Publisher Health

New insight on the death toll of the COVID-19 pandemic worldwide has been published in the open-access eLife journal.
Comparing the impact of COVID-19 between countries or during a given period of time is challenging because reported numbers of cases and deaths can be affected by testing capacity and reporting policy. The current study provides a more accurate picture of the effects of COVID-19 than using these numbers, and may improve our understanding of this and future pandemics.
In any given period of time, a certain number of people die due to many particular reasons, such as old age, illness, violence, traffic accidents and more. Researchers are able to predict the number of deaths from these causes over coming months or years, known as expected deaths, using the same information gathered from previous months and years. However, pandemics, conflicts, and natural and man-made disasters cause additional deaths above and beyond those expected, which are known as ‘excess deaths’.
“Measuring excess deaths allows us to quantify, monitor and track pandemics such as COVID-19 in a way that goes above testing and reporting capacity and policy,” says Ariel Karlinsky, a graduate student at the Hebrew University of Jerusalem in Israel, and co-author alongside research scientist Dmitry Kobak, from Tübingen University, Germany. “However, until now, there has been no global, frequently updated repository of mortality data across countries.”
To fill this gap, Karlinsky and Kobak collected weekly, monthly or quarterly mortality data from 103 countries and territories, which they have made openly available as the World Mortality Dataset. They then used the data to work out the number of excess deaths in each country during the COVID-19 pandemic.
“We used our data to answer a number of questions,” Karlinsky explains. “Specifically, we wanted to find out whether the pandemic caused excess deaths in the countries we covered and, if so, to what extent. We were also curious to see whether the numbers of excess deaths were matched across countries.”
Their analyses showed that, in several of the countries worst affected by COVID-19 — namely Peru, Ecuador, Bolivia and Mexico — excess deaths were more than 50% above the expected annual mortality rate, or above 400 excess deaths per 100,000 people as in Peru, Bulgaria, North Macedonia and Serbia. At the same time, in countries such as Australia and New Zealand, mortality during the pandemic was below the usual level, which the authors suggest is likely due to social distancing measures reducing the number of deaths caused by other infections besides COVID-19.
Furthermore, the researchers found that while many countries have been reporting their COVID-19 death rates accurately, some including Nicaragua, Belarus, Egypt and Uzbekistan have underreported these numbers by more than 10 times.
“Together, our results present a comprehensive picture of the impact of COVID-19, which we hope will contribute to better understanding of the pandemic and assessing the success of different mitigation strategies,” Kobak concludes. “The work also highlights the importance of open and rapid mortality reporting for monitoring the effects of COVID-19. We hope that our dataset will provide a valuable resource to help other investigators answer their own questions about the pandemic. We are constantly expanding our dataset and will continue to track excess mortality around the world.”
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University of Virginia School of Medicine researchers have determined the location of natural blood-pressure barometers inside our bodies that have eluded scientists for more than 60 years.
These cellular sensors detect subtle changes in blood pressure and adjust hormone levels to keep it in check. Scientists have long suspected that these barometers, or “baroreceptors,” existed in specialized kidney cells called renin cells, but no one has been able to locate the baroreceptors until now.
The new findings, from UVA Health’s Maria Luisa S. Sequeira-Lopez and colleagues, finally reveal where the barometers are located, how they work and how they help prevent high blood pressure (hypertension) or low blood pressure (hypotension). The researchers hope the insights will lead to new treatments for high blood pressure.
“It was exhilarating to find that the elusive pressure-sensing mechanism, the baroreceptor, was intrinsic to the renin cell, which has the ability to sense and react, both within the same cell,” said Sequeira-Lopez, of UVA’s Department of Pediatrics and UVA’s Child Health Research Center. “So the renin cells are sensors and responders.”
Sensing Blood Pressure
The existence of a pressure sensor inside renin cells was first proposed back in 1957. It made sense: The cells had to know when to release renin, a hormone that helps regulate blood pressure. But even though scientists suspected this cellular barometer had to exist, they couldn’t tell what it was and whether it was located in renin cells or surrounding cells.
Sequeira-Lopez and her team took new approaches to solving this decades-old mystery. Using a combination of innovative lab models, they determined that the baroreceptor was a “mechanotransducer” inside renin cells. This mechanotransducer detects pressure changes outside the cell, then transmits these mechanical signals to the cell nucleus, like how the cochlea in our ear turns sound vibrations into nerve impulses our brain can understand.
