Culture

A joint research project based in Kumamoto University, Japan has developed a new, highly sensitive analytical method that can detect degraded β-lactam antibacterial agents used in the treatment of bacterial infections. With this method, researchers found that reactive sulfur species produced by bacteria degrade and inactivate β-lactam antibiotics.

Bacteria are different from animal cells in that their outer layer is covered with a rigid structure called a cell wall. β-lactam antimicrobial agents interfere with the processes that form the cell wall. This results in bacteria no longer being able to withstand their own internal pressure so they rupture and die. β-lactam antimicrobial agents are very potent because they selectively inhibit bacterial cell wall synthesis and have few side effects on hosts such as humans. These antimicrobial agents have a common structure called the β-lactam ring that is essential for inhibiting cell wall development. If this ring is degraded, the antimicrobial effect disappears.

Previous studies have reported that hydrogen sulfide (H2S), which bacteria produce during sulfur metabolism, reduces their susceptibility to antimicrobial agents leading to resistance. However, the detailed mechanism causing this are not yet understood. Researchers at Kumamoto University previously showed that the molecule cysteine persulfide, a combination of H2S and the amino acid cysteine, has an extremely potent antioxidant effect that is not found in H2S or cysteine alone.

In this study, researchers examined how this reactive sulfur species is involved in the acquisition of resistance to β-lactam antibiotics. They discovered that β-lactam antibiotics such as penicillin G, ampicillin, and meropenem (carbapenem antibiotics) rapidly lose bactericidal activity when exposed to cysteine persulfide but not with hydrogen sulfide. A detailed study of the reaction between β-lactam antimicrobial agents and cysteine persulfide revealed that the β-lactam ring, which is essential for bactericidal action, decomposes and a sulfur atom is inserted into part of the ring creating carbothioic acid. The production of carbothioic acid from a β-lactam antimicrobial agent appears to be a novel degradation metabolite.

Researchers thus developed a highly sensitive analytical method to detect and quantify carbothioic acid using mass spectrometry, and then analyzed carbothioic acid production from bacteria that were exposed to β-lactam antimicrobials. They found that bacteria can absorb antimicrobial agents and use cysteine persulfide to degrade the agents into carbothioic acid which is then discharged. This is believed to be a previously undescribed inactivation and degradation mechanism of β-lactam antimicrobial agents into carbothioic acid by cysteine persulfide.

"Our newly developed analytical method makes it possible to quantify the amount of carbothioic acid discharged from bacteria with high sensitivity," said Professor Tomohiro Sawa, who led the study. "We believe it will be possible to screen for compounds that inhibit bacterial synthesis of cysteine persulfide by using carbothioic acid as a biomarker. Such a cysteine persulfide synthesis inhibitor in combination with β-lactam antibiotics is expected to inhibit antibiotic degradation and result in successful treatments with a lower concentration of β-lactam antibiotics. This should also help to reduce the emergence of new resistant bacteria."

KINSHASA, Democratic Republic of Congo (June 9, 2021) - A new study led by the Wildlife Conservation Society (WCS) has updated the global population estimate for the Critically Endangered Grauer's gorillas (Gorilla beringei graueri) - the world's largest gorilla subspecies- to 6,800 individuals from a previous global estimate of 3,800 individuals. This revised estimate comes from recent field surveys conducted in one of this animal's largest remaining strongholds, in areas that were previously inaccessible for surveys. However, these gorillas continue to be heavily impacted by ongoing insecurity, and by human incursion into their remaining habitat in eastern Democratic Republic of Congo.

Publishing in the American Journal of Primatology, the authors found a total of 3815 Grauer's gorillas remaining in Kahuzi-Biega National Park and the contiguous Oku community forests These two areas hold almost 60 percent of the global population.

A previous peer-reviewed paper led by WCS in 2016 showed a decline of almost 80 percent in the population of these gorillas since the last range-wide survey carried out in the mid-1990s. However, due to insecurity, the 2016 estimate did not include data from all areas of the Grauer's gorilla range. The 2021 population estimate includes new field surveys in the Oku forests conducted over the past four years and provide the most up to date assessment of the subspecies to date. These new findings still maintain Grauer's gorillas as Critically Endangered, but suggest declines were not as great as previously feared. The findings also provide hope for the conservation of Grauer's gorilla in this challenging area. Gorilla populations in the Oku forests and the highland sectors of the Kahuzi-Biega National Park have remained relatively stable over the past 20 years, highlighting the importance of these areas for the future of this subspecies.

"This is one of the most extensive surveys ever of this great ape, carried out under very difficult circumstances. It is a tribute to the courage and dedication of the Congolese biologists who took part, often at great risk from the ongoing insecurity." said the study's lead author Dr. Andrew Plumptre, Key Biodiversity Area Secretariat hosted by Birdlife International, who conducted the research while with WCS. "We show that gorillas and chimpanzees are avoiding areas where people are extracting minerals, an occupation that contributes to the insecurity in the region"

Additionally, there is good news for chimpanzee populations, which have also held steady over the past twenty years. Many other primates have declined however, likely due to bushmeat hunting, especially the Endangered Ulindi River Red Colobus (Piliocolobus lulindicus).

Grauer's gorillas are a subspecies of eastern gorilla found only in the eastern Democratic Republic of Congo and can weigh over 450 pounds (204 kilograms).

The authors say that the results of the study underscore the importance of good forest protection in the region. They note that the Oku community forests probably has more Grauer's gorillas than any other site across its range, and together with the Kahuzi?Biega National Park is the last stronghold for this ape. In 2018, three local community forest concessions comprising a total area of 1,465 square kilometers (565 square miles) were created and attributed to community management in Oku. Additionally, WCS is working with these communities, the Government's Nature Conservation Agency, ICCN, and the local NGO Reserve des Gorilles de Punia (RGPu), to create an additional Wildlife Reserve in the Oku forests to secure up to 3,000 square kilometers (1,158 square miles) of forest for gorillas and other flora and fauna in this area.

