Culture

A team of researchers from New York University and the New York Genome Center has developed a new computational tool to help understand the function and regulation of human genes. The results, published today in the journal Nature Genetics, demonstrate how to interpret experiments that combine the use of CRISPR to perturb genes along with multimodal single-cell sequencing technologies.

The article describes how the new approach, called mixscape, helped to identify a new molecular mechanism for the regulation of immune checkpoint proteins that govern the immune system's ability to identify and destroy cancer cells.

"Our approach will help scientists to connect genes to the specific cellular behaviors and molecular pathways that they regulate," explains Rahul Satija, the study's senior author, who is an associate professor of biology at NYU's Center for Genomics and Systems Biology and a core faculty member at the New York Genome Center.

The researchers set out to better understand how cancer cells alter the regulation of key genes, such as the immune checkpoint molecule PD-L1, in order to avoid detection and evade the body's immune system. To do so, they performed a pooled genetic screen, where they 'knocked out' a set of genes in a cancer cell line model in order to observe the effect of each change or perturbation on PD-L1 levels. They utilized ECCITE-seq, a technology that allows researchers to capture single-cell profiles of different types of biomolecules--such as RNA and protein--after perturbing each gene with a CRISPR "guide RNA." The ability to measure multiple types of molecular data, referred to as multimodal analysis, allowed the team to distinguish between transcriptional and post-transcriptional modes of regulation.

After completing its experiments, however, the team realized that significant computational challenges limited its ability to analyze and interpret the data. For example, the researchers found that when they tried to knock out the same gene in multiple different cells, they observed striking variability in the results. In particular, a substantial fraction of cells--up to 75% in some cases--appeared to escape any observable effects after attempted perturbation and represented a confounding source of noise in downstream analysis.

"Facing these challenges made us realize that we needed new computational methods to identify and remove confounding sources of variation in our dataset," says Efthymia Papalexi, a biology graduate student at NYU and lead author of the study.

To achieve this, the team developed a statistical approach--mixscape--to model each perturbation as giving rise to a mixture of cells with different responses. In doing so, the mixscape method can identify and remove sources of noise from the data, allowing the user to focus on the most important biological signals that remain.

"When we applied mixscape in our screen, we boosted our power to connect gene perturbations with changes in the transcriptome and protein expression. This allowed us to discover that the kelch-like protein KEAP1 and the transcriptional activator NRF2 mediate a cell's expression level of PD-L1," says Satija.

While these studies were conducted in cancer cell lines, KEAP1 and NRF2 are frequently mutated in human lung cancer samples, suggesting that these genes may play important roles in the development and progression of human tumors.

Looking forward, the researchers are leveraging multimodal single-cell pooled CRISPR screens and mixscape to understand the molecular regulation of dozens of additional pathways and cellular behaviors.

Mixscape is freely available online through the Satija lab's Seurat package, a software toolkit for biomedical researchers.

"We hope our method will be useful for the community and assist in the study of how genes and molecular pathways interact with each other," says Papalexi.

By analyzing blood samples from individuals infected with SARS-CoV-2, researchers in Singapore have begun to unpack the different responses by the body’s T cells that determine whether or not an individual develops COVID-19. The study, published today in the Journal of Experimental Medicine (JEM), suggests that clearing the virus without developing symptoms requires T cells to mount an efficient immune response that produces a careful balance of pro- and anti-inflammatory molecules.

Many people infected with the SARS-CoV-2 virus do not develop any symptoms, and the infection is cleared by both antibodies and T cells that specifically recognize the virus. In some cases, however, this protective immune response can trigger excessive inflammation that damages tissues and causes many of the symptoms associated with COVID-19.

What determines whether or not an infected individual develops symptoms remains unknown. Some studies have suggested that asymptomatic individuals produce fewer anti–SARS-CoV-2 antibodies than individuals that develop symptoms. But whether their T cell responses are also reduced was unclear.

“Asymptomatic individuals constitute a variable but often large proportion of infected individuals, and they should hold the key to understanding the immune response capable of controlling the virus without triggering pathological processes,” says Antonio Bertoletti, a professor at the Duke-NUS Medical School in Singapore.

Bertoletti and colleagues, including Nina Le Bert, a senior research fellow at Duke-NUS Medical School, and Clarence C. Tam, an assistant professor at the National University of Singapore Saw Swee Hock School of Public Health, studied a group of migrant workers who were exposed to SARS-CoV-2 in their dormitories in April 2020. Over the course of six weeks, the researchers took regular blood samples from 85 workers who were infected but remained asymptomatic and compared their T cells to those of 75 patients who were hospitalized with mild to moderate COVID-19.

Surprisingly, the researchers found that, shortly after infection, the frequency of T cells recognizing SARS-CoV-2 was similar in both asymptomatic individuals and COVID-19 patients. “The overall magnitude of T cell responses against different viral proteins was similar in both cohorts,”  Nina Le Bert  says.

However, the T cells of asymptomatic individuals produced greater amounts of two proteins called IFN-γ and IL-2. These signaling proteins, or cytokines, help to coordinate the immune system’s response to viruses and other pathogens.

