Culture

For the first time, scientists have introduced minuscule tracking devices directly into the interior of mammalian cells, giving an unprecedented peek into the processes that govern the beginning of development.

This work on one-cell embryos is set to shift our understanding of the mechanisms that underpin cellular behaviour in general, and may ultimately provide insights into what goes wrong in ageing and disease.

The research, led by Professor Tony Perry from the Department of Biology and Biochemistry at the University of Bath in the UK, involved injecting a silicon-based nanodevice together with sperm into the egg cell of a mouse. The result was a healthy, fertilised egg containing a tracking device.

The tiny devices are a little like spiders, complete with eight highly flexible 'legs'. The legs measure the 'pulling and pushing' forces exerted in the cell interior to a very high level of precision, thereby revealing the cellular forces at play and showing how intracellular matter rearranged itself over time.

The nanodevices are incredibly thin - similar to some of the cell's structural components, and measuring 22 nanometres, making them approximately 100,000 times thinner than a pound coin. This means they have the flexibility to register the movement of the cell's cytoplasm as the one-cell embryo embarks on its voyage towards becoming a two-cell embryo.

"This is the first glimpse of the physics of any cell on this scale from within," said Professor Perry. "It's the first time anyone has seen from the inside how cell material moves around and organises itself."

WHY PROBE A CELL'S MECHANICAL BEHAVIOUR?

The activity within a cell determines how that cell functions, explains Professor Perry. "The behaviour of intracellular matter is probably as influential to cell behaviour as gene expression," he said. Until now, however, this complex dance of cellular material has remained largely unstudied. As a result, scientists have been able to identify the elements that make up a cell, but not how the cell interior behaves as a whole.

"From studies in biology and embryology, we know about certain molecules and cellular phenomena, and we have woven this information into a reductionist narrative of how things work, but now this narrative is changing," said Professor Perry. The narrative was written largely by biologists, who brought with them the questions and tools of biology. What was missing was physics. Physics asks about the forces driving a cell's behaviour, and provides a top-down approach to finding the answer.

"We can now look at the cell as a whole, not just the nuts and bolts that make it."

Mouse embryos were chosen for the study because of their relatively large size (they measure 100 microns, or 100-millionths of a metre, in diameter, compared to a regular cell which is only 10 microns [10-millionths of a metre] in diameter). This meant that inside each embryo, there was space for a tracking device.

The researchers made their measurements by examining video recordings taken through a microscope as the embryos developed. "Sometimes the devices were pitched and twisted by forces that were even greater than those inside muscle cells," said Professor Perry. "At other times, the devices moved very little, showing the cell interior had become calm. There was nothing random about these processes - from the moment you have a one-cell embryo, everything is done in a predictable way. The physics is programmed."

The results add to an emerging picture of biology that suggests material inside a living cell is not static, but instead changes its properties in a pre-ordained way as the cell performs its function or responds to the environment. The work may one day have implications for our understanding of how cells age or stop working as they should, which is what happens in disease.

The study is published this week in Nature Materials and involved a trans-disciplinary partnership between biologists, materials scientists and physicists based in the UK, Spain and the USA.

The study is published this week in Nature Materials and involved a trans-disciplinary partnership between embryologists in Bath and the USA led by Professor Perry, and materials scientists and physicists led by Professor José Antonio Plaza at the Instituto de Microelectrónica de Barcelona (IMB-CNM) in Spain.

Scientists at the U.S. Department of Energy's National Renewable Energy Laboratory (NREL) report a breakthrough in developing a next-generation thermochromic window that not only reduces the need for air conditioning but simultaneously generates electricity.

Heat generated by sunlight shining through windows is the single largest contributor to the need for air conditioning and cooling in buildings. Because residential and commercial buildings use 74% of all electricity and 39% of all energy in the United States, the shading effect from tinting windows helps buildings use less energy.

The technology, termed "thermochromic photovoltaic," allows the window to change color to block glare and reduce unwanted solar heating when the glass gets warm on a hot, sunny day. This color change also leads to the formation of a functioning solar cell that generates on-board power. Thermochromic photovoltaic windows can help buildings turn into energy generators, increasing their contribution to the broader energy grid's needs. The newest breakthrough now enables myriad colors and a broader range of temperatures that drive the color switch. This increases design flexibility for improving energy efficiency as well as control over building aesthetics that is highly desirable for both architects and end users.

The research builds upon earlier work at NREL into a thermochromic window that darkened as the sun heated its surface. As the window shifted from transparent to tinted, perovskites embedded within the material generated electricity. Perovskites are a crystalline structure shown to have remarkable efficiency at harnessing sunlight.

"A prototype window using the technology could be developed within a year," said Bryan Rosales, a postdoctoral researcher at NREL and lead author of the paper, "Reversible Multicolor Chromism in Layered Formamidinium Metal Halide Perovskites," which appears in the journal Nature Communications. His co-authors from NREL are Lance Wheeler, who developed the first thermochromic photovoltaic window, Taylor Allen, David Moore, Kevin Prince, Garry Rumbles, and Laura Schelhas. Other authors are Laura Mundt from SLAC National Accelerator Laboratory, and Colin Wolden from Colorado School of Mines.

The first-generation solar window was able to switch back and forth between transparent and a reddish-brown color, requiring temperatures between 150 degrees and 175 degrees Fahrenheit to trigger the transformation. The latest iteration allows a broad choice of colors and works at 95 degrees to 115 degrees Fahrenheit, a glass temperature easily achieved on a hot day.

