Culture

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.

WASHINGTON, June 9, 2021 -- The World Health Organization and the Centers for Disease Control recommend keeping a certain distance between people to prevent the spread of COVID-19. These social distancing recommendations are estimated from a variety of studies, but further research about the precise mechanism of virus transport from one person to another is still needed.

In Physics of Fluids, by AIP Publishing, researchers from Stony Brook University, Harvard, ETH Zurich, and Hanyang University demonstrate normal breathing indoors without a mask can transport saliva droplets capable of carrying virus particles to a distance of 2.2 meters, or 7.2 feet, in a matter of 90 seconds.

The use of a face mask significantly reduces the distance these droplets travel. After almost two minutes, the saliva droplets restricted by a mask had traveled only 0.72 meters, under 2.4 feet and well below the distance of 1.8 meters, or 6 feet, suggested by the CDC.

The study used computer simulations with a more realistic model for the situation of interest than those used in previous studies. Previous work considered aerosol transport after coughing or sneezing, while this study specifically looked at normal human breathing. A normal breath produces periodic jet flows that contain saliva droplets, but the velocity at which the jet travels is less than a tenth that of a cough or sneeze.

The investigators found even normal breathing produces a complex field of vortices that can move saliva droplets away from the person's mouth. The role of these vortices has not previously been understood.

"Our results show that normal breathing without a facial mask generates periodic trailing jets and leading circular vortex rings that propagate forward and interact with the vortical flow structures produced in prior breathing cycles," said author Ali Khosronejad.

This complex vorticity field can transport aerosol droplets over long distances. A face mask dissipates the kinetic energy of the jet produced by an exhaled breath, disrupting the vortices and limiting the movement of virus-laden droplets.

The investigators considered the effect of evaporation of the saliva droplets. In the case of no mask, they found the saliva droplets near the front of the plume of exhaled breath had partially evaporated, reaching a size of only one-tenth of a micron. In stagnant indoor air, droplets this size would not settle to the ground for days.

The use of a mask partially redirects the exhaled breath downward and significantly restricts forward movement of the plume, so the risk of suspended droplets remaining in the air is substantially reduced.

"To simplify the breathing process, we did not consider the flow of air-saliva mixture through the nose and solely accounted for the flow through the mouth," Khosronejad said. "In future studies, we will explore the effect of normal breathing via both the nose and mouth."

GRAND RAPIDS, Mich. (JUNE 8, 2021) -- Chronic inflammation in the gut may propel processes in the body that give rise to Parkinson's disease, according to a study by scientists at Van Andel Institute and Roche.

The study, published in Free Neuropathology, is the latest in a growing list that links the gut and the immune system to Parkinson's. The researchers' findings in an experimental mouse model of gut inflammation track with several large-scale epidemiological studies that show an association between Parkinson's and inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease.

Epidemiological evidence from other groups indicates the risk of developing Parkinson's fades in certain people whose inflammatory bowel disease is treated with anti-TNF, a standard-of-care anti-inflammatory therapy, which suggests that reducing gut inflammation may have promise for mitigating Parkinson's onset.

"There is increasing evidence that changes in the gut can affect a variety of neurological and psychiatric brain disorders," said Patrik Brundin, M.D., Ph.D., VAI deputy chief scientific officer and co-corresponding author of the study. "Parkinson's is a complex disease with a wide range of factors that work in concert to spark its onset and progression. We need to understand the gut's likely influence on Parkinson's development better. This study provides novel insights, and this new knowledge can facilitate the development of improved treatment approaches."

In their disease models, the team found that chronic gut inflammation triggers a protein called alpha-synuclein to clump together in walls of the colon, as well as in local immune cells called macrophages. A similar process may play out in the colons of some people -- such as those with inflammatory bowel diseases -- thereby increasing their risk to develop Parkinson's as shown in studies by other groups.

Similarly, in the brains of people with Parkinson's, "sticky" alpha-synuclein aggregates also develop. For reasons that still are unclear, these aggregates can clog the molecular machinery that keep neurons alive. The resulting loss of some of these critical cells -- and the chemical messenger they produce called dopamine -- causes Parkinson's hallmark movement-related symptoms, such as freezing and loss of voluntary movement. The additional wide-spread development of alpha-synuclein aggregates throughout the brain also may be associated with the disease's non-motor symptoms and may fuel its progression, which cannot be slowed or stopped with existing treatments.

