Publisher Health

Since the beginning of the pandemic, a loss of smell has emerged as one of the telltale signs of COVID-19. Though most people regain their sense of smell within a matter of weeks, others can find that familiar odors become distorted. Coffee smells like gasoline; roses smell like cigarettes; fresh bread smells like rancid meat.
This odd phenomenon is not just disconcerting. It also represents the disruption of the ancient olfactory circuitry that has helped to ensure the survival of our species and others by signaling when a reward (caffeine!) or a punishment (food poisoning!) is imminent.
Scientists have long known that animals possess an inborn ability to recognize certain odors to avoid predators, seek food, and find mates. Now, in two related studies, researchers from the Yu Lab at the Stowers Institute for Medical Research show how that ability, known as innate valence, is encoded. The findings, published in the journals Current Biology and eLife, indicate that our sense of smell is more complicated — and malleable — than previously thought.
Our current understanding of how the senses are encoded falls into two contradictory views — the labeled-line theory and the pattern theory. The labeled-line theory suggests that sensory signals are communicated along a fixed, direct line connecting an input to a behavior. The pattern theory maintains that these signals are distributed across different pathways and different neurons.
Some research has provided support for the labeled-line theory in simple species like insects. But evidence for or against that model has been lacking in mammalian systems, says Ron Yu, PhD, an Investigator at the Stowers Institute and corresponding author of the reports. According to Yu, if the labeled-line model is true, then the information from one odor should be insulated from the influence of other odors. Therefore, his team mixed various odors and tested their impact on the predicted innate responses of mice.
“It’s a simple experiment,” says Qiang Qiu, PhD, a research specialist in the Yu Lab and first author of the studies. Qiu mixed up various combinations of odors that were innately attractive (such as the smell of peanut butter or the urine of another mouse) or aversive (such as the smell of rotting food or the urine of a predator). He then presented those odor mixtures to the mice, using a device the lab specially designed for the purpose. The device has a nose cone that can register how often mice investigate an odor. If mice find a particular mixture attractive, they poke their nose into the cone repeatedly. If they find the mixture aversive, they avoid the nose cone at all costs.

Far more work is needed to understand how the pandemic began, the report says, but it is not clear that Beijing will cooperate. “We may never find the true origins,” an expert said.For 27 days, they searched for clues in Wuhan, visiting hospitals, live animal markets and government laboratories, conducting interviews and pressing Chinese officials for data, but an international team of experts departed the country still far from understanding the origins of the coronavirus pandemic that has killed nearly 2.8 million people worldwide.The 124-page report of a joint inquiry by the World Health Organization and China — to be released officially on Tuesday but leaked to the media on Monday — contains a glut of new detail but no profound new insights. And it does little to allay Western concerns about the role of the Chinese Communist Party, which is notoriously resistant to outside scrutiny and has at times sought to hinder any investigation by the W.H.O. The report is also not clear on whether China will permit outside experts to keep digging.“The investigation runs the risk of going nowhere, and we may never find the true origins of the virus,” said Yanzhong Huang, senior fellow for global health at the Council on Foreign Relations.The report, an advance copy of which was obtained by The New York Times, says that China still does not have the data or research to indicate how or when the virus began spreading. Some skeptics outside the country say that China may have more information than it admits.The expert team also dismisses as “extremely unlikely” the possibility that the virus emerged accidentally from a Chinese laboratory, even though some scientists say that is an important question to explore.The Chinese government, while granting some degree of access and cooperation, has repeatedly tried to bend the investigation to its advantage. The report was written jointly by a team of 17 scientists from around the world, chosen by the W.H.O., and 17 Chinese scientists, many of whom hold official positions or work at government-run institutions, giving Beijing great influence over its conclusions.Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Research Center in Seattle, said he was not convinced that a laboratory leak was extremely unlikely, after seeing a copy of the report. He said he agreed that it was highly plausible that the virus could have evolved naturally to spread to humans, but he did not see any reasoning in the report to dismiss the possibility of a lab escape.One member of the team of experts, Peter Daszak, a British disease ecologist who runs EcoHealth Alliance, a New York-based pandemic prevention group, pushed back against the criticism of the team’s work and of China’s level of cooperation. He said the lab leak hypothesis was “political from the start.” Dr. Daszak added that the W.H.O. team was not restricted in its interviews with scientists who were on the ground at the start of the pandemic.He himself has been accused of having a conflict of interest because of his past research on coronaviruses with the Wuhan Institute of Virology, which, he said, was what a disease ecologist should be doing.“We were in the right place because we knew that there was a risk of the virus emerging,” said Dr. Daszak. “We were working there with this exact viral group and it happened.”The prevailing theory remains that the virus originated in bats, jumped to another animal, and then mutated in a way that enabled it to transmit to humans, and from human to human. But the process of tracing the origins of a virus is notoriously painstaking.To answer numerous remaining questions, the report recommends further retrospective studies of human infections, including the earliest cases, and more virus testing of livestock and wildlife in China and Southeast Asia. It also calls for more detailed tracing of pathways from farms to markets in Wuhan that would require extensive interviews and blood tests for farmers, vendors and other workers.But it is unclear to what degree China will cooperate, and the country’s secretive and defensive behavior has helped fuel theories that it was somehow to blame for the start of the pandemic. Local officials in Wuhan at first tried to conceal the outbreak; Beijing has since expelled many Western journalists and has floated evidence-free theories about the virus originating elsewhere — though the earliest known cases were all in China, and experts agree it almost certainly first appeared there.“We’ve got real concerns about the methodology and the process that went into that report, including the fact that the government in Beijing apparently helped to write it,” Secretary of State Antony J. Blinken said a CNN interview broadcast on Sunday.China’s increasingly acrimonious relationship with the United States and other countries has also complicated the inquiry. The Biden administration has repeatedly criticized China’s lack of transparency, including its refusal to hand over raw data about early Covid-19 cases to investigators when they visited Wuhan. Chinese officials have bristled, suggesting that the United States should welcome the W.H.O. to examine the unfounded theory that the virus might have originated in a U.S. Army laboratory.“We will never accept the groundless accusations and wanton denigration by the United States on the issue of the epidemic,” Zhao Lijian, a spokesman for the Chinese foreign ministry, said at a regular news briefing in Beijing on Monday.In bombastic news articles, Chinese propagandists have hailed the inquiry as a sign of China’s openness to the world and a vindication of the government’s handling of the epidemic.The W.H.O. has come under pressure to demand more data and research from the Chinese government. But by design, the global health agency is beholden to its member countries, which did not grant the W.H.O. team sweeping powers to carry out, for example, forensic investigations of laboratory mishaps in China.While much of the report was heavy on detail about molecular studies, virus evolution and possible animal hosts, the section dealing with the possibility of a lab leak was cursory at best. While the virus’s animal origin is largely undisputed, some scientists maintain that the virus could have been collected and present in the lab of the Wuhan Institute of Virology, even though Chinese scientists say it was not.China’s lack of transparency as well as other concerns prompted a small group of scientists not affiliated with the W.H.O. to call this month for a new inquiry into the origin of the pandemic. They said such an inquiry should consider the possibility that the virus escaped from a laboratory in Wuhan or infected someone inside it.The lab leak theory has been promoted by some officials in the Trump administration, including Dr. Robert Redfield, the former director of the Centers for Disease Control and Prevention, in comments to CNN last week. He offered no evidence and emphasized that it was his opinion; the theory has been widely dismissed by scientists and U.S. intelligence officials.Matt Apuzzo and Apoorva Mandavilli contributed reporting. Albee Zhang contributed research.

A team led by investigators at Weill Cornell Medicine and NewYork-Presbyterian has used advanced technology and analytics to map, at single-cell resolution, the cellular landscape of diseased lung tissue in severe COVID-19 and other infectious lung diseases.