Accordingly, the immune response to SARS-CoV-2 appears to be more coordinated in asymptomatic individuals. Bertoletti and colleagues challenged some of the blood samples with fragments of viral proteins and found that the immune cells of asymptomatic individuals produce a balanced, well-proportioned mix of pro- and anti-inflammatory molecules. In contrast, the immune cells of COVID-19 patients produced a disproportionate amount of proinflammatory molecules.

“Overall, our study suggests that asymptomatic SARS-CoV-2–infected individuals are not characterized by a weak antiviral immunity; on the contrary, they mount a highly efficient and balanced anti-viral cellular response that protects the host without causing any apparent pathology,” the researchers say.

The molecular details of this response, and how it safely controls SARS-CoV-2 infections, can now be studied in more detail. However, because most of the participants in the study were male and of Indian/Bangladeshi origin, the researchers caution that their results will need to be confirmed in women and other populations around the world.

UNIVERSITY PARK, Pa. -- The rate of suicide among post-9/11 military veterans has been rising for nearly a decade. While there are a number of factors associated with suicide, veterans have unique experiences that may contribute to them thinking about killing themselves.

"Compared to their civilian peers, veterans are more likely to report having experienced traumatic adverse childhood experiences (ACEs) such as physical and emotional abuse," stated Keith Aronson, associate director of the Clearinghouse for Military Family Readiness at Penn State and the Social Science Research Institute (SSRI). "Veterans also engage in life-threatening combat and witness the corollaries of combat such as seeing colleagues killed or wounded."

A recent study of nearly 10,000 post-9/11 veterans sought to determine if traumatic childhood and combat experiences were associated with suicidal thinking.

The research published on Feb. 24 in the Journal of Community Psychology.

Compared to veterans who had no ACEs or combat exposure (reference group), male and female veterans who had experienced one ACE but no combat were two-and-a-half times more likely to report thoughts of suicide. Females who experienced three or more ACEs but no combat were five times more likely to think of suicide, while males were three times more likely compared to the reference group.

"This data shows that veterans' suicidal thinking and mental well-being is influenced by factors that happen both before and during military," noted Daniel Perkins, principal scientist at the Clearinghouse and professor of Family and Youth Resiliency and Policy in the College of Agricultural Sciences who is also an SSRI cofunded faculty member.

Female veterans who were exposed to three or more ACEs and corollaries of combat were more than five times more likely and males were more than three times more likely to have thoughts of suicide compared to the reference group.

Female veterans who only were exposed to combat were nine times more likely to have thoughts of suicide, while males were four times more likely. Female veterans exposed to one or more ACEs and combat were more than eight times more likely to think about suicide than females in the reference group. Males exposed to one or more ACEs and combat were between two and five times more likely to have suicidal thoughts than male veterans in the reference group.

There was no association between suicidal thinking and exposure to the corollaries of combat irrespective of exposure to ACEs.

"Clearly exposure to ACEs and combat increase the odds that post-9/11 veterans will think about suicide," said Nicole Morgan, assistant research professor at the Clearinghouse. "Female veterans appear particularly vulnerable to suicidal thinking and they likely need enhanced support and programs to decrease their suicidality and work to resolve their childhood and combat traumatic experiences through appropriate evidence-based treatment."

The study is a part of The Veterans Metrics Initiative (TVMI). The initiative focuses on understanding veterans' use and non-use of VA and non-VA resources designed to support healthy reintegration over the first three-years of military disconnection.

Amsterdam, March 1, 2021 - Comfort is a daily human experience central to the perception of our environment and the continuous processing of sensory input. Environmental factors such as smell, temperature and light can influence comfort, as can our interaction with products, such as the design of a chair or a mattress. Increasingly, researchers investigating the science of comfort and discomfort are focusing on the role of human behavior. A special supplement to the journal WORK presents the latest advances, from optimal seat design in offices and transportation to the influence of smell on comfort and the interaction between time and comfort.

"This special supplement adds unique findings to comfort knowledge. It shows that not only is the environment or a product itself comfortable, but also that the comfort experience depends on the way the user interacts with the product or environment," explain Guest Editors Peter Vink, PhD, Faculty of Industrial Design Engineering, Delft University of Technology, Delft, The Netherlands; Susanne Frohriep, PhD, Grammer AG, Ursensollen, Germany; Neil Mansfield, PhD, Department of Engineering, School of Science and Technology, Nottingham Trent University, UK; Alessandro Naddeo, PhD, Department of Industrial Engineering, University of Salerno, Fisciano, Italy; and Karen Jacobs, EdD, OT, OTR, CPE, Department of Occupational Therapy, Boston University, Boston, MA, USA, and Editor-in-Chief of WORK.

The supplement presents 26 peer-reviewed papers from the International Comfort Congress (2019) representing 99 authors and co-authors from 12 countries.

In their contribution to the supplement, Dr. Vink and his co-author Maxim Smulders, PhD candidate, also at the Faculty of Industrial Design Engineering, Delft University of Technology, note that comfort research that has no information on the behavior of participants can be incomplete, as major influencing factors can be missed. For example, a straight spine in the sagittal plane is sometimes considered ideal for sleeping, but in reality, humans have different preferred postures and change positions frequently in bed. They discuss how posture and movement can affect comfort.

