Culture

As COVID-19 surges nationwide, 78% of New York City residents believe it is likely or very likely the city will again experience a resurgence of cases similar to that seen last April. However, the November Presidential election appears to have triggered an optimism among New Yorkers: more than half feel "more hopeful" about the country's economic recovery (55%) and the government's ability to control the pandemic (58%).

These are key findings from the tracking survey of public perceptions and experiences in NYC during the COVID-19 pandemic conducted by the City University of New York Graduate School of Public Health & Health Policy (CUNY SPH). One thousand NYC residents were polled from November 20-22, 2020. The same panel of respondents were surveyed at the end of September and will be surveyed once more in January 2021.

"As we head into the most challenging winter of our lifetimes, this combination of clear-eyed acceptance of our current reality and cautious optimism bodes well for New York's eventual recovery," says Dr. Ayman El-Mohandes, Dean of CUNY SPH.

Asked whether the recent election had influenced their willingness to accept a COVID-19 vaccine, 43% report that it is now more likely that they will accept the vaccine compared to 18% who were less likely to take it. "This post-election boost in vaccine confidence is heartening," says Dr. Scott Ratzan, Distinguished Lecturer at CUNY SPH, "but the number of people who accept the new vaccines will still have to grow substantially if we are to curb the pandemic."

Subtle changes in indicators of mental health and trust

New Yorkers' levels of anxiety and depression held steady from September to November, with 21% of respondents feeling anxious more than half the time and 19% of respondents feeling depressed (an insignificant increases of 2% and 1% percent respectively). Notably, however, hopefulness about the future rose by 11%, with 43% of respondents feeling hopeful more than half the time.

Trust in federal and state government remained unchanged over the past three months. Only 23% of respondents say they trust that the federal government has their best interest and safety in mind, 38% feel the same about the state government. Fifteen percent (15%) trust both governments while 14% trust neither. The remaining 10% are unsure.

However, as the pandemic lingers trust in fellow citizens appears to have eroded substantially, dropping 12% since September with only 31% of respondents agreeing that "most people can be trusted."

Economic pain persists

The same percentage (30%) of New Yorkers reported they had changed their living arrangements since the pandemic began. The majority of them reported moving to cheaper housing (48%) or returning home to live with parents or family (34%). Employment numbers worsened slightly. Of those who said they had lost their jobs due to the pandemic, 48% remained unemployed in September; in November, that number has dropped slightly to 44%. Three in ten New York City households (29%) ran out of food in November before they had money to buy more, roughly the same (31%) as in September. Communities of color continue to be impacted disproportionately: 38% and 34% of Latinx and Black respondents respectively ran out of food in November before they had the money to buy more, compared to 19% of Whites.

Most New Yorkers to prefer to slow down the return to routine business and daily activities

The surge in COVID-19 cases across New York led 40% of respondents to believe normal daily activities and business operations should be rolled back or delayed, a substantial increase over September, when only 28% of respondents felt the pace of reopening was too quick. In contrast, when it came to reopening schools following the Thanksgiving holiday, just under half (49%) of respondents thought the city should keep them closed.

When considering only parents with a child in public school, over half (55%) believe that schools should remain closed following the Thanksgiving break; 20% said they believe schools should reopen while 24% were unsure.

Residents appear to be exercising greater caution in their personal behavior: compared to September, there was a 5% drop in those who worked outside of the home (47% vs. 42%) and a 7% drop in those who worked out in an indoor gym (25% vs. 18%). Only 18% of respondents participated in an indoor cultural or social event with more than 20 people present in November, compared to 25% in September.

Bluestar Genomics, an innovative company leading the development of next-generation epigenomic approaches to cancer detection, and University of Chicago today announce the publication of a genome-wide 5-hydroxymethylcytosine (5hmC) map across multiple human tissue types. The study, published in the peer-reviewed journal Nature Communications, demonstrated the robust performance of 5hmC as a global biomarker for the detection of multiple serious illnesses, such as cancer and various chronic diseases. Unlike 5mC which is a gene repression mark, 5hmC is a gene activation mark representing one of the most prevalent pathways involved in the regulation of embryogenesis, neurological processes, and carcinogenesis. The new map advances the understanding of diverse biological drivers in various diseases, which is necessary for the development of next-generation diagnostic tests.

"While previous studies have shown that 5hmC can serve as an excellent biomarker for the diagnosis and prognosis of human diseases including cancer, the lack of a whole-body tissue map limits our global understanding of this mark and its potential tissue specificity," says Dr. Chuan He, Professor of Chemistry at the University of Chicago and the senior author of the study. "Through this collaboration with Bluestar Genomics, the new publication significantly expands our understanding of this global biomarker, delivering what we believe is the broadest reported human tissue map that catalogs 5hmC modifications. The new map confirms 5hmC as a prevalent gene activation mark for both gene bodies and enhancers with superb tissue and cell type specificity, which is key to future early diagnosis of human cancer and monitoring of human chronic diseases."

In this study, the University of Chicago scientists collaborated with Bluestar Genomics to evaluate the performance and reproducibility of 5hmC as a biomarker across 19 tissue types from multiple male and female organs. The published results demonstrate that the 5hmC profiles identified in the new map provide an unprecedented database of potential diagnostic development, specifically in cancer.

Based on a study of 96 samples representing ten major organ systems: nervous, cardiovascular, digestive, reproductive, endocrine, respiratory, urinary, integumentary, skeletal, and lymphatic, the map represents the most comprehensive examination of 5hmC as a biomarker for cancer detection. The data confirms the profiling accuracy (Spearman r = 0.82 compared with gold standard TAB-seq profiles) and reproducibility (Spearman r = 0.974) of the genome-wide 5hmC profiles obtained in various tissues, which underscores its clinical relevance and provides a unique resource to study distributions of 5hmC in the human genome.