Said Deo Kujirakwinja, co-author and WCS DRC Technical Director: "Without good protection and forest management, Grauer's gorillas would be on the brink of extinction. They face growing pressure from habitat destruction from mining and poaching for food. We must secure these forests to safeguard Grauer's gorillas and other primates."

The civil war in DRC and continued presence of armed rebel groups have made conservation exceedingly difficult. Furthermore, expansion of mining in the area brings further pressures on gorilla habitat and from hunting of gorillas for food to feed the burgeoning mining towns. More than 80 percent of the world's supply of coltan - used in many electronic devices and electric cars - is found in the DRC, including much of the Grauer's gorilla habitat. The focus of conservation efforts must now be on supporting local community management of the Oku forests to protect gorillas and their habitats from outside threats.

Researchers at Vanderbilt University Medical Center (VUMC) have identified a common mechanism underlying a spectrum of epilepsy syndromes and neurodevelopmental disorders, including autism, that are caused by variations in a gene encoding a vital transporter protein in the brain.

Their findings, reported last month in the journal Brain, suggest that boosting transporter function via genetic or pharmacological means could be beneficial in treating brain disorders linked to these genetic variations.

"This points (to) a clear direction of treating a wide spectrum of neurodevelopmental disorders, from various epilepsy syndromes (and) autism to neurodevelopmental delay and intellectual disabilities, caused by the pathological variants in this gene," said Jing-Qiong (Katty) Kang, MD, PhD, associate professor of Neurology and Pharmacology, and the paper/s corresponding author.

"The disorders associated with the gene mutations are rare and there is no effective treatment available," Kang said. "If ... the clinical syndromes we see are the tip of an iceberg, we now know what is going on underneath, and we start to know how to correct the problems."

The gene, SLC6A1, encodes the GABA transporter 1 (GAT-1) at the axonal termini (ends) of neurons (nerve cells) and astrocytes (star-shaped glial cells that support and protect neurons). GAT-1 removes or "reuptakes" GABA, the major inhibitory neurotransmitter, from the synaptic cleft between two neurons.

GABA regulates nerve signals throughout the brain and plays a key role in normal brain development. Reuptake enables the brain to precisely regulate the supply of the neurotransmitter in concert with GABAA receptors, ion channels that bind it.

Kang and her colleagues have extensively studied GABAA receptors and are world
leaders in determining how disrupted GABA signaling can affect brain function and development.

SLC641 variants previously have been associated with a spectrum of epilepsy syndromes, autism and impaired cognition. But until now scientists did not know how these variants could cause such a broad range of brain disorders.

Using high-throughput assays such as flow cytometry and a radioactive labeling technique for measuring GABA reuptake by neurons and astrocytes, the VUMC researchers determined the impact of 22 different variants of SLC6A1 on GAT-1 function in several types of nerve cells derived from patients with neurodevelopmental disorders, epilepsy and autism.

The work was validated in patient-induced pluripotent stem cells that were "reprogrammed" to form neurons and astrocytes.

The researchers found that disease-causing variants were associated with misfoldings of the GAT-1 protein that led to its degradation and which reduced its expression on cell surfaces. Less GAT-1, in turn, lowered GABA reuptake by nerve cells and astrocytes and disrupted neurotransmitter function.

"This is the first large-scale study on SLC6A1 pathological variants," Kang said. "Our work indicates that SLC6A1-mediated disorders are good candidates for pharmacological as well as gene therapy that restore the functional transporter at the cell surface."

A compound identified at VUMC that corrects GAT-1 function in mouse models and cells from patients with urea cycle disorder is now being tested in a clinical trial. The inherited disease causes a buildup of ammonia in the bloodstream that can damage the brain and may be fatal.

Another potential approach is the use of antisense oligonucleotides, short, synthetic pieces of genetic material that may increase expression of the normal, "wild-type" GAT-1 protein.

Kang said the research could not have been done without the help of two "hero" mothers of children with rare genetic disorders: Amber Freed, founder and CEO of the Denver-based advocacy group SLC6A1 Connect; and Terry Jo Bichell, PhD, founder and director of Nashville-based COMBINEDBrain, which supports brain research.

"I have been very lucky and privileged to work with them," Kang said. "They have taught me so much along the way and inspired me to do meaningful research."

"She loves kids with SLC6A1 as her own and selflessly works to improve their lives with the urgency of a mother," Freed responded. "Throughout this journey, Katty has been a loving person, inquisitive scientist and pillar of strength."

"That empathy kept her discoveries progressing through the pandemic," Bichell added. "She would ride her bicycle to the lab and care for the mouse and cell models at night, on weekends and even holidays ... Dr. Kang is doing basic science that will translate to real treatments for real children she has met--and hugged."

Felicia Mermer and Sarah Poliquin are the paper's first authors. Other VUMC co-authors are Kathryn Rigsby, Anuj Rastogi, Wangzhen Shen, MD, Alejandra Romero-Morales, Gerald Nwosu and Vivian Gama, PhD.

A University of Oklahoma doctoral student, graduate and undergraduate research assistants, and an associate professor in the Homer L. Dodge Department of Physics and Astronomy in the University of Oklahoma College of Arts and Sciences are lead authors on a paper describing a "changing-look" blazar - a powerful active galactic nucleus powered by supermassive blackhole at the center of a galaxy. The paper is published in The Astrophysical Journal.