By using a different chemical composition and materials, the researchers also were able to rapidly speed up the color transformation. The time was reduced to about seven seconds from the three minutes it took during the proof-of-concept thermochromic photovoltaic window demonstrated in 2017.

The scientists sandwiched a thin perovskite film between two layers of glass and injected vapor. The vapor triggers a reaction that causes the perovskite to arrange itself into different shapes, from a chain to a sheet to a cube. The colors emerge with the changing shapes. Lowering the humidity returns the perovskite to its normal transparent state.

A model that can calculate a person's risk of becoming infected and then seriously ill due to COVID-19 has been shown to accurately estimate risk during the first wave of the pandemic in England, in new research funded by the National Institute for Health Research (NIHR).

The model, developed using routine anonymised data from more than 8 million adults in 1205 general practices across England, uses a number of factors such as a person's age, ethnicity and existing medical conditions to predict their risk of catching COVID-19 and then dying or being admitted to hospital.

The model has the potential to provide doctors and the public with more nuanced information about risk of serious illness due to COVID-19, and to help patients and doctors reach a shared understanding of risk, within the context of individual circumstances, risk appetite and the sorts of preventative measures people can take in their daily lives.

Throughout the pandemic, new information has emerged about what factors may influence whether someone is seriously affected by COVID-19, creating an opportunity to develop a detailed risk prediction model.

Researchers at the University of Oxford and collaborators across the UK have used anonymous data from primary care, hospitals, COVID-19 test results and death registries to determine which factors were associated with poor outcomes during the first wave of COVID-19.

This data was used to create a risk prediction model - QCovid - that provides a weighted, cumulative calculation of risk using the variables associated with poor COVID-19 outcomes. The factors incorporated in the model include age, sex, ethnicity, level of deprivation, obesity, whether someone lived in residential care or was homeless, and a range of existing medical conditions, such as cardiovascular disease, diabetes, respiratory disease and cancer.

This model was then tested in two independent sets of anonymised data, from January to April 2020 and from May 2020 to June 2020, to find out whether it accurately predicted severe outcomes due to COVID-19 during the first wave of the pandemic in England.

The research results, published in the BMJ, showed that the model performed well in predicting outcomes. People in the dataset whose calculated risk put them in the top 20% of predicted risk of death accounted for 94% of deaths from COVID-19.

Lead researcher Professor Julia Hippisley-Cox, a general practitioner and Professor of Clinical Epidemiology and General Practice at University of Oxford's Nuffield Department of Primary Care Health Sciences, said: "Risk assessments to date have been based on the best evidence and clinical expertise, but have focused largely on single factors. The QCovid risk model provides a much more nuanced assessment of risk by taking into account a number of different factors that are cumulatively used to estimate risk."

"This model will help inform clinical advice so that people can take proportionate precautions to protect themselves from COVID-19."

The researchers plan to regularly update their model as levels of immunity change, more data become available and behaviour in the population changes, so that the model could also be used to support risk stratification for public health purposes as the infection rate changes over time.

The research was funded by the NIHR following a commission by the Chief Medical Officer for England.

Deputy Chief Medical Officer for England Dr Jenny Harries said: "Continuing to improve our understanding of the virus and how it affects different members of the population is vital as prevalence continues to rise.

"This is why we commissioned and funded this research, and I'm pleased it is providing useful evidence to help us move towards a more nuanced understanding of COVID-19 risk.

"We are working at pace and will maintain our ongoing engagement with patients, the healthcare profession and the voluntary sector on how we use this knowledge to ensure we continue protecting and supporting the most clinically vulnerable."

The research team is led by the University of Oxford and includes researchers from the universities of Cambridge, Edinburgh, Swansea, Leicester, Nottingham and Liverpool with the London School of Hygiene & Tropical Medicine, Queen's University Belfast, Queen Mary University of London, University College London, the Department of Health and Social Care, NHS Digital and NHS England.

Professor Jonathan Valabhji, National Clinical Director for Diabetes and Obesity at NHS England, said: "Along with other characteristics like age and ethnicity, the evidence shows that both diabetes and obesity are risk factors for COVID-19 and this risk prediction tool has the potential to much more accurately gauge risk for each individual, drawing together all of their relevant characteristics and ultimately helping them to stay as safe as possible during this pandemic."

Researchers at the University of Cincinnati have identified new clues into ways tobacco use impacts patients with kidney cancer.

The study, published in the Journal of Clinical Investigation, provides the first steps in developing personalized treatments for patients with this type of cancer.

Expanding on previous work that identified the mutations of kidney cancer cells, this study reveals metabolic fingerprints that distinguish cancers from nonsmokers compared to smokers.

"Standard analysis of mutations may not have detected the effects of tobacco smoking in kidney cancer, so these results and this study provides important steps toward new and better therapeutic strategies for kidney cancers in both smoking and nonsmoking populations," says Maria Czyzyk-Krzeska, MD, PhD, professor in the UC Department of Cancer Biology.

The disease studied, called "clear cell renal cell carcinoma," is the most common type of kidney cancer, but there are few chemotherapy options for advanced cancers, she says.

