Culture

Oncotarget published "Frame-shift mediated reduction of gain-of-function p53 R273H and deletion of the R273H C-terminus in breast cancer cells result in replication-stress sensitivity" which reported that these authors recently documented that gain-of-function mutant p53 R273H in triple negative breast cancer cells interacts with replicating DNA and PARP1. The missense R273H GOF mtp53 has a mutated central DNA binding domain that renders it unable to bind specifically to DNA, but maintains the capacity to interact tightly with chromatin.

Both the C-terminal domain and oligomerization domain of GOF mtp53 proteins are intact and it is unclear whether these regions of mtp53 are responsible for chromatin-based DNA replication activities.

These included a frame-shift mtp53 R273Hfs387, which depleted mtp53 protein expression; mtp53 R273HΔ381-388, which had a small deletion within the CTD; and mtp53 R273HΔ347-393, which had both the OD and CTD regions truncated.

The mtp53 R273HΔ347-393 existed exclusively as monomers and disrupted the chromatin interaction of mtp53 R273H.

Taken together these Oncotarget findings show that the CTD and OD domains of mtp53 R273H play critical roles in mutant p53 GOF that pertain to processes associated with DNA replication.

Taken together these Oncotarget findings show that the CTD and OD domains of mtp53 R273H play critical roles in mutant p53 GOF that pertain to processes associated with DNA replication.

Dr. Jill Bargonetti said "The p53 tumor suppressor protein is well known as a transcription factor but p53 also has transcription independent functions."

While tumor-derived missense mtp53 proteins have altered functions they contain the two N-terminal transactivation domains, followed by a proline rich domain, an altered central DNA binding domain, and the oligomerization domain and the C-terminal regulatory domain.

Herein they further examine the ability of mtp53 R273H, and its OD and CTD regions, to influence cell proliferation, DNA replication, and cell cycle progression of breast cancer cells.

The choice to investigate a potential role for the OD and CTD domains within the context of the mtp53 R273H allele was two-fold:

They delineated the above GOF pathway in this background and in parallel with the studies reported, worked to generate more tools to elucidate the role of each domain in mtp53 GOF activity;
Their pursuit of a genetic approach using CRISPR-Cas9 technology to create specific alterations within each domain necessitated that we focus first on one mtp53 R273H expressing-cell line.

They saw that a frameshift mutation in C-terminal end of mtp53 reduced stable mtp53 R273H protein levels compared to the parental MDA-MB-468 cells, reduced cell proliferation, and reduced the chromatin association of replication proteins that mirrored their slow progression through S-phase.

The CRISPR-Cas9 targeting also produced cell clones with C-terminal truncated mtp53 R273H proteins; such cells with truncated mtp53 R273H showed decreased proliferation as compared to the parental cells but progressed through S phase in a similar manner.

The Bargonetti Research Team concluded in their Oncotarget Research Output that their current studies do not point to a specific function executed by the OD and CTD domains in response to thymidine; however, they can show that their loss does not impact replisome assembly at the onset of S-phase as measured by PCNA chromatin loading and they will address this finding in the future.

Thus, OD and CTD domain function(s) correlate with events post S-phase entry, in contrast with that function conferred by other p53 domain(s) deficient in the mtp53fs387 cell line, whose loss impedes S-phase entry. Although currently the authors are unable to articulate the precise roles of these distinct regions of p53 in response to thymidine, their studies suggest that they may function at temporally distinct stages of S-phase.

AMES, Iowa - A new study led by an Iowa State University scientist sheds light on how organisms have evolved to address imbalances in sex chromosomes.

The study looks at a species of softshell turtle, but the results could help to illuminate an important evolutionary process in many species, said Nicole Valenzuela, professor of ecology, evolution and organismal biology and lead author of the study.

Many organisms determine their sex by a pair of specialized chromosomes that appear in virtually every cell of an organism's body. A matched pair of chromosomes results in one sex, while a mismatched pair results in another sex. For instance, in humans and many other species, sex chromosomes are referred to as X and Y. Typically, two X chromosomes result in a female while XY chromosomes result in males. These chromosomes also contain the genetic codes for the production of essential proteins, and the disproportion in chromosomes in XY individuals caused by them carrying only a single X for every pair of non-sex chromosomes (called autosomes) can lead to an imbalance in the production of proteins. The study sheds light on how organisms have evolved to address such imbalances through a process called sex chromosome dosage compensation, or SCDC.

The study focused on a species of softshell turtle known as Apalone spinifera, which are among the largest of freshwater turtles and inhabit a large portion of North America, including Iowa. But the research could help scientists understand the process in other organisms as well. The study also could generate better understanding of how disease can arise if the SCDC process doesn't function correctly.