Hora D. Mishra, a Ph.D. student, and faculty member Xinyu Dai are lead authors of the paper, along with Christopher Kochanek and Kris Stanek at the Ohio State University and Ben Shappee at the University of Hawaii. The paper represents the findings of researchers from 12 different institutions who participated in a two-year collaborative project involving the collection of spectra or imaging data in different electromagnetic bands. The OU team led the effort in analyzing all the data collected from the collaboration and contributed primarily on the interpretation of the analysis results, assisted by OU graduate student Saloni Bhatiani and undergraduate students Cora DeFrancesco and John Cox who performed ancillary analyses to the project.

Blazars, explains Mishra, who also serves as president of Lunar Sooners, appear as parallel rays of light or particles, or jets, pointing to observers and radiating across all wavelengths of the electromagnetic spectrum. These jets span distances on the million light-year scales and are known to impact the evolution of the galaxy and galaxy cluster in which they reside via the radiation. These features make blazars ideal environments in which to study the physics of jets and their role in galaxy evolution.

"Blazars are a unique kind of AGN with very powerful jets," she said. "Jets are a radio mode of feedback and because of their scales, they penetrate the galaxy into their large-scale environment. The origin of these jets and processes driving the radiation are not well-known. Thus, studying blazars allows us to understand these jets better and how they are connected to other components of the AGN, like the accretion disk. These jets can heat up and displace gas in their environment affecting, for example, the star formation in the galaxy."

The team's paper highlights the results of a campaign to investigate the evolution of a blazar known as B2 1420+32. At the end of 2017, this blazar exhibited a huge optical flare, a phenomenon captured by the All Sky Automated Survey for SuperNovae telescope network.

"We followed this up by observing the evolution of its spectrum and light curve over the next two years and also retrieved archival data available for this object," Mishra said. "The campaign, with data spanning over a decade, has yielded some most exciting results. We see dramatic variability in the spectrum and multiple transformations between the two blazar sub-classes for the first time for a blazar, thus giving it the name 'changing-look' blazar."

The team concluded that this behavior is caused by the dramatic continuum flux changes, which confirm a long-proposed theory that separates blazars into two major categories.

"In addition, we see several very large multiband flares in the optical and gamma-ray bands on different timescales and new spectral features," Mishra said. "Such extreme variability and the spectral features demand dedicated searches for more such blazars, which will allow us to utilize the dramatic spectral changes observed to reveal AGN/jet physics, including how dust particles around supermassive black holes are destructed by the tremendous radiation from the central engine and how energy from a relativistic jet is transferred into the dust clouds, providing a new channel linking the evolution of the supermassive black hole with its host galaxy."

"We are very excited by the results of discovering a changing-look blazar that transforms itself not once, but three times, between its two sub-classes, from the dramatic changes in its continuum emission," she added. "In addition, we see new spectral features and optical variability that is unprecedented. These results open the door to more such studies of highly variable blazars and their importance in understanding AGN physics."

"It is really interesting to see the emergence of a forest of Iron emission lines, suggesting that nearby dust particles were evaporated by the strong radiation from the jet and released free Iron ions into the emitting clouds, a phenomenon predicted by theoretical models and confirmed in this blazar outburst," Dai said.

A new study identifies a novel biomarker indicating resilience to chronic stress. This biomarker is largely absent in people suffering from major depressive disorder, and this absence is further associated with pessimism in daily life, the study finds.

Nature Communications published the research by scientists at Emory University.

The researchers used brain imaging to identify differences in the neurotransmitter glutamate within the medial prefrontal cortex before and after study participants underwent stressful tasks. They then followed the participants for four weeks, using a survey protocol to regularly assess how participants rated their expected and experienced outcomes for daily activities.

"To our knowledge, this is the first work to show that glutamate in the human medial prefrontal cortex shows an adaptive habituation to a new stressful experience if someone has recently experienced a lot of stress," says Michael Treadway, senior author of the study and professor in Emory's Department of Psychology and Department of Psychiatry and Behavioral Science. "Importantly, this habituation is significantly altered in patients with depression. We believe this may be one of the first biological signals of its kind to be identified in relation to stress and people who are clinically depressed."

"Learning more about how acute stress and chronic stress affect the brain may help in the identification of treatment targets for depression," adds Jessica Cooper, first author of the study and a post-doctoral fellow in Treadway's Translational Research in Affective Disorders Laboratory.

The lab focuses on understanding the molecular and circuit-level mechanisms of psychiatric symptoms related to mood disorders, anxiety and decision-making.

It's long been known that stress is a major risk factor for depression, one of the most common and debilitating of mental illnesses. "In many ways, depression is a stress-linked disorder," Treadway says. "It's estimated that 80 percent of first-time depressive episodes are preceded by significant, chronic life stress."

Around 16 to 20 percent of the U.S. population will meet the criteria for a major depressive disorder during their lifetimes. Experts are predicting rates of depression to climb even further in the wake of the ongoing COVID-19 pandemic. During the pandemic, about four in 10 adults in the United States have reported symptoms of anxiety or depressive disorder, up from one in 10 who reported them in 2019, according to the Kaiser Family Foundation.

"The pandemic has created more isolation for many people, while also increasing the amount of severe stressors and existential threats they experience," Treadway says. "That combination puts a lot of people at high risk for becoming depressed."

Although the link between stress and depression is clearly established, the mechanisms underlying this relationship are not. Experiments with rodents have shown an association between the response of glutamate -- the major excitatory neurotransmitter in the mammalian brain -- and stress. The role of glutamate in humans with depression, however, has been less clear.

The 88 participants in the current study included people without a mental health disorder and unmedicated patients diagnosed with a major depressive disorder. Participants were surveyed about perceived recent stress in their lives before they underwent experiments using a brain scanning technique known as magnetic resonance spectroscopy.

While in the scanner, participants were required to alternate between performing two tasks that served as acute stressors: Putting their hand up to the wrist in ice water and counting down from the number 2,043 by steps of 17 while someone evaluated their accuracy.