Another study found that in self-driving cars, inattentive occupants move their heads relatively more, which may influence their perception of comfort. Other behavior factors that influence comfort include previous experience, distracting stimuli and time. Two studies found that when a person sits for a long time with no possibility to change posture, such as on an airplane or while taking an exam, comfort is reduced.

Among the environmental factors explored in this supplement is the relationship between scent and comfort. One study found that the scent of mandarin is liked by many people, but the preferred intensity varied. Another study found that olfactory comfort is as important as thermal comfort in overall perceived comfort in cars. Radiative heating panels are more energy efficient than air heating in cars and offer the same quality of comfort. High intensity light was found to reduce visual and cognitive fatigue and increase comfort in computer users.

Comfort factors related to the body's contact with products such as a floor, seat or bed are also discussed. The best design for a chair, based on several studies, is one that can be adjusted to various positions and buttock forms. A tilted backrest provides the most comfort for texting while in bed. Employees whose work requires that they stand for long periods of time may be more comfortable standing on a platform inclined between 5? and 10?.

The supplement includes an important contribution to future research in the field. Comfort is an individual and subjective concept, depending on the personal experience and state of the person over time. Questionnaires are important in the evaluation of a user's experience of comfort or discomfort over time, along with objective measurements. Selecting the most suitable questionnaire in comfort research for product design can be a challenge, even for experienced researchers. A workshop of 55 comfort experts reviewed a number of standard comfort or discomfort questionnaires to develop an instrument for questionnaire selection. The resulting list of Preferred Comfort Questionnaires (PCQ) for product design lets researchers select the most appropriate questionnaire depending on application, design phase and use case. "We expect the PCQ will be a useful instrument for researchers," says Dr. Vink, who was the lead investigator in the study.

In conclusion the Guest Editors observe that "Reporting these factors allows for better evaluation and comparison of comfort research results, which should contribute to an increase of scientific knowledge on discomfort."

Scientists have identified that the COVID-19 virus could be transmitted through faecal contaminated river water.

A team of researchers, including water quality, epidemiology, remote sensing and modelling experts, led by Dr Jamie Shutler at the University of Exeter, have developed a fast and simple way to assess the potential risk of water-borne transmission of the COVID-19 virus, posed by sewage spills into open and closed freshwater networks.

The new study, published in the journal Environmental Science and Technology - Water, identifies the relative risk of viral transmission by sewerage spills, across 39 different counties.

The study used information on the environment, a population's infection rate, and water usage to calculate the potential potency of viral loads in the event of a sewerage spill.

The research team believe the new study could provide fresh impetus in identifying new ways in which to prevent the spread of the virus amongst communities and the environment.

Dr Jamie Shutler, lead author of the study and at the University of Exeter's Penryn Campus in Cornwall said: "it's important to identify and break all viable transmission routes if we want to stop any future outbreaks".

Airborne water droplets have previously been highlighted as the main route for transmission of the virus which causes COVID-19, but we know that other forms of transmission are likely to exist.

Previous studies have shown that COVID-19 viral pathogens can be found in untreated wastewater, in concentrations consistent with population infection rates. While studies are still relatively early in relation to COVID-19, other human coronaviruses are documented to survive in wastewater, with colder water temperature likely to increase viral survival.

Using this knowledge and existing methods, the research team identified how the transmission risk from water contaminated with sewage reduces over time.

This issue is likely to be especially problematic in parts of the world with a large proportion of temporary settlements, such as shanty towns, favellas or refugee camps, which are less likely to have safe sanitisation systems. Or any densely populated region that has high infection rates that also suffers from a sewage spill.

Modifying established pollution analysis methods, the team were able to estimate the viral concentration in rivers after a sewage spill. This meant they could calculate the relative transmission risk posed to humans by contaminated waterways for 39 countries.

These methods, the team argue, provides a fast way to assess the transmission risk associated to sewage spills through the use of easily available population, infection rate and environmental data, allowing evidence based guidance following a spill.

Dr Shutler added: "we hope that water companies or NGOs will use our simple spreadsheet calculator, that is freely available, to estimate the transmission risk after a spill. They can then use this information to advise the public."

The anti-inflammatory drug hydroxychloroquine should not be used to prevent infection in people who do not have covid-19, say a WHO Guideline Development Group (GDG) panel of international experts in The BMJ today.

Their strong recommendation is based on high certainty evidence from six randomised controlled trials involving over 6,000 participants with and without known exposure to a person with covid-19 infection.

High certainty evidence showed that hydroxychloroquine had no meaningful effect on death and admission to hospital, while moderate certainty evidence showed that hydroxychloroquine had no meaningful effect on laboratory confirmed covid-19 infection and it probably increases the risk of adverse effects.

As such, the panel considers that this drug is no longer a research priority and that resources should be used to evaluate other more promising drugs to prevent covid-19.

This guideline applies to all individuals who do not have covid-19, regardless of their exposure to a person with covid-19 infection.

The panel judged that almost all people would not consider this drug worthwhile, and also decided that factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation.