"Understanding the diversity of SCDC mechanisms in nature, how they happen and evolve, informs more broadly on how animals and humans compensate for gene dose imbalance, and why the failure to properly compensate for these differences leads to disease states," Valenzuela said.

The study was published this week in the peer-reviewed scientific journal Philosophical Transactions of the Royal Society B.

What is sex chromosome dosage compensation?

Sex chromosome dosage compensation comes into play for individuals who have mismatched sex chromosomes. In the case of the softshell turtles included in the study, the sex chromosomes are referred to as Z and W, and it's the females of the species who have mismatched, or ZW, chromosomes. That mismatch means they lack a second copy of the Z chromosome, unlike their male counterparts who have two Z chromosomes.

The Z chromosomes contain instructions for some of the proteins normally functioning cells should produce, and having only a single copy of a chromosome can result in a reduced amount of proteins produced, because protein production is often affected by the number of gene copies. More copies means more protein production. Thus, unevenness in the number of copies of genes that work together can lead to developmental, physiological or other disorders. But SCDC mechanisms work to upregulate, or increase the level, of protein production from genes in the single Z (or X) chromosomes. The importance of maintaining a proper balance is made evident by diseases caused by abnormal numbers of sex chromosomes, including Klinefelter syndrome and Turner syndrome in humans, and Valenzuela said these processes have evolutionary and health implications in many other organisms as well.

Valenzuela and her co-authors sampled softshell turtles at various stages of development, including embryos, young hatchlings and adults, and analyzed various tissues to determine which genes were activated. The researchers then compared the activity of genes from sex chromosomes and from autosomes, broken down by male and female turtles.

The study represents not only the first such study to analyze sex chromosome dosage compensation in turtles, but the findings also show that remarkably, temperature appears to affect the SCDC process in the turtles. Valenzuela has studied temperature-dependent sex determination (TSD), or the way environmental temperatures influence whether a turtle embryo develops into a male or female in species that lack sex chromosomes, in previous research. But because softshell turtles lost this ancestral TSD system, this thermal sensitivity in the SCDC came as a surprise, she said. And the way in which softshell turtles carry out SCDC is also unusual and complex.

The study found that both sexes of softshell turtles double the activity of the Zs in early embryonic development, which fixes the expression imbalance in ZW females (twice Z expression now matches autosomal expression). But this same response creates an imbalance in males (Z expression now doubles autosomal expression). At later embryonic stages, male Z expression decreases, and this effect is more pronounced at cooler than at warmer incubation temperatures, according to the study. Valenzuela said the new study is likely the first to show that temperature can impact SCDC not just in turtles, or in animals, but as broadly as in eukaryotes, or organisms in which genetic material is contained in a cell nucleus. Eukaryotic species include a huge range of organisms, including animals, plants and fungi.

Researchers created a global dataset of job footprints in 50 countries and used a model to investigate how trying to meet the Paris Agreement global climate target of staying well below 2°C would affect energy sector jobs. They found that action to reach said target would increase net jobs by about 8 million by 2050, primarily due to gains in the solar and wind industries. The analysis appears July 23 in the journal One Earth.

"Currently, an estimated 18 million people work in the energy industries--a number that is likely to increase, not decrease, to 26 million or by over 50% if we reach our global climate targets," says corresponding author Johannes Emmerling (@JohannesEmm), an environmental economist at the RFF-CMCC European Institute on Economics and the Environment in Italy. "Manufacturing and installation of renewable energy sources could potentially become about one third of the total of these jobs, for which countries can also compete in terms of location."

The study conducted by Emmerling and colleagues is the first based on a comprehensive dataset of over 50 countries, including major fossil fuel producing economies. The team combined this dataset with an integrated assessment model to make job projections. The model helps see how the development of humans and the choices societies make affect each other. Almost all previous analysis relied on jobs data for OECD countries and generalized the results for the rest of the world using a multiplier.

"The energy transition is increasingly being studied with very detailed models, spatial resolutions, timescales, and technological details," says Emmerling. "Yet, the human dimension, energy access, poverty, and also distributional and employment implications are often considered at a high level of detail. We contributed to this gap by collecting and applying a large dataset across many countries and technologies that can also be used in other applications."

In the researcher's model, of the total jobs in 2050, 84% would be in the renewables sector, 11% in fossil fuels, and 5% in nuclear. While fossil fuel extraction jobs, which constitute 80% of current fossil fuel jobs, would rapidly decline, these losses will be compensated by gains in solar and wind manufacturing jobs.