Building on Bluestar Genomics' previously published work, the new publication highlights that 5hmC reveals known biology in human tissues by enabling the measurement of gene transcriptional and gene regulation activity with the same assay. The published map, which characterizes the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems lays the foundation for the future development of diagnostic tests.

"With the ultimate goal of developing a robust cancer screening test, this map brings us a step closer to enhancing our ability to accurately read and interpret cancer signals coming from tumor tissues in cell-free DNA," says Samuel Levy, Ph.D., Chief Executive and Chief Scientific Officer at Bluestar Genomics, co-senior author of the study. "I'm proud that our work will also contribute to the broader scientific community by deepening scientists' precise understanding of the breadth of biology through the utilization of 5hmC."

Shipping pallets -- often used as display platforms in retail settings or seen as raw material for household projects -- were responsible for sending more than 30,000 people to the emergency rooms of U.S. hospitals over a recent five-year period, according to a new study.

With approximately 400 million new wooden pallets produced in the United States every year, and nearly 2 billion in use at any given time in the country, pallets are indispensable components of domestic supply chains. But they present unique hazards when used by retailers and homeowners for unintended purposes, pointed out researcher Judd Michael, Penn State Nationwide Insurance Professor of Agricultural Safety and Health.

The first-ever investigation of non-occupational injuries that occur due to unintentional contact with pallets yielded startling statistics, Michael noted. From Jan. 1, 2014, to Dec. 31, 2018, there were an estimated 30,493 people who visited hospital emergency rooms for pallet-related injuries.

To reach their conclusions, researchers combed through data in the U.S. Consumer Product Safety Commission's National Electronic Injury Surveillance System. That database is used for safety-related research, and similar studies using its data have examined injuries from products ranging from bunk beds to trampolines.

The National Electronic Injury Surveillance System collects emergency department data from approximately 100 hospitals selected as a probability sample for all of the more than 5,000 U.S. hospitals with emergency departments. In addition to patient demographics, incident date, emergency room diagnosis, injury location and patient disposition, the system contains brief narratives describing incident scenarios. Analysts then extrapolate data from the sample to estimate injuries across the entire U.S.

According to the data, people ages 35-44 were most likely to be injured -- 5,481 over the study years. But about 3,000 children and youth under 18 years of age were injured, and more than 4,000 people 65 years of age or older suffered injuries. The elderly, especially, were likely to suffer injuries from tripping over pallets and falling, Michael noted.

The lower extremities were the most often injured body parts in pallet-related accidents. The overall severity of injuries is likely low given the 97% discharge rate for pallet-related injuries. However, a small percentage were severe enough to require hospitalization or transfer, and there was a single fatality during this time period.

Significantly, Michael said, an estimated 3,964 persons -- accounting for approximately 14% of all pallet-related injuries -- were treated for injuries incurred while at a retail establishment. He expects the findings, recently published in the Journal of Safety Research, to be of great interest to operators of grocery stores, warehouse chains and "big-box" retailers, where pallets are often used in retail space as platforms to display merchandise.

"Based on our findings, the first obvious practical application of these results would be to eliminate pallets from being used in consumer-facing retail locations where unintentional contact could occur," he said. "Retailers can cover all floor-level pallets with a brightly colored material to make them more visible, and never leave unused pallets laying on floors."

Keeping pallets out of the hands of homeowners looking for materials to accomplish do-it-yourself projects is more problematic, Michael suggested. It would require preventing used pallets from leaking out of supply chains from manufacturer to retailer and into the possession of individuals.

"This strategy, however, would be effectively impossible given the near-ubiquitous availability of millions of used pallets that have little or no value to businesses and are discarded," he said. "Given the difficulty of preventing people from obtaining used pallets, the most appropriate preventative measures would seemingly relate to education on the dangers of used pallets."

Social media could be an effective tool to warn homeowners and counteract the increasing use of pallets for unintended residential use, Michael said. The prevalence of warm-weather injuries implies communications should be targeted during those months.

"The immense number of pallets allows for broken or beaten-up pallets to be lost from the system and grabbed by homeowners for DIY projects," he said. "Or they break up pallets for firewood or stack firewood on them. They're not careful and they get hurt."

Michael is often asked why he focused on the risks of pallets. It was a natural progression, he believes.

"Broadly speaking, in the College of Agricultural Sciences we have worked with industrial packaging for 10 to 15 years, and we've become experts in the area," he said. "We've done research on other aspects of pallet use, so this seemed like a logical extension as I have begun to work more on the safety side."

ANN ARBOR, Mich. - Quality of life is important for persons with traumatic brain injury, and new studies find it's just as important for the person's caregiver.

"Caregivers are often not the focus of treatments; It's usually about the patient or person with the condition," says Noelle E. Carlozzi, Ph.D., an associate professor of physical medicine and rehabilitation, and director of the Center for Clinical Outcomes Development and Application at Michigan Medicine.

She is the leading author of several papers included in a new special edition of Rehabilitation Psychology that examine quality of life in caregivers of persons with TBI.

"The special issue focuses on the diverse ways that caring for an individual can impact well-being, including family life, mood, physical health, sleep and social relationships," says Carlozzi, also a member of the University of Michigan Institute for Healthcare Policy and Innovation.

A unique tool

The papers in the special issue highlight the research team's focus on understanding the experiences of caregivers of persons with TBI, and illustrate the team's ability to efficiently capture those experiences through a tool Carlozzi created called the TBI-CareQOL Measurement System.

"We developed the TBI-CareQOL tool as a way to have standard measures for quality of life in caregivers of persons with TBI," Carlozzi says. "We're able to use the same measures across multiple studies, which allows us to compare and contrast findings to move research forward faster."

The tool was validated through previous research by Carlozzi and her colleagues, and one of its unique features is the ability to administer surveys as 'smart tests.'

