surgery than non-Appalachian Kentuckians, according to a new study by the University of Kentucky Markey Cancer Center.

Published in Annals of Plastic Surgery, researchers used data from the Kentucky Cancer Registry to examine the disparities of breast cancer care between women in Appalachian and non-Appalachian Kentucky.

Breast cancer patients from Appalachia were 46% less likely to receive breast reconstruction surgery following a mastectomy. They were also older than their non-Appalachian counterparts and were more likely to have advanced stages of cancer -- signs that suggest a lack of adequate care.

Health disparities in Appalachia are well-documented and access to and delivery of care remain a challenge for women with breast cancer who live in the region, says Dr. Henry Vasconez, UK HealthCare's William S. Farish Endowed Chair of Plastic Surgery, and Dr. Ryan DeCoster, a postdoctoral research fellow with the UK Division of Plastic and Reconstructive Surgery and Markey Cancer Center.

While geographic distance to a plastic surgeon is a contributing factor, the lack of patient education plays a big role in the disparity. Many patients in Appalachian Kentucky are not told breast reconstruction is an option during their initial diagnosis and are therefore not referred to a reconstructive surgeon.

"Timely access to reconstructive breast surgery can improve quality of life," Vasconez said. "Better education and awareness to all affected patients, especially those in Appalachia, provides for overall better comprehensive care."

"The hope is that these findings will raise awareness of the benefits of breast reconstructive surgery and support efforts to increase access to comprehensive breast cancer care for women in the region--and that includes access to a reconstructive plastic surgeon," DeCoster said.

DURHAM, N.C. -- Engineers at Duke University have developed a microscope that adapts its lighting angles, colors and patterns while teaching itself the optimal settings needed to complete a given diagnostic task.

In the initial proof-of-concept study, the microscope simultaneously developed a lighting pattern and classification system that allowed it to quickly identify red blood cells infected by the malaria parasite more accurately than trained physicians and other machine learning approaches.

The results appear online on November 19 in the journal Biomedical Optics Express.

"A standard microscope illuminates a sample with the same amount of light coming from all directions, and that lighting has been optimized for human eyes over hundreds of years," said Roarke Horstmeyer, assistant professor of biomedical engineering at Duke.

"But computers can see things humans can't," Hortmeyer said. "So not only have we redesigned the hardware to provide a diverse range of lighting options, we've allowed the microscope to optimize the illumination for itself."

Rather than diffusing white light from below to evenly illuminate the slide, the engineers developed a bowl-shaped light source with LEDs embedded throughout its surface. This allows samples to be illuminated from different angles up to nearly 90 degrees with different colors, which essentially casts shadows and highlights different features of the sample depending on the pattern of LEDs used.

The researchers then fed the microscope hundreds of samples of malaria-infected red blood cells prepared as thin smears, in which the cell bodies remain whole and are ideally spread out in a single layer on a microscope slide. Using a type of machine learning algorithm called a convolutional neural network, the microscope learned which features of the sample were most important for diagnosing malaria and how best to highlight those features.

The algorithm eventually landed on a ring-shaped LED pattern of different colors coming from relatively high angles. While the resulting images are noisier than a regular microscope image, they highlight the malaria parasite in a bright spot and are correctly classified about 90 percent of the time. Trained physicians and other machine learning algorithms typically perform with about 75 percent accuracy.

"The patterns it's picking out are ring-like with different colors that are non-uniform and are not necessarily obvious," said Horstmeyer. "Even though the images are dimmer and noisier than what a clinician would create, the algorithm is saying it'll live with the noise, it just really wants to get the parasite highlighted to help it make a diagnosis."

Horstmeyer then sent the LED pattern and sorting algorithm to another collaborator's lab across the world to see if the results were translatable to different microscope setups. The other laboratory showed similar successes.

"Physicians have to look through a thousand cells to find a single malaria parasite," said Horstmeyer. "And because they have to zoom in so closely, they can only look at maybe a dozen at a time, and so reading a slide takes about 10 minutes. If they only had to look at a handful of cells that our microscope has already picked out in a matter of seconds, it would greatly speed up the process."

The researchers also showed that the microscope works well with thick blood smear preparations, in which the red blood cells form a highly non-uniform background and may be broken apart. For this preparation, the machine learning algorithm was successful 99 percent of the time.

According to Horstmeyer, the improved accuracy is expected because the tested thick smears were more heavily stained than the thin smears and exhibited higher contrast. But they also take longer to prepare, and part of the motivation behind the project is to cut down on diagnosis times in low-resource settings where trained physicians are sparse and bottlenecks are the norm.