"Extraction sector jobs are more susceptible to decarbonization, so there needs to be just transition policies in place," says first author Sandeep Pai (@Sandeeppaii), who recently graduated with a Ph.D. in Resources, Environment, and Sustainability at The University of British Columbia. "For example, the mobility of manufacturing jobs will be useful in areas where decarbonization is rife. In many cases, fossil fuel workers also hold political influence because of their history and high rates of unionization among others, so as we move to low carbon sources, it is important to have a plan in place for the general acceptability of climate policies."

The researcher's next goal is to explore the shifts in skill levels, education requirements, and wages that may result from trying to meet the global climate target of the Paris Agreement. They also anticipate that, since this is accessible to all these different groups around the world, it will inspire other data analysts to use it for running multiple scenarios, further clarifying the extent of jobs.

Humid tropical forests, vital in global efforts to limit rising temperatures, are under threat as a result of changes in land use and climate. Now, researchers reporting in the journal One Earth on July 23 have developed a new way to keep tabs on the vulnerability of these forests on a global scale using satellite data. Called the tropical forest vulnerability index (TFVI), the hope is that this method will serve as an early warning for areas that are under the greatest threat to enable actions aimed at protecting these forests before it's too late.

"Frequent droughts, higher temperature, and longer dry seasons, along with increasing pressures from deforestation and degradation in the last two decades, have pushed the tropical rainforests to the verge of a tipping point," said Sassan Saatchi of NASA's Jet Propulsion Laboratory. "What we predicted using climate models a decade ago, we are observing on the ground. Now is the time to do something and not later. This work takes advantage of a suite of satellite observations made for the past few decades to show how and where the tipping points may be reached and to help policy makers plan for conservation and restoration of these forests."

There have been other ways to measure the vulnerability of rainforests. However, most of them relied on local studies and couldn't easily be extended to larger regions or the globe. This lack of consistency and ability to make comparisons from one region to another has led to confusion and inaction. To get around these stumbling blocks, Saatchi and colleagues set out to develop a unique tropical rainforest vulnerability index that could work across all rainforests based on observations of climate and vegetation from satellites.

The new index combines numerous measurements and indicators of forest ecological functions and services, including carbon and water fluxes and biodiversity. It also provides spatial information with monthly updates and allows researchers to identify and monitor areas with increasing vulnerability or potential threats before it's too late.

Their studies have shown that different regions of the tropics are responding differently to climate threats, with some regions showing more apparent resilience than others. For instance, forests in the Americas appear to be more vulnerable to stresses than those in Africa, where they are showing relative resilience to changing climate. In Asia, tropical forests appear more vulnerable to land use and fragmentation.

Individual rain forests also show important differences in their response to climate and land use pressures. For instance, the Amazon Basin shows large-scale vulnerability to drying condition in the atmosphere, with frequent droughts and large-scale land use changes. The Congo Basin, on the other hand, appears more resilient because of the historical impacts of droughts, the overall dryer condition, and smaller-scale land use change and fragmentation.

The researchers also uncovered strong interactions between climate, land use, and biodiversity that define the vulnerability and resilience of forests. The new index allowed them to identify the nature of these interactions over all global rainforests.

"The findings show that the vulnerability of rainforests is much larger than predicted in the past, and areas that are disturbed or fragmented have almost no resilience to climate warming and droughts," Saatchi said. "In addition, the results of our study suggest that rainforests are losing their capacity to cycle carbon and water as before. This is occurring gradually at the continental scale and more rapidly at the regional scale, with significant implications for the global carbon sink and climate."

The TFVI was developed by many scientists and conservationists assembled by the National Geographic Society and Rolex and therefore represents a consensus approach from the broader community, Saatchi notes. The hope is that the larger global community of scientists and policy makers, particularly in tropical countries, will now make use of the index to systematically assess the vulnerability of rainforest resources and to develop nature-based solutions to meet their commitments to the Paris Agreement. To keep tabs on future changes and threats to the world's tropical forests, the researchers say that the new index will continue to be renewed automatically as time goes on.

Recently, a research group led by Prof. YUAN Kaijun and Prof. YANG Xueming from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences revealed strong isotope effects in photodissociation of the water isotopologue (HOD) using the Dalian Coherent Light Source.

Their findings were published in Science Advances on July 23.

"Our experimental results illustrate dramatically different quantum state population distributions of OH and OD fragments from HOD photodissociation. The branching ratios of the H+OD and D+OH channels display large wavelength-dependent isotopic fractionation," said Prof. YUAN.

Because water is one of the most abundant species in the solar nebula, photodissociation of water and its isotopologue by solar vacuum ultraviolet photons may be an alternative source of the D/H isotope heterogeneity, and this effect must be considered in photochemical models.