"This means the individual only sees the items that are most relevant to them, since the survey administers items based on the respondent's previous answers," Carlozzi says. "This is important because it saves our respondents' time, as they're not answering questions that aren't pertinent to them. It also helps ensure we aren't collecting unnecessary data, or data that the respondent felt they had to supply an answer to even if it isn't truly applicable to them."

The papers included in the special issue utilize the TBI-CareQOL to analyze quality of life in caregivers of both military members and civilians who experience a TBI. The special issue highlights the common experiences caregivers of persons with TBI share, as well as experiences and challenges faced by caregivers for military personnel who have experienced a TBI.

"We also want to draw attention to the different problems that caregivers encounter," Carlozzi says. "While there are certainly a number of common experiences for caregivers of civilians and caregivers of service members and veterans, caregivers of military personnel often feel the need to suppress their emotions, or put on a brave face for others. They often find themselves being constantly on guard trying to protect the person with injury from further harm."

Future work

Carlozzi hopes the work included in the special issue, as well as the fact that there is little research available to physicians that focuses on the caregiver, demonstrate the need for continued research on this topic.

"We hope that all of this work will encourage clinicians to pay a bit more attention to the caregiver, even when the focus may be primarily on the person with TBI," Carlozzi says.

She also notes this research will be helpful when finding interventions for caregivers of persons with TBI.

"We need interventions to improve quality of life for caregivers, and this research can lay the groundwork for doing just that," Carlozzi says.

BIRMINGHAM, Ala. - Research by Kai Jiao, M.D., Ph.D., and colleagues at the University of Alabama at Birmingham and in Germany has yielded fundamental insights into the causes of severe birth defects known as CHARGE syndrome cases. These congenital birth defects include severe and life-threatening heart malformations.

The researchers successfully inactivated the gene for CHD7 in the neural crest cells of mouse embryos, and then rigorously probed how this change in developing cardiac neural crest cells caused severe defects in the outflow tract and great arteries, leading to perinatal lethality. The heart defects in the embryos, and other birth defects, resembled human CHARGE syndrome defects. Human mutations in CHD7 are known to cause about 70 percent of CHARGE syndrome cases.

The study in Proceedings of the National Academy of Sciences, led by Jiao, co-corresponding author Karim Bouazoune, Ph.D., Philipps Universität Marburg, Marburg, Germany, and first author Shun Yan, Ph.D., a researcher V in Jiao's lab, also clarifies a longstanding controversy. Previous attempts by others to alter CHD7 function in neural crest cells had failed to cause heart defects in several mouse models. This study's improvement was use of better molecular scissors to delete a portion of the CHD7 gene.

A surprising finding in the current research was discovery of a new epigenetic function for CHD7, in addition to its well-established ATP-dependent chromatin remodeling activity. Chromatin is a DNA-protein complex consisting of the mammalian genome tightly wound around histone proteins to create a string of nucleosomes, like pearls on a necklace. Chromatin remodeling factors like CHD7 use the energy of ATP to remodel the chromatin, making selected genes available for expression. The turning-on and turning-off of select sets of genes is fundamental to embryonic development, during the time that a single fertilized egg grows into a complex fetus with at least 200 different types of cells, all originating from the same DNA genome, but differentiated using different gene programs.

In addition to the chromatin remodeling activity, Jiao and colleagues discovered that CHD7 acts in an ATP-independent fashion to recruit histone-modifying enzymes to target promoter or enhancer loci on the genome.

"Our findings strongly suggest that CHD7 can also directly recruit an H3K4 methyltransferase writer to target elements," said Jiao, a professor in the UAB Department of Genetics. "The dual activities of CHD7 may represent an efficient mechanism to coordinate nucleosome remodeling and H3K4 methylation at these target loci. The mutual interaction between the CHD7 nucleosome remodeler and histone methylation machinery could form a positive feedback loop to stabilize epigenetic states at target elements."

In other key findings of the study -- in addition to showing an essential cell-autonomous role for CHD7 to regulate cardiac neural crest cell development -- the researchers showed that a single point mutation in the CHD7 gene was sufficient to cause severe developmental defects and embryonic lethality in mammals. The researchers also used transcriptomic analyses to show that CHD7 fine-tunes the expression of a gene network critical for cardiac neural crest cell development. They followed that with a protein-protein interaction screen and found that CHD7 directly interacted with multiple developmental disorder-mutated proteins. One of these was WDR5, a core component of H3K4 methyltransferase complexes. That interaction with WDR5 led to the discovery of CHD7's ability to recruit histone-modifying enzymes to target promoter or enhancer loci on the genome.

The researchers say that the CHD7 protein interactome suggests CHD7 is likely implicated in an even wider range of physiological processes and human diseases than previously anticipated.

"Importantly," Jiao said, "we now provide a molecular framework of direct candidate interactors to investigate known or new CHD7 functions, as well as the molecular etiology of CHD7-associated diseases or phenotypes."

The discovery of two different functions for CHD7 also could have clinical relevance. "Our data imply that patients carrying a premature stop codon versus missense mutations will likely display different molecular alterations," Jiao said. "These patients might therefore require personalized therapeutic interventions."

ST. LOUIS - Research from Saint Louis University finds that among patients at risk for opioid misuse, the odds of receiving a schedule II opioid for non-cancer pain were similar to those not at risk, despite new prescribing guidelines from the Centers for Disease Control (CDC).

The study, "Comparison of Opioids Prescribed for Patients at Risk for Opioid Misuse Before and After CDC Opioid Prescribing Guidelines," by Jeffrey Scherrer, Ph.D., a professor in Family and Community Medicine at SLU, was published online Dec. 2 in JAMA Network Open.

In March 2016, the CDC issued its Guideline for Prescribing Opioids for Chronic Pain. The guidance offered recommendations for opioid therapy in primary care patients with non-cancer pain. The guidelines were followed by a decline in opioid prescription rates.