Today's recommendation is the first version of a living guideline for drugs to prevent covid-19, developed by the World Health Organization with the methodological support of MAGIC Evidence Ecosystem Foundation. It's aim is to provide trustworthy guidance on the management of covid-19 and help doctors make better decisions with their patients.

Living guidelines are useful in fast moving research areas like covid-19 because they allow researchers to update previously vetted and peer reviewed evidence summaries.

New recommendations for other preventive drugs for covid-19 will be added to this guideline as more evidence becomes available.

Philadelphia, Pa. -- More than one out of every 10 seniors (10.5%) enrolled in a Medicare Advantage plan, also known as a Medicare managed care option, and living in a rural area, switched to traditional Medicare during 2010-2016. The switch was driven primarily due to low satisfaction with care access, according to a study published this week in Health Affairs from researchers at Drexel University's Dornsife School of Public Health. By contrast, only 1.7% of rural traditional Medicare enrollees made the switch to Medicare Advantage during this period.

The findings, among the first to look at rates of switching between the two options among rural versus nonrural enrollees, found a similar, yet more muted, effect among nonrural enrollees, with 2.2% of traditional Medicare enrollees and 5% of Medicare Advantage enrollees making the switch.

Switching was most common among Medicare Advantage enrollees who experienced higher costs, such as hospitalization or long-term facility stay. Among those requiring more expensive services, rural enrollees were about twice as likely to switch from Medicare Advantage to traditional Medicare as nonrural enrollees (16.8% versus 8.3%), suggesting that limited provider options in rural areas were a major factor leading consumers to change their coverage plan.

"We studied 11 factors that might make someone switch their health insurance and found that much of this transfer from Medicare Advantage to traditional Medicare among rural residents came from limited provider availability. However, care quality or out-of-pocket costs played a limited role." said lead author Sungchul Park, PhD, an assistant professor in the Dornsife School of Public Health. "It's not that rural patients were sicker than nonrural patients, they might just have a much tougher time than their counterparts did when it came to finding an approved medical provider."

Unlike traditional Medicare, which is administered by the Centers for Medicare and Medicaid Services, Medicare Advantage is operated by private companies approved by the government. Both traditional Medicare and Medicare Advantage include hospital (Part A) and medical (Part B) insurance. However, funding for the two programs differs and influences how they're delivered. In traditional Medicare, the federal government pays for services performed, but the government pays Medicare Advantage insurers using fixed, pre-negotiated rates. This creates incentive for Medicare Advantage plans to implement cost-saving measures, such as programs to keep their enrollees healthy, implement networks and require prior authorization restrictions to care.

"Medicare Advantage plans might have lower premiums and/or supplemental coverage in some areas, but that value is not enough for patients in more restrictive provider networks that prevent them from accessing care they need," said Park. "We found that levels of satisfaction with out-of-pocket costs had little very little influence in patients who decided to change their plan."

Data was gathered from a nationally representative sample of seniors over age 65 from the Medicare Current Beneficiary Survey from 2010-2016, (expect for 2014, when data was not reported), including demographics, socioeconomic characteristics, health data and satisfaction with care. Rural residency was based on county-level 2013 data from the Department of Agriculture.

The authors suggest the importance of developing policies to incentivize the health care workforce to practice in rural areas. For example, loan repayment or forgiveness programs may attract needed health care professionals to areas of shortages. Also, the federal government could consider changing Medicare Advantage network adequacy standards for rural areas to make sure that there are enough providers included. Finally, offering a rural payment add-on for Medicare Advantage plans that operate in rural areas may improve access to high-quality Medicare Advantage plans among rural enrollees.

CHICAGO --- Public attitude toward COVID-19 and its treatments is more "infectious" than the disease itself, according to a new Northwestern Medicine study using Artificial Intelligence (AI) to analyze tweets about the virus. Researchers studied the influence of Twitter on COVID-19 health beliefs as well as the competing influence of scientific evidence versus the speeches of politicians.

The study's key findings:

People's biases are magnified when they read tweets about COVID-19 from other users, and the more times it has been retweeted, the more they tend to believe it and retweet it themselves.

Scientific events, such as scientific publications, and non-scientific events, such as speeches of politicians, equally influence health belief trends on social media.

"In the pandemic, social media has contributed to much of the information and misinformation and bias of the public's attitude toward the disease, treatment and policy," said corresponding study author Yuan Luo, chief Artificial Intelligence officer at the Institute for Augmented Intelligence in Medicine at Northwestern University Feinberg School of Medicine.

"Our study helps people to realize and re-think the personal decisions that they make when facing the pandemic," Luo said. "The study sends an 'alert' to the audience that the information they encounter daily might be right or wrong, and guide them to pick the information endorsed by solid scientific evidence. We also wanted to provide useful insight for scientists or health care providers, so that they can more effectively broadcast their voice to targeted audiences."

The study was published recently in the Journal of Medical Internet Research.

How can scientists counter inaccurate information from politicians?

"Politicians may talk inaccurately about a certain treatment's effectiveness or say that COVID-19 is no big deal; it's just like the flu," said Luo said, also chief AI officer at Northwestern University Clinical and Translational Sciences Institute. "These comments have as strong effect as real scientific evidence and drive people's beliefs. This is what we are concerned about."