The photochemical processes identified in this work may vary the D/H isotopic ratios in the inner and outer regions, and/or in different periods of the solar nebula, which may cause the D/H isotope heterogeneity in the solar system.

What The Study Did: Researchers investigated the association between net worth at midlife and subsequent longevity in individuals as well as with siblings and twins.

Authors: Eric D. Finegood, Ph.D., of Northwestern University in Evanston, Illinois, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamahealthforum.2021.1652)

Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: Using survey responses from students in some Pittsburgh, Pennsylvania, high schools, researchers investigated how experiences of bullying based on race/ethnicity/national origin and other marginalized identities are associated with outcomes for health, mental health and violence among adolescents.

Authors: Chardée A. Galán, Ph.D., of the University of Pittsburgh, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.16364)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Hershey, Pa. -- Financial instability, lack of infrastructure, a deteriorating sense of community and family fragmentation are key contributors to diseases of despair in Pennsylvania communities, according to Penn State College of Medicine and Highmark Health researchers. The researchers conducted four focus groups in Pennsylvania communities identified as having high rates of despair-related illnesses.

Diseases of despair are medical diagnoses involving alcohol-related disorders, substance-related disorders and suicidal thoughts and behavior. Princeton economists Anne Case and Angus Deaton proposed the concept of deaths of despair in 2015 after observing a decline in life expectancy of middle-aged white men and women between 1999 and 2015 -- the first such decline since the flu pandemic of 1918. They theorized that this decline is associated with the social and economic downturn in rural communities and small towns over the last several decades, leading to feelings of despair and loss of hope for the future.

"The crisis in recent years has broadened past this initial demographic that Case and Deaton established, and we are now seeing rising excess mortality in other groups of working-class Americans, including people of color," Daniel George, associate professor of humanities and public health sciences, Penn State College of Medicine, said. George is a researcher with a Penn State Clinical and Translational Science Institute project looking at diseases of despair in Pennsylvania.

The first phase of this project analyzed Highmark Health insurance claims and found that the rate of diagnoses related to diseases of despair -- alcohol-related disorders, substance-related disorders and suicidal thoughts and behaviors -- increased significantly in the past decade.

"Nearly one in 20 people in the study sample of 12 million people were diagnosed with a disease of despair in our earlier research," Emily Brignone, Highmark Health, said. "Following Case and Deaton's findings, we saw the most substantial percentage increase in disease of despair diagnoses among men ages 35 to 74, followed by women ages 55 to 74 and 18 to 34. The issue is one of great importance that we are proud to be addressing with Penn State."

Using the data from the first study, the researchers then identified hotspots in Pennsylvania with a high rate of diagnoses related to diseases of despair for the second phase of the project. A disease of despair rate was determined by dividing the number of unique members with a qualifying diagnosis during that year by the total number of members. Researchers selected communities in Dauphin and Lebanon counties and conducted focus groups through existing community partnerships. Researchers report their results in the journal JAMA Network Open.

"Most of the research on deaths and diseases of despair have been at the epidemiological level; in other words, looking at large data sets and trying to identify patterns over time," George said. "There has been less done qualitatively - basically exploring the perceptions and beliefs of people who are affected by diseases of despair, trying to understand what is happening on the ground."

Four focus groups included a total of 60 participants. Focus group members were both residents and community health workers who interact with those affected by diseases of despair. The research team analyzed transcripts of the focus groups to identify themes.

The first theme researchers identified was the role of financial instability and how United States domestic policy contributes to self-harming behavior.

"One of the main findings was that financial distress is at the heart of it," George said. "It is something that has been driving instability in people's lives and increases the risk for drug abuse and escape through drugs and drink. People identified jobs with full benefits and a living wage not being as available as they used to be and people having to choose groceries over medical care and their anti-anxiety medications."

The second theme that researchers identified was a lack of infrastructure, especially in rural communities.

"Focus group participants noted a lack of public transportation that could help people get to their jobs or to their health care appointments, and the role that played in compounding distress in people's lives," George said. "They also identified failures in our school systems that were resulting in schools not preparing kids to have trades or skills to make them competitive in a 21st-century economy."

The third theme that researchers identified was a deteriorating sense of community. Participants discussed fragmentation over the last several decades that has led to rising isolation and distrust, and a lack of neighborly support. These trends have been worsened, in part, by social media.

"There was a really interesting perception that there has just been a general decline in the community," George said. "There is more loneliness, more alienation, a loss of trust among people, less neighborly interactions. People talked about just feeling an absence of actual human connection online with technology and electronic devices, and that it has taken the place of tangible, real human connection-- and that that compounds loneliness."

The final theme researchers identified was the fragmentation of the family.

"There is more pressure on two-earner families, and that was leading to kids being less bio-psychosocially developed and leaving home at greater risk for despair-related behaviors," George said.