A multidisciplinary team of UC researchers led by Czyzyk-Krzeska in Cancer Biology, Jarek Meller, PhD, in Environmental and Public Health Sciences, and Julio Landero Figueroa, PhD, in Chemistry, analyzed tissues of patients who were tobacco users as well as those who were not, uncovering the widespread effects of smoking in this form of kidney cancer.

"Importantly, this integrated approach was key to identifying the major metabolic reprogramming in energy and biosynthesis, associated with the presence of cadmium and inorganic arsenic found in cigarettes, together with a distinct signature of copper in tumors from tobacco smokers," says Maria Czyzyk-Krzeska.

The data show that tumors from longtime smokers represent a separate metabolic subtype of kidney cancer with different weaknesses and which could require a dedicated treatment strategy.

"There is a need for an in-depth analysis of metabolic subtypes of these cancers to establish the best way to treat each individual tumor," she says. "This is one of the earliest studies to establish that this type of analysis is necessary. Personalized, or precision medicine, has the promise of offering a specific and unique therapy based on the molecular landscape of each patient's cancer.

"This has huge potential to change outcomes for patients, leading to better and longer lives."

A cutting-edge technique that allows scientists to zoom into tiny details in a 3D image of a whole animal heart may lead to new insights on congenital heart disease.

Surgery and other interventions can help repair structural heart defects in many of the 1% of infants born with congenital heart disease. But 10-25% of these children still do not survive their first year and 44% do not survive to age 18. The new technique, originally described in a paper posted on bioRxiv* and now published in eLife, reveals defects in cells and the components within them found in hearts affected by congenital heart disease. This may lead to treatments to correct these defects and further improve survival.

When pumping blood, the chambers of the heart fill up and then contract to push the blood back out into circulation. To efficiently contract, the heart cells and tiny muscle fibers inside them must be precisely organised.

"When the heart is diseased or has defects, this organisation can be lost or partially lost, and the heart may no longer pump blood efficiently, leading to complications and even death," explains lead author Graham Rykiel, MS, a biomedical engineer who conducted the study as a graduate student in a research team led by senior author Sandra Rugonyi at Oregon Health & Science University (OHSU), Portland, Oregon, US.

By combining two imaging techniques, 3D microcomputed tomography and 3D scanning electron microscopy, the OHSU team was able to create high-resolution, 3D images of the whole heart of a chicken embryo, and zoom in to study the organisation within the heart cells. They then used this tool to examine the differences in cells and the structures within them between a healthy, normal developing chicken heart and one with a defect called tetralogy of Fallot, a relatively common form of congenital heart disease in humans. This revealed structural differences between cellular components within the healthy chicken heart and the heart with the defect.

"Our imaging technology will allow us to study exactly what happens within the heart and its cells when the heart has a defect or is diseased," Rykiel says. "This knowledge will give us clues to design better treatments for patients with heart defects and other anomalies."

The technique will be useful for studying normal heart development in chickens and other animals, and how factors such as drugs or environmental differences might influence congenital heart disease - a focus of Rugonyi's group for over 15 years. This in turn may help explain how tiny structural differences in the heart cells can cause heart problems or heart failure in people with congenital heart disease even after a successful surgery.

"By using our imaging technology on chicks with heart defects, we can start to understand how hearts from human babies with similar defects differ from normal hearts and what needs to be done beyond surgery to repair them and avoid their failure," concludes senior author Sandra Rugonyi, PhD, Professor of Biomedical Engineering at OHSU.

About 30 years ago, Dr. Richard Sifers set out on a journey to discover why people with a rare condition known as alpha1-antitrypsin (AAT) deficiency present with high variation in the severity of liver disease. His journey led him to the discovery of fundamental underpinnings of this condition and, unexpectedly, to uncovering a novel cellular mechanism for disposing of misfolded proteins. The latter has implications not just for AAT-deficiency, but also for other more common conditions associated with accumulation of defective proteins, including neurological disorders, such as Alzheimer's disease.

AAT deficiency can develop in people who carry the AAT gene with a mutation called Z.

"I began studying AAT deficiency because I was intrigued by the wide range of severity of the condition. Some of the people carrying two copies of the Z mutation developed lung disease late in life and some developed liver disease. Interestingly, the condition also could appear very early in life. Some newborns and infants developed severe liver disease and needed to have a transplant to live," said Sifers, professor of pathology & immunology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine.

Other groups had shown that about 1 in 1,700 people carry two copies of the AAT-Z gene. However, only about 17 percent of these newborns with AAT-Z had clinically significant liver disease, and less than 3 percent of those progressed to life-threatening, end-stage disease as infants.

One of Sifers's first contributions was to help develop the first screening test to determine whether a newborn was at risk of developing severe liver disease.

"Developing the screening method made me realize that I could tell whether a child was at a high risk of having liver disease, but still did not know what was causing the condition," Sifers said.

Understanding AAT-deficiency

AAT is a protein produced by the liver and transported through the blood to the lungs, where it protects them from damage caused by other enzymes that breakdown proteins in the lung. The Z mutation produces a defective AAT protein that cannot fold into an appropriate 3-D conformation. Inappropriately folded AAT-Z proteins cannot exit the liver, so they do not travel to the lungs to protect them from destruction. This can lead to lung damage contributing to emphysema and other lung conditions.

"As I studied the disease, I noticed that AAT-Z, which should be released from the liver, was actually accumulating," Sifers said. "This suggested that the naturally disposing mechanism of the cell might not be working."