The study also revealed that chronic inflammation in the gut early in life can exacerbate alpha-synuclein clumping throughout the brain in older mice. While it isn't clear exactly how this happens, the team has two theories: first, they suggest inflammatory chemicals may travel from the gut to the brain via the bloodstream, triggering a runaway inflammatory immune response that leads to protein aggregation. Another idea is that alpha-synuclein aggregates may travel to the brain via the vagus nerve, one of the longest nerves in the body and a "superhighway" between the gut and the brain. Once there, the proteins may then execute their toxic activity in the brain.

"We now know that systems throughout the body contribute to Parkinson's," said Emmanuel Quansah, Ph.D., a postdoctoral fellow in Brundin's lab and a key contributor and co-author of the study. "It was striking to see protein aggregation pathology in the brain that mirrored pathology in the colon brought on by inflammation. A particularly intriguing observation was the loss dopamine-producing nerve cells -- which play a major role in Parkinson's onset -- in our models that had gut inflammation a year-and-a-half earlier."

Notably, the team also found that modulating immune activation in the colitis mouse model by genetic or therapeutic means tuned the level of alpha-synuclein clumps in the colon up or down.

"Our results in mice, together with the genetic and epidemiological data by others in humans, make a strong case for further exploring systemic immune pathways for future therapies and biomarkers for Parkinson's," said Markus Britschgi, Ph.D., Senior Principal Scientist and Section Head in the Neuroscience and Rare Diseases Research Department at the Roche Innovation Center Basel and co-corresponding author of the study.

Authors include first author Stefan Grathwohl, Ph.D. (previously a Roche postdoctoral fellow), Nazia Maroof, Ph.D. (previously a Roche postdoctoral fellow), Liz Spycher, Krisztina Oroszlan-Szovik, M.S., Helga Remy, Markus Haenggi M.S., and Marc Stawiski of Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel; Jennifer A. Steiner, Ph.D., Zachary Madaj, M.S., and Martha L. Escobar Galvis, Ph.D., of VAI; Fethallah Benmansour, Ph.D., of Roche Pharma Research and Early Development, pREDi, Roche Innovation Center Basel; Gonzalo Duran-Pacheco, Ph.D., Juliane Siebourg-Polster, Ph.D., Matthias Selhausen, Pierre Maliver, EVCP, Arel Su, DVM, and Annika Herrmann, DECVP, of Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel; Andreas Wolfert and Thomas Emrich, Ph.D., of Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich; and Christoph Mueller, Ph.D., of Institute of Pathology, University of Bern.

Vertebrate life began in the water, but around 340-360 million years ago, four-limbed creatures, or tetrapods, made the transition onto land. In the years that followed, some species adapted to terrestrial life, while others turned back to the water and readapted to an aquatic lifestyle.

A new study of these early amphibians, published in the journal PLOS ONE and led by Penn paleontologist Aja Carter, suggests that these environmental shifts left an impression--on the shape of the animals' spines.

"I'm interested in how the shapes of the vertebrae affect how animals move," she says. "Our findings suggest that, in at least one part of the vertebrae, the shape of the bones correlated with the environment in which the animals were living." Those associations, Carter says, may be a result of the different physical demands of living on land versus in the water.

Diversity, now and then

Many characteristics distinguish creatures as diverse as humans, dogs, snakes, and even Stegasaurus, but one thing that unites them is the basic shape of their vertebrae.

"They all have this hockey puck-shaped thing, the centrum, fused to these sticky-outy parts, the neural arch, the transverse processes," says Carter, a paleontologist who earned her doctoral degree from Penn's Department of Earth and Environmental Science in the School of Arts & Sciences and is now a postdoctoral fellow in the School of Engineering and Applied Science. "But that's not always how it's been."