Researchers will next consider potential solutions, including the role of health care facilities in identifying despair-related risk factors, partnerships with community organizations that work with those most at risk and the use of big data analysis and machine learning to identify at-risk communities and guide state-level policy changes. Focus group attendees shared their beliefs that more needed to be done at the local and state levels to address the causes of despair, including non-profit initiatives, peer support, infrastructure building, economic development and rebuilding a sense of community as well as social safety nets.

"A key message is really that we do not want to blame the victims here," George said. "Despair is something that is an indictment of the way that we have organized our society rather than a personal failing or an individuated sense of despair that somebody may feel. People are responding to objectively worsening material circumstances in their lives. What we are trying to do with the diseases of despair construct is essentially create a parameter whereby we can measure it, study it, try to understand what is going on and then address root causes."

University of Virginia School of Medicine researchers have discovered a previously unknown repair process in the brain that they hope could be harnessed and enhanced to treat seizure-related brain injuries.

Common seizure-preventing drugs do not work for approximately a third of epilepsy patients, so new and better treatments for such brain injuries are much needed. UVA's discovery identifies a potential avenue, one inspired by the brain's natural immune response.

Using high-powered imaging, the researchers were able to see, for the first time, that immune cells called microglia were not just removing damaged material after experimental seizures but actually appeared to be healing damaged neurons.

"There has been mounting generic support for the idea that microglia could be used to ameliorate seizures, but direct, visualized evidence for how they could do this has been lacking," said researcher Ukpong B. Eyo, PhD, of UVA's Department of Neuroscience, the UVA Brain Institute and UVA's Center for Brain Immunology and Glia (BIG). "Our results indicate that microglia may not be simply clearing debris but providing structural support for neuronal integrity that may have implications even beyond the scope of seizures and epilepsy."

A Surprising Response to Seizures

The new findings come from a collaboration of scientists at UVA, Mayo Clinic and Rutgers University. They used an advanced imaging technique called two-photon microscopy to examine what happened in the brains of lab mice after severe seizures. What they saw was strange and unexpected.

Rather than simply cleaning up debris, the microglia began forming pouches. These pouches didn't swallow up damaged material, as many immune cells do. Instead, they began tending to swollen dendrites - the branches of nerve cells that transmit nerve impulses. They weren't removing, the scientists realized; they appeared to be healing.

These odd little pouches - the scientists named them "microglial process pouches" - stuck around for hours. They often shrank, but they were clearly doing something beneficial because the dendrites they targeted ended up looking better and healthier than those they didn't.

"We did not find microglia to be 'eating' the neuronal elements in this context," Eyo said. "Rather, we saw a strong correlation between these interactions and a structural resolution of injured neurons suggestive of a 'healing' process."

The new insights into the brain's immune response points scientists in promising new directions. "Although these findings are exciting, there is yet a lot to follow-up on them. For example, the precise mechanisms that regulate the interactions remain to be identified. Moreover, at present, the 'healing' feature is suggested from correlational results and more definitive studies are required to certify the nature of the 'healing,'" Eyo said. "If these questions can be answered, they will provide a rationale for developing approaches to enhance this process ... in seizure contexts."

Eyo has already received two grants totaling almost $5 million from the National Institutes of Health to continue his study of microglia. The funding will allow him to study how the immune cells help regulate vascular function, which could be important in diseases such as Alzheimer's, and their role in brain-hyperactivity disorders such as febrile seizures that can trigger epilepsy.

"With this new funding, we are eager to clarify roles for microglia in seizure disorders and vascular function," he said. "UVA's continued investment is neuroscience research provides a suitable home for our lab's research."

Many disease-causing bacteria such as Pseudomonas aeruginosa crawl on surfaces through a walk-like motility known as "twitching". Nanometers-wide filaments called type IV pili are known to power twitching, but scientists ignore which sensory signals coordinate the microbes' movements.

Now, EPFL researchers have found that Pseudomonas bacteria use a mechanism similar to our sense of touch to navigate on surfaces. "This study changes the way we think about motility in bacteria," says senior author Alexandre Persat, a tenure track assistant professor at EPFL's School of Life Sciences.

Scientists have known that cells from humans and other animals can direct themselves in the direction of stiffer or looser surfaces, but it was unclear whether bacteria could also guide their movement based on mechanical force, Persat says. That's because most studies have focused on identifying mechanisms that guide bacteria to swim towards chemicals such as food, a phenomenon known as chemotaxis.

Research in the Persat lab has instead focused on how bacteria sense and respond to mechanical forces. Previous studies showed that Pseudomonas' pilus works like a harpoon: after it extends and touches a surface, the pilus activates a molecular motor that retracts the filament, thus propelling the cell forward.