Sifers and others dug deeper into how cells dispose of misfolded proteins. They discovered that cells shuttle defective proteins from their place of synthesis, the endoplasmic reticulum (ER), to the cytosol, where they are degraded in a cellular structure called a proteasome. Key to this process is to tag the proteins for destruction.

"We showed that removing certain sugars from proteins would flag them for degradation," Sifers said. "Specifically, we found that the human enzyme mannosidase Man1b1 acted like a quality-control factor that mediated the removal of the sugar mannose from misfolded AAT-Z proteins, promoting their degradation."

The AAT deficiency model has been used by many other researchers studying conditions also linked to toxic accumulation of misfolded proteins in cells, altogether called conformational diseases. This approach has accelerated the understanding of the underlying causes of these conditions, offering novel opportunities for potential treatments.

Connecting Man1b1 and AAT deficiency-associated liver disease in infants

Although researchers knew that liver injury associated with AAT deficiency was linked to accumulation of misfolded AAT-Z proteins in the liver, there was still no explanation for the severe liver disease in infants.

In a 2009 paper, Sifers and his colleagues studied liver tissue samples from unrelated infants or children older than 2 years who had undergone liver transplantation for end-stage liver disease. They also conducted genetic linkage and functional laboratory experiments with other cells cultured in the lab.

They showed that certain genetic modification, a single nucleotide polymorphism, that leads to changes in the expression of the Man1b1 gene results in lower levels of Man1b1protein in the endoplasmic reticulum of liver cells.

Sifers and colleagues proposed that lower levels of Man1b1 impair the liver's capacity to deal with the accumulation of misfolded AAT-Z. This likely accelerates reaching the tolerable threshold for protein accumulation, resulting in earlier liver failure.

Having AAT-Z and a genetic variant that slows down the disposal of misfolded AAT-Z proteins can explain the condition in the youngest patients.

"I was delighted that after years of research, we had found an explanation for the mystery of AAT deficiency-associated liver disease in infants and wondered whether my lab would make other major contributions in the future," Sifers said.

Man1b1 has more than one role

As Sifers and colleagues continued studying Man1b1, they unexpectedly came across a role for this protein that had not been described before.

"We found that, in addition to tagging misfolded proteins for degradation by enzymatically removing mannose groups, Man1b1 also promotes protein degradation by another mechanism that is independent from the first," Sifers said.

Sifers and his co-authors, Dr. Ashlee H. Sun, now at Polypus-transfection Biotechnology, and Dr. John R. Collette, postdocs in his lab, reported in the Proceedings of the National Academy of Sciences, U.S.A., that the conventional enzymatic removal system resides in one side of Man1b1, the C-terminal domain. In contrast, the new unconventional system is controlled by the other side of Man1b1, the N-terminal domain. Further studies will elucidate whether and how both systems operate in synergy.

The researchers propose that the new unconventional system might be involved in the elimination of soluble protein aggregates that have been associated with conformational diseases. For instance, human Man1b1 has been linked to the causes of multiple congenital disorders of intellectual disability and HIV infection, and to poor prognosis in patients with bladder cancer.

"Our work is a clear example that studying rare diseases can bring solutions for more common conditions."

By investigating a rare liver disease in babies, we have stumbled upon a pathway that could possibly be targeted to prevent more common neurological disorders occurring in late age," Sifers said.

Weather forecasters can more accurately predict when a tornado is likely to hit the UK thanks to a new tool devised in a partnership between the University of Leeds and the Met Office.

Around 30 tornadoes occur in the UK each year, 40% of which develop on cold fronts - but a lack of forecasting methods for these conditions means they strike without warning.

Now researchers at Leeds and the Met Office have for the first time created a prediction for how likely tornadoes are to occur on cold fronts, meaning a more accurate assessment of tornado risk can be made before a cold front crosses the UK.

Matthew Clark, a Met Office scientist who is currently studying for a PhD at Leeds's School of Earth and Environment, said: "Tornadoes are a relatively common weather hazard on UK cold fronts, but the Met Office have never before had any way of predicting which cold fronts are likely to produce tornadoes, nor did we understand why tornadoes occurred in some fronts but not others.

"These findings should help to improve the UK forecasts of localised, intense wind damage associated with these kinds of weather system. This should enable organisations and people to take precautions and minimise damage and risk."

Mr Clark and Douglas Parker, Professor of Meteorology at Leeds' School of Earth and Environment, analysed tornado reports from the Tornado and Storm Research Organisation (TORRO), radar imagery and surface analysis charts from 114 weather events over a 35 year period. One such event was the largest tornado outbreak in European history when 104 tornadoes touched down across England and Wales on 23 November, 1981, leaving a trail of damage in their wake.

The researchers identified patterns across the weather events, establishing which cold fronts were likely to produce a single tornado, which could produce several, and which would produce none. The research found that most of these tornadoes form when a region of strong winds approaches the front from the cold side. This creates a bulge in the front which helps to make it sharper, increasing the contrast in wind speed and direction across the front. Where this contrast increases over time, tornadoes are more likely to "spin up" along the front. Occasionally, relatively large outbreaks of tornadoes can occur in this situation. Forecasters can recognise these weather patterns, which alert them to the general risk of a tornado.

Clark and Parker also used their findings to create a predictive tool, which is already being used on an experimental basis by the Met Office to pinpoint regions at increased risk of tornadoes. Using the wind fields ahead and behind the cold front, forecasters can now compute a percentage probability that tornadoes will happen.

