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.

Researchers at the University of Southampton have developed a new way of using nanomaterials to identify and enrich skeletal stem cells — a discovery which could eventually lead to new treatments for major bone fractures and the repair of lost or damaged bone.
Working together, a team of physicists, chemists and tissue engineering experts used specially designed gold nanoparticles to ‘seek out’ specific human bone stem cells — creating a fluorescent glow to reveal their presence among other types of cells and allow them to be isolated or ‘enriched’.
The researchers concluded their new technique is simpler and quicker than other methods and up to 50-500 times more effective at enriching stem cells.
The study, led by Professor of Musculoskeletal Science, Richard Oreffo and Professor Antonios Kanaras of the Quantum, Light and Matter Group in the School of Physics and Astronomy, is published in ACS Nano — an internationally recognised multidisciplinary journal.
In laboratory tests, the researchers used gold nanoparticles — tiny spherical particles made up of thousands of gold atoms — coated with oligonucleotides (strands of DNA), to optically detect the specific messenger RNA (mRNA) signatures of skeletal stem cells in bone marrow. When detection takes place, the nanoparticles release a fluorescent dye, making the stem cells distinguishable from other surrounding cells, under microscopic observation. The stem cells can then be separated using a sophisticated fluorescence cell sorting process.
Stem cells are cells that are not yet specialised and can develop to perform different functions. Identifying skeletal stems cells allows scientists to grow these cells in defined conditions to enable the growth and formation of bone and cartilage tissue — for example, to help mend broken bones.

Why do some people with cold sores around their lips experience painful lesions, while others have no symptoms at all, yet still spread the virus? A new study conducted at Penn State finds that these differences could be due to variations in the way certain strains of herpes simplex (HSV-1) — the virus that causes cold sores, as well as genital herpes — activate gene expression in neurons.
“HSV-1 occurs in more than half the global population,” said Moriah Szpara, associate professor of biology and biochemistry and molecular biology. “Not only does it cause recurrent problems, such as cold sores and genital herpes, but recent research has implicated chronic HSV-1 infection with the development of disease later in life, including neurodegenerative diseases like Alzheimer’s.”
Szpara explained that the HSV-1 lifecycle begins upon contact with mucosal surfaces, where it invades skin cells, replicates, and can induce local lesion formation. The virus also enters local nerve endings in the skin, and transits into neurons in the nervous system. There the virus can lie dormant until it reactivates on future occasions. Neuronal damage and host immune responses triggered by viral reactivations are thought to contribute to long-term neurodegeneration.
“Since every person carries a subtly different version of HSV-1, this might explain some of the variation in human responses to infection; for example, why people have different triggers for their outbreaks or why some people experience more painful sores. Differences in the frequency of viral outbreaks, or in virus-induced gene expression patterns, might also affect the different rates at which people with chronic infections go on to develop neurodegenerative diseases.”
To investigate the causes of this variation in responses, Szpara and her colleagues infected human neuronal cells with one of three HSV-1 strains that are known to differ in their ability to cause disease in the nervous system. Next, they used deep sequencing to identify and quantify the transcriptomes — the entire set of messenger RNAs (mRNAs) made in a cell at any given time — of the neurons during infection by HSV-1.
According to Szpara, when a neuronal cell is infected with HSV-1, the resulting transcriptome includes the whole collection of mRNAs produced by both the human neuron and the HSV-1 virus. By looking at the timing and amount of mRNAs expressed during infection, scientists can gain insights on the proteins that will soon be produced from those mRNAs. It is the viral proteins and new viral progeny produced during infection that ultimately lead to health problems.