With this initial success in hand, Horstmeyer is continuing to develop both the microscope and machine learning algorithm.

A group of Duke engineering graduate students has formed a startup company SafineAI to miniaturize the reconfigurable LED microscope concept, which has already earned a $120,000 prize at a local pitch competition.

Meanwhile, Horstmeyer is working with a different machine learning algorithm to create a version of the microscope that can adjust its LED pattern to any specific slide it's trying to read.

"We're basically trying to impart some brains into the image acquisition process," said Horstmeyer. "We want the microscope to use all of its degrees of freedom. So instead of just dumbly taking images, it can play around with the focus and illumination to try to get a better idea of what's on the slide, just like a human would."

New Rochelle, NY, November 20, 2019 -- Diagnostic agreement between practitioners is an ongoing challenge in the evaluation of Traditional Chinese Medicine (TCM) and other healthcare systems that rely on constitutional types. The topic is the subject of a Special Focus Issue on Challenges in Inter-Rater Reliability in Traditional Chinese Medicine that is published as the November 2019 issue of JACM, The Journal of Alternative and Complementary Medicine, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers, dedicated to paradigm, practice, and policy advancing integrative health. Click here to read the full Special Issue free on the JACM website through December 20, 2019.

The Special Issue was led by Guest Editors Rosa Schnyer, DAOM, LAc, IFMCP, Clinical Assistant Professor in the School of Nursing at the University of Texas and adjunct faculty at the Oregon College of Oriental Medicine and Bastyr University and Claudia Citkovitz, PhD, MS, LAc, Department of Rehabilitation Medicine, NYU Medical School, and Director of the Acupuncture Program at Lutheran Medical Center. The special issue includes an exploratory editorial from the Guest Editors, 4 invited commentaries, a systematic review, and 7 original articles.

In their editorial, "Inter-Rater Reliability in Traditional Chinese Medicine: Challenging Paradigmatic Assumptions," Schnyer and Citkovitz note the issue's timeliness. The WHO's newly updated International Classification of Diseases (ICD-11) includes standardized terminology for Traditional Chinese Medicine (TCM) pattern diagnosis. This change reflects increasing prevalence of TCM's use in the United States and other countries throughout the world and "stronger evidence of acupuncture's effect on pain over and above placebo and increasing integration of TCM into mainstream healthcare systems." Yet, as their editorial shares, the issue of reliability is fraught with multiple paradigmatic challenges.

The systematic review, from a 6-member team led by Eric Jacobson, PhD, MPH, Department of Global Health and Social Medicine, Harvard Medical School, "Experimental Studies of Inter-Rater Agreement in Traditional Chinese Medicine: A Systematic Review," found 21 studies that met the criterion set by the 6-member team. They found that "with few exceptions, the levels of agreement were low to moderate." Noting "significant deficits" in methods, they urge future studies to have "better experimental controls and more thorough reporting of outcomes" together with increased utilization of "methods of complex systems analysis."

A trio of articles led by Australian researcher Michael Popplewell, PhD, Faculty of Health, School of Life Sciences, University of Technology, Sydney, Australia, suggests that new statistical approaches may be more suited to the work and concludes with "A Novel Approach to Describing Traditional Chinese Medical Patterns: The 'Traditional Chinese Medical Diagnostic Descriptor'." After applying the methods previously recommended, they conclude that "simple agreement was significantly greater" than that obtained with the typical TCM format.

Three of the commentaries were invited by Schnyer and Citkovitz to respond to subsets of the original submissions: Steve Birch, PhD from Kristiania University College, Oslo, Norway, on the Popplewell set; Ayurvedic medicine clinician and researcher Jennifer Rioux, PhD, AD, AYT, C-IAYT, CCA-III on the Jacobson and two other studies examining reliability; and Scott Mist, PhD, MAOM, MS, MA from the Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University on two studies using big data approaches.

JACM Editor-in-Chief John Weeks, johnweeks-integrator.com, Seattle, WA, states: "Schnyer and Citkovitz have waded into an arena that is especially controversial for informing optimal utilization of TCM practices, particularly with the recent WHO inclusion and as some TCM researchers seek to cross-walk TCM and Western diagnoses." He notes that the Guest Editors have indicated that this is a revitalization of what they hope will be an ongoing dialogue about pattern recognition and reliability at JACM.