By understanding how the public's attitudes are affected, scientists can take actions to make sure scientific fact and evidence have a loud enough voice.

"As a scientist, you need to be aware that you need to get the science out to people. If you don't put energy into this, your efforts can be easily offset by those who talk irresponsibly," Luo said. "Going forward, we may want to pay more attention to a public information campaign to educate people about the vaccine in order to maximize the inoculation impact."

How are people's attitudes toward COVID-19 influenced by tweets?

"As a lay person, you should become aware of what you retweet and do a fact check first," Luo said. "And be aware anything you see on Twitter is shaping your attitude. You need to become aware of this before you let others' tweets and opinions shape yours and you become part of that megaphone."

"A lot of people aren't aware of how much their beliefs are impacted by tweets, and don't bother to fact check what they read and retweet. When the information is biased, they ignore or did not notice it. It's like a viral marketing effect. It's just about catching eyeballs on a trending topic, but it affects everyone on social media."

How is this study novel?

The study is novel because it integrates machine learning algorithms and classic epidemiology models to retrospectively investigate the contents on social media and its effects, Luo said.

The study also allows other researchers to "look under the hood" to understand how this AI algorithm works.

Machine learning and deep learning algorithms are usually opaque, blackbox mechanisms. But in this study, investigators paid special attention to improve the model's interpretability.

"We identified the fluctuating trends of public attitudes from the tweets, then aligned the important scientific and non-scientific events that are associated with these trends," Luo said. "As a result, we are offering insights people can take action on."

How many tweets did the AI analyze?

Luo's team, led by the study's first author Hanyin Wang, a Ph.D. student in the Driskill Graduate Program, retrospectively collected COVID-19-related tweets using the Twitter API. In total, they retrieved 92,687,660 tweets corresponding to 8,967,986 users from January 6 to June 21, 2020. To train the AI model, they randomly selected 5,000 of the tweets for annotation. Each tweet was doubly reviewed to decide if it met any of the four core constructs of the health belief model, perceived susceptibility, perceived severity, perceived benefits and perceived barriers.

Next step: using AI to analyze how social media affects attitudes toward COVID-19 vaccines

Luo's team is currently integrating machine learning and deep learning in the study of how social media can affect the general public's attitude toward COVID-19 vaccines. The goal is to identify specific public concerns and inform targeted vaccination campaigns to maximize inoculation impact. They are also looking at using social media data as a way to detect gender or race disparities in and out of the pandemic.

DURHAM, N.C. - Anyone who has ever developed a urinary tract infection (UTI) knows that it can be painful, pesky and persistent. UTIs have a high recurrence rate and primarily afflict women -- as many as 50% of women will experience at least one UTI during their lifetime.

However, what if patients could take a vaccine that would prevent future UTIs? In a March 1 study in the Proceedings of the National Academy of Sciences, Duke researchers describe a new vaccination strategy that they think could re-program the body to fight off the bacteria that cause urinary tract infections.

"Although several vaccines against UTIs have been investigated in clinical trials, they have so far had limited success," said Soman Abraham, Ph.D., Grace Kerby Distinguished Professor of Pathology, Immunology and Molecular Genetics & Microbiology in the School of Medicine and senior author on the paper.

"There are currently no effective UTI vaccines available for use in the U.S. in spite of the high prevalence of bladder infections," Abraham said. "Our study describes the potential for a highly effective bladder vaccine that can not only eradicate residual bladder bacteria, but also prevent future infections."

The strategy, which the team showed to be effective in mouse models, involves re-programming an inadequate immune response that the team identified last year. They observed that when mouse bladders get infected with E. coli bacteria, the immune system dispatches repair cells to heal the damaged tissue, while launching very few warrior cells to fight off the attacker. This causes bacteria to never fully clear, living on in the bladder to attack again.

According to lead author Jianxuan Wu, Ph.D., who recently earned his doctorate from the Department of Immunology at Duke, "the new vaccine strategy attempts to 'teach' the bladder to more effectively fight off the attacking bacteria. By administering the vaccine directly into the bladder where the residual bacteria harbor, the highly effective vaccine antigen, in combination with an adjuvant known to boost the recruitment of bacterial clearing cells, performed better than traditional intramuscular vaccination."

The researchers reported that bladder-immunized mice effectively fought off infecting E. coli and eliminated all residual bladder bacteria, suggesting the site of administration could be an important consideration in determining the effectiveness of a vaccine.

"We are encouraged by these findings, and since the individual components of the vaccine have previously been shown to be safe for human use, undertaking clinical studies to validate these findings could be done relatively quickly," Abraham said.

Scientists from Far Eastern Federal University (FEFU) together with Russian and German colleagues, continue studying antitumor compounds synthesized based on bioactive molecules isolated from a sea sponge. One of them fights cancer cells resistant to standard chemotherapy, and at the same time has an interesting dual mechanism of action. A related article appears in Marine Drugs.