This retrospective cohort study reviewed Optum de-identified electronic medical record data of 5 million adults distributed throughout the United States 18 months before and after CDC guidance was issued on March 15, 2016. from 2008 to 2015. Eligible patients were 18 years of age or older, did not have an HIV and cancer diagnosis and had a non-cancer painful condition that resulted in a new prescription for codeine, hydrocodone, oxycodone or tramadol.

Researchers determined if patients with benzodiazepine prescriptions, depression, anxiety or substance abuse disorders had a greater decrease in receipt of Schedule II (codeine, hydrocodone or oxycodone) versus Schedule IV (tramadol) opioids.

There were 279,435 (141,219 pre-guideline issuance and 138,216 post-guideline) eligible patients.

"Except for a 14% decrease in oxycodone prescriptions, we found no evidence for substantial changes in odds of receiving a Schedule II opioid versus tramadol in the 18 months after the CDC guidance, compared with before the guidance," Scherrer said.

The study was limited by the lack of data on dispensed prescriptions. Researchers were unable to determine whether prescriptions were appropriate to a patient's pain severity and interference.

Continued education is needed, Scherrer says, to reduce prescribing of high abuse potential opioids to patients with benzodiazepine prescriptions and comorbid psychiatric and substance abuse disorders.

Take-aways

Among patients at risk for opioid misuse, the odds of receiving a schedule II opioid for non-cancer pain, compared to receiving tramadol, in post- versus pre-guideline periods were similar to those not at risk.

In 18 months after CDC prescribing guidelines, compared to before the CDC prescribing guidelines, research found a 14% decrease in oxycodone prescriptions, relative to tramadol.

There was little change in other schedule II opioid prescribing.

The odds of receiving hydrocodone and oxycodone versus tramadol in post and pre-guideline periods in patients with psychiatric disorders did not differ significantly from patients without.

Schedule II opioids continue to be prescribed to high-risk patients 18 months after the CDC guideline.

PARAMUS, N.J. (December 2, 2020) - Clinical research presented by Octapharma USA at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition will highlight the investigational use of high-dose Octagam® 10% [Immune Globulin Intravenous (Human)] for the most severe COVID-19 patients. Octapharma's intravenous immunoglobulin (IVIg) portfolio also will be featured in a study design poster focused on primary infection prophylaxis in patients with chronic lymphocytic leukemia during ASH, to be held virtually December 5 - 8 due to the coronavirus pandemic.

The poster, "Use of Intravenous Immunoglobulin Therapy Reduces Progression to Mechanical Ventilation in COVID?19 Patients with Moderate to Severe Hypoxia," reports on a randomized open label study that evaluated the standard of care (SOC) plus high-dose Octagam® 10% compared to SOC alone in the treatment of COVID-19 infection. The study enrolled 33 COVID-19 patients experiencing hypoxia who were at risk of requiring mechanical ventilation. The investigator-initiated study (IIS) reported that IVIg significantly improved hypoxia and reduced hospital length of stay and progression to mechanical ventilation in patients with COVID-19 pneumonia. Principal investigator: George Sakoulas, M.D. of Sharp Memorial Hospital and the Sharp Rees-Stealy Medical Group in San Diego, Calif.

"IVIg has been used to treat patients with immune-mediated diseases for almost 40 years," said Octapharma USA President Flemming Nielsen. "Octapharma is very pleased to share this research with colleagues at ASH. Our team believes the use of IVIg in the prophylaxis of severe infections, especially in immunocompromised patients, may be an attractive therapeutic possibility for COVID-19."

Octapharma USA is conducting a larger multicenter, randomized, double-blind, placebo-controlled study approved by the U.S. Food and Drug Administration (FDA) under an Investigational New Drug Application. The primary objective of this study is to determine if high-dose Octagam® 10% therapy will slow or stop respiratory deterioration in patients with severe coronavirus disease. The secondary objectives of the study are to measure the effects of a high-dose of Octagam® 10% on slowing or stopping the clinical progression of COVID-19 by improving pulmonary function, quality of life, and correlated impact on metabolic factors. For more information, please visit clinicaltrials.gov (NCT04411667).

The investigational use of IVIg in Lymphocytic Leukemia is the focus of an Octapharma study design poster to be presented at ASH entitled, "The Prosid Study: Evaluating Efficacy and Safety of Intravenous Immunoglobulin 10% in Primary Infection Prophylaxis in Patients with Chronic Lymphocytic Leukemia." Secondary immunodeficiency (SID) occurs, among other reasons, as a consequence of hematological malignancies, most commonly in chronic lymphocytic leukemia (CLL) and multiple myeloma. About 25% of patients present with SID at diagnosis of CLL and this incidence may increase to 85% during the course of disease. This increase is also due to recent advances in CLL therapy leading to cumulative immunosuppression. Infections are the main cause of morbidity and mortality in CLL patients, causing between 30% and 50% of deaths within the first year after diagnosis. IVIg is established as secondary prophylaxis to reduce infectious complications in patients with hypogammaglobulinemia. To date, no large randomized study has established efficacy of IVIg as primary prophylaxis in CLL patients with hypogammaglobulinemia although several small studies suggest an up to four-fold reduction of infection rates. This prospective, placebo-controlled study will evaluate the efficacy and safety of IVIg 10% as primary prophylaxis of infections in CLL patients with SID in a large clinical setting for the first time. Principal investigator: Anthony Mato, MD, MSCE, Memorial Sloan Kettering Cancer Center, New York, N.Y.

For more information on the ASH annual meeting, please visit hematology.org.

A favorite healthy snack, almonds are a staple on grocery store shelves worldwide. More than 80% of these almonds are grown in California. As permanent crops, almond trees have unique needs and challenges for farmers.

Sat Darshan Khalsa, a member of the Soil Science Society of America, studies how almond trees use the key nutrient nitrogen. He recently presented his research at the virtual 2020 ASA-CSSA-SSSA Annual Meeting.