The researchers have unlocked exactly how the baroreceptors work. They found that applying pressure to renin cells in lab dishes triggered changes within the cells and decreased activity of the renin gene, Ren1. The scientists also compared differences in gene activity in kidneys exposed to lower pressure and those exposed to higher pressure.
Ultimately, when the baroreceptors detect too much pressure outside the renin cell, production of renin is restricted, while blood pressure that is too low prompts the production of more renin. This marvelous mechanism is vital to the body’s ability to maintain the correct blood pressure. And now, after more than 60 years, we finally understand how and why.
“I feel really excited about this discovery, a real tour de force several years in the making. We had a great collaboration with Dr. [Douglas] DeSimone from the Department of Cell Biology,” Sequeira-Lopez said. “I am also excited with the work to come, to unravel the signaling and controlling mechanisms of this mechanotransducer and how we can use the information to develop therapies for hypertension.”
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The coronavirus that causes COVID-19 has demonstrated a stubborn ability to resist most nucleoside antiviral treatments, but a new study led by an Iowa State University scientist could help to overcome the virus’s defenses.
The study, published recently in the peer-reviewed journal Science, details the structure of a critical enzyme present in SARS-CoV-2, the coronavirus that causes COVID-19. This enzyme, known as the proofreading exoribonuclease (or ExoN), removes nucleoside antiviral medications from the virus’s RNA, rendering most nucleoside analogs-based antiviral treatments ineffective. The new study presents the atomic structures of the ExoN enzyme, which could lead to the development of new methods for deactivating the enzyme and opening the door to better treatments for patients suffering from COVID-19.
“If we could find a way to inhibit this enzyme, maybe we can achieve better results to kill the virus with existing nucleoside antiviral treatments. Understanding this structure and the molecular details of how ExoN works can help guide further development of antivirals,” said Yang Yang, lead author of the study and assistant professor in the Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology at Iowa State University.
SARS-CoV-2 is an RNA virus, which means its genetic material is composed of ribonucleic acid. When the virus replicates, it must synthesize RNA. But the virus’s genome is unusually large when compared to other RNA viruses, which creates a relatively high likelihood that errors arise during RNA synthesis. These errors take the form of mismatched nucleotides, and too many errors can prevent the virus from propagating.
But the ExoN enzyme acts as a proofreader, recognizing mismatches in the virus RNA and correcting errors that occur during RNA synthesis, Yang said. The enzyme is present only in coronaviruses and a few other closely related virus families, he said.
The same process that eliminates replication errors also eliminates antiviral agents delivered by the treatments commonly used to fight other RNA viruses, such as HIV, HCV and Ebola virus, which partially explains why SARS-CoV-2 has proven so difficult to treat, Yang said.
But Yang and his colleagues utilized cryogenic electron microscopy, a technique in which samples are flash cooled to cryogenic temperatures in vitreous ice to preserve their native structures, to detail the structure of the enzyme. Understanding that structure could allow for the development of molecules that bind to the enzyme and disable it. Yang said that’s the next step for his laboratory and his colleagues. Finding such a molecule could make the virus more susceptible to newly developed antivirals, Yang said. Or, it could allow for the optimization of current antivirals, such as Remdesivir.
Scott Becker, an ISU graduate student in the Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, also contributed to the study. The study also included scientists from Yale University and the Hormel Institute at the University of Minnesota.
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Proteins — long chains of amino acids — each play a unique role in keeping our cells and bodies functioning, from carrying out chemical reactions, to delivering messages, and protecting us from potentially harmful foreign invaders. More recent research has shown that these proteins not only serve their individual purpose, but also interact with other proteins to carry out even more numerous and complex functions through these protein-protein interactions (PPI).
Collectively, all the protein-protein interactions in a cell form a PPI network. Experimentally identifying a PPI network within human cells has required a tremendous amount of time and resources, with experiments required to identify every individual PPI, and many additional experiments to investigate these protein pairs for network-level interactions.
Now, bioengineers at the University of California San Diego have developed a technology capable of revealing the PPIs among thousands of proteins, in a single experiment. The tool, called PROPER-seq (protein-protein interaction sequencing), allows researchers to map the PPI network from their cells of interest within several weeks, without any specialized resources such as antibodies or premade gene libraries.