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NEW YORK, Nov. 20, 2019 (GLOBE NEWSWIRE) -- BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leader in the development of innovative autologous cellular therapies for highly debilitating neurodegenerative diseases, today announced publication of "NurOwn Phase 2 Randomized Clinical Trial in ALS: Safety, Clinical and BioMarker Results," in the international, peer-reviewed journal Neurology: Volume 93, Number 24 (Published ahead of print.)

The objective of the randomized placebo-controlled Phase 2 clinical trial was to determine the safety and efficacy of a single transplantation of autologous bone-marrow derived MSC-NTF cells (NurOwn) in participants with ALS. The clinical trial enrolled 48 participants randomized 3:1 (treatment: placebo) at three leading U.S. investigative sites: Massachusetts General Hospital, Mayo Clinic and University of Massachusetts Medical School. After a three-month pre-transplant run-in period, participants received one dose of MSC-NTF cells (n=36) or placebo (n=12) and were followed for six-months. CSF was collected prior to and two-weeks post-transplantation. The clinical trial confirmed that a single transplantation of MSC-NTF (NurOwn) cells was safe and well-tolerated. BrainStorm's NurOwn cell therapy is the furthest advanced autologous stem cell treatment in development for ALS. On October 11, the Company announced that the NurOwn, Phase 3 clinical trial for ALS was fully enrolled.

Key efficacy findings:

The rate of ALS disease progression (ALSFRS-R slope) was stabilized for up to 12-16 weeks in a pre-specified group of participants with rapid progression (p
A higher proportion of MSC-NTF treated study participants experienced ?1.5 point/month improvement in ALSFRS-R slope at all post-treatment time points, and this was statistically significant at 4 and 12 weeks post-transplantation (p=0.004 and 0.046, respectively)

CSF neurotrophic factors increased and inflammatory biomarkers decreased 2 weeks post-transplantation (p
CSF MCP-1 levels (a marker of microglial activation and neuroinflammation) significantly decreased post-transplantation and correlated with ALSFRS-R slope improvement at all time points (p

"The entire investigative team working on the study are highly encouraged by the promising clinical results," said Phase 2 trial manuscript lead author Robert Brown DPhil, Leo P. and Theresa M. LaChance Chair in Medical Research and Chair of the Department of Neurology at the University of Massachusetts Medical School (UMMS) and UMass Memorial Medical Center, "In addition, we observed a clear biological effect of the treatment on CSF biomarkers to support its proposed mechanism of action in ALS."

"This was a high quality Phase 2 study that identified dosing, safety, and an important efficacy signal. These data are exactly what is needed to move forward with the current Phase 3 testing," added Dr. Merit Cudkowicz the Julieanne Dorn Professor of Neurology at Harvard Medical School and the Director of the Healey Center for ALS and Chair of Neurology at Mass General Hospital. "These promising results encourage us to complete the pivotal Phase 3 trial as rapidly as possible," said Dr. Anthony Windebank, Judith and Jean Pape Adams Foundation Professor of Neuroscience at the Mayo Clinic.

"The team at BrainStorm and the clinical investigators, led by Professors Brown, Cudkowicz and Windebank, have made a significant contribution to ALS research and to the peer reviewed-scientific literature with the publication of this study in Neurology," said Ralph Kern, MD, MHSc, Chief Operating Officer and Chief Medical Officer of BrainStorm. He added, "We met our primary endpoint and demonstrated that a single dose of NurOwn was safe and well-tolerated while supporting NurOwn's mechanism of action on neuroprotection and neuroinflammation pathways in ALS. We look forward to completing the current Phase 3 study to confirm the promising Phase 2 findings and expand our understanding of the potential of MSC-NTF cell therapy in ALS."

"Having a major study peer-reviewed, accepted and published by the highly respected journal Neurology is a significant milestone for BrainStorm, and I thank the entire team for the many hours they have contributed to the research and publication process," said Chaim Lebovits, President and CEO of BrainStorm. "Results from the study underscore the importance of conducting a larger Phase 3 clinical trial that will build upon the data collected in our Phase 2 study. Our Phase 3 study has recently reached full recruitment. All 200 ALS patients have been enrolled. We look forward to reporting our clinical results in the scientific literature and through corporate announcements."

"We are pleased that the U.S. Phase 2 results of NurOwn are published, and that the Phase 3 trial enrollment is now complete," said Dr. Neil Thakur, PhD, Executive Vice President for Mission Strategy at the ALS Association. The initial testing of NurOwn in ALS is promising. We stand ready to support rapid review by the FDA of BrainStorm's biologics license application of NurOwn."