In the study, published online March 29 in Nature, the researchers imaged autopsied lung tissue in a way that simultaneously highlighted dozens of molecular markers on cells. Analyzing these data using novel analytical tools revealed new insights into the causes of damage in these lung illnesses and a rich data resource for further research.
“COVID-19 is a complex disease, and we still don’t understand exactly what it does to a lot of organs, but with this study we were able to develop a much clearer understanding of its effects on the lungs,” said co-senior author Dr. Olivier Elemento, professor of physiology and biophysics, director of the Caryl and Israel Englander Institute for Precision Medicine, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine at Weill Cornell Medicine and co-Director of the WorldQuant Initiative for Quantitative Prediction, which funded the technology for single cell analysis of tissue. “I think the technological approach we used here is going to become standard for studying such diseases.”
Traditional tissue analysis, often using chemical stains or tagged antibodies that label different molecules on cells and can reveal important features of autopsied tissues. However, this approach is limited in the number of features it can mark simultaneously. It also usually doesn’t allow detailed analyses of individual cells in tissues while retaining information about where the cells were in the tissue.
The main technology the investigators employed in the study, a technology called imaging mass cytometry, largely overcomes those limitations. It uses a collection of metal-tagged antibodies that can simultaneously label up to several dozen molecular markers on cells within tissues. A special laser scans the labeled tissue sections, vaporizing the metal tags, and the metals’ distinct signatures are detected and correlated with the laser position. The technique essentially maps precisely where cells are in the sample as well as each cell’s surface receptors and other important identifying markers. Altogether over 650,000 cells were analyzed.
The researchers applied the method to 19 lung tissue samples autopsied from patients who had died of severe COVID-19, acute bacterial pneumonia, or bacterial or influenza-related acute respiratory distress syndrome, plus four lung tissue samples autopsied from people who had had no lung disease.

Chimeric antigen receptor T-cell therapy, or CAR T, is a relatively new type of therapy approved to treat several types of aggressive B cell leukemias and lymphomas. Many patients have strong responses to CAR T; however, some have only a short response and develop disease progression quickly. Unfortunately, it is not completely understood why these patients have progression. In an article published in Proceedings of the Royal Society B, Moffitt Cancer Center researchers use mathematical modeling to help explain why CAR T cells work in some patients and not in others.
CAR T is a type of personalized immunotherapy that uses a patient’s own T cells to target cancer cells. T cells are harvested from a patient and genetically modified in a laboratory to add a specific receptor that targets cancer cells. The patient then undergoes lymphodepletion with chemotherapy to lower some of their existing normal immune cells to help with expansion of the CAR T cells that are infused back into the patient, where they can get to work and attack the tumor.
Mathematical modeling has been used to help predict how CAR T cells will behave after being infused back into patients; however, no studies have yet considered how interactions between the normal T cells and CAR T cells impact the dynamics of the therapy, in particular how the nonlinear T cell kinetics factor into the chances of therapy success. Moffitt researchers integrated clinical data with mathematical and statistical modeling to address these unknown factors.
The researchers demonstrate that CAR T cells are effective because they rapidly expand after being infused back into the patient; however, the modified T cells are shown to compete with existing normal T cells, which can limit their ability to expand.
“Treatment success critically depends on the ability of the CAR T cells to multiply in the patient, and this is directly dependent upon the effectiveness of lymphodepletion that reduces the normal T cells before CAR T infusion,” said Frederick Locke, M.D., co-lead study author and vice chair of the Blood and Marrow Transplant and Cellular Immunotherapy Department at Moffitt.
In their model, the researchers discovered that tumor eradication is a random, yet potentially highly probable event. Despite this randomness of cure, the authors demonstrated that differences in the timing and probability of cures are determined largely by variability among patient and disease factors. The model confirmed that cures tend to happen early, within 20 to 80 days before CAR T cells decline in number, while disease progression tends to happen over a wider time range between 200 to 500 days after treatment.