The researchers describe this technology in Molecular Cell on August 3. They applied PROPER-seq on human embryonic kidney cells, T lymphocytes, and endothelial cells, and identified 210,518 PPIs involving 8,635 proteins.
“PROPER-seq is capable of scanning the order of 10,000×10,000 protein pairs in one experiment,” said Kara Johnson, a recent UC San Diego bioengineering Ph.D. alumna and the first author of this paper. The research was conducted in bioengineering professor Sheng Zhong’s lab.
The central idea of PROPER-seq is to label every PPI with a unique DNA sequence, and then read these DNA sequence labels through next-generation sequencing. To implement this idea, Zhong’s team developed a technique called SMART-display, which attaches a unique DNA barcode to every protein. They also devised a method called “Incubation, ligation and sequencing” (INLISE) to sequence the pair of DNA barcodes that are attached to two interacting proteins. The third component of PROPER-seq is a software package called PROPERseqTools, that incorporates statistical tools to identify the PPIs from the DNA sequencing data. This trio of tools — SMART-display, INLISE, and PROPERseqTools — together is known as PROPER-seq.

Ovarian cancer devastates more than 20,000 women in the U.S. every year, due in part to its tendency to evade detection and present after metastatic spread. A key element to slowing metastasis is understanding the mechanisms of how tumor cells invade tissues.
In APL Bioengineering, by AIP Publishing, biophysics researchers at the University of Wisconsin explain how microscopic defects in how healthy cells line up can alter how easily ovarian cancer cells invade tissue. Using an experimental model, where the cellular makeup mimics the lining of the abdominal cavity, the group found that disruptions in the normal cellular layout, called topological defects, affect the rate of tumor cell invasion.
“My lab is very interested in identifying ways to slow metastasis. This study is exciting, because it demonstrates a unique role for organization of nontumor cells to either aid or slow that process,” said author Pamela Kreeger. “Identifying factors that regulate this organization could help us to achieve our goal.”
Topological defects are well known to the world of physics, ranging from quantum field theory to cosmological phenomena, but are only starting to find use in medicine and biology.
The group’s model consisted of a single layer of healthy cells, called mesothelial cells, the predominant cell type that covers structures inside the abdomen, where ovarian cancer often metastasizes.
“A common way to fill space is a honeycomblike packing, in which each ‘cell’ would be nearly spherical,” said author Jacob Notbohm. “But in our case, the mesothelial cells were elongated, making the honeycomb packing not possible.”
Such elongation led to areas of well-ordered cell layers and left other areas with alignment imperfections, causing the topological defects. These flaws in this alignment have been associated with a host of microscopic influences, including altered cell density, motion, and forces.
They seeded ovarian cancer cells on top of the mesothelial cell layer and compared what effect the arrangement of the mesothelial cells had on how the tumor cells passed through this barrier.
The patterns of cell flow were different near the defects, with certain defects causing inward cell flow, toward the center of the defect. At those locations of inward flow, the cancer cells passed through the mesothelial barrier more slowly.
In addition to pursuing the impact of topographical organization in cancer cell metastasis, the group is looking to investigate the cause of topological defects, with the hopes of finding ways to direct cell patterning in uses, such as tissue engineering.
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In efforts to fight obesity and enhance drug absorption, scientists have extensively studied how gastric juices in the stomach break down ingested food and other substances. However, less is known about how the complex flow patterns and mechanical stresses produced in the stomach contribute to digestion.
Researchers from France, Michigan, and Switzerland built a prototype of an artificial antrum, or lower stomach, to present a deeper understanding of how physical forces influence food digestion based on fluid dynamics. In Physics of Fluids, by AIP Publishing, they reveal a classifying effect based on the breakup of liquid drops combined with transport phenomena derived from complementary computer simulations.
The relevant parts of the stomach are the corpus, where food is stored; the antrum, where food is ground; and the pylorus, or pyloric sphincter, the tissue valve that connects to the small intestine. Slow-wave muscle contractions begin in the corpus, with wave speed and amplitude increasing to form the antral contraction waves (ACWs) as they propagate toward the pylorus.
The researchers’ antrum device consists of a cylinder, capped at one end to imitate a closed pylorus, and a hollow piston that moves inside the cylinder to replicate ACWs. As verified through computer simulations and experimental measurements, the protype produces the characteristics of retropulsive jet flow that exist in the antrum.