How does farming almonds, considered a deciduous permanent crop, differ from a traditional crop?

"These crops are an intersection between agricultural and forest ecosystems," Khalsa explains. "Similar to annual cropping systems, deciduous permanent crops like almonds are intensively farmed. They receive high inputs of fertilizer and water with high nutrient outputs."

At the same time, crops like almonds are managed under no-till conditions where soil is minimally disturbed. Tilling or digging of any kind would disturb the trees' roots. In addition, almond trees shed leaves, grow woody tissue, and undergo other processes similar to trees in a real forest. These all have effects on carbon, nitrogen, and other nutrient cycles.

These characteristics can often mean that nutrients flow off of the field. They can get into areas like groundwater aquifers, where they can impact drinking water supplies for rural communities. Khalsa's work has tried to minimize this issue.

"Nitrogen is the primary nutrient tied to productivity," he says. "At the same time, it's an important pollutant that impacts air and water quality. Through our work, we can show that many almond growers in California are in a good position to continue to be highly productive. At the same time, they can protect, or even improve, environmental quality."

Khalsa and his colleagues specifically studied a concept called nitrogen use efficiency. It helps farmers balance putting enough nitrogen on a field with protecting environmental quality. In their research, they show it is possible to have a high level of nitrogen use efficiency by using various conservation practices.

One of the conservation techniques is called nutrient budgeting. It's a technique where inputs and outputs from a field are precisely measured to try to make them as balanced as possible. They also monitor the nutrients in leaves and soil.

Another technique is called fertigation, where fertilizer is applied through the irrigation system in a very targeted way. This allows it to be precisely measured and timed to meet the plants' needs. The work of Khalsa's team can also be applied to other specialty crops around the world to help farmers have a higher income while producing nutritious food.

"Matching supply and demand is the foundation of the 4R framework with the goal of improving the efficiency of nutrient management," Khalsa says. "The 4R framework is: the right fertilizer source at the right rate, at the right time, in the right place. That's what will help us be more efficient."

Challenges remain in understanding how crops like almonds cycle nitrogen year to year and how farmers apply nitrogen fertilizer. Khalsa also says his research highlights the importance of integrating their research with information networks, including Certified Crop Advisers and Cooperative Extension.

Efforts to address these agricultural issues must focus on the desires and needs of the farmers, growers, and industry organizations. That kind of work helps promote adoption and create new research opportunities such as assessing soil health practices in orchards.

Khalsa encourages researchers to maintain curiosity throughout each step of the food value chain. This allows them to better understand how their research interests align with other scientists, policy makers, and individuals like consumers within food and farming industries.

"After decades of working with plants, soil, and water, I personally think that through understanding people, we will be able to solve the biggest problems," he says. "Agriculture plays an essential role in communities worldwide. I find no better way to connect with anyone, anywhere than through the food we share."

Differences in the immune systems and better blood vessel health were among the factors protecting children from severe COVID-19, according to a new review.

A huge body of global COVID-19 literature was reviewed by experts at the Murdoch Children's Research Institute (MCRI), the University of Melbourne and the University of Fribourg and published in the Archives of Disease in Childhood to unravel the reasons for age-related differences in COVID-19 severity and symptoms.

MCRI and University of Melbourne Professor Nigel Curtis said that while a number of hypotheses provided potential explanations as to why adults were at higher risk and children protected from severe disease and death from COVID-19, most do not explain why COVID-19 severity rises steeply after the age of 60-70 years.

Professor Curtis said in stark contrast to other respiratory viruses, severe disease and death due to COVID-19 was relatively rare in children.

"Most children with COVID-19 have no or only mild symptoms, most commonly fever, cough, sore throat and changes in sense of smell or taste," he said. "Even children with the usual risk factors for severe infections, such as immunosuppression, were not at high risk of severe COVID-19 disease."

Professor Curtis said damage to the thin layer of endothelial cells lining various organs, especially the blood vessels, heart, and lymphatic vessels, increased with age and there was an association between conditions that affect these cells and severe COVID-19.

"We know pre-existing blood vessel damage plays an important role in COVID-19 severity and can lead to blood clots, causing strokes and heart attacks. COVID-19 can infect these endothelial cells and cause blood vessel inflammation," he said.

"The endothelium in children has experienced far less damage compared with adults and their clotting system is also different, which makes children less prone to abnormal blood clotting."

Professor Curtis said diseases associated with chronic inflammation that develop with advanced age including diabetes and obesity were also linked with severe COVID-19.

He said more recent immunisation with live vaccines, such as the MMR vaccine against measles, mumps, and rubella, that could boost the immune system might play a role in protecting children.

Dr Petra Zimmermann from the University of Fribourg said there were also other important differences in the immune system between children and adults.

"Children have a stronger innate immune response, which is the first-line defence against COVID-19," she said.

"Another important factor is 'trained immunity' which primes innate immune cells after mild infections and vaccinations, leading to a type of 'innate immune memory'.

"Children infected with COVID-19 often have co-infections with other viruses. Recurrent viral infections could lead to improved trained immunity, making kids more effective at clearing COVID-19."

Dr Zimmermann said different levels of microbiota (bacteria and other germs) in the throat, noise, lung and stomach, also influenced susceptibility to COVID-19.

"The microbiota plays an important role in the regulation of immunity, inflammation and in the defence against illnesses," she said. "Children are more likely to have viruses and bacteria, especially in the nose, where these bugs might limit the growth of COVID-19."

Dr Zimmermann said the vitamin D level, with its anti-inflammatory properties, was also generally higher in children.

"The overlap between risk factors for severe COVID-19 and vitamin D deficiency, including obesity, chronic kidney disease and being of black or Asian origin, suggests that vitamin D supplementation may play a role in helping prevent or treat COVID-19," she said.

"In many countries, vitamin D is routinely supplemented in infants younger than one year of age and in some countries even up to the age of three years."