The researchers’ model could also be used to test new treatments or propose refined clinical trial designs. For example, the researchers used their model to demonstrate that another round of CAR T-cell therapy would require a second chemotherapy lymphodepletion to improve patient outcomes.
“Our model confirms the hypothesis that sufficient lymphodepletion is an important factor in determining durable response. Improving the adaptation of CAR T cells to expand more and survive longer in vivo could result in increased likelihood and duration of response,” explained Philipp Altrock, Ph.D., lead study author and assistant member of the Integrated Mathematical Oncology Department at Moffitt.
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Materials provided by H. Lee Moffitt Cancer Center & Research Institute. Note: Content may be edited for style and length.

The tooth fairy is a welcome guest for any child who has lost a tooth. Not only will the fairy leave a small gift under the pillow, but the child can be assured of a new tooth in a few months. The same cannot be said of adults who have lost their teeth.
A new study by scientists at Kyoto University and the University of Fukui, however, may offer some hope. The team reports that an antibody for one gene — uterine sensitization associated gene-1 or USAG-1 — can stimulate tooth growth in mice suffering from tooth agenesis, a congenital condition. The paper was published in Science Advances.
Although the normal adult mouth has 32 teeth, about 1% of the population has more or fewer due to congenital conditions. Scientists have explored the genetic causes for cases having too many teeth as clues for regenerating teeth in adults.
According to Katsu Takahashi, one of the lead authors of the study and a senior lecturer at the Kyoto University Graduate School of Medicine, the fundamental molecules responsible for tooth development have already been identified.
“The morphogenesis of individual teeth depends on the interactions of several molecules including BMP, or bone morphogenetic protein, and Wnt signaling,” says Takahashi.
BMP and Wnt are involved in much more than tooth development. They modulate the growth of multiple organs and tissues well before the human body is even the size of a raisin. Consequently, drugs that directly affect their activity are commonly avoided, since side effects could affect the entire body.

Researchers specialised in psychiatry and psychology at the University of Helsinki investigated the effects of depression on visual perception. The study confirmed that the processing of visual information is altered in depressed people, a phenomenon most likely linked with the processing of information in the cerebral cortex.
The study was published in the Journal of Psychiatry and Neuroscience.
In the study, the processing of visual information by patients with depression was compared to that of a control group by utilising two visual tests. In the perception tests, the study subjects compared the brightness and contrast of simple patterns.
“What came as a surprise was that depressed patients perceived the contrast of the images shown differently from non-depressed individuals,” says Academy of Finland Research Fellow Viljami Salmela.
Patients suffering from depression perceived the visual illusion presented in the patterns as weaker and, consequently, the contrast as somewhat stronger, than those who had not been diagnosed with depression.
“The contrast was suppressed by roughly 20% among non-depressed subjects, while the corresponding figure for depressed patients was roughly 5%,” Salmela explains.
Identifying the changes in brain function underlying mental disorders is important in order to increase understanding of the onset of these disorders and of how to develop effective therapies for them.
This is why the researchers consider it necessary to carry out further research on altered processing of visual information by the brain caused by depression.
“It would be beneficial to assess and further develop the usability of perception tests, as both research methods and potential ways of identifying disturbances of information processing in patients,” Salmela says.
Perception tests could, for example, serve as an additional tool when assessing the effect of various therapies as the treatment progresses.
“However, depression cannot be identified by testing visual perception, since the observed differences are small and manifested specifically when comparing groups,” Salmela points out.
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Materials provided by University of Helsinki. Original written by Anu Koivusipilä. Note: Content may be edited for style and length.