Go back further in evolutionary time, Carter says, starting even before dinosaurs arose, and one will find a highly diverse set of vertebral shapes. Yet it's not clear why all this diversity was present, or why vertebrates today have landed on one basic vertebral structure almost without exception.

Scientists have long debated whether a particular vertebral shape was important for these animals to colonize land or subsequently recolonize water. To explore the question, Carter focused on early amphibians, a group known as temnospondyls, which were the most diverse tetrapods living in the Carboniferous through the late Permian, or about 360 to 250 million years ago. Some lived exclusively on land, some exclusively in water, and some were amphibious. In addition, some that were known to be terrestrial had evolved from ancestors that were aquatic, and vice versa.

"If we want to understand macro-evolutionary trends, we need a lot of specimens," Carter says. "There are about 290 species of temnospondyls, and they come in different sizes, and we know a lot about them. So this was a great group to focus on."

Shapes by the numbers

Though previous studies had used qualitative techniques to assess the relationship between vertebral form and a land- or water-based lifestyle, Carter and colleagues opted to use a quantitative approach known as geometric morphometrics. This strategy quantifies shape by assigning points to the outline of a structure. In the current study, they used a two-dimenisonal approach, imagining the outline of the vertebrae viewed from the side.

The researchers focused in particular on the shape of two parts of the vertebrae, the intercentrum, a weight-bearing structure, and the neural arch, sites of muscle attachment. Many in the field presumed that a land-based lifestyle required a stiffer spine than one in water, so the team's prediction was that terrestrial temnospondyls would have longer neural arches and longer intercentra to restrict flexibility through the spine.

Yet that's not what they discovered. Instead, they found no association between the neural arches and the environment in which they animals lived. "That suggests there is some plasticity," Carter says. In other words, there is not just one type of neural arch that enables successful movement on land.

The intercentrum shape, however, did correlate with environment and not in the way that that earlier scientists had predicted. Terrestrial species tended to have shorter, more curved intercentra, while aquatic and semi-aquatic animals had intercentra that were taller and flatter.

"The intercentra are weight-bearing, and these seem to fall out based on environment," says Carter. "But the neural arches' shape don't seem to bend to the constraints that we think of in terms of terrestrial versus aquatic."

Indeed, in terrestrial species, the researchers found some with a high degree of spinal flexibility, contrary to previous beliefs, Carter says. "In fact, in our results, a lot of terrestrial taxa seemed to have spines that were a lot less stiff than their aquatic counterparts."

In addition, aquatic species that were known to have ancestors that had lived on land maintained morphologies more akin to their terrestrial counterparts. "They don't go back," she says.

Questions for the future

Carter notes, however, that there are other ways to gain spinal flexibility, including increasing the total number of vertebrae, but the new findings still buck earlier notions of what morphologies enabled a successful move to the land.

"This tells us there is more diversity than what these labels--terrestrial, aquatic--are saying, when it comes to vertebral composition and shape," Carter says.

Carter acknowledges that paleontological studies such as these leave a lot of room for doubt. Measurements are coming from fossils that may have been reshaped during the fossilization process, for example. Plus, muscle attachments, lost to the fossilization process, would have a significant impact on movement. So she won't be surprised if future studies challenge these findings.

"Science is both iterative and overturned all the time," she says.

Yet in the not-so-distant future, in her new position at Penn Engineering, Carter hopes to build paleontologically inspired robots in which she could test how differently formed vertebrae impact funcational movement.

"I'm learning that's going to be a difficult challenge, but I'm excited to work on it," she says.

New research shows what is often assumed to be 'fair' in conservation practice may not be considered so by the very people most affected by it--and a new approach is needed if protected areas are to be effective.

Lead author Dr Georgina Gurney, from the ARC Centre of Excellence for Coral Reef Studies based at James Cook University, said considering local stakeholder conceptions of fairness in conservation is critical.

"If conservation is perceived as unfair it can lead to conflict, undermining support and cooperation," Dr Gurney said.

She said it is not only an ethical matter but key to achieving good outcomes for people and the environment.

"But what is fairness? Very few studies have asked this question in the context of conservation, especially marine protected areas."