Professor Curtis said understanding the underlying age-related differences in the severity of COVID-19 would provide important insights and opportunities for prevention and treatment of SARS-CoV-2 infections.

Tsukuba, Japan - Occasionally, following a transplant procedure, the donor's immune cells recognize the recipient's tissues as foreign and trigger a multisystem disorder called graft-versus-host disease (GVHD). Occurring commonly after bone marrow or stem cell transplants performed to treat some blood cancers, GVHD may even follow solid organ transplants and is, in essence, the reverse of transplant rejection. Now, researchers at the University of Tsukuba have clarified the pathogenesis of the characteristic skin changes in chronic GVHD as being mediated by transforming growth factor-β1 (TGFβ1) a cytokine that keratinocytes - epidermal skin cells - undergoing apoptosis (regulated cell death) express on stimulation by interferon-γ (IFNγ).

All living organisms from single-celled bacteria to complex higher animals possess an 'awareness' of immunologic distinctiveness to discriminate between self and non-self. Unfortunately, these recognition systems and defense mechanisms work against therapeutic transplantation between individuals with differing genetic identities. The skin, gastrointestinal tract and liver are often affected in GVHD; this may be acute (aGVHD) or, if occurring after 100 days, chronic (cGVHD). The former usually results in erythematous mucocutaneous erosions seen as surface redness or rashes, and the latter in sclerodermatous changes manifested as skin thickening.

The research team sought to establish the mechanisms underlying keratinocyte death and sclerodermatous change. "We first demonstrated increased expression of TGFβ1 in cGVHD compared with aGVHD by immunohistochemical staining on biopsy tissue from skin lesions of human patients," explains Professor Naoko Okiyama, corresponding author and dermatologist at the Faculty of Medicine. "Then, in order to explore the role of keratinocytes in the sclerodermatous changes, we established an experimental model of genetically modified mice transferred with keratinocyte-specific CD8 T cells. We found that transfer of IFNγ-deficient CD8 T cells caused comparatively severe acute mucocutaneous injury but milder sclerodermatous changes, and recipients had lower TGFβ1 expression than controls."

Additionally, in murine keratinocytes undergoing apoptosis and incubated with IFNγ in vitro, the increased production of TGFβ1 was inhibited by zVAD, an apoptosis inhibitor, but not by Nec-1, which inhibits necroptosis (inflammatory death). This suggests that IFNγ promotes TGFβ1 production specifically in apoptotic keratinocytes.

"We have gained a deeper insight into the pathogenesis of sclerodermatous cGVHD, which also helps explain dermal fibrosis in discoid lupus erythematosus and Stevens-Johnson syndrome," says Professor Okiyama. "Moreover, as IFNγ promotes autoimmune and inflammatory tissue fibrosis in conditions such as cGVHD and systemic sclerosis, we recommend further research into the potential of anti-IFNγ and anti-apoptosis therapeutic protocols against scleroderma."

A cross-sectional analysis of NHANES (National Health and Nutrition Examination Survey) data found that more than 40% of U.S. adults with overweight and nearly 10% with obesity did not consider themselves to be overweight. This trend has increased over the last two decades and was especially true of non-Hispanic Blacks and persons with low socioeconomic status. The findings are published in Annals of Internal Medicine.

The researchers from the University of Chicago Medicine analyzed NHANES data to investigate the trends of overweight and obesity self-awareness among U.S. adults with overweight or obesity. They also looked at factors associated with obesity self-awareness and weight loss attempts among adults with obesity. Survey participants were asked about self-perception of weight using the question: "Do you consider yourself to be overweight, underweight, or about the right weight?" They found that more than a significant proportion of those with overweight or obesity did not recognize the issue.

The authors say that as BMIs of Americans increase, people adjust their views on normal weight range to promote positive body images, and suggest use of varying BMI cutoffs to define overweight and obesity may be necessary when comparing varying demographic subsets. The authors still emphasize that this study data showed persons with obesity who did not view their weight to be overweight were less likely to try to lose weight and this may contribute to increasing obesity rates in the United States. The authors also found that health professional-guided education on weight improved both obesity self-awareness and attempts to lose weight among persons with obesity. However, having health insurance did not affect obesity self-awareness, suggesting health professionals are not routinely providing weight counseling to patients with obesity.

New method to customise lysins to specifically target unwanted bacteria while leaving others unharmed

Lysins are enzymes that help break open the bacteria cells while treating infections, and have demonstrated potential as a novel class of antimicrobials

Discovery can help pharmaceutical industries as well as skincare and consumer care industries in targeted killing of bacteria

Singapore, 1 December 2020 - Researchers from the Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) at Singapore-MIT Alliance for Research and Technology (SMART), MIT's research enterprise in Singapore, have developed a method to produce customisable engineered lysins that can be used to selectively kill bacteria of interest while leaving others unharmed. The discovery presents a promising alternative to antibiotics for treating existing drug-resistant bacteria and bacterial infections without the risk of causing resistance.

Lysins are enzymes produced by bacteriophages to break open the bacteria cells while treating infections, and have demonstrated potential as a novel class of antimicrobials. A major advantage of lysins is that they allow fast and targeted killing against specific bacterium of choice without inducing resistance.

The emergence of multidrug-resistant bacteria has left even minor bacterial infections incurable by many existing antibiotics, with at least 700,000 deaths each year due to drug-resistant diseases according to the World Health Organisation.

In a paper titled "Engineered Lysins with Customized Lytic Activities Against Enterococci and Staphylococci" recently published in the prestigious journal Frontiers in Microbiology, the SMART AMR team demonstrates one of the methods to customise the lytic spectrum of engineered lysins.

The study reveals how SMART's engineered lysins were able to selectively kill bacteria like Staphylococci, Enterococcus faecalis, while leaving the Enterococcus faecium bacteria of the same genus unharmed. This is the first report of a chimeric lysin that can both target bacteria of multiple genera as well as selectively kill one bacterial species within a genus over another.

