Publisher Health

When a person is infected with SARS-CoV-2, the virus that causes COVID-19, it invades their cells and uses them to replicate — which puts the cells under stress. Current approaches to dealing with infection target the virus itself with antiviral drugs. But Cambridge scientists have switched focus to target the body’s cellular response to the virus instead.
In a new study, published today in the journal PLOS Pathogens, they found that all three branches of a three-pronged signalling pathway called the ‘unfolded protein response’ (UPR) are activated in lab-grown cells infected with SARS-CoV-2. Inhibiting the UPR to restore normal cell function using drugs was also found to significantly reduce virus replication.
“The virus that causes COVID-19 activates a response in our cells — called the UPR — that enables it to replicate,” said Dr Nerea Irigoyen in the University of Cambridge’s Department of Pathology, senior author of the report.
She added: “Using drugs we were able to reverse the activation of this specific cellular pathway, and remarkably this reduced virus production inside the cells almost completely, which means the infection could not spread to other cells. This has exciting potential as an anti-viral strategy against SARS-CoV-2.”
Treatment with a drug that targets one prong of the UPR pathway had some effect in reducing virus replication. But treatment with two drugs together — called Ceapin-A7 and KIRA8 — to simultaneously target two prongs of the pathway reduced virus production in the cells by 99.5%. This is the first study to show that the combination of two drugs has a much greater effect on virus replication in cells than a single drug.
The approach would not stop a person getting infected with the coronavirus, but the scientists say symptoms would be much milder, and recovery time would be quicker.
Anti-viral drugs currently in use to treat COVID-19, such as remdesivir, target replication of the virus itself. But if the virus develops resistance to these drugs they will no longer work. In contrast, the new treatment targets the response of the infected cells; this will not change even if new variants emerge, because the virus needs this cellular response in order to replicate.
The next step is to test the treatment in mouse models. The scientists also want to see whether it works against other viruses, and illnesses such as pulmonary fibrosis and neurological disorders that also activate the UPR response in cells.
“We hope this discovery will enable the development a broad-spectrum anti-viral drug, effective in treating infections with other viruses as well as SARS-CoV-2. We’ve already found it has an effect on Zika virus too. It has the potential to have a huge impact,” said Irigoyen.
SARS-CoV-2 is the novel coronavirus responsible for the COVID-19 pandemic. Since the end of 2019 there have been over 150 million cases of the disease worldwide, and over 3 million people have died.
Story Source:
Materials provided by University of Cambridge. The original story is licensed under a Creative Commons License. Note: Content may be edited for style and length.

In the mid-14th century Europe was devastated by a major pandemic — the Black Death — which killed between 40 and 60 per cent of the population. Later waves of plague then continued to strike regularly over several centuries.
Plague kills so rapidly it leaves no visible traces on the skeleton, so archaeologists have previously been unable to identify individuals who died of plague unless they were buried in mass graves.
Whilst it has long been suspected that most plague victims received individual burial, this has been impossible to confirm until now.
By studying DNA from the teeth of individuals who died at this time, researchers from the After the Plague project, based at the Department of Archaeology, University of Cambridge, have identified the presence of Yersinia Pestis, the pathogen that causes plague.
These include people who received normal individual burials at a parish cemetery and friary in Cambridge and in the nearby village of Clopton.
Lead author Craig Cessford of the University of Cambridge said, “These individual burials show that even during plague outbreaks individual people were being buried with considerable care and attention. This is shown particularly at the friary where at least three such individuals were buried within the chapter house. Cambridge Archaeological Unit conducted excavations on this site on behalf of the University in 2017.”
“The individual at the parish of All Saints by the Castle in Cambridge was also carefully buried; this contrasts with the apocalyptic language used to describe the abandonment of this church in 1365 when it was reported that the church was partly ruinous and ‘the bones of dead bodies are exposed to beasts’.”
The study also shows that some plague victims in Cambridge did, indeed, receive mass burials.
Yersinia Pestis was identified in several parishioners from St Bene’t’s, who were buried together in a large trench in the churchyard excavated by the Cambridge Archaeological Unit on behalf of Corpus Christi College.
This part of the churchyard was soon afterwards transferred to Corpus Christi College, which was founded by the St Bene’t’s parish guild to commemorate the dead including the victims of the Black Death. For centuries, the members of the College would walk over the mass burial every day on the way to the parish church.
Cessford concluded, “Our work demonstrates that it is now possible to identify individuals who died from plague and received individual burials. This greatly improves our understanding of the plague and shows that even in incredibly traumatic times during past pandemics people tried very hard to bury the deceased with as much care as possible.”
Story Source:
Materials provided by University of Cambridge. Note: Content may be edited for style and length.