The researchers asked Indigenous communities in Fiji (who hold customary tenure rights to land and sea) about the fairness of five alternative approaches to distributing money paid by tourists to dive in a new co-managed marine protected area.

"Our study found local stakeholders considered the 'most fair' way to distribute money from the area was according to who held rights over the area," said co-author Dr Sangeeta Mangubhai, Director of the Wildlife Conservation Society Fiji Country Program.

"They thought the least fair way to distribute money was according to the costs incurred to fishers who were affected by the new rules prohibiting fishing."

The findings challenge common assumptions in much of the conservation literature and practice about what constitutes distributional fairness. These often focus on equality and forgone economic benefits of resource extraction, such as fishing.

"Our findings help clarify fairness in global environmental policies and agreements," Dr Mangubhai said. "Explicitly identifying what is considered fair by those most affected by conservation is important during both the planning and evaluation processes."

"This practice is especially important in low- and middle-income countries. Conservation practice and policy undertaken in these countries are often shaped by that developed in rich Western countries, which means they are underpinned by Western ideas about fairness."

"As the coverage of conservation areas is expected to grow to 30% of the world's surface by 2030, more attention should be given to what local stakeholders consider is fair with regards to related decision-making and the distribution of associated costs and benefits," Dr Gurney said.

"To help make sure existing and new protected areas work, we need to move beyond tacit assumptions about what constitutes fair management to explicit identification of local conceptions of fairness."

"Otherwise, we risk the chance of support for the protected area being eroded."

Since the early days of the COVID-19 pandemic, there were questions about how people in active cancer treatment would fare if they became infected with SARS-CoV-2. The worries were due, in large part, to the effects that cancer and its treatments can have on the immune system. Now that COVID-19 vaccines are widely available, concerns have shifted to the safety and effectiveness of vaccination in this potentially vulnerable population. A study published June 5 in the journal Cancer Cell aims to allay those fears.

In a review of 200 patients with a wide spectrum of cancer diagnoses, researchers at Montefiore Health System and Albert Einstein College of Medicine in the Bronx, NY, found that after full vaccination, 94% of patients overall demonstrated seroconversion, which was determined by the presence of antibodies to the SARS-CoV-2 spike protein. Response rates were very high among patients with solid tumors and were lower in people with certain blood cancers, but even the majority of those patients mounted an immune response.

"Studies from early in the pandemic found that cancer patients who get COVID-19 have higher rates of morbidity and mortality compared to the general population," says senior co-author Amit Verma, director of the Division of Hemato-Oncology at Montefiore and professor of medicine and of developmental and molecular biology at Einstein, and associate director, translational science, Albert Einstein Cancer Center. "We really need efforts to protect these vulnerable patients from infection. This study should help people feel reassured that these vaccines work very well, even in those receiving chemotherapy or immunotherapy."

"This study confirms that there is no need for patients to wait for vaccination until they finish their chemotherapy or immunotherapy," says senior co-author Balazs Halmos (@DrSteveMartin), director of the Multidisciplinary Thoracic Oncology Program at Montefiore, professor of medicine at Albert Einstein College of Medicine, and a member of the Albert Einstein Cancer Center (AECC). "The side effects from vaccination seen in these populations were not substantially worse than in other groups. Not a single patient had to go to the emergency room or be admitted to the hospital because of side effects from the vaccines."

This study was the largest of its kind to look at seroconversion rates in cancer patients who have been fully vaccinated. Previous studies have looked at much smaller populations or have analyzed antibody levels after only the first dose of two-dose vaccines.

In serum tests to look for IgG levels after vaccination, the researchers found that among patients with solid tumors, 98% showed seroconversion. Among patients with hematologic cancers, the rate of seroconversion was 85%.

Patients receiving some treatments fared worse than others. Those receiving therapies for blood cancers that work by killing B cells (such as rituximab or CAR T therapies) had seroconversion rates of 70%. For those who had recently had bone marrow or stem cell transplants, the rate was 74%. But those rates were still much higher than expected, the researchers say.

"Although those receiving treatments that affect B cells didn't do as well, patients with blood cancers that affect the myeloid cells rather than the lymphoid cells had a pretty good response with regard to seropositivity," says first author Astha Thakkar (@asthakkar15) a Montefiore hematologic oncology fellow. "This includes people with acute myeloid leukemia and myelodysplastic syndrome."