Brian Wallach, Co-Founder of I AM ALS, said, "The publication of this important Phase 2 data is a significant milestone in the clinical development program for BrainStorm's NurOwn. I AM ALS supports the development of potentially transformative therapies like NurOwn and shares in the hope that when the Phase 3 is completed that it will be the first disease modifying therapy for ALS."

Hamilton, ON (November 20, 2019) - A study from McMaster University has shown that traditional ways of learning anatomy remain superior to those that rely on digital media.

The research suggests that virtual reality (VR) and mixed reality (MR) are inferior to traditional physical models of learning, and have major disadvantages in cost and functionality.

The findings also support the pivotal role of stereoscopic vision - the ability to perceive depth using the slightly different view from each eye - in efficient anatomy learning.

The study results were published today in the journal Anatomical Sciences Education.

"These newer technologies promise to provide dynamic and vivid imagery that the user can interact with for an active and self-paced learning experience, without having to enter an anatomy laboratory," said Bruce Wainman, first author and director of the education program in anatomy at McMaster.

"Surprisingly, the evidence for this apparent advantage over traditional instructional materials is scarce."

The study of human anatomy has traditionally included cadaveric dissection and the viewing of prosections, illustrations, photographs and physical models of anatomy.

Rapid advancements in computer technology have led to many different forms of digital anatomic simulations designed to supplement, and even replace, traditional instructional materials, said Wainman.

The McMaster study compared an MR model (Microsoft HoloLens) and a VR model (HTC VIVE) derived from a physical model to the actual model. The researchers focused on overall learning performance and the effects of stereopsis by using a strategy where the non-dominant eye was covered in one test condition.

Groups of 20 undergraduate students at McMaster with no prior anatomic training learned pelvic anatomy under seven conditions: physical model with and without stereo vision; MR with and without stereo vision; VR with and without stereo vision, and key views on a computer monitor. All were tested with a real human pelvis and a 15-item, short-answer recognition test. Students were not allowed to touch any of the physical models.

The results showed that, compared to the key views on a computer monitor, the physical model had a 70 per cent increase in accuracy; the VR a 25 per cent increase, and the MR a non-significant 2.5 per cent advantage.

"At the end of the day, there was little advantage to learning from virtual or mixed reality compared to a photo on a piece of paper, and they were much worse than a solid model," said Wainman.

"We found that that when you took away the stereo vision from the virtual reality headset tested, it was even worse than learning from a piece of paper. Promoters of this technology often say it is a superior way to learn, but our research shows that isn't true."

Geoff Norman, co-author of the paper and professor emeritus of health research methods, evidence, and impact at McMaster has spent the past 20 years focused on educational research, including the last decade working with Wainman on anatomical education best practices.

"There are claims about virtual reality being better, but then you find it is not just worse, but significantly worse, and a lot worse for segments of the population who have challenges already with their stereoscopic vision," said Norman.

"We encourage more quantitative research in this area to further assess mixed and virtual reality systems prior to implementation in anatomical education programs."

Prior to primary testing, 40 undergraduate students from McMaster were recruited to obtain qualitative data regarding the optimal environment for the MR and VR models.

"When we surveyed people about how long they were willing to learn in that virtual environment, no one indicated they were able to learn for more than 30 minutes," said Wainman. "Meanwhile, we have students who study in the anatomy lab six or seven hours a day looking at human material.

"We're not thinking about the technology so much as what is the best way to learn. We want technology to be in the service of education, and not the other way around."

Researchers from the Institute of Neurosciences of the University of Barcelona (UBNeuro) and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) described a mechanism, the increase of proteinaceous synthesis, which takes part in the degeneration of the type of neurons that are affected in Huntington's disease, a genetic neurodegenerative disease. These results, published in the science Brain, could help researchers design new therapies to treat this and other brain-affecting diseases.

The study is led by Esther Pérez-Navarro, lecturer at the Faculty of Medicine and Health Sciences of the UB and researcher at the August Pi i Sunyer Biomedical Research Institute (IDIBAPS). Other researchers from the University Pablo de Olavide have taken part in the study too.

Huntington's disease is a genetic neurodegenerative disease caused by the mutation of the huntingtin gene, which causes the early loss of striatal projection neurons, with effects in the motor coordination and cognitive and psychiatric damage. The new study analysed the role in this proteinaceous synthesis altering process, a mechanism that allows neurons read the genetic code to synthetize proteins.