Brain scans before and after the acute stressor measured glutamate in the medial prefrontal cortex, an area of the brain involved with thinking about one's state and forming expectations. Previous research has also found that this brain area is involved in regulating adaptive responses to stress.

Participants submitted saliva samples while in the scanner, allowing the researchers to confirm that the tasks elicited a stress response by measuring the amount of the stress hormone cortisol in the sample.

In healthy individuals, the brain scans revealed that glutamate change in response to stress in the medial prefrontal cortex was predicted by individual levels of recent perceived stress. Healthy participants with lower levels of stress showed increased glutamate in response to acute stress, while healthy participants with higher levels of stress showed a reduced glutamate response to acute stress. This adaptive response was comparatively absent in the patients diagnosed with depression.

"The decrease in the glutamate response over time appears to be a signal, or a marker, of a healthy adaptation to stress," Treadway says. "And if the levels remain high that appears to be a signal for maladaptive responses to stress."

The initial result was strong for the adaptation in healthy participants, but was in a modest sample size, so the researchers decided to see if they could replicate it. "Not only did we get a replication, it was an unusually strong replication," Treadway says.

The experiment also included a group of healthy controls who underwent scanning before and after performing tasks. Rather than stressful tasks, however, the controls were asked to place a hand into warm water or to simply count out loud consecutively. Their glutamate levels were not associated with perceived stress and they did not show a salivary cortisol response.

To expand their findings, the researchers followed participants for four weeks after scanning. Every other day, the participants reported on their expected and experienced outcomes for activities in their daily lives. The results showed that glutamate changes that were higher than expected based on an individual's level of perceived stress predicted an increased pessimistic outlook -- a hallmark for depression.

"We were able to show how a neural response to stress is meaningfully related to what people experience in their daily lives," Cooper says. "We now have a large, rich data set that gives us a tangible lead to build upon as we further investigate how stress contributes to depression."

Scientists have developed polypeptide-based materials that act as effective vectors for delivering gene therapies. The first-of-its-kind platform enables the vectors to be adapted to suit the specific gene therapy cargo.

The work, led by researchers from RCSI University of Medicine and Health Sciences and funded by Science Foundation Ireland, is published in Biomaterials Science.

A major challenge for gene therapies is preparing them in a way that can deliver the genetic information into the host cells. For the Covid-19 vaccines that use mRNA technology, the genetic information is delivered in a lipid nanoparticle to maintain its stability and deliver it into cells. The success of the COVID vaccines has established nanoparticles as key to the development of many advanced therapies.

The researchers developed a platform that produces bespoke star-shaped polypeptide nanoparticles, which effectively deliver a range of therapies, including gene therapies. Crucially, these polypeptides are more flexible and easier to handle than lipids. To demonstrate the potential of this material, the researchers used it to deliver a gene therapy that regenerated bone.

In preclinical work, the researchers loaded the material with DNA molecules that promote bones and blood vessels to regrow. They placed these nanomedicines in a scaffold that could be implanted into a defect site and deliver the genetic cargo into infiltrating host cells. The gene-loaded scaffold accelerated bone tissue regeneration, with a six-fold increase in new bone formation compared to a scaffold alone.

"With the success of the COVID-19 vaccines, the potential of gene therapies is becoming apparent, and advanced nanoparticle delivery systems are key to enabling their use clinically. We have shown that these nanoparticles have real potential to be a game changer in the delivery of gene therapies," said Professor Sally-Ann Cryan, the study's senior author and Professor of Drug Delivery, RCSI.

"While more testing is needed before these therapies can be used clinically, our platform allows us to design our polypeptides to meet a variety of delivery scenarios and provide tailored solutions to gene delivery challenges," added Professor Andreas Heise, project collaborator and Professor of Polymer Chemistry, RCSI.

"We are developing this patent-protected technology towards commercialisation, with support from an Enterprise Ireland Commercialisation Fund Award, and are seeking expressions of interest from industry partners and investors."

DARIEN, IL - A study of nearly 2,500 adults found that having trouble falling asleep, as compared to other patterns of insomnia, was the main insomnia symptom that predicted cognitive impairment 14 years later.

Results show that having trouble falling asleep in 2002 was associated with cognitive impairment in 2016. Specifically, more frequent trouble falling asleep predicted poorer episodic memory, executive function, language, processing speed, and visuospatial performance. Further analysis found that associations between sleep initiation and later cognition were partially explained by both depressive symptoms and vascular diseases in 2014 for all domains except episodic memory, which was only partially explained by depressive symptoms.

"While there is growing evidence for a link between insomnia and cognitive impairment in older adults, it has been difficult to interpret the nature of these associations given how differently both insomnia and cognitive impairment can present across individuals," said lead author Afsara Zaheed, a graduate student in clinical science within the department of psychology at the University of Michigan. "By investigating associations between specific insomnia complaints and cognition over time using strong measures of cognitive ability, we hoped to gain additional clarity on whether and how these different sleep problems may lead to poor cognitive outcomes."

Insomnia involves difficulty falling asleep or staying asleep, or regularly waking up earlier than desired, despite allowing enough time in bed for sleep. Daytime symptoms include fatigue or sleepiness; feeling dissatisfied with sleep; having trouble concentrating; feeling depressed, anxious, or irritable; and having low motivation or energy.

The study analyzed data from the Health and Retirement Study, which involved 2,496 adults who were at least 51 years of age. In 2002 they reported the frequency of experiencing insomnia symptoms. In 2016 the participants' cognition was assessed as part of the Harmonized Cognitive Assessment Protocol and operationalized with a comprehensive neuropsychological battery tapping episodic memory, executive function, language, visuoconstruction, and processing speed. Analyses controlled for sociodemographics and baseline global cognitive performance.