The B.1.1.7 and B.1.351 variants of SARS-CoV-2 were first detected in the UK and South Africa respectively, and have since spread to many other countries. Scientists from the Institut Pasteur joined forces with Orléans Regional Hospital, Tours University Hospital, Créteil Intercommunal Hospital, Strasbourg University Hospital and Georges Pompidou European Hospital to study the sensitivity of these two variants to neutralizing antibodies present in the serum samples of people who have been vaccinated or previously infected with SARS-CoV-2. They compared this sensitivity with that of the reference virus (D614G), which was until recently the most widespread strain in France. The scientists demonstrated that the UK variant is neutralized to the same degree as D614G, whereas the South African variant is less sensitive to neutralizing antibodies. To neutralize the South African variant, the antibody concentrations need to be six times higher than for D614G. This difference in sensitivity was also observed in vaccinated individuals; the antibodies in their serum are effective against the UK variant but less so against the South African one. The study was published in Nature Medicine on March 26th, 2021.
On December 14, 2020, the UK authorities informed WHO that a variant (B.1.1.7) had been detected in the south east of England. Within a few weeks, this variant took over from the viral strains circulating in this region and in London. On December 18, 2020, the South African authorities reported that a variant (B.1.351) had been detected and was spreading rapidly throughout three provinces of South Africa. According to WHO’s epidemiological bulletin dated February 14, the UK and South African variants are now present in 94 and 48 countries respectively. These two variants are considered to be ‘variants of interest’ and are subject to epidemiological surveillance at national and international levels.
In a new study, scientists from the Institut Pasteur joined forces with Orléans Regional Hospital, Tours University Hospital, Créteil Intercommunal Hospital, Strasbourg University Hospital and Georges Pompidou European Hospital to study the sensitivity of the UK and South African variants to antibodies in comparison with the reference strain circulating in France (D614G). The aim of this study was to characterize the capability of antibodies developed by people who had been vaccinated or previously infected with SARS-CoV-2 to neutralize these new variants.
The scientists isolated the SARS-CoV-2 variants B.1.1.7 and B.1.351 using samples provided by the National Reference Center for Respiratory Infection Viruses, hosted at the Institut Pasteur. Serum samples of people who had been vaccinated or previously exposed to SARS-CoV-2 were used to study the sensitivity of the variants to the antibodies present in this serum.
“Previously, the efficacy of neutralization had been mainly assessed using tests with pseudoviruses. We believe that it’s crucial to use authentic infectious virus strains in addition to pseudoviruses to assess viral sensitivity to neutralizing antibodies. In this study, we isolated and used authentic B.1.1.7 and B.1.351 strains and developed a novel rapid semi-automated neutralization assay based on ‘reporter’ cells that turn fluorescent after a few hours of infection,” explained Olivier Schwartz, co-last author of the study and Head of the Virus and Immunity Unit at the Institut Pasteur.
The results of the study showed that the UK variant (B.1.1.7) was neutralized by 95% (79 out of 83) of the serum of people who had been infected with SARS-CoV-2 and whose samples were taken up to nine months after the onset of symptoms. The same proportions were observed for the D614G strain, which has been the most widespread strain in France since the start of the epidemic. Moreover, there was no major difference in the antibody concentrations required to neutralize the D614G or B.1.1.7 strains.

A team of scientists led by Nanyang Technological University, Singapore (NTU Singapore) has developed a diagnostic test that can detect the virus that causes COVID-19 even after it has gone through mutations.
Called the VaNGuard (Variant Nucleotide Guard) test, it makes use of a gene-editing tool known as CRISPR, which is used widely in scientific research to alter DNA sequences and modify gene function in human cells under lab conditions, and more recently, in diagnostic applications.
Since viruses have the ability to evolve over time, a diagnostic test robust against potential mutations is a crucial tool for tracking and fighting the pandemic. Over its course so far, thousands of variants of SARS-CoV-2, the virus that causes COVID-19, have arisen, including some that have spread widely in the United Kingdom, South Africa, and Brazil .
However, the genetic sequence variations in new strains may impede the ability of some diagnostic tests to detect the virus, said NTU Associate Professor Tan Meng How, who led the study.