The tool is currently being tested in the Met Office, and was put to use on 29 February this year, successfully predicting the risk of tornadoes in southeast England, with a tornado occurring in Kent as the cold front swept through during the morning. Although use of the product is experimental at the moment, it is hoped that in time it will allow for appropriate messaging to be issued to local responders and other organisations such as airports.

Met Office Chief Meteorologist Paul Davies said: "By explaining, for the first time, "how" and "why" tornadoes form in a given weather system, meteorologists are much better prepared to anticipate events in advance, to interpret and challenge the results of numerical weather prediction models, and to communicate their confidence in a given forecast."

ITHACA, N.Y. - If an initial COVID-19 vaccine is about as effective as a flu shot, uptake by the American public may fall far short of the 70% level needed to achieve herd immunity, new Cornell research suggests.

In surveys of nearly 2,000 American adults, barely half said they would be willing to take a hypothetical vaccine with an efficacy, or effectiveness, of 50% - the U.S. Food and Drug Administration's minimum threshold for a COVID-19 vaccine, and comparable to flu vaccines.

Vaccine acceptance increased by 10 percentage points, to 61%, if its effectiveness increased to 90%, making efficacy among the most important factors in Americans' willingness to adopt a COVID-19 vaccine, the research found.

"Our results suggest that 50% efficacy will lead to significant vaccine hesitancy," said Douglas Kriner, professor of government at Cornell. "We might not get enough people to take it at that level, even though it would be a valuable public health intervention."

Kriner and Sarah Kreps, professor of government at Cornell, conducted surveys in July asking respondents to choose between hypothetical COVID-19 vaccines based on four medical factors: efficacy, duration of protection and the chances of major or minor side effects.

They also analyzed how political factors influenced vaccine acceptance, including if it was fully approved by the FDA or made available through an Emergency Use Authorization; if it was developed in the United States, United Kingdom or China; and if it was endorsed by President Donald Trump, former Vice President Joe Biden, the U.S. Centers for Disease Control and Prevention or the World Health Organization.

Survey respondents evaluated pairs of vaccines with varying profiles, expressing a preference for one or neither. They then reported their willingness to take each vaccine individually.

Along with improved efficacy, vaccine acceptance improved with a longer protection duration (five years vs. one year) and a lower incidence of major side effects, but by smaller margins (2% and 4%, respectively).

Politically, average willingness to receive a vaccine was lowest when endorsed by Trump, at 52%, but only slightly better for Biden at 55%. Uptake was stronger when endorsements came from U.S. or global public health institutions, improving to 58% for the WHO and 59% for the CDC.

Geopolitics also mattered: Americans' 60% average willingness to receive a vaccine developed in the U.S. dropped slightly if the vaccine came from the U.K. and significantly if it came from China, an outcome that appeared more plausible when the survey was conducted in July, the authors said.

Even one of the best-case hypothetical vaccines presented - developed in the U.K. and approved by the FDA with 90% efficacy, five years of protection, few side effects and CDC endorsement - barely reached the estimated threshold for herd immunity, with 71% of Americans willing to take it.

Kriner and Kreps said the findings can help public health authorities and political leaders develop appropriate endorsements, incentives and messages to broaden vaccine uptake.

A promising new biomarker that appears in patients before stomach cancer develops may help with early detection of the disease and improve patient response to therapy, according to findings in a study led by University of Arizona Health Sciences researchers.

The biomarker can be detected through a simple blood test, saving time and lowering costs. Currently, stomach cancer diagnosis requires endoscopic collection of stomach tissue through a biopsy procedure, and then analysis by pathology.

Published in Gut, the journal of the British Society of Gastroenterology, the study was led by Juanita L. Merchant, MD, PhD, chief of the Division of Gastroenterology and Hepatology at the UArizona College of Medicine - Tucson, a cancer biology program researcher at the UArizona Cancer Center and an elected member of the National Academy of Medicine.

The biomarker, MiR130b, is a microRNA - or small non-coding RNA molecule that can play an important role in regulating gene expression, affecting disease development and progression. MiR130b can be produced by a group of immune cells called myeloid-derived suppressor cells (MDSCs), commonly associated with infections caused by Helicobacter pylori (H. pylori), a bacteria associated with ulcers. These particular cell types in the stomach correlate with early, preneoplastic changes (before a tumor develops) that can lead to gastric cancer long after an H. pylori infection has passed.

The study included collaboration with Yana Zavros, PhD, associate head for research in the College of Medicine - Tucson's Department of Cellular and Molecular Medicine and the Cancer Center's shared resource director for Tissue Acquisition Cellular and Molecular Analysis.

"Even though you get can get rid of the bacteria, oftentimes the infection itself already has initiated a cascade of events that inevitably may lead to cancer," Dr. Zavros said. "That is why early detection is so important."

A Blood Test Instead of a Procedure

The study arose out of basic science mouse models that simulated changes in the stomach similar to that caused by H. pylori. This led the researchers to identify MiR130b in the mouse models, and they also detected the same microRNA in the plasma of human patients that either had precancerous changes or those that already had progressed to cancer.

"This was a retrospective study," said Dr. Merchant, who is a member of the university's BIO5 Institute. "It is very exciting because now we can begin looking at this biomarker more prospectively in different patient populations."