"These results are important given the lack of currently available treatments for late-life cognitive disorders, like Alzheimer's disease and other dementias," said Zaheed. "Sleep health and sleep behaviors are often modifiable. These results suggest that regular screening for insomnia symptoms may help with tracking and identifying people with trouble falling asleep in mid-to-late life who might be at risk for developing cognitive impairments later in life. Additional intervention research is needed to determine whether intervening on insomnia symptoms can help prevent or slow the progression of cognitive impairments in later life."

DARIEN, IL - A 15-year longitudinal study shows that childhood insomnia symptoms that persist into adulthood are strong determinants of mood and anxiety disorders in young adults.

Results show that insomnia symptoms persisting from childhood through adolescence and into adulthood were associated with a 2.8-fold increased risk of internalizing disorders. Insomnia symptoms that newly developed over the course of the study were associated with a 1.9-fold increased risk of internalizing disorders. No increased risk of internalizing disorders was found for those children in whom insomnia symptoms remitted during the study period.

"We found that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood," said lead author Julio Fernandez-Mendoza, who has a doctorate in psychobiology and is an associate professor at Penn State College of Medicine. He is a psychologist board certified in behavioral sleep medicine at Penn State Health Sleep Research and Treatment Center in Hershey, Pennsylvania.

Data were analyzed from the Penn State Child Cohort, a population-based sample of 700 children with a median age of 9 years. The researchers had followed up 8 years later with 421 participants when they were adolescents (median age of 16 years) and now 15 years later with 492 of them when they were young adults (median age of 24 years). Insomnia symptoms were defined as moderate-to-severe difficulties initiating or maintaining sleep.

The symptoms were parent-reported in childhood and self-reported in adolescence and young adulthood. The presence of internalizing disorders was defined as a self-report of a diagnosis or treatment for mood and/or anxiety disorders. Results were adjusted for sex, race/ethnicity, age, and any prior history of internalizing disorders or use of medications for mental health problems.

According to the authors, childhood insomnia symptoms have been shown to be associated with internalizing disorders, which include depressive disorders and anxiety disorders. "These new findings further indicate that early sleep interventions are warranted to prevent future mental health problems, as children whose insomnia symptoms improved over time were not at increased risk of having a mood or anxiety disorder as young adults," said Fernandez-Mendoza.

India's national government has inappropriately prioritised people for covid-19 vaccination

Current approach is causing huge numbers of avertable deaths, warn experts

India's national government has inappropriately prioritised people for covid-19 vaccination, argue doctors and researchers in The BMJ today.

Peter Lloyd-Sherlock and colleagues warn that the government's current approach to vaccination - focusing on younger age groups - "is causing huge numbers of avertable deaths and is deeply inequitable."

From 3 May to 5 June 2021, more first doses were administered to people under 45 than over 60, even though at least 77 million people aged 60 remain unvaccinated, they say.

As such, they urge the government to take a more targeted approach and reallocate available doses to older people, especially in more deprived areas.

They explain that in January 2021, India's vaccination programme began with health professionals and "frontline workers." In March, it was extended to people aged 60 or over and those aged 45 or over with comorbidities, and in April to anyone aged 45 or over. From 1 May, vaccine entitlement was extended to all people aged 18 or over, although people under 45 had to pay.

Earlier this week, the government announced that vaccines would now also be free for people aged 18-45, which the authors suggest is likely to increase the focus of vaccination on people in this age group, rather than those aged 45 or over.

In practice, they say access to covid-19 vaccination is mainly determined by socioeconomic status, with very low coverage in rural areas and among disadvantaged urban populations.

As a result, Indians of all ages are increasingly resorting to private purchases, and the country's minimal pension system makes this especially unaffordable for older people.

What's more, no special provision has been made to facilitate vaccine access for adults with impaired mobility, they add, and older people tend to be less familiar with the digital technology required to make a booking.

They note that some Indian states have now reallocated available doses to older people and they urge the national government to do the same until all older people in India have received at least one dose.

"Its current approach to vaccination is causing huge numbers of avertable deaths and is deeply inequitable, both between age groups and within them," they conclude.

[Ends]

Externally peer reviewed? No
Evidence type: Letter; Opinion
Subject: Covid-19 vaccination in India

The SARS-CoV-2 papain-like protease (PLpro) plays an essential role in processing viral proteins needed for replication. In addition, the enzyme can cut and inactivate some human proteins important for an immune response. Now, researchers reporting in ACS Infectious Diseases have found other targets of PLpro in the human proteome, including proteins involved in cardiovascular function, blood clotting and inflammation, suggesting a link between the inactivation of these proteins and COVID-19 symptoms.

Viruses like SARS-CoV-2 make multiple proteins as one long "polyprotein." Viral enzymes called proteases recognize specific amino acid sequences in this polyprotein and cut them to release individual proteins. However, some human proteins also contain these sequences (known as homologous host-pathogen sequences, or SSHHPS), including ones involved in generating the innate immune response, which could help protect the virus from the host. Patricia Legler and colleagues wanted to comprehensively identify human proteins that contain SSHHPS, examine their functions and see whether PLpro can cleave them in a test tube.

The researchers developed a computational method to search a database of all known human proteins for sequences similar or identical to the SARS-CoV-2 SSHHPS. The analysis revealed that the proteins with highest sequence identity were those that had cardiovascular, inflammatory, kidney, respiratory or blood-related functions. For example, two of the proteins containing SSHHPS were cardiac myosins, one was an anti-coagulant and another was an anti-inflammatory protein. Inactivation of these proteins by PLpro is consistent with COVID-19 symptoms of heart damage, blood clots and inflammation. The team confirmed that PLpro could cut these protein sequences in vitro. Performing the same analysis on SSHHPS for the Zika viral protease identified proteins associated with neurological development and disorders, consistent with Zika symptoms. These results suggest that the symptoms and virulence of viruses can be predicted directly from their genomic sequences, the researchers say.