To understand what coordinates the pili motors, researchers in the Persat group and their collaborators at the University of California, San Francisco, looked at how individual Pseudomonas bacteria move on surfaces such as the bottom of a laboratory dish. The team suspected that a network of proteins called Chp system regulates twitching, so they analyzed bacteria that lacked different components of the Chp system. Some of these mutant bacteria could barely move as they kept twitching back and forth; others always moved forward, even when they bumped into an obstacle.

By combining fluorescent tags with a microscopy technique that helps to look at single pili in living cells, the researchers found that one messenger protein activates the pili to extend, propelling the cell forward, whereas another protein inhibits the formation of pili at the front of the moving cell. The two opposing messengers aren't found in the same place within the cell. "The activator localizes to the front, where the cell feels the surface with its pili, while the inhibitor localizes everywhere else," says study co-first author Marco Ku?hn.

When bacteria bump into an obstacle such as another cell, the inhibitor allows them to stop and change direction, the researchers found. "This helps the cells navigate based on what they feel in front of them -- like a blind person using a white cane," Persat says. The ability to sense the surrounding environment is useful when bacteria move as a group, he adds, as it helps the microbes to all crawl forward in the same direction.

The findings, published in PNAS, shed light on how bacteria move and could have important implications for human health. Pseudomonas aeruginosa, an opportunistic pathogen that is commonly found in soil, is a leading cause of hospital-acquired infections. Aggregates of Pseudomonas bacteria typically form on surfaces such as catheters and respirators and can be extremely resistant to disinfectants and antimicrobial drugs.

What's more, past research from the Persat group showed that Pseudomonas uses its pili to regulate the secretion of toxins. For this reason, understanding more about the microbes' "sense of touch" could help to develop new therapeutic strategies, Persat says.

Next, the researchers aim to uncover how the bacteria convert a mechanical stimulus into a cellular response, says study co-first author Lorenzo Talà. "We would like to understand the molecular mechanism behind the [bacteria's] sense of touch," he says.

How does a view of nature gain its gloss of beauty? We know that the sight of beautiful landscapes engages the brain's reward systems. But how does the brain transform visual signals into aesthetic ones? Why do we perceive a mountain vista or passing clouds as beautiful? A research team from the Max Planck Institute for Empirical Aesthetics has taken up this question and investigated how our brains proceed from merely seeing a landscape to feeling its aesthetic impact.

In their study, the research team presented artistic landscape videos to 24 participants. Using functional magnetic resonance imaging (fMRI), they measured the participants' brain activity as they viewed and rated the videos. Their findings have just been published in the open-access journal Frontiers in Human Neuroscience. First author A. Ilkay Isik encapsulates:

"We would have expected the aesthetic signals to be limited to the brain's reward systems, but surprisingly, we found them already present in visual areas of the brain while the participants were watching the videos. The activations occurred right next to brain regions deployed in recognizing physical features in movies, such as the layout of a scene or the presence of motion."

Senior author Edward Vessel suggests that these signals may reflect an early, elemental form of beauty perception:

"When we see something beyond our expectations, local patches of brain tissue generate small 'atoms' of positive affect. The combination of many such surprise signals across the visual system adds up to make for an aesthetically appealing experience."

With this new knowledge, the study not only contributes to our understanding of beauty, but may also help clarify how interactions with the natural environment can affect our sense of well-being. The results might have potential applications in a variety of fields where the link between perception and emotion is important, such as clinical health care and artificial intelligence.

Alexandria, Va., USA - Ruth Lipman, American Dental Association (ADA) Science and Research Institute, Chicago, Ill., U.S., presented the poster "Strategies for Disseminating Guidance to Dentists during the COVID-19 Pandemic" at the virtual 99th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 50th Annual Meeting of the American Association for Dental Research (AADR) and the 45th Annual Meeting of the Canadian Association for Dental Research (CADR), on July 21-24, 2021.

Rapidly formulated, actionable infection risk mitigation strategies for dental care professionals were needed during the initial acceleration phase of the COVID-19 pandemic. Between March 2020 and February 2021, the content developed by the ADA to address dentists' needs for COVID-19 related practice guidance has been cataloged. Insight about the strategies and approaches to their formulation, intended use, publication/posting date and utility as assessed by number of downloads and visits from ADA.org was evaluated with respect to the chronology of the pandemic.

The ADA established a centralized hub online to disseminate the latest COVID-19 evidence, policy and guidance. In April 2020, the ADA received more than 2,360 COVID-19 related member queries. Initial ADA guidance to mitigate virus transmission relied on information about safety considerations extrapolated from medical rather than dental settings to produce several decision algorithms (16,529 downloads) and a reference document (22,176 downloads) citing supporting information sources.