Improvement of motor coordination in mice

In order to study this mechanism, researchers analysed the total and phosphorylate levels of 4E-BP1, a protein that inhibits proteinaceous synthesis, in mice models with the disease. "The results show the total levels of the protein are reduced, while the phosphorylate levels increase, in striatal projection neurons in mice with the disease, compared to control mice, so the protein synthesis increases, as seen in samples from patients' brains", notes Esther Pérez-Navarro, also researcher at the Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED).

To confirm this relation between inappropriate activity of proteinaceous synthesis and the disease, researchers blocked this mechanism pharmacologically and observed the motor function improved in mice and that different molecular values were recovered in normal levels in the brains. "These results show an increase in the proteinaceous synthesis in the Huntington's disease is damaging and therefore, it represents a potential therapeutic target for new treatments such as a drug that can be administrated in a non-invasive manner to normalize proteinaceous synthesis", noted the researcher.

A common mechanism in other brain diseases

Although this is the first time the proteinaceous synthesis alteration is related to this disease, this is a mechanism that was described in other neurodegenerative diseases (such as Alzheimer's and Parkinson's) and other mental disorders such as autism. "Finding common mechanisms in different diseases affecting the brain makes it more attractive, since the same therapy could benefit different diseases", says the researcher.

Biomarker search

This research study opens the door to identifying biomarkers that can help detect the disease before the first symptoms appear. In this sense, the researchers, in collaboration with the Unit of Movement Disorders in Hospital de la Santa Creu i Sant Pau, are studying whether the proteinaceous synthesis is also altered in outside brain cells, such as blood cells and fibroblasts (skin cells). "The advantage of this study being conducted in Huntington's, associated with a genetic mutation, is that we can analyse these changes in carriers who do not show symptoms and we can make a long-term monitoring", concludes the researcher.

The human genome contains 4.5 million copies of transposable elements (TEs), so-called selfish DNA sequences capable of moving around the genome through cut-and-paste or copy-and-paste mechanisms. Accounting for 30-50% of all of the DNA in the average mammalian genome, these TEs have conventionally been viewed as genetic freeloaders, hitchhiking along in the genome without providing any benefit to the host organism. More recently, however, scientists have begun to uncover cases in which TE sequences have been co-opted by the host to provide a useful function, such as encoding part of a host protein. In a new study published in the journal Nucleic Acids Research, Professor Hidenori Nishihara has undertaken one of the most comprehensive analyses of TE sequence co-option to date, uncovering tens of thousands of potentially co-opted TE sequences and suggesting that they have played a key role in mammalian evolution.

"I was specifically interested in the potential influence of TE sequences on the evolution of the mammary gland," notes Dr. Nishihara, "an organ that is responsible for producing milk and is, as the name suggests, a key distinguishing feature of mammals." To identify potentially co-opted TE sequences, Dr. Nishihara used four proteins--ERα, FoxA1, GATA3, and AP2γ--that bind to DNA to regulate the production of proteins involved in mammary gland development. Dr. Nishihara then located all of the DNA sequences in the genome to which these proteins bind. Surprisingly, 20-30% of all of the binding sites across the genome were located in TEs, with as many as 38,500 TEs containing at least one binding site. The majority of these were in a copy-and-paste type of TE known as a retrotransposon, which duplicates itself, leaving a new copy in a new location.

The TE-derived binding site sequences were more conserved across species than expected, indicating that they are being preserved by evolution because they serve some important function. Dr. Nishihara believes that these TE sequences have been co-opted to serve as enhancers, DNA elements that increase the transcription of nearby genes (Fig. 1). By binding to one of the four master regulators of mammary gland development, these enhancers ultimately increase the production of proteins involved in mammary gland development.

Dr. Nishihara then investigated when in mammalian evolution these TE sequences were acquired and found two distinct phases of acquisition: roughly 60-70% were acquired in the ancestor of all placental mammals (Eutheria), while 10-20% could be traced back to the ancestor of New World monkeys (Simiiformes) (Fig. 2, left). In addition, there appeared to be another wave of acquisition of ERα binding sites in the ancestor of mice and rats (Muridae) (Fig. 2, right). Thus, by providing a vast number of potential regulatory element binding sites throughout the genome, TEs may have had a substantial impact on the emergence of the mammary gland and its evolution within mammals.