Scientists have tested the biological effect of the marine alkaloid 3,10-dibromofascaplysin on various prostate cancer cells, including those resistant to standard docetaxel-based chemotherapy. The compound was first isolated from the sea sponge Fascaplysinopsis reticulata and subsequently chemically synthesized in FEFU. The substance forces tumor cells to die via a programmed cell death mechanism. This process is called "apoptosis" and is considered the most favorable mode of action of anticancer drugs.

"The examined compound, while killing cancer cells, even ones resistant to standard chemotherapy, simultaneously activates an enzyme (so-called &laquokinase») protecting these tumor cells. However, it can't be considered as a "good" or "bad" effect. This is just a mechanism of action, an understanding of which suggests us to apply 3,10-dibromofascaplysin together with inhibitors of these enzymes," says Dr. Sergey Dyshlovoy, from the Laboratory of biologically active substances of FEFU School of Natural Sciences, senior researcher in the laboratory of the pharmacology of National Scientific Centre of Marine Biology (Vladivostok, Russia).

According to the scientist, the synthesized compound in addition to its own activity, works well in combination with several already approved anticancer drugs, enhancing their antitumor effect.

Next, scientists are planning to examine how 3,10-dibromofascaplysin affects non-cancer cells. They already run a related project supported by the Russian Foundation for Basic Research, aiming to report the outcomes during 2021.

"Fascaplysins are rather toxic to non-cancer cells. In our laboratory, we are trying to modify the structure of these compounds in order to reduce their cytotoxic effect on normal cells, while maintaining the necessary antitumor effect. The goal is to create a substance for targeted therapy, with a minimum of side effects for healthy cells of the body," says Dr. Maxim Zhidkov, Head of Department of Organic Chemistry, FEFU School of Natural Sciences.

Commented on the time needed for the development of the on-the-shelf drug, scientists speak about the horizon of 10-15 years, given the necessity for long preliminary and further clinical trials.

SILVER SPRING, Md. - A recent preclinical study by U.S. Military HIV Research Program (MHRP) researchers showed that an experimental therapy combining a TLR7 agonist and two broadly neutralizing antibodies delayed viral rebound in SHIV-infected macaques after antiretroviral therapy (ART) interruption.

The experimental combination therapy consisted of TLR7 agonist GS-986 and two broadly neutralizing antibodies (bnAbs), N6-LS and PGT121, targeting different regions of the HIV envelope. The rhesus macaques were initiated on viral suppressive antiretroviral therapy 14 days post infection, a timespan from infection to treatment which mirrors what is feasible in acute HIV infection. Researchers then administered the experimental combination therapy, followed by ART pause and measured how long it took for SHIV viral load to rebound.

"This study demonstrated that the combination of TLR7 agonist and dual bnAbs delayed viral rebound after ART interruption by 2-fold," said Dr. Denise Hsu, MHRP Associate Director of Therapeutics. "This approach may represent a potential strategy to target the HIV reservoir in HIV-infected individuals."

A critical barrier to curing HIV is the reservoir of latent virus that remains hidden and infects cells throughout the body, leading to viral rebound in the vast majority of HIV-infected individuals after they discontinue ART. The hypothesis behind this strategy is that an agent such as the TLR7 agonist, bolstered by therapeutic bnAbs, can stimulate the immune system to clear latent HIV. The paper was published in PLOS Pathogens.

MHRP, part of the Walter Reed Army Institute of Research, collaborates with the Thai Red Cross AIDS Research Centre in Bangkok to identify acutely infected individuals and immediately start them on ART in a study called RV254. For the last few years, small clinical trials within this cohort have evaluated strategies aimed at inducing a cure or long-term remission of HIV. Interventions are wide-ranging and include therapeutic HIV vaccines and broadly neutralizing antibodies.

During these studies, volunteers are taken off ART to test the effects of a candidate intervention. This method, called analytical treatment interruption (ATI), looks at the time it takes for the viral load to rebound after the interruption. Participants are followed closely and restart ART when viral load rises to a certain threshold.

According to Dr. Sandhya Vasan, HJF Director for MHRP, "While we have seen some promise in our ATI trials, it has become clear that we need a combination intervention strategy to generate longer lasting viral suppression."

Based on these new preclinical data and building, MHRP hopes to evaluate the combination of innate immune stimulation, active and passive immunization for the induction of HIV remission in early treated people living with HIV.

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009339

NEW YORK, NY (March 1, 2021)--By harnessing the immune system against cancer, immunotherapies have revolutionized the way some types of cancer are treated. But most patients--across cancer types--do not respond, and in most cases, scientists are at a loss as to why.

Researchers at Columbia and MIT have created a new technique that can uncover nearly all of the tricks cancer cells use to evade immunotherapies, which could lead to the development of more effective treatments.

The researchers tested their new technique with cancer cells and matching immune cells from melanoma patients and identified previously unknown resistance mechanisms to immune checkpoint inhibitors, a powerful and widely used class of immunotherapy drugs.

The findings were published online March 1 in Nature Genetics.

Immunotherapies fail or stop working in two-thirds of melanoma patients  

Immune checkpoint inhibitors are drugs that are designed to release the "brakes" that prevent the immune system from operating at full power and attacking the cancer cells.