The researchers say that one reason their data are so significant is that they include patients who had a broad range of cancers and who were undergoing a number of different treatments. "The patients themselves were also diverse and were representative of the patients we treat in the Bronx," Halmos says. "About one-third were Black and 40% were Hispanic."

"Vaccination among these populations have been lower, even though these groups were hardest hit by the pandemic," Verma concludes. "It's important to stress how well these patient populations did with the vaccines."

The routes and schedules of public transit, the presence or absence of sidewalks, the availability of different transportation options, and the design of highways that divide cities--these are examples of aspects of transportation systems that can profoundly impact underserved communities' access to basic needs like jobs, health care, education and even food.

A new study by University of Michigan researchers reveals common barriers that transportation decision-makers face in considering these issues and addressing them.

To conduct the study, a team from a multidisciplinary project involving engineering, public policy and data science interviewed 59 transportation practitioners in government, industry, the nonprofit sector and academia.

Increasing the equitable access to resources that transportation provides has risen on transportation practitioners' priority lists in recent decades, to the point that 80% of those interviewed said that they directly address social equity and fairness in their work. But common barriers they face include the need for more and better data on equity and transportation needs, as well as more effective ways to measure transportation equity.

How transportation system can perpetuate inequities

Historically, transportation systems have deepened inequity by, for instance, building highways that cut off and divide Black and low-income neighborhoods, among other decisions that prioritized the convenience of white residents. In addition to not repeating these injustices, many modern transportation practitioners view their role as having a responsibility to actively improve access to transportation. Poor mobility options can make it difficult for people in low-income communities to access healthy food, attend school, find and keep jobs, and receive adequate health care. It eats up time that people with limited resources can't afford to waste.

"There's a woman in Detroit who spends three hours riding the bus with her kid to go to school every day. That's three hours she's not earning the money that might help her move closer to that school or buy a car to reduce the commute. It's three hours she can't spend preparing healthy food, from a grocery store that might be as inaccessible as the school, and could lead to long term health problems. These inequities stack," said Kaylla Cantilina, a Ph.D. student in design science and first author on the paper in the journal
Transportation Research Record.

Barriers to progress in transportation equity

Practitioners cited these crucial barriers to improving transportation equity:

Collecting and connecting data sets: Policymakers said they couldn't get access to data in private companies, and private companies said that they couldn't seamlessly connect public data sets with their own data.

Lack of information on needs: Transportation practitioners need more information about the gaps experienced by underserved communities--where they need to go, when they need to go there and why current services are inadequate. In some cases, moving people won't be the sole solution. Cities may need to work with schools, hospitals and grocery stores to support the populations that need them.

"A lot of problems aren't purely transportation, but if we get more information about those problems, then we can address the pieces that relate to transportation," Cantilina said..

How better communication could lead to solutions

One potential solution is to improve communication between engineers and policymakers, and between data scientists and policymakers.

"Transportation equity practitioners, including engineers and data scientists, cannot develop solutions isolated from contexts and communities," said Shanna Daly, U-M associate professor of mechanical engineering who co-authored the paper.

"Transportation work has both technical and social dimensions that must be considered in parallel, even in disciplines that have been conventionally 'boxed off' as having only a technical focus."

As for how to facilitate those connections, some practitioners shared their approaches that could serve as models--such as a partnership between a city and a ride-sharing or automotive company to share data under agreed-upon parameters. Another example came from a state metropolitan planning organization, which handles regional mapping, allocation of funding and regulation of transportation around cities. The organization has an open office in which departments are mixed, making it easy to solicit knowledge without asking for a meeting.

One of the surprises was that for more than half of the transportation practitioners, money wasn't considered a major barrier. But reallocating money from other projects was often a challenge. Transportation decision-makers need structures in place to advocate for apportioning money with equity in mind, the researchers said.

"If you have a clump of money that automatically goes to highway management, is it really that hard to convince people not to use all of it for the highway? Why can't we build a sidewalk on this low-income road so kids can walk to school safely? It's a matter of priority," Cantilina said.