Although less common in the United States, the National Cancer Institute reports gastric (stomach) cancer is the third most common cause of cancer-related deaths in the world. The findings, however, could have major implications for Arizona's rural areas and Hispanic and Native American populations, which are at greater risk for developing gastric and other gastrointestinal (GI) cancers, because these diseases often are caused by dietary and environmental factors and may go undetected for long periods.

Dr. Merchant's lab has a "sub-project" in the Cancer Center's U54 grant (Partnership for Native American Cancer Prevention) to study detection of the microRNA described in the Gut paper in members of Native American populations with H. pylori.

"This molecular signature (the microRNA - MiR130b) that we discovered may help us see if patients have changes in their mucosa (the membrane that lines the stomach) related to having H. pylori," Dr. Merchant said. "And a blood sample would be less invasive and then could be a way to make the decision whether we need to bring a patient in for an endoscopy."

Broader Implications for Treatment

Once diagnosed, gastric cancer can be difficult to treat. Immunotherapies with proven effectiveness in treating other types of cancer are not as successful against most GI cancers, including stomach cancer. The researchers believe these new findings in gastric cancer may help to address why other GI cancers also are resistant to therapy.

"The underlying mechanism by which a patient may not respond well in gastric cancer may be applicable in other organs as well" Dr. Zavros said. "The way the cells interact with each other to render that patient resistant to therapy may be quite similar between gastric, pancreatic and colon cancers."

Dr. Merchant added: "There may be dual-purposes. We can look at it as a biomarker to help us from a diagnostic perspective, but we also can look at therapies that can be developed based on what this microRNA itself is targeting."

Another project funded by the Cancer Center's "Sparking Bench-to-Bedside Team Science Project" award is building from results of this study to explore therapies for pancreatic and gastric cancer. The investigators are exploring the tumor microenvironment, in particular the immune cell MDSCs, referred to previously, that appears to dampen the chemotherapeutic response to immunotherapies.

The project relies heavily on Dr. Zavros' "BioDroid" program, which develops miniature organs in the lab with a realistic microanatomy, also known as organoids. These are used in collaboration with the Tissue Acquisition Repository for Gastrointestinal and HEpaTic Systems (TARGHETS), created by Dr. Merchant. TARGHETS is a GI/Hepatology biorepository that collects samples from patients who undergo endoscopy.

Both Drs. Zavros and Merchant are looking to the BioDroid and TARGHETS efforts to reveal additional information that will allow them to develop new approaches to address resistance of gastric cancer to immunotherapies.

"We want to find a way to reprogram the cancer cells or the immune cells within that patient's tumor environment to make the patient more responsive to the therapy," Dr. Zavros said. "A biomarker gives us a place to start."

Inflammatory bowel disease (IBD) affects more than 70,000 children in the United States and the prevalence is rising. In fact, 25% of the 3.1 million individuals with IBD present before 21 years of age. There is no cure for IBD, and treatment often includes medication to block a molecule that causes inflammation in the intestines called tumor necrosis factor (TNF). Unfortunately, the TNF-blocking therapy doesn't work for many children and its therapeutic effects can be short-lived.

In a new study in Cell Reports, investigators at The Saban Research Institute at Children's Hospital Los Angeles have uncovered a role that TNF and its receptor play in intestinal health that will lead to a better understanding of TNF. This could positively impact future treatments for patients with IBD.

Children with IBD, a broad term which includes Crohn's disease and ulcerative colitis, can experience abdominal pain and weight loss, which can impact a child's growth. Patients with these conditions often have elevated levels of TNF in their bloodstream and intestines.

"Increased expression of TNF is one of the body's first responses to infection or injury," says D. Brent Polk, MD, a physician and investigator who studies intestinal development and associated disorders. "In many patients, antibodies that block TNF are effective, but most patients don't benefit from the therapy long term."

Sometimes, says Dr. Polk, patients initially show improvement, but then the treatment stops working. Oddly, some children even develop IBD when they receive anti-TNF therapy for an unrelated condition, such as juvenile arthritis.

Dr. Polk's investigations take a different approach to studying IBD. Instead of viewing TNF signaling as either pro- or anti-IBD, his work examines whether there is a range of TNF levels that maintain intestinal health.

"We know that TNF signaling leads to inflammation," he says, "but when we blocked the TNF receptor in a pre-clinical model of IBD, it led to early-onset colitis. So, it's not a simple matter of blocking TNF outright. The body is really fine tuned to maintain health."

His study shows that the timing of TNF signaling and which receptors are activated developmentally could be more important than merely the levels of the inflammatory molecule.

"It's not that TNF signaling is 'good' or 'bad,'" explains Dr. Polk. "It's more complicated than the field previously understood." He says that TNF does cause inflammation in the intestines, but it also appears to play a protective role, especially early in life.

The study is preclinical but has important implications for patients. Future therapies depend on a better understanding of how molecules like TNF function. Work like Dr. Polk's could lead to treatments that give relief to all children with IBD.

KINGSTON, R.I., -- October 20, 2020 -- For the first time, researchers have mapped the biological diversity of marine sediment, one of Earth's largest global biomes. Although marine sediment covers 70% of the Earth's surface, little was known about its global patterns of microbial diversity.