The initial guidance algorithms were for provision of urgent and emergency care and addressed patient screening, use of professional protective equipment, operatory disinfection and patients' treatment. A companion document that defined urgent and emergency care (58,551 downloads) was reviewed by the ADA Board of Trustees. As restrictions on provision of dental care were lifted, increased member volunteer engagement was considered prudent to better ensure the relevance and feasibility of the guidance informing about a more comprehensive range of dental care. The resultant return-to-work toolkit (32,441 downloads) has been accessed more than 640,370 times.

This presentation summarizes and evaluates the clinical guidance and other evidence-based resources developed for dentists and patients by the American Dental Association (ADA) during the COVID-19 pandemic.

A new optogenetic tool, a protein that can be controlled by light, has been characterized by researchers at Ruhr-Universität Bochum (RUB). They used an opsin - a protein that occurs in the brain and eyes - from zebrafish and introduced it into the brain of mice. Unlike other optogenetic tools, this opsin is not switched on but rather switched off by light. Experiments also showed that the tool could be suitable for investigating changes in the brain that are responsible for the development of epilepsy.

The teams led by Professor Melanie Mark from the Behavioural Neurobiology Research Group and Professor Stefan Herlitze from the Department of General Zoology and Neurobiology describe the experiments and results in the journal Nature Communications, published online on 23 July 2021.

Role assumed in various conditions

The opsin Opn7b is a G protein-coupled receptor which is found in zebrafish. Unlike many other light-activated G protein-coupled receptors, it can be activated without a light stimulus and is thus permanently active; researchers call this constitutively active. Normally, activation of G protein-coupled receptors leads to an opening of certain ion channels and thus to the influx of ions into the cell as well as to further signalling processes in the cell. In the case of Opn7b, light deactivates this permanently active signalling chain.

Little research has so far been conducted on G protein-coupled receptors that are activated without stimulation, although it is presumed that they play a role in various neuropsychiatric conditions and night blindness. They also appear to be involved in the development of virally induced cancers.

Receptor characterized more precisely

Dr. Raziye Karapinar, Dr. Ida Siveke and Dr. Dennis Eickelbeck characterized the function of Opn7b in detail and, to their surprise, identified that the receptor is deactivated by light. In contrast, conventional optogenetic tools are switched on by light.

The researchers consider Opn7b well-suited to gain further insights into the function of G protein-coupled receptors that are constitutively active - and obtain new knowledge of their role in the development of diseases in which the receptors can be examined in a time-controlled manner in specific cell types.

Epileptic seizures

The Bochum researchers Dr. Jan Claudius Schwitalla and Johanna Pakusch changed certain cells in the cerebral cortex of mice in such a way that they produced Opn7b. If they deactivated the receptor with light, it triggered epileptiform activity in the animals, which could be specifically controlled with light and interrupted with the help of other light-controlled proteins. The researchers hope that it will be possible to use this optogenetic tool to understand more precisely both the underlying mechanisms and the timescales in the development of epileptic seizures.

As the SARS-CoV-2 virus that causes COVID-19 continues to evolve, immunologists and infectious diseases experts are eager to know whether new variants are resistant to the human antibodies that recognized initial versions of the virus. Vaccines against COVID-19, which were developed based on the chemistry and genetic code of this initial virus, may confer less protection if the antibodies they help people produce do not fend off new viral strains. Now, researchers from Brigham and Women's Hospital and collaborators have created an "atlas" that charts how 152 different antibodies attack a major piece of the SARS-CoV-2 machinery, the spike protein, as it has evolved since 2020. Their study, published in Cell, highlights antibodies that are able to neutralize the newer strains, while identifying regions of the spike protein that have become more resistant to attack.

"Emerging data show that vaccines still confer some protection from new SARS-CoV-2 variants, and our study shows how that works from an antibody standpoint," said corresponding author Duane Wesemann, MD, PhD, of the Division of Allergy and Clinical Immunology and Division of Genetics at the Brigham and an associate professor at Harvard Medical School. "These data can help us think about what the best kind of booster vaccine might be by studying how the repertoire of human antibodies recognizes the spike protein."

The researchers examined the antibody-producing Memory B cells of 19 patients who were infected with SARS-CoV-2 in March of 2020, before the emergence of new variants. They studied how these antibodies, as well as other antibodies that have been characterized by researchers, bind to spike protein models of the B.1.1.7 (Alpha), B.1351 (Beta) and P.1 (Gamma) variants of SARS-CoV-2, which were first identified in the United Kingdom, South Africa, and Brazil, respectively. An analysis of the Delta variant is currently underway.