"With drugs called immune checkpoint inhibitors, we're now getting as close as we have ever been to curing one-third of patients with metastatic melanoma, even at a stage when the disease has spread throughout the body," says study leader Benjamin Izar, MD, PhD, assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons.

"So the question is, what is happening in the other two-thirds of patients?" Izar says. "What are the mechanisms of intrinsic or adaptive drug resistance?"

In a previous study published in Cell in 2018, Izar and his team identified 250 genes in metastatic melanoma cells that allow them to evade the immunotherapy. The new study was devised to provide a systematic way to functionally decipher how each of those genes contributes to immunotherapy resistance. 

First Test of CRISPR Tool

The study is the first test of a new tool that combines two advanced technologies--CRISPR gene editing and single-cell RNA and -protein sequencing--in a way that allows researchers to determine the full landscape of how cancer cells can evade the immune system.

Using CRISPR, the researchers inactivated those 250 genes--one by one but in a pooled fashion--to create a mixture of 250 batches of melanoma cells, each with a different mutation. The entire heterogenous population of "edited" cancer cells was then exposed to T cells--the immune cells unleashed by checkpoint inhibitors in patients. 

Cells that resisted being killed by T cells were isolated, and a snapshot of all active processes within these cells was measured using single-cell RNA and protein profiling, providing a high-resolution molecular map of several gene perturbations resulting in immune escape.

"Our approach is unique in that we study these mechanisms in patient-derived models, and rather than looking at how a gene changes a cell's phenotype one gene at a time, we were able to study many genes with potential roles in drug resistance in patients in one sweep. It's the first time that such tools have been used at such a large scale," says Izar.

All told, close to a quarter million cells were analyzed. Computational biology tools, developed by Izar and co-senior author Aviv Regev, PhD, professor of biology at MIT, were employed to make sense of this tremendous data set.

New and Old Resistance Mechanisms Identified

The analysis identified new mechanisms of resistance to immunotherapy along with mechanisms that were previously known. "Basically, we recovered the majority of known mechanisms described over the last 10 years--validating that our approach works and giving us confidence that the new findings are important," Izar says.

"We also uncovered many new mechanisms of resistance," says Johannes C. Melms, MD, a postdoctoral fellow in the Izar lab and the study's co-first author (with Chris J. Frangieh, a doctoral student at MIT). 

One of the new resistance mechanisms involves a gene called CD58. "Our data suggests that loss of CD58 in melanoma cells confers immune escape through three potential mechanisms: impairing activation of T cells, reducing the ability of T cells getting into the tumor, and increasing the production of PD-L1," Melms says. "Because the CD58 gene is not mutated per se but rather just turned off, it raises the possibility that therapies that turn it on could overcome drug resistance in some patients." 

The researchers plan to develop therapies to improve response to immunotherapies based on this finding. 

Izar and his team expect to learn more about resistance to immunotherapy from the study data. "CD58 is just one of many genes that warrant a closer look," Izar says.

In future experiments, the researchers plan to inactivate various combinations of cancer cell genes at once. "In this study, we looked at what happens to cells when only one gene is inactivated," he says. "But it's likely that no single gene is sufficient to confer all the types of resistance to immunotherapy that we see in clinical practice."

The study focused on melanoma, but the same approach could be used to study resistance to immunotherapy in many other forms of cancer, the researchers note. 

Tissue engineering has long-depended on geometrically static scaffolds seeded with cells in the lab to create new tissues and even organs. The scaffolding material -- usually a biodegradable polymer structure -- is supplied with cells and the cells, if supplied with the right nutrients, then develop into tissue as the underlying scaffold biodegrades. But this model ignores the extraordinarily dynamic morphological processes that underlie the natural development of tissues.

Now, researchers at the University of Illinois Chicago have developed new 4D hydrogels -- 3D materials that have the ability to change shape over time in response to stimuli -- that can morph multiple times in a preprogrammed or on-demand manner in response to external trigger signals.

In a new Advanced Science study, the UIC researchers, led by Eben Alsberg, show that these new materials may be used to help develop tissues that more closely resemble their natural counterparts, which are subject to forces that drive movement during their formation.

"The hydrogels can be programmed or induced to undergo multiple controllable shape changes over time. This strategy creates experimental conditions to partially mimic or stimulate the continuous different shape changes that developing or healing tissues undergo, and it may let us study morphogenesis and also help us engineer tissue architectures that more closely resemble native tissues," said Alsberg, the Richard and Loan Hill Professor of Biomedical Engineering and corresponding author on the paper.

The novel material is made up of different hydrogels that swell or shrink at different rates and extents in response to water or the concentration of calcium. By creating complex layering patterns, the researchers can guide the conglomerate material to bend one way or another as the layers swell and/or shrink.

"We can change the shape of these materials by adjusting, for example, the amount of calcium present," said Alsberg, who also is professor of orthopaedics, pharmacology and mechanical and industrial engineering at UIC.

In their experiments, the researchers were able to cause the hydrogel to form into pockets similar in shape to alveoli, the tiny sac-like structures in the lung where gas exchange takes place.

Not only are Alsberg's hydrogels able to change their architecture multiple times, but they also are highly cytocompatible, which means they can have incorporated cells and the cells remain alive -- something that many existing 4D materials are unable to do.