Food disintegration is quantified by determining the breakup of liquid drops in flow fields produced by ACWs. The researchers studied different model fluid systems with various viscosity to account for the broad physical properties of digested food. The drop size and other parameters resemble conditions in a real stomach.
Drop breakup occurred near the surface of the hollow piston, where the flow field exhibited slower velocities but higher strain rates, thus exposing the drop to higher shear stresses during a longer period of time. No breakup occurred for drops near the center of the piston, because the stresses and residence times are smaller and shorter.
“The results extracted from this simple prototype have deepened insights into the disintegration process that takes place in the stomach,” co-author Damien Dufour said. “Drops near the wall will break up as they are transported toward the pylorus. The drops in the center return toward the corpus, without major size reduction, to disintegrate later. One may perceive this combined action of the ACWs as a classifying effect.”
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Opioid therapy is complex. In recent years, a rise in opioid-related deaths and changing prescribing guidelines and regulatory policies have led many physicians to reduce daily doses for patients prescribed stable opioid therapy for chronic pain.
Some patients have reported that this dose reduction process — called tapering -has been difficult, sometimes involving worsened pain, symptoms of opioid withdrawal and depressed mood.
In a study published Aug. 3 in JAMA, a team of UC Davis Health researchers examined the potential risks of opioid dose tapering. Their study found that patients on stable opioid therapy who had their doses tapered had significantly higher rates of overdose and mental health crisis, compared to patients without dose reductions.
“Prescribers are really in a difficult position. There are conflicting desires of ameliorating pain among patients while reducing the risk of adverse outcomes related to prescriptions,” said Alicia Agnoli, assistant professor of Family and Community Medicine at UC Davis School of Medicine and first author on the study. “Our study shows an increased risk of overdose and mental health crisis following dose reduction. It suggests that patients undergoing tapering need significant support to safely reduce or discontinue their opioids.”
De-prescribing opioids for patients on long-term therapy
The study used enrollment records and medical and pharmacy claims for 113,618 patients prescribed stable higher opioid doses (the equivalent of at least 50 morphine milligrams per day) for a one-year baseline period and at least two months of follow-up.

Researchers from UCLA and Cedars-Sinai have developed a new way to detect a potentially life-threatening condition that can occur during pregnancy.
The condition, placenta accreta spectrum disorder, occurs when the placenta grows too deeply into the uterine wall and fails to detach from the uterus after childbirth. It can lead to significant blood loss during pregnancy and delivery, requiring blood transfusions and intensive care, and it can result in serious illness and infection and can even be fatal for the mother. The condition occurs in less than 0.5% of pregnancies.
Currently, placenta accreta spectrum disorder is diagnosed by ultrasound in combination with an assessment of a mother’s pregnancy history. For example, a previous cesarean birth and a history of placenta previa, a condition in which the placenta that covers the birth canal, can indicate a heightened risk. But those factors alone are usually not reliable enough to detect cases other than the most severe ones.
The new blood test can be performed as early as the first trimester of pregnancy, which allows for early referrals to doctors who specialize in high-risk pregnancies. In tests with more than 100 women, the blood test was 79% accurate in confirming the presence of placenta accreta and 93% accurate in ruling it out with a negative result.
“Early and precise detection of this very high-risk obstetrical problem can greatly improve outcomes for both the mother and baby,” said Dr. Yalda Afshar, assistant professor of obstetrics and gynecology at the David Geffen School of Medicine at UCLA, and co-first author of the study. “With the unreliability of the current screening methods for placenta accreta, we saw a pressing need to create an easy-to-implement screening that can be conducted early in the pregnancy in all healthcare settings regardless of resources available to patients.”
A paper detailing the new method is published today in Nature Communications.
The new approach uses a technology called the NanoVelcro Chip, which has been developed over the past 15 years by Dr. Yazhen Zhu and Hsian-Rong Tseng, UCLA professors of molecular and medical pharmacology. Originally created to detect tumor cells in people with cancer, the chip is a postage stamp-sized device with nanowires that are 1,000 times thinner than a human hair and coated with antibodies that can recognize specific cells.