Overall, the authors confirmed that the hundreds of antibodies they studied largely bind to seven major "footprints" on the spike protein. While many of these antibodies "compete" to bind to the same regions of the early version of the SARS-CoV-2 spike protein, when it comes to newer strains, some of these antibodies lose their potency while others emerge as broadly responsive neutralizers.

In particular, antibodies binding to two of these spike protein regions, dubbed RBD-2 and NTD-1, were the most potent neutralizers of initial forms of the spike protein. The B.1.351 spike variant proved to exhibit the greatest ability to evade existing antibody arsenals, escaping many RBD-2- and NTD-1-binding antibodies. Some antibodies binding another region, called S2-1, could recognize spike proteins from more distantly related viruses such as MERS, SARS, and common cold coronaviruses.

"Making different antibodies that compete for one region of the virus allows the immune system to be more flexible," Wesemann said. "Otherwise-redundant recognition by antibodies targeting the same footprint of one version of the virus confers recognition depth of the same footprint on variants, and some antibodies maintain high neutralization potency against all the variants. Now that we can identify the antibodies that are more broadly reactive to all of the variants, we can think about how to elicit them more strongly in a vaccine."

The body's first encounter with SARS-CoV-2, the virus behind COVID-19, happens in the nose and throat, or nasopharynx. A new study in the journal Cell suggests that the first responses in this battleground help determine who will develop severe disease and who will get through with mild or no illness.

Building on work published last year identifying SARS-CoV-2-susceptible cells, a team of collaborators at Boston Children's Hospital, MIT, and the University of Mississippi Medical Center comprehensively mapped SARS-CoV-2 infection in the nasopharynx. They obtained samples from the nasal swabs of 35 adults with COVID-19 from April to September 2020, ranging from mildly symptomatic to critically ill. They also got swabs from 17 control subjects and six patients who were intubated but did not have COVID-19.

"Why some people get more sick than others has been one of the most puzzling aspects of this virus from the beginning," says José Ordovás-Montañés, PhD, of Boston Children's, co-senior investigator on the study with Bruce Horwitz, MD, PhD of Boston Children's, Alex K. Shalek, PhD, of MIT and Sarah Glover, DO, of the University of Mississippi. "Many studies looking for risk predictors have looked for signatures in the blood, but blood may not really be the right place to look."

COVID-19's first battlefield: the nasopharynx

To get a detailed picture of what happens in the nasopharynx, the researchers sequenced the RNA in each cell, one cell at a time. (For a sense of all the work this entailed, each patient swab yielded an average of 562 cells.) The RNA data enabled the team to pinpoint which cells were present, which contained RNA originating from the virus -- an indication of infection -- and which genes the cells were turning on and off in response.

It soon became clear that the epithelial cells lining the nose and throat undergo major changes in the presence of SARS-CoV-2. The cells diversified in type overall. There was an increase in mucus-producing secretory and goblet cells. At the same time, there was a striking loss of mature ciliated cells, which sweep the airways, together with an increase in immature ciliated cells (which were perhaps trying to compensate).

The team found SARS-CoV-2 RNA in a a diverse range of cell types, including immature ciliated cells and specific subtypes of secretory cells, goblet cells, and squamous cells. The infected cells, as compared to the uninfected "bystander" cells, had more genes turned on that are involved in a productive response to infection.

A failed early immune response

The key finding came when the team compared nasopharyngeal swabs from people with different severity of COVID-19 illness:

In people with mild or moderate COVID-19, epithelial cells showed increased activation of genes involved with antiviral responses -- especially genes stimulated by type I interferon, a very early alarm that rallies the broader immune system.

In people who developed severe COVID-19, requiring mechanical ventilation, antiviral responses were markedly blunted. In particular, their epithelial cells had a muted response to interferon, despite harboring high amounts of virus. At the same time, their swabs had increased numbers of macrophages and other immune cells that boost inflammatory responses.

"Everyone with severe COVID-19 had a blunted interferon response early on in their epithelial cells, and were never able to ramp up a defense," says Ordovás-Montañés. "Having the right amount of interferon at the right time could be at the crux of dealing with SARS-CoV-2 and other viruses."

Boosting interferon responses in the nose?

As a next step, the researchers plan to investigate what is causing the muted interferon response in the nasopharynx, which evidence suggests may also occur with the new SARS-CoV-2 variants. They will also explore the possibility of augmenting the interferon response in people with early COVID-19 infections, perhaps with a nasal spray or drops.

"It's likely that, regardless of the reason, people with a muted interferon response will be susceptible to future infections beyond COVID-19," Ordovás-Montañés says. "The question is, 'How do you make these cells more responsive?'"