In addition to its ability to detect SARS-CoV-2 even when it mutates, the VaNGuard test can be used on crude patient samples in a clinical setting without the need for RNA purification, and yields results in 30 minutes. This is a third of the time required for the gold standard polymerase chain reaction (PCR) test, which requires purification of RNA in a lab facility.
The team of scientists led by NTU hopes that the VaNGuard test can be deployed in settings where quickly confirming COVID-19 status of individuals is paramount.

“I’ve been studying how plants regulate their water balance for over 35 years. To find a completely new and unexpected way for saving water has certainly been one of the most surprising discoveries in my life.” So says Professor Rainer Hedrich, plant scientist and biophysicist from Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany.
Hedrich’s group discovered this new strategy together with researchers from the University of Adelaide in Australia. The results have been published in the journal Nature Communications.
GABA quantity as stress memory
The publication shows: plants use the signalling molecule GABA (gamma-aminobutyric acid) to remember the dryness of a day. The drier it is, the more GABA accumulates in the plant tissue during the day. And the next morning, the amount of GABA determines how wide the plant opens its leaf pores. The opening width of these pores can limit water loss.
GABA is a signalling molecule that also occurs in humans and animals: there it is a messenger substance of the nervous system. Plants have no nerve cells and no brain. And yet GABA is now also found in them in connection with memory-like processes.
Rainer Hedrich names another connection: Short-term memory, which the carnivorous Venus flytrap uses to count the number of times its prey touches it, depends on the calcium level in the cell. And it is the calcium level that regulates the enzymatic biosynthesis of GABA in plants.
Low water needs, high drought tolerance
The GABA effect has been demonstrated in various crops, as Professor Matthew Gilliham of the University of Adelaide explains: “Under the influence of GABA, barley, broad beans and soybeans, for example, close their leaf pores.” Laboratory plants that produce more GABA due to mutations also react in this way. In experiments, these mutants need less water and survive drought longer.
Scientists know of other signalling substances in plants that cause the leaf pores to close. But GABA relies on a completely different mechanism of action, explains the lead author of the publication, Dr Bo Xu from the Australian Research Council Centre of Excellence in Plant Energy Biology.
Drought-tolerant plants for the future
Insights into the water-saving mechanisms and drought tolerance of plants are becoming increasingly important in times of climate change. For some years now, increasing heat and drought have been affecting many crops. The earth’s water resources that can be used for agriculture are also threatened. Mankind is therefore likely to be increasingly dependent on new varieties that still produce good yields with as little water as possible.
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Materials provided by University of Würzburg. Original written by Robert Emmerich. Note: Content may be edited for style and length.

Applied physicists at the University of Sydney have proposed new standards to measure moisture leaks into bionic devices such as pacemakers, cochlear hearing implants and retinal replacements.
The researchers, who received an industry partnership funding through the Australian Research Council to undertake the study, say the new moisture standards could give the wearers of bionic implants extra confidence in the operation of the life-changing devices. They also say that the improved moisture-testing regime could be used in the emerging renewable energy industry where new-generation solar cells require high standards of humidity control.
Bionic implants must be able to operate successfully in moist environments in the human body. While the potential for large leaks into the devices are easy to detect during manufacturing, small leaks can escape detection and standard testing is required to ensure safety and prevent moisture-induced failure.
Professor David McKenzie from the School of Physics at the University of Sydney said: “The accurate measurement of moisture penetration into medical devices is essential to guarantee long-term performance. Accurate measurement needs an accurate industry standard to assess leak risks.”
He said there are commercially available systems that measure relative humidity, but these are not sensitive enough for the most demanding applications in implantable biomedical devices. Using mass spectroscopy technology, the measurement of helium as a proxy for moisture leakage is a de facto industry standard test for the critical small leaks that are hard to pick up.
In practice and in most cases, helium testing of bionic devices is a good standard, but by improving the compliance by a factor of 10, we think the industry can further guarantee the safety of biomedical implants,” Professor McKenzie said.