"The human body contains trillions of bacteria, which form the microbiome, and the majority of the bacteria is either harmless or beneficial to us," says AMR Research Scientist and corresponding author of the paper Dr Boon Chong Goh. "What happens when we are on an antibiotic course is that the antibiotics kill all of the bacteria, leaving us vulnerable to a worse re-infection after we have completed the antibiotic course. Since lysins respect the microbiome and only eliminate the bad pathogenic bacteria, they are a very promising alternative for treating bacterial infections."

Awarded with the Ignition and Innovation Grants from SMART Innovation Centre, Dr Goh's team has established the foundation of a technology platform by producing the lysins and testing them in vitro, and are in the process of developing a series of techniques to engineer the lysins.

"Since lysins are essentially proteins, they can be engineered and mass produced," says Ms. Hana Sakina Bte Muhammad Jai, lead author of the paper and Laboratory Assistant under Dr Goh's team at SMART. "Our study clearly shows how modifying these proteins translates to improvements of their specificity and antibacterial activities"

"In the lab, we have observed that once a small amount of lysin is added, it only takes 30 minutes to completely kill the bacteria making them a very safe and efficient choice for removing unwanted bacteria," says Ms. Linh Chi Dam, the co-first author of the paper and Laboratory Technologist under Dr Goh's team at SMART. "While developments in the production of customised lysins would greatly impact pharmaceutical industries where lysins can be used to treat bacterial infections, skincare and consumer care industries would also benefit by using lysins as a targeted agent to remove unwanted bacteria from their products."

The research is carried out by SMART and supported by the National Research Foundation (NRF) Singapore under its Campus for Research Excellence And Technological Enterprise (CREATE) programme. The SMART AMR team was also recently awarded the Intra-CREATE Seed Collaboration Grant to investigate lysins targeting Gram-negative bacteria such as, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae.

Neurological diseases of the brain such as dementia, autism and schizophrenia are now a growing social problem. Nevertheless, studies on their definitive cause are still insufficient. Recently, a POSTECH research team has identified the mechanism in which such neurological diseases occur, thus solving the enigma to treating them.

In the case of neurological diseases of the brain, problems arise when certain effects modify the synaptic plasticity and signal transmissions of the brain-derived neurotrophic factor (BDNF), which has a profound effect on the development and differentiation of neurons. The information between nerve cells is transferred through synapses, where the synaptic activity and the synaptic structure are dynamically changed and regulated according to stimulations. During this moment, BDNF has prominent effects on the survival and synaptic plasticity of nerve cells. When it malfunctions, it not only interferes with the smooth information exchange between the brain cells but also kills neurons, leading to learning and memory impairment.

Professor Kyong-Tai Kim and Dr. Young-Seop Jeong of POSTECH's Division of Integrative Biosciences and Biotechnology have identified the mechanism by which BDNF regulates the local expression of AMPA receptors, which are important for synaptic function of nerve cells. The findings of the study were published in the November issue of Science Advances, a prominent international journal.

AMPA receptors are ion channel receptors that glutamic acid acts on and are responsible for excitatory neural signals. They are located on the dendrites' spines of nerve cells and transmit signals when they recognize glutamic acid secreted in the synapses. For synaptic plasticity, it is normal for the AMPA receptors to synthesize locally and efficiently translocate to the postsynaptic membrane according to the strength, duration, and frequency of neural stimulation. The presence of the AMPA receptor mRNA in the dendrites was already known, but the mechanism of how this mRNA is translated into a receptor protein was unknown until now.

The research team found that there is an internal ribosome entry site (IRES) activity in the 5' untranslated region of the AMPA receptor mRNA, and unlike the general method, protein translation increases when a protein hnRNP A2/B1 - an RNA-binding protein - binds to this site.

It was confirmed that the AMPA receptor mRNA, created by transcription from the nucleus, moves to the dendrites and waits there until a simulation occurs to quickly produce receptor proteins in response to various stimuli. In particular, when BDNF stimulates nerve cells, the amount of hnRNP A2/B1 increases, thus promoting the synthesis of AMPA receptor proteins. These proteins locally synthesized in the synapses efficiently carry out the neural signal transduction.

"This is a study that revealed a key mechanism of synaptic plasticity to prevent brain developmental disorders or brain nerve cells from degeneration," explained Professor Kyong-Tai Kim who led the study. "We expect to provide important clues to the treatment of development or degenerative brain diseases such as autism and dementia in the future."

A group of experts from academic, governmental and international organisations have identified five large-scale 'megatrends' affecting forests and forest communities, published today in Nature Plants. These are likely to have major consequences - both positively and negatively - over the coming decade.

Around the world, 1.6 billion people live within 5km of a forest, and millions rely on them for their livelihoods, especially in poorer countries. They are also home to much of the world's biodiversity, and regulate key aspects of the carbon cycle. In short, forests are vital in global and national efforts to combat climate change and biodiversity loss, and eradicate hunger and poverty.

Despite their importance, research on forests and livelihoods to date has mainly focused on understanding local household and community-level dynamics - identifying the links between human and natural systems at the regional and global scales is critical for future policy and action.

The five trends revealed by the research are:

1. Forest megadisturbances

Droughts and excessive precipitation are increasing forests' susceptibility to diseases and human-induced wildfires and floods - this is leading to defoliation, tree mortality and declines in forest productivity at unprecedented scales, and there is increasing evidence that forest disturbance can result in the emergence of diseases with the ability to spread globally.

Policy responses to these disturbances will require balancing a range of mitigation and adaptation efforts - whilst opportunities and challenges are likely to arise from efforts to align forest conservation and restoration with other sustainability priorities, such as poverty alleviation.

2. Changing rural demographics

Increased migration to urban areas is causing an unprecedented exodus among forest-reliant communities. The effects of these demographic shifts, including forest resurgence on formerly agricultural lands and participation in decision-making, are not well understood.