Closing the gap between academic researchers and practitioners

The study uncovered gaps between academic research and transportation practice. Often, the academic research in transportation equity focuses on approaches and tools that are not always easily applied, Cantilina said. Meanwhile, practitioners aren't necessarily taking advantage of the groundwork laid in research, though they sometimes come to the same conclusions.

In addition, academic researchers aren't aware of many of the problems that transportation practitioners in governments, nonprofits and private companies run into. With better connections, researchers could look into more relevant questions and practitioners could avoid reinventing the wheel. One open question is how to measure transportation equity.

Better solutions would free up talent that is currently stuck at home or lost to excessively long bus rides.

"Transportation is a form of freedom," Cantilina said. "You don't have time to dream when you're trying to access the resources just to survive."

A new study conducted by the researchers at the University of Liverpool reveals how the ancient photosynthetic organisms - cyanobacteria - evolve their photosynthetic machinery and organise their photosynthetic membrane architecture for the efficient capture of solar light and energy transduction.

Oxygenic photosynthesis, carried out by plants, algae, and cyanobacteria, produces energy and oxygen for life on Earth and is arguably the most important biological process. Cyanobacteria are among the earliest phototrophs that can perform oxygenic photosynthesis and make significant contributions to the Earth's atmosphere and primary production.

Light-dependent photosynthetic reactions are performed by a set of photosynthetic complexes and molecules accommodated in the specialised cell membranes, called thylakoid membranes. While some studies have reported the structures of photosynthetic complexes and how they perform photosynthesis, researchers still had little understanding about how native thylakoid membranes are built and further developed to become a functional entity in cyanobacterial cells.

The research team, led by Professor Luning Liu from the University's Institute of Systems, Molecular and Integrative Biology, developed a method to control the formation of thylakoid membranes during cell growth and used state-of-the-art proteomics and microscopic imaging to characterise the stepwise maturation process of thylakoid membranes. Their results are published in the journal Nature Communications.

"We are really thrilled about the findings," said Professor Liu. "Our research draws a picture about how phototrophs generate and then develop their photosynthetic membranes, and how different photosynthetic components are incorporated and located in the thylakoid membrane to perform efficient photosynthesis - a long-standing question in this field."

The first author of the study, Dr Tuomas Huokko, said: "We find that the newly synthesised thylakoid membranes emerge between the peripheral cell membrane, termed the plasma membrane, and the pre-existing thylakoid layer. By detecting the protein compositions and photosynthetic activities during the thylakoid development process, we also find that photosynthetic proteins are well controlled in space and time to evolve and assemble into the thylakoid membranes."

The new research shows that the cyanobacterial thylakoid membrane is a truly dynamic biological system and can adapt rapidly to environmental changes during bacterial growth. In thylakoids, photosynthetic proteins can diffuse from one position to another and form functional "protein islands" to work together for high photosynthetic efficiency.

"Since cyanobacteria perform plant-like photosynthesis, the knowledge gained from cyanobacteria thylakoid membranes can be extended to plant thylakoids," added Professor Liu. "Understanding how the natural photosynthetic machinery is evolved and regulated in phototrophs is vital for tuning and enhancing photosynthetic performance. This offers solutions to sustainably improve crop plant photosynthesis and yields, in the context of climate change and growing population. Our research may also benefit the bioinspired design and generation of artificial photosynthetic devices for efficient electron transfer and bioenergy production."

Laser-produced high energy density plasmas, akin to those found in stars, nuclear explosions, and the core of giant planets, may be the most extreme state of matter created on Earth. Now scientists at the U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory (PPPL), building on nearly a decade of collaboration with the National Ignition Facility (NIF) at the DOE's Lawrence Livermore National Laboratory (LLNL), have designed a novel X-ray crystal spectrometer to provide high-resolution measurements of a challenging feature of NIF-produced HED plasmas.