A team of researchers from the Japan Agency for Marine-Earth Science and Technology (JAMSTEC), the University of Hyogo, the University of Kochi, the University of Bremen, and the University of Rhode Island delineated the global diversity of microbes in marine sediment. For the study, published in the Proceedings of the National Academy of Sciences, Tatsuhiko Hoshino, senior researcher at JAMSTEC, and his colleagues including URI Graduate School of Oceanography Professor Steven D'Hondt analyzed 299 samples of marine sediment collected as core samples from 40 sites around the globe. Their sample depths ranged from the seafloor to 678 meters below it. To accurately determine the diversity of microbial communities, the authors extracted and sequenced DNA from each frozen sample under the same clean laboratory condition.

The 16S rRNA gene sequences (approximately 50 million sequences) obtained through comprehensive next-generation sequencing were analyzed to determine microbial community composition in each sample. From these 50 million sequences, the research team discovered nearly 40,000 different types of microorganisms in marine sediment, with diversity generally decreasing with depth. The team found that microbial community composition differs significantly between organic-rich sediment of continental margins and nutrient-poor sediment of the open ocean, and that the presence or absence of oxygen and the concentration of organic matter are major factors in determining community composition.

By comparing their results to previous studies of topsoil and seawater, the researchers discovered that each of these three global biomes--marine sediment, topsoil, and seawater--has different microbial communities but similar total diversity. "It was an unexpected discovery that microbial diversity in the dark, energy-limited world beneath the seafloor is as diverse as in Earth's surface biomes," said Hoshino.

Furthermore, by combining the estimates of bacterial and archaeal diversity for these three biomes, the researchers found that bacteria are far more diverse than archaea--microbes distinct from bacteria and known for living in extreme environments--on Earth.

"In this respect as well, microbial diversity in the dark realm of marine sediment resembles microbial diversity in the surface world," said D'Hondt. "It's exciting to glimpse the biological richness of this dark world."

To efficiently infect human cells, SARS-CoV-2, the virus that causes COVID-19, is able to use a receptor called Neuropilin-1, which is very abundant in many human tissues including the respiratory tract, blood vessels and neurons. The breakthrough discovery was made by a German-Finnish team of researchers led by neuroscientists Mika Simons ,Technical University of Munich, Germany and virologist Giuseppe Balistreri, University of Helsinki, Finland.

Why is the new coronavirus so infectious?

"That SARS-CoV-2 uses the receptor ACE2 to infect our cells was known, but viruses often use multiple factors to maximize their infectious potential" says Dr. Giuseppe Balistreri, head of the research group Viral Cell Biology at the University of Helsinki involved in the study.

Unlike other respiratory viruses, SARS-CoV-2 infects also the upper respiratory system including the nasal mucosa and consequently spreads rapidly. "This virus is able to leave our body even when we simply breath or talk", Balistreri adds. "The starting point of our study was the question why SARS-CoV, a coronavirus that led to a much smaller outbreak in 2003, and SARS-CoV-2, spread in such a different way even if they use the same main receptor ACE2", explains Ravi Ojha, a young researcher in the Balistreri's team, and one of the main contributors of the study.

A mysterious extra key on the virus surface

To understand how these differences can be explained, in collaboration with the team of Professor Olli Vapalahti, University of Helsinki, the researchers took a look at the viral surface proteins, the spikes, that, like hooks, anchor the virus to the cells. Balistreri reveals that "when the sequence of the SARS-CoV-2 genome became available, at the end of January, something surprised us. Compared to its older relative, the new coronavirus had acquired an 'extra piece' on its surface proteins, which is also found in the spikes of many devastating human viruses, including Ebola, HIV, and highly pathogenic strains of avian influenza, among others. We thought this could lead us to the answer". In collaboration with giant virologist Ari Helenius, ETH Zurich, Switzerland, and cancer biologists Professor Tambet Teesalu, University of Tartu, Estonia, the mystery was solved: the extra key binds to neuropilin-1.

Together, the coordinated team of international researchers, including more than 30 scientists from Germany, Finland, Estonia and Australia, looked at whether neuropilins were important for infection by SARS-CoV-2. Their experiments now support this hypothesis. Interestingly, an independent team of scientists at the University of Bristol , UK, has obtained similar results and confirmed that the virus spike binds directly to neuropilin-1 (Ref. DOI: 10.1126/science.abd3072). The two studies complement each other.

New antiviral strategy in making

By specifically blocking neuropilin-1 with antibodies, the researchers were able to significantly reduce infection in laboratory cell cultures. "If you think of ACE2 as a door lock to enter the cell, then neuropilin-1 could be a factor that directs the virus to the door. ACE2 is expressed at very low levels in most cells. Thus, it is not easy for the virus to find doors to enter. Other factors such as neuropilin-1 might help the virus finding its door", says Balistreri.

Balistreri cautiously concludes "it is currently too early to speculate whether blocking directly neuropilin could be a viable therapeutic approach, as this could lead to side effects. This will have to be looked at in future studies. Currently our laboratory is testing the effect of new molecules that we have specifically designed to interrupt the connection between the virus and neuropilin. Preliminary results are very promising and we hope to obtain validations in vivo in the near future."

BROOKLYN, New York, Tuesday, October 20, 2020 - A new report from The Governance Lab (The GovLab) at NYU's Tandon School of Engineering launched today at an event at the Nesta Centre for Collective Intelligence, has found organizations that tap the wisdom of the crowd are better at solving many of the problems that trouble governments, including those exacerbated by COVID-19 -- from air pollution and chronic illness, to sustainable development, climate change and disaster response.