"We are really looking forward to pushing the limits of what our unique hydrogel systems can do in terms of tissue engineering," said Aixiang Ding, postdoctoral research associate at UIC and co-first author on the paper. UIC's Oju Jeon, research professor, is also a co-first author.

A team of international researchers led by a Florida State University assistant professor has analyzed reams of data from the Neolithic to Late Roman period looking at migration patterns across the Mediterranean and found that despite evidence of cultural connections, there's little evidence of massive migration across the region.

"Because of the prevailing scholarly attitude of the 'connected' Mediterranean -- one with high degrees of mobility and migration that drive the archaeological patterns we see -- we'd imagined we'd see comparatively high levels of migration reflected in the strontium isotope data," said Thomas Leppard, assistant professor of anthropology at Florida State. "That instead we saw low levels of migration, and that these in fact decreased over time, was very surprising."

Leppard and his colleagues found that from about 7,500 BC to AD 500, migration rates ranged from about 6% to 9% of the population within the dataset. These rates seem to have decreased over time.

The research is published in the Journal of Mediterranean Archaeology.

Many historians and archaeologists consider the Mediterranean basin to have been interconnected for much of its history. However, that theory is largely built on material culture that suggests such connections - for example, Greek-looking pots in Sicily in the Late Bronze Age, Arabic coins in Medieval Sardinia, or Roman-style dining sets in 2nd century AD Portugal.

Leppard wondered if the same pattern would be obvious if they brought human biochemistry into the mix.

For several years, scientists have been able to understand individual life histories by analyzing the chemistry of human remains. In humans, bodily tissues, including most bones, remake themselves constantly so that their chemical composition reflects their current environment. However, dental enamel and a small skull bone called the petrous portion are extremely hard and don't remodel, so once a human reaches adulthood, the isotope ratios in those two areas of the body don't change.

"As a result, if you spend childhood somewhere, and then move as an adult to a different place with different underlying chemistry, we can see a difference in the chemistry - and critically in the ratios of different strontium isotopes - between your dental enamel and your other bones," Leppard said. "If, however, you grew up and died in the same location, the ratios will be the same. That means we can start to quantify percentages of locals, and percentages of nonlocals in a given area."

Archaeologists have employed this technique for a while in the Mediterranean, but the sample sizes are generally very small because the experiments are expensive and there often aren't many samples of human remains. Leppard and his colleagues compiled all the data from many smaller experiments capturing a large time frame and re-analyzed it.

He cautioned that this is a starting place to assess the migration patterns of this region.

"It's important to say that migration is only one aspect of human mobility; we can't access seasonal or habitual mobility with this method, for example," Leppard said. "That said, we thought this would be a powerful method for assessing large-scale trends in Mediterranean migration across time. That these trends don't really match the current scholarship should generate productive debate and prompt new research."

The human gut consists of a complex community of microbes that consume and secrete hundreds of small molecules--a phenomenon called cross-feeding. However, it is challenging to study these processes experimentally. A new study, published in Nature Communications, uses models to predict cross-feeding interactions between microbial species in the gut. Predictions from such computational methods could eventually help doctors get a more complete understanding of gut health.

The microbial community, or microbiome, of the gut is known to influence human health. Previous studies have focused on determining the types of microbes that are present. Unfortunately, this information is not enough to understand the microbiome.

"The gut environment is shaped by small molecules known as metabolites, which are excreted by the microbial community," said Sergei Maslov (BCXT/CABBI), a professor of bioengineering and Bliss faculty scholar. "Although it is possible to measure these metabolites experimentally, it is cumbersome and expensive."

The researchers had previously published a study where they used experimental data from other studies to model the fate of metabolites as they pass through the gut microbiome. In the new study, they have used the same model to predict new microbial processes that have not been determined before.

"What we eat passes into our gut, and there is a cascade of microbes which release metabolites," said Akshit Goyal, a postdoctoral fellow at MIT and a collaborator of the Maslov lab. "Biologists have measured these molecules in human stools, we have shown that you can use computational models to predict the levels of some."

Measuring every metabolite and trying to understand which microbe might be releasing it can be challenging. "There is a large universe of possible cross-feeding interactions. Using this model, we can aid experiments by predicting which ones are more likely to occur in the gut," Goyal said.

The model was also supported by genomic annotations, which explain which microbial genes are responsible for processing the metabolites. "We are confident of our modelling predictions because we also checked whether the microbes contain the genes necessary for carrying out the associated reactions. About 65% of our predictions were supported by this information," said Veronika Dubinkina, a PhD student in bioengineering.

The researchers are now working to improve the model by including more experimental data. "Different people have different strains of gut microbes. Although these different strains have many genes in common, they differ in their capabilities," Dubinkina said. "We need to collect more data from patients to understand how different microbial communities behave in different hosts."

"We are also interested in determining how fast the microbes consume and secrete the metabolites," said Tong Wang, a PhD student in physics. "Currently the model assumes that all the microbes consume metabolites at the same rate. In reality, the rates are different and we need to understand them to capture the metabolite composition in the gut."