Most powerful lasers

The collaboration with NIF, home to the world's largest and most powerful lasers, represents a major expansion for PPPL's X-ray crystal spectrometer designs, which are used by fusion laboratories around the world to record on detectors the spectrum of X-rays from the plasma - gases of electrons and atomic nuclei, or ions -- that fuel fusion reactions. These PPPL instruments measure profiles of key parameters such as the ion and electron temperatures in large volumes of hot plasmas that are magnetically confined in doughnut-shaped tokamak fusion devices to facilitate fusion reactions. By contrast, NIF laser-produced HED plasmas are tiny, point-like substances that require differently designed spectrometers for high-resolution studies.

"We previously built a spectrometer for the NIF that has been quite successful," said physicist Manfred Bitter, a long-time member of the PPPL design team. That spectrometer, delivered in 2017, provides high-resolution measurements of the temperature and density of NIF extreme plasmas for inertial confinement fusion experiments, and the data obtained have been presented in invited talks and peer-reviewed publications.

The HED experiments differ from the magnetically confined experiments that PPPL conducts in many respects. A major difference that affects the design of spectrometers is the small size of laser-produced HED plasmas, whose volumes are typically on the order of a cubic millimeter and can be considered as point-like X-ray sources. This small size compares with extended tokamak plasmas, which have volumes of several cubic meters and require very different diagnostic designs.

New design challenges

PPPL's new spectrometer for the NIF responds to new design challenges. They call for measuring a fine structure in the X-ray spectra of HED plasmas that reveals their state of matter under extreme conditions. Such measurements can show whether the ions in the highly-compressed plasma are in a random, or fluid-like arrangement, or in a more ordered lattice-like arrangement that is typical for a solid.

This critical state of matter can be detected in what is called the Extended X-ray Absorption Fine-Structure (EXAFS) -- the technical term for the tiny intensity variations, or wiggles, in the X-ray energy spectrum recorded by crystal spectrometers. "The standard crystal forms which have been used for the diagnosis of HED plasmas, so far, cannot be used in this case," said Bitter, lead author of a paper in the Review of Scientific Instruments that describes the PPPL spectrometer being fabricated for the NIF. "Their resolution and photon throughput are not high enough and they introduce imaging and other errors."

These are the challenges the new crystal spectrometer must meet, Bitter said:

To reduce statistical errors, the design must be adapted to a high throughput of photons, the particles of light that X-ray sources and all other light sources emit. The X-ray reflecting crystal must therefore have a large area without introducing any of the imaging errors that large standard crystals tend to produce.

The crystal must reflect the wide range of X-ray energies over which the fine structure is observed.

Finally, the crystal and detector arrangements must minimize the effects of what is called source-size broadening. This problem results from the tiny, but not negligible, size of a laser-produced HED plasma that deteriorates, or muddles, the spectral resolution. The standard crystal forms that have been used until now cannot fully eliminate or minimize these broadening effects.

Bitter and PPPL physicist Novimir Pablant worked together to design the new spectrometer. Bitter came up with the idea of shaping the crystal that mirrors the spectrum in the form of what is called a sinusoidal spiral. These spirals denote a family of curves whose shapes can be determined to assume any real value, making it possible to select a special shape of crystal. Pablant, who co-authored the Review of Scientific Instruments paper, created a computer code to design the sinusoidal crystal in a process that he outlines in a recently submitted companion paper to the same journal.

"I developed a code that would allow me to model the complicated 3-D shape of the crystal and simulate the performance of this new spectrometer design," Pablant said. The simulations showed that the performance of the crystal marked "a five-times improvement in energy resolution for this NIF project compared to their previous spectrometer design."

The collaboration will move to NIF in October when the new spectrometer is scheduled for testing there, with researchers at both laboratories eagerly awaiting the results. "Experiments at the NIF that measure the EXFAS spectrum at high X-ray energies have had low signals," said Marilyn Schneider, leader of the Radiative Properties Group at the Physics and Life Sciences Directorate of LLNL and a co-author of the paper. "The spectrometer design described in the paper concentrates the low signal and increases the signal-to-noise ratio while maintaining the high resolution required for observing EXAFS," she said.

Experimental verification is the next step required. "We arrived at this design after several attempts and are confident that it will work," said Bitter. "But we have not yet tested the design at NIF and must see how it performs in the fall."