A cell-penetrating peptide developed by researchers at Vanderbilt University Medical Center can prevent, in an animal model, the often-fatal septic shock that can result from bacterial and viral infections.

Their findings, published this week in Scientific Reports, could lead to a way to protect patients at highest risk for severe complications and death from out-of-control inflammatory responses to microbial infections, including COVID-19.

"Life-threatening microbial inflammation hits harder (in) patients with metabolic syndrome, a condition afflicting millions of people in the United States and worldwide," said the paper's corresponding author, Jacek Hawiger, MD, PhD, the Louise B. McGavock Chair in Medicine and Distinguished Professor of Medicine at VUMC.

An international authority on inflammation as the mechanism of multiple diseases, Hawiger also is professor of Molecular Physiology and Biophysics at Vanderbilt and a Health Research Scientist at the Nashville Veterans Affairs (VA) Medical Center.

"We explore the pathways to the cell's nucleus, the command center of inflammation," he said.

In response to bacterial infection, transcription factors are ferried to the nucleus of immune and vascular cells, where they reprogram gene expression to ramp up production of infection-fighting inflammatory molecules. Like a wildfire, however, the inflammatory response, if unchecked, can damage small blood vessels, leading to multiple organ failure and death.

Patients with pre-existing health conditions, including obesity and high blood levels of glucose (diabetes), triglycerides and cholesterol (hyperlipidemia) -- hallmarks of metabolic syndrome -- are at increased risk of developing a damaging inflammatory response to infection.

They also are more likely to die of complications of COVID-19, which include acute respiratory distress syndrome, septic cardiomyopathy (damage to heart muscle), microvascular thrombosis (tiny blood clots) and acute kidney injury. These complications result from infection-induced septic shock due to the collapse of small blood vessels.
Pre-existing conditions, notably hyperlipidemia, already can cause inflammation in these small vessels. Infection, the researchers reasoned, may only make it worse.

In 2014 Hawiger and colleagues developed a cell-penetrating peptide, or protein fragment, that blocked signaling pathways leading to lethal shock in animals exposed to the endotoxin lipopolysaccharide (LPS), which is released during infection by Gram-negative bacteria.

This "parent" peptide, called cSN50.1, selectively suppressed the transport into the nucleus of transcription factors responsible for the out-of-control inflammatory response, and dramatically increased survival in mice exposed to high doses of LPS.

In a 2017 the Hawiger team used a polymicrobial sepsis model to show that the same treatment combined with an antibiotic increased survival in mice from 30% (using antibiotic alone) to 55%.

In 2019 the U.S. Food and Drug Administration designated the peptide as an "Investigational New Drug" and allowed a clinical trial in an inflammatory skin disease sponsored by Amytrx, a start-up company co-founded by Hawiger.

In the current study, the researchers tested whether, in a mouse model of hyperlipidemia, two novel, pathway-selective forms of this peptide could, as they put it, "stop pro-inflammatory and metabolic transcription factors in their tracks" at the nuclear transport checkpoint.

One peptide, which selectively targets the nuclear shuttle for proinflammatory transcription factors, protected against the acute stage of lethal microbial inflammation, while extended treatment with the other peptide, which targets the nuclear transport checkpoint for metabolic transcription factors, reduced production of cholesterol, triglycerides and fatty acids.

"Experimentally, by targeting the nuclear transport checkpoint, we suppressed the burst of inflammatory mediators while lowering elevated levels of blood glucose, triglycerides, and cholesterol and protecting small blood vessels from injury in the liver, lungs, heart and kidneys," Hawiger said.

"Our findings are of significant relevance to individuals displaying signs of metabolic syndrome that predisposes them to life-threatening microbial diseases, including recent outbreaks of COVID-19 as well as autoimmune and allergic disorders," the researchers concluded.

Our genetic material is stored in our cells in a specific way to make the meter-long DNA molecule fit into the tiny cell nucleus of each body cell. An international team of researchers at the Max Planck Institute for Biology of Ageing, the CECAD Cluster of Excellence in Ageing research at the University of Cologne, the University College London and the University of Michigan have now been able to show that rapamycin, a well-known anti-ageing candidate, targets gut cells specifically to alter the way of DNA storage inside these cells, and thereby promotes gut health and longevity. This effect has been observed in flies and mice. The researchers believe this finding will open up new possibilities for targeted therapeutic interventions against ageing.

Our genetic material lies in the form of DNA in every cell nucleus of our body cells. In humans, this DNA molecule is two meters long - yet it fits into the cell nucleus, which is only a few micrometres in size. This is possible because the DNA is precisely stored. To do this, it is wound several times around certain proteins known as histones. How tightly the DNA is wound around the histones also determines which genes can be read from our genome. In many species, the amount of histones changes with age. Until now, however, it is unclear whether changes in cellular histone levels could be utilized to improve the ageing process in living organisms.

A well-known anti-ageing compound with a new target

The drug rapamycin recently became one of the most promising anti-ageing substances and shows positive effects on health in old age. "Rapamycin turns down the TOR signalling pathway that regulates a wide spectrum of basic cellular activities such as energy, nutritional and stress status. In short, we use rapamycin to fine-tune the master regulator of cellular metabolism", explains Yu-Xuan Lu, postdoc in the department of Linda Partridge and first author of the study. "Meanwhile, we know that histone levels have a critical impact on the ageing process. However, we had no idea whether there is a link between the TOR signalling pathway and histone levels, and more importantly, whether histone levels could be a druggable anti-ageing target."