For the new study, the researchers adapted the chip so that it could detect placenta cells in the mother’s blood that are linked to placenta accreta spectrum disorder. Those cells, called trophoblasts, appear in the first few days of pregnancy. When a blood sample is tested using the chip, trophoblasts stick to the chip and can be detected under a microscope. An abnormally high count of trophoblasts or a trophoblast cluster in the blood indicates an elevated risk for placenta accreta disorder.
“Seeing a trophoblast cluster for the first time was like seeing glistening pearls,” said Zhu, one of the study’s senior authors. “When we saw the cells on the microscope, it felt like we had a direct view into the placenta in the developing pregnancy.”
Dr. Margareta Pisarska, professor of obstetrics and gynecology at Cedars-Sinai, said the research team’s multidisciplinary approach was a key to the study’s success.
“The efficacy of this test, and the strength of our work comes from bringing together experts from many disciplines, including obstetrics, nanotechnology, pathology, engineering, chemistry, microfluidics and biostatistics,” said Pisarska, a co-senior author of the study. “The diversity in our team allowed us to create an innovative solution to improving maternal and neonatal outcomes.”
The researchers are exploring ways to refine the test to improve its accuracy and reliability.

Princess Margaret Cancer Centre researchers have made new findings which provide a broader understanding of how dormant hematopoietic stem cells are activated and could pave the way towards therapeutic treatments for a number of cancers.
The team has made the discovery by performing a deep mechanistic study of lysosomes, which are membrane-bound organelles found in all cells. Lysosomes were once believed to merely be the “garbage bin” of the stem cell, recycling waste material, regulating cellular regeneration and functioning the same in all cell types. But the PM team’s research builds on new knowledge about lysosomes which shows they act as key signaling hubs, regulating long-term hematopoietic stem cells.
Work done by the researchers examines why a hematopoietic stem cell can remain dormant for years, and how the lysosome constantly acts as a sensor even in that deeply inactive state. The Princess Margaret team found that in spite of the cell’s dormancy, the lysosome inside it is still very active, “clipping and inactivating” receptors involved in growth signaling and nutrient transport within the stem cell membrane, allowing it to remain asleep.
The findings could have implications beyond the study, potentially allowing for control of the balance between cell dormancy and when stem cells are activated to help replenish the blood supply.
The results come from the laboratory of Princess Margaret senior scientist Dr. John Dick and are published in Cell Stem Cell on Aug. 2.,2021. Post-doctoral fellow Dr. Laura Garcia-Prat is first author, and affiliate scientist Dr. Stephanie Xie is co-senior author along with Dr. Dick.
“The study has discovered a new mechanism of dormancy, which is to harness an organelle, a lysosome, and keep that cell dormant,” says Dr. Garcia-Prat. “This opens a way that lysosomes could potentially be harnessed as a therapeutic target.”
Every year, tens of thousands of people around the world receive bone marrow transplants to help fight leukemia. High doses of chemotherapy are used to kill the rapidly dividing cancer cells, but at the same time it also kills stem cells needed to reproduce healthy blood.

A research group focused on embryos has begun its work in Finland, comprehensively surveying for the first time the short RNA molecules that regulate genome function during embryonic development. Information gained from human ova and embryos helps to understand problems occurring during pregnancy and develop increasingly effective infertility treatments.
Not much is known about early embryonic development in humans. After fertilisation, the genetic material in the mother’s ovum and the father’s sperm are combined, forming the genome of the embryo. A couple of days from fertilisation, when the embryo consists of four cells, the embryonic genome is already active, producing for the first time several RNA molecules.
No more than roughly 2% of the human genome is composed of protein-coding genes, while the rest, some 98-99%, constitutes non-coding genome. The non-coding genome produces RNA molecules, which regulate the function of the entire genome.
Protein-coding RNA molecules in human embryos have been studied earlier, but research on non-coding RNA molecules is extremely limited.
The group active at the University of Helsinki has now surveyed the short non-coding RNA molecules which regulate the functioning of the embryonic genome. The researchers investigated what kind of RNA molecules of 18 to 30 nucleotides ova and embryos contain in different stages of development.
“For the first time, we have identified short non-coding RNA molecules in ova at different stages of maturity, in fertilised ova and in early embryos with the help of sequencing, as well as determined their editing on the molecular level in embryos. This is an important milestone on the path to a better understanding of embryonic development,” says Sanna Vuoristo, PhD, from the University of Helsinki, who heads the embryo research group.