Populations shifts could result in opportunities for effective forest conservation, whilst on the other hand could lead to deforestation as greater urban demand and large industrial projects are created.

3. The rise of the middle class

By 2030 the middle class in low and middle income countries will grow to almost 5 billion people - around 50% of the global population. The growth in demand that this creates will increase pressure on land and other resources.

Growing consumption and demand of commodities has already seen large scale corporate-led land acquisitions for industrial production of cattle, soy and palm oil in Latin America, Africa and Southeast Asia. Between 2001-2015, 27% of forest disturbance was attributed to commodity-driven deforestation. Further growth in demand and a continuing culture of consumerism will alter local and global consumption patterns, with potentially severe effects on deforestation rates, emissions, wildlife populations, ecosystem services and rural communities.

4. Use of digital technologies

Access to digital communication technology has grown exponentially in recent years, with a sevenfold increase in internet and mobile cellular use since 2000. The majority of this growth has come outside industrialised countries, and is likely to have a transformational impact on the forest sector. Technologies that collect and disseminate data are increasingly accurate and easy-to-use, including land mapping tools, real-time satellite data and crowd-sourced data.

Although they can be accessed by those involved in illicit activity such as logging and mining, these technologies also provide opportunities. Increasingly available data can benefit a wide range of forest sector stakeholders including policymakers, oversight bodies, non-governmental actors, managers and local communities. New technologies are already supporting the surveillance and certification of global production networks, which is aiding regulatory control of forest-based products and people threatening forests.

5. Infrastructure development

Large scale infrastructure projects such as China's Belt and Road initiative are likely to have transformational impacts on forests and rural communities. To accommodate demand for energy, natural resources and transport, many countries have planned ambitious infrastructure growth.

By 2050, there is expected to be at least 25 million km of new roads globally to help facilitate commodity flow between transport hubs; governments in the Amazon basin alone are developing 246 new hydroelectric dams; and illegal mining activities are expanding rapidly across the globe. These can lead to forest loss, displaces people, disrupts livelihoods and provokes social conflicts as communities lose access to land and resources.

These five megatrends are creating new agricultural and urban frontiers, changing landscapes, opening spaces for conservation and facilitating an unprecedented development of monitoring platforms that can be used by local communities, civil society organisations, governments and international donors. Understanding these larger-scale dynamics is key to support not only the critical role of forests in meeting livelihood aspirations locally, but also a range of other sustainability challenges globally.

"Our study allows us to take stock of key socioeconomic, political and environmental issues affecting forests and rural communities, and identify trends likely to have disproportionate impacts on forests and forest-livelihoods in the coming decade," says Johan Oldekop, an associate professor in the Global Development Institute at the University of Manchester and a lead author of the report.

"The trends we identify are important, because they represent human and environmental processes that are exceptionally large in geographical extent and magnitude, and are difficult to reverse," Oldekop says. "Developing a new research agenda that is able to better understand these trends and identify levers of change will require novel ways of combining new and existing data sources, the strengthening of existing collaborations between researchers, local communities and policymakers, as well as the development of new types of partnerships with public and private stakeholders."

"The assembled expert panel is unique as it brings together a range of subject expertise, region-specific knowledge, as well as academic, governmental and non-governmental institutions, including international donor organizations," adds Laura Vang Rasmussen, an assistant professor in the Department of Geosciences and Natural Resource Management at the University of Copenhagen, and one of the lead authors of the report.

The report can be accessed at https://www.nature.com/articles/s41477-020-00814-9.

Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome , prevent noise-related hearing loss, fight certain types of prostate cancer , and even enhance cognition in healthy animals.

In the new study, published December 1, 2020 in the open-access journal eLife , researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

"ISRIB's extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological "blockage" rather than more permanent degradation," said Susanna Rosi , PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science (http://ptrehab.ucsf.edu/) .

"The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress," added Peter Walter , PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. "Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time."

Could Rebooting Cellular Protein Production Hold the Key to Aging and Other Diseases?

Walter has won numerous scientific awards, including the Breakthrough , Lasker  and Shaw  prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter's lab, works by rebooting cells' protein production machinery after it gets throttled by one of these stress responses -- a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

The ISR normally detects problems with protein production in a cell -- a potential sign of viral infection or cancer-promoting gene mutations -- and responds by putting the brakes on cell's protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the on position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, Walter and colleagues have found.

In particular, recent animal studies by Walter and Rosi, made possible by early philanthropic support from The Rogers Family Foundation, have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life's many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.

"We've seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline," said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. "It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step."

ISRIB Improves Cognition, Boosts Neuron and Immune Cell Function

In the new study, researchers led by Rosi lab postdoc Karen Krukowski , PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice, much better than animals of the same age who didn't receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily -- a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons' electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB's cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system's T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer's to diabetes that have been linked to heightened inflammation caused by an aging immune system.

"This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus," said Rosi. "At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.

ISRIB May Have Wide-Ranging Implications for Neurological Disease

It turns out that chronic ISR activation and resulting blockage of cellular protein production may play a role in a surprisingly wide array of neurological conditions. Below is a partial list of these conditions, based on a recent review by Walter and colleague Mauro Costa-Mattioli of Baylor College of Medicine, which could potentially be treated with an ISR-resetting agent like ISRIB: 

Frontotemporal Dementia

Alzheimer's Disease

Amyotrophic Lateral Sclerosis (ALS)

Age-related Cognitive Decline

Multiple Sclerosis

Traumatic Brain Injury

Parkinson's Disease

Down Syndrome

Vanishing White Matter Disorder

Prion Disease

ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by other pharmaceutical companies, Walter says.

One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form -- against an aggressive viral infection, for example.

Naturally, both of these factors make the molecule much less likely to have negative side effects -- and more attractive as a potential therapeutic. According to Walter: "It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window.