To study the effect of rapamycin on histone proteins, the researchers analysed various organs of the fruit fly Drosophila melanogaster. "We looked in different tissues and organs of the fly for noticeable changes in histone levels before and after treatment with rapamycin, this means before and after switching off the TOR signalling pathway", explains Yu-Xuan Lu. "Surprisingly, we observed an increase in histone proteins after rapamycin treatment. This effect occurred exclusively in the gut of the flies, but not in other tissues." In further experiments, Yu-Xuan Lu and his colleagues were able to show that the increased levels of certain histone proteins in a specific gut cell type called enterocytes reduced tumour growth, improved gut health and extended lifespan of the animals. Similar observations were made in mouse gut enterocytes after rapamycin treatment.

"Our results show for the first time a link between the TOR signalling pathway and histone levels that determines longevity", says Yu-Xuan Lu. "The increased levels of histone proteins subsequently change how the DNA is stored in the nucleus. The fact that we were also able to make similar observations in mice shows that this is a widespread mechanism." Looking ahead to future experiments, he adds: "Given the central role of histones on DNA storage in the cell, this finding not only broadens our knowledge on the ageing process, but also provides new possibilities for targeted therapeutic interventions against ageing."

HOUSTON -- Results from the multi-cohort Phase I/II ARROW clinical trial, conducted by The University of Texas MD Anderson Cancer Center researchers, showed that a once-daily dose of pralsetinib, a highly selective RET inhibitor, was safe and effective in treating patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) and RET-altered thyroid cancer. The findings for each cohort were published today in The Lancet Oncology and The Lancet Diabetes & Endocrinology, respectively.

"Targeted therapies have dramatically improved care for patients with NSCLC and thyroid cancer driven by oncogenes, and the rapid clinical translation of selective RET inhibitor pralsetinib marks another milestone in a paradigm shift toward precision medicine," said principal investigator Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics.

The Food and Drug Administration approved pralsetinib for metastatic RET fusion-positive NSCLC in September 2020 and advanced RET-altered thyroid cancers in December 2020.

RET fusions occur when part of the DNA containing the RET gene breaks off and fuses with a different gene, which activates the kinase enzyme that continuously sends growth signals to the cell and drives cancer development. RET alterations are caused by a mutation in the DNA sequence and are oncogenic drivers in a variety of tumor types, most commonly in medullary thyroid cancers (approximately 90% of advanced cases), papillary thyroid cancers (approximately 10-20% of cases) and NSCLC (approximately 1-2% of cases).

Because standard cancer treatments -- including surgery, radiation, chemotherapy and immunotherapy -- have shown limited efficacy in patients with RET fusion-positive solid tumors, RET fusions have become an emerging target for novel therapies.

"Patients with RET-altered cancer are in need of personalized therapies," Subbiah said. "Based on this published data, pralsetinib shows durable responses in both the treatment-naïve and treatment-refractory settings in RET-positive NSCLC and thyroid cancer, providing evidence that this drug can be an option as a new standard of care for patients with this rare cancer."

In the NSCLC cohort, the analysis included 233 patients with RET fusion-positive NSCLC, as of a data cutoff of May 22, 2020. Ninety-two patients previously received platinum-based chemotherapy and 29 had no prior systemic treatment. The findings showed that pralsetinib achieved an overall response rate (ORR) of 70% and a complete response rate of 11% in patients with no prior systemic treatment, and a 61% ORR and 6% complete response rate in patients who previously received platinum-based chemotherapy.

In the thyroid arm of the study, researchers enrolled patients with RET-altered locally advanced/metastatic solid tumors, including 122 patients with RET-mutant medullary thyroid cancer and 20 patients with RET fusion-positive thyroid cancers, as of a data cutoff of May 22, 2020. The ORR was 71% in patients with treatment-naïve RET-mutant medullary thyroid cancer, 60% in patients previously treated with cabozantinib and/or vandetanib and 89% in patients with RET fusion-positive thyroid cancer.

"Until 2020, standard approved therapies for advanced thyroid cancer included multikinase inhibitors, which are effective but associated with a broad spectrum of potentially dose-limiting adverse effects," said trial co-investigator Mimi Hu, M.D., professor of Endocrine Neoplasia and Hormonal Disorders. "The highly potent RET-inhibitors, such as pralsetinib, led to a high response rate and have a more tolerable side-effect profile, thus improving patient satisfaction. Development of novel precision therapies is essential for our patients with this rare disease."

Five thyroid cancer patients (4%) discontinued therapy due to treatment-related adverse events (TRAEs), one patient died due to a TRAE and 14 NSCLC patients (6%) discontinued treatment due to TRAEs. Ultimately, the results showed that pralsetinib was a potent yet well-tolerated treatment for patients with RET fusion-positive NSCLC and RET-altered thyroid cancer.

"These data reiterate the importance of continued clinical implementation of genomic testing to identify actionable oncogenic drivers that include RET alterations," Subbiah said.

Blueprint Medicines Corporation funded the ARROW study. A full list of co-authors and their disclosures can be found in The Lancet Oncology and The Lancet Diabetes & Endocrinology papers.

Watching what was happening around the world in early 2020, University of California San Diego School of Medicine researchers knew their region would likely soon be hit with a wave of patients with COVID-19, the infection caused by the coronavirus SARS-CoV-2. They wondered how the virus persists on surfaces, particularly in hospitals, and they knew they had only a small window of time to get started if they wanted to capture a snapshot of the "before" situation -- before patients with the infection were admitted.

After a call late one Sunday night, a team assembled in the hospital lobby the next day, ready to swab.

In the resulting study, described June 8, 2021 in Microbiome, researchers swabbed patient room surfaces before, during and after occupancy, and repeatedly collected samples from the skin, noses and stool of COVID-19 patients and their health care workers over time. In total, they tested 972 hospital-associated samples for traces of SARS-CoV-2 over two months.