The report, entitled Using Collective Intelligence to Solve Public Problems, examined global examples of how public institutions are using new technology to take advantage of the collective action and collective wisdom of people in their communities and around the world to address problems like climate change, loneliness and natural disaster response. The GovLab has also published 30 case studies to show how leaders have designed the most successful projects. These include Lakewood, Colorado, whose Sustainable Neighborhoods Program has engaged more than 20,000 residents in running 500 sustainability events and projects. SynAthina from Athens, Greece is a platform where 443 civic groups have posted 4,050 activities, enabling residents to collectively revitalize their city. Founded in Kenya in 2007 as an election monitoring tool, Ushahidi (Swahili for "Testimony") has been used for 150,000 "crowdmapping" projects to rescue victims from the Haitian earthquake in 2010, prevent forest fires in Italy and Russia, and crowdsource incidents of sexual harassment in Egypt, among other campaigns in 160 countries.

The report is part of a broader "Collective Intelligence to Solve Public Problems" project that includes the 30 original case studies, an online course, a podcast, report and design guide all aimed at helping leaders respond to problems more efficiently and inclusively.

"As novel challenges continue to present themselves around the world, it is becoming increasingly apparent that traditional ways of solving problems are outdated and ineffective," said Beth Simone Noveck, director of The GovLab. "Through this research, we have observed that institutions which choose to work more openly and collaboratively with local organizations and citizens are better able to respond to public problems, including emergencies and crises such as the challenges brought on by COVID-19."

The accompanying practical guide Collective Intelligence: A Checklist for the Public Sector lays out nine questions which serve as a checklist for those who aim to design a collective intelligence initiative. The questions focus thinking on how to tap the capabilities of the crowd that are relevant for solving the problem at hand and help to ensure public engagement is meaningful and impactful.

Matt Ryan, Senior Fellow at The GovLab and report co-author, said: "The speed, scale and complexity of public problems, combined with the trust crisis confronted by many public institutions, make using the skills and knowledge of 'the crowd' much more than a 'nice-to-have'. For serious public policy makers and service providers it's a necessity."

New Rochelle, NY, October 20, 2020--Synthetic estrogens from pharmaceuticals contaminate rivers and threaten the health of humans and fish. An effective and cost-efficient method for removing synthetic estrogen from bodies of water has been demonstrated in the peer-reviewed journal Environmental Engineering Science. Click here (http://doi.org/10.1089/ees.2020.0048) to read the article now.

The researchers compared non-modified and modified forms of bentonite, a natural, low-cost absorbent that can remove pharmaceutical micropollutants from water bodies.

One particular bentonite complex "can be considered a promising low-coast modified absorbent for the removal of 17α-ethinylestradiol and, potentially, of other relevant pharmaceutical organic micropollutants from wastewater environments," state Carla Daniel, Universidade Nova de Lisboa, and coauthors.

Manajit Hayer-Hartl, head of the research group "Chaperonin-assisted Protein Folding", has a long-standing interest in the central enzyme of photosynthesis called Rubisco. Her team has already reported on many of the interacting partners of Rubisco that are required for the folding and assembly of this highly abundant protein. In the current study, they have elucidated how Rubisco activase works. As the name indicates, this enzyme is critical for repairing Rubisco once it has lost its activity. The study was published in Cell.

The enzyme Rubisco catalyzes the assimilation of CO2 from the atmosphere into organic matter. This is the central step in photosynthesis that generates sugar molecules for the production of essentially all biomass. Despite its pivotal role, Rubisco works relatively slowly and is easily inhibited by sugar products. By improving the function of Rubisco Hayer-Hartl hopes to be able to boost the process of photosynthesis. The goal is to address the growing global demand for food and reduce the current greenhouse gas-induced climate change.

The enzyme Rubisco activase, Rca, is present in plants, algae and certain cyanobacteria. Rca is a ring-shaped complex of six subunits with a central pore. How exactly Rca interacts with the inhibited Rubisco and releases the bound sugar from the active site pocket of Rubisco, restoring its CO2 fixing activity, was unclear until now. With the help of biochemistry, crystallography and cryo-electron microscopy, Hayer-Hartl & colleagues have now succeeded in deciphering the molecular mechanism of a cyanobacterial Rca.

They discovered that the Rca grabs the N-terminal tail of Rubisco and by pulling and pushing actions, using the energy of ATP, opens the active site pocket. This results in the release of the inhibitory sugar molecule. In cyanobacteria Rubisco is packaged into specialized micro-compartments called carboxysomes, in which a high concentration of CO2 is generated to facilitate the function of Rubisco.

In an earlier study, Hayer-Hartl showed how Rubisco is recruited into carboxysomes via interactions with the SSUL domains of the scaffolding protein CcmM. Interestingly, the researchers now found that Rca is recruited into carboxysomes using a very similar trick. The Rca hexamer also contains SSUL domains that dock onto Rubisco during carboxysome formation. This makes sure that enough Rca is present inside carboxysomes to perform its essential repair function. Thus, Rca not only functions in Rubisco activation but also mediates its own recruitment into carboxysomes.

Manajit Hayer-Hartl concludes: "Rca is absolutely required for Rubisco to function optimally. Deciphering its mechanism and dual function in cyanobacteria will further help us to make photosynthesis more effective in the future. Hopefully, this will get us closer to our ultimate goal, to increase agricultural productivity".