Dr. Nishihara's study sheds light on the deep involvement of TEs in the evolution of mammary gland regulatory elements. However, it remains unclear how common this mode of TE-mediated regulatory network evolution is. Dr. Nishihara, at least, believes that the mammary gland is not unique in this respect. He notes that, "in addition to mammary glands, mammals share many features, such as the neocortex, closed secondary palate, and hair. I expect future research to uncover many additional kinds of TEs that have been similarly involved in the evolution of these features in mammals."

New observations from the NASA/ESA Hubble Space Telescope have investigated the nature of the gamma-ray burst GRB 190114C.

Gamma-ray bursts are the most powerful explosions in the Universe. They emit most of their energy in gamma rays, light which is much more energetic than the visible light we can see with our eyes.

In January 2019, an extremely bright and long gamma-ray burst (GRB) was detected by a suite of telescopes, including NASA's Swift and Fermi telescopes, as well as by the Major Atmospheric Gamma Imaging Cherenkov (MAGIC) telescopes. Known as GRB 190114C, some of the light detected from the object had the highest energy ever observed: 1Tera electron volt (TeV) -- about one trillion times as much energy per photon as visible light. Scientists have been trying to observe such very high energy emission from GRB's for a long time, so this detection is considered a milestone in high-energy astrophysics.

Previous observations revealed that to achieve this energy, material must be emitted from a collapsing star at 99.999% the speed of light. This material is then forced through the gas that surrounds the star, causing a shock that creates the gamma-ray burst itself. For the first time, scientists have observed extremely energetic gamma rays from this particular burst.

Several ground- and space-based observatories have set out to study GRB 190114C. European astronomers were provided observing time with the NASA/ESA Hubble Space Telescope to observe the gamma-ray burst, to study its environment and find out how this extreme emission is produced[1].

"Hubble's observations suggest that this particular burst was sitting in a very dense environment, right in the middle of a bright galaxy 5 billion light years away," explained one of the lead authors, Andrew Levan of the Institute for Mathematics, Astrophysics & Particle Physics Department of Astrophysics at Radboud University in the Netherlands. "This is really unusual, and suggests that might be why it produced this exceptionally powerful light."

Astronomers used the NASA/ESA Hubble Space Teleescope, together with the European Southern Observatory's Very Large Telescope and the Atacama Large Milimeter/submilimeter Array to study the host galaxy of this GRB. Hubble's Wide Field Camera 3 was instrumental in studying whether the environmental properties of the host system, which is composed of a close pair of interacting galaxies, might have contributed to the production of these very-high-energy photons. The GRB occurred within the nuclear region of a massive galaxy, a location that is rather unique. This is indicative of a denser environment than that in which GRBs are typically observed and could have been crucial for the generation of the very-high-energy photons that were observed.

"Scientists have been trying to observe very-high-energy emission from gamma-ray bursts for a long time," explained lead author Antonio de Ugarte Postigo of the Instituto de Astrofísica de Andalucía in Spain. "This new observation is a vital step forward in our understanding of gamma-ray bursts, their immediate surroundings, and just how matter behaves when it is moving at 99.999% of the speed of light."

Plant growth-promoting Streptomyces assemble into the internal, root endophytic compartments of a wide variety of plants around the world. These bacteria are well-known for their ability to produce a huge array of secondary metabolites and also protect against pests.

Recent research published in Phytobiomes Journal demonstrates that melanin-producing Streptomyces are more likely to colonize plants, which has been shown to be protective for many different organisms.

According to corresponding author Sarah Lebeis, "We show that the ability to produce melanin protects microbes from harmful chemicals they encounter when they live inside of a plant and that it is active when bacteria are inside plants. We believe that our findings provide a protective pathway potentially utilized by a variety of other microbes when they try to grow inside of plants."

Lebeis and her fellow researchers at the University of Tennessee had access to an extensive collection of Streptomyces isolates from Arabidopsis thaliana roots grown in two soils in North Carolina. Upon analysis, they came up with the hypotheses that Streptomyces that produces melanin colonizes plants better. They tested this hypothesis using strains from another collection isolated from Poplar trees mostly on the West Coast but also from Appalachia and found similar results.

"This makes us think that this mechanism is more generalizable between plant-microbe interactions," Lebeis explained. "The soils are very different between the collections, and the potential time required for the association could be very different (6 weeks for Arabidopsis, and potentially years for the Poplar). This make us think that the protection being able to make melanin provides is in response to a strong selective pressure from the plant."