"Although it feels like we've been living with this virus for a long time, the study of the interactions between SARS-CoV-2 and other microbes is still new, and we still have a lot of questions," said co-senior author Sarah Allard, PhD, assistant project scientist at UC San Diego School of Medicine and Scripps Institution of Oceanography. "The more we know about how a virus interacts with its environment, the better we can understand how it's transmitted and how we might best disrupt transmission to prevent and treat the disease."

Their findings: The virus, or at least its genetic signature, abounds. The team detected the virus on the floors next to the beds of patients with COVID-19 (39 percent of samples tested), floors outside patient rooms (29 percent) and surfaces inside the rooms (16 percent). SARS-CoV-2 detection tended to be highest during the first five days after a patient's onset of symptoms.

The researchers are quick to point out that just because they can detect the virus' unique genetic signatures on a surface, it doesn't mean the virus is able to infect people. Since they started the study, it has been well documented that SARS-CoV-2 spreads primarily through close human interactions, while surface transmission is likely very rare. What's more, none of the health care workers actively caring for patients in the study tested positive for the virus. The study focused on one hospital, but the researchers expect they would find similar results in any hospital treating patients with COVID-19.

"This is huge on so many levels," said co-senior author Daniel Sweeney, MD, critical care and infectious disease physician at UC San Diego Health. "We need to know if our personal protective equipment, PPE, is adequate, and fortunately we know now that things like masks, gloves, gowns and face shields really do work. This pandemic has been a global disaster, but it could've been even worse if our health care workers were getting infected, especially if we didn't know why."

Viruses don't typically hang out alone. Whether on people or surfaces, they are part of complex communities known as microbiomes, which may include a variety of other viruses, bacteria and additional microbes. In looking for the coronavirus, the team discovered something else: one particular type of bacteria from the genus Rothia was found alongside SARS-CoV-2 more often than not, regardless of collection site. In other words, the presence of Rothia strongly predicted that they would also detect SARS-CoV-2 in the same sample.

"Why that relationship?" asked Allard. "Does the bacteria help the virus survive, or vice versa? Or is it just that these bacteria are associated with the underlying medical conditions that put patients at higher risk for severe COVID-19 in the first place? That's an area for future research."

The study was a challenge from the beginning, and became more difficult as the hospital's intensive care unit began to take in more patients with COVID-19. The team specifically designed their approach to leverage existing resources to not stress the supply chain needed for clinical care and testing. In a separate effort, some of the team and their colleagues developed alternative swabs for research purposes. They collected samples as quickly and as efficiently as possible to minimize disruption to patient care. The samples were transported back to the lab in alcohol, preserving the virus for analysis but not exposing researchers to active organisms.

"A lot of people did a lot of basic and clinical research these last few months, and we did it well," Sweeney said. "We added to our infrastructure. We acquired the experience. I hope the same sort of focus, drive and spirit carry forward in whatever comes next."

[RALEIGH, N.C.] - How are the squirrels doing this year? The bears? The armadillos? How would you know? A new paper published June 8 sets up the framework for answering these questions across the United States by releasing the data from the first national mammal survey made up of 1,509 motion-activated camera traps from 110 sites located across all 50 states.

Unlike birds, which have multiple large-scale monitoring programs, there has been no standard way to monitor mammal populations at a national scale. To address this challenge, scientists from the North Carolina Museum of Natural Sciences and the Smithsonian Conservation Biology Institute recently collaborated with more than 150 scientists on the first-ever nationwide wildlife survey, called Snapshot USA. "Our goal was to provide a space for researchers from all 50 states to contribute a subset of their data to a broader initiative to maximize our coverage of the country and better understand drivers of mammal distributions to best inform conservation as rapidly as possible," said the Museum's Curator of Mammalogy Michael Cove, lead author of the new paper.

For two months in fall 2019 researchers collected more than 166,000 images of 83 different mammal species. White-tailed deer were the most common species detected (34,000+ times at 1,033 sites), followed by eastern gray squirrels and raccoons. Pygmy rabbits, mountain beavers, hog-nosed skunks and marsh rabbits were among the least common mammals photographed. Yet, the overall detection winner was the coyote, which was detected in all 49 continental states -- they have not made it to Hawaii yet. All the data are archived at the Smithsonian Institution's eMammal database and published as part of the new paper.

In an interesting twist, developed areas tended to have the highest overall mammal detections, with three of the top five sites for total mammal activity being urban -- Urbana, IL.; Baltimore, MD.; and Washington, D.C. "These new data show that the urban mammal paradox, with more animals actually living close to people, is not just an isolated phenomenon," said coauthor Roland Kays, a scientist at the museum and at NC State University.

When comparing particular species across the country, North Carolina stood out for being in the "Top 10" for the relative abundance of black bears (#3 Dare County, #4 Craven County, #7 Pender County, #8 Haywood County); bobcats (#5 Dare County); coyotes (#8 Haywood County); white-tailed deer (#5 Surrey County, #9 Alamance County, #10 Moore County); and turkeys (#8 Craven County, #9 Burke County and #10 Moore County). Nationally, ranking of top sites for select mammal species can be found at https://public.tableau.com/app/profile/roland.kays/viz/SS_USA_rankings/Dashboard1.

The research results appeared June 8 in Ecology, a publication of the Ecological Society of America, the nation's largest organization of professional ecologists. The publication makes the 2019 survey data available online for anyone to use for research questions, such as the evaluation of changes in animal populations over time or informing conservation strategies for threatened and endangered species. "This project involved a remarkable level of cooperation and data sharing that will have to be the standard going forward to adequately monitor our valuable wildlife resources at the national scale," adds William McShea of the Smithsonian Conservation Biology Institute.

The scientists repeated the survey in fall 2020 likely providing insights on the effects of the COVID-19 pandemic on wildlife distributions and habitat use -- resulting data will be available as the eMammal database is updated in 2021.