A faster method for collecting pure malaria parasites from infected mosquitos could accelerate the development of new, more potent malaria vaccines.
The new method, developed by a team of researchers led by Imperial College London, enables more parasites to be isolated rapidly with fewer contaminants, which could simultaneously increase both the scalability and efficacy of malaria vaccines.
The parasite that causes malaria is becoming increasingly resistant to antimalarial drugs, with the mosquitoes that transmit the disease also increasingly resistant to pesticides. This has created an urgent need for new ways to fight malaria, which is the world’s third-most deadly disease in under-fives, with a child dying from malaria every two minutes.
Existing malaria vaccines that use whole parasites provide moderate protection against the disease. In these vaccines, the parasites are ‘attenuated’ — just like some flu vaccines and the MMR vaccine — so they infect people and raise a strong immune response that protects against malaria, but don’t cause disease themselves.
However, these vaccines require several doses, with each dose requiring potentially tens of thousands of parasites at an early stage of their development, known as sporozoites. Sporozoites are normally found in the salivary glands of mosquitoes, and in a natural infection are passed to humans when the mosquito bites. They then travel to the human liver, where they prepare to cause infection in the body.
Extracting sporozoites for use in a live vaccine currently requires manual dissection of the mosquito salivary glands — miniscule structures behind the mosquito head — by a skilled technician, which is a time-consuming and costly process.

Thousands of years ago, archaic humans such as Neanderthals and Denisovans went extinct. But before that, they interbred with the ancestors of present-day humans, who still to this day carry genetic mutations from the extinct species.
Over 40 percent of the Neanderthal genome is thought to have survived in different present-day humans of non-African descent, but spread out so that any individual genome is only composed of up to two percent Neanderthal material. Some human populations also carry genetic material from Denisovans — a mysterious group of archaic humans that may have lived in Eastern Eurasia and Oceania thousands of years ago.
The introduction of beneficial genetic material into our gene pool, a process known as adaptive introgression, often happened because it was advantageous to humans after they expanded across the globe. To name a few examples, scientists believe some of the mutations affected skin development and metabolism. But many mutations are yet still undiscovered.
Now, researchers from GLOBE Institute at the University of Copenhagen have developed a new method using deep learning techniques to search the human genome for undiscovered mutations.
“We developed a deep learning method called ‘genomatnn’ that jointly models introgression, which is the transfer of genetic information between species, and natural selection. The model was developed in order to identify regions in the human genome where this introgression could have happened,” says Associate Professor Fernando Racimo, GLOBE Institute, corresponding author of the new study.
“Our method is highly accurate and outcompetes previous approaches in power. We applied it to various human genomic datasets and found several candidate beneficial gene variants that were introduced into the human gene pool,” he says.

The ability to insert desirable genes into animal or human cells is the basis of modern life science research and of widespread biomedical applications. The methods used to date for this purpose are mostly non-specific, making it difficult for scientists to control which cell will or will not take up a gene. For this gene transfer, the target genes are often packaged into “viral vectors.” These are viruses in which part of the genetic material has been replaced by the target genes. When researchers add these viral vectors to cells, the vectors introduce the genes into the cells. This is the principle behind some of the current SARS-CoV-2 vaccines such as those from AstraZeneca or Johnson&Johnson. However, it is difficult — even impossible — to control into which cells the target genes enter, since the viral vectors tend to dock non-specifically onto all cells of a certain cell type. A team of researchers from the Cluster of Excellence CIBSS — Centre for Integrative Biological Signalling Studies at the University of Freiburg, led by Dr. Maximilian Hörner, Prof. Dr. Wolfgang Schamel and Prof. Dr. Wilfried Weber, has developed a new technology that enables them to introduce target genes in a controlled manner and thereby control processes in individual selected cells. The researchers have published their work in the current issue of Science Advances.
Alteration to a viral vector
In their new method, the Freiburg researchers introduce the genetic information with an optical remote control. As a result, only cells that are illuminated with red light take up the desired genes. To do this, the scientists modified a type of viral vector known as an AAV vector, which is already in clinical use. “We took away the viral vector’s ability to dock with cells,” Hörner explains, “which is an essential step before the genetic material can be introduced.”
To enable this control by light, the researchers have taken a red light photoreceptor system from the plant Arabidopsis thaliana (thale cress). This system consists of two proteins, PhyB and PIF, which bind to each other as soon as PhyB is illuminated with red light. The Freiburg team placed the protein PIF on the surface of the viral vector and modified the other protein PhyB so that it could bind to human cells. Once this modified vector, called OptoAAV, is in a cell culture along with the cell-binding protein, the protein binds to all cells. “If a selected cell is now illuminated with red light, the modified vector can bind to this cell and introduce the target genes into the illuminated cell,” Hörner explains.
A key aspect of biological signal research
This new approach allows the researchers to introduce target genes into the desired cells within a tissue culture. The scientists also succeeded in illuminating the tissue culture successively at different locations, thus enabling the targeted introduction of different genes into different cells within a culture. With this technique, it is now possible to control desired processes in individual cells. This is essential for understanding how a single cell communicates with cells in its environment, for example, to control the development or regeneration of an organ. “As these viral vectors become more widely used in the therapeutic field,” Weber says, “we think this new technology has the potential to make such biomedical applications more precise.”
Cluster of Excellence CIBSS — Centre for Integrative Biological Signalling Studies
Researchers in the Cluster of Excellence CIBSS — Centre for Integrative Biological Signalling Studies at the University of Freiburg are investigating the fundamental communication processes that determine multicellular life in humans, animals and plants. In this way, they aim to gain a higher-level, integrative understanding of biological signaling processes in order to develop tailored molecular tools using methods from synthetic and chemical biology to precisely control signaling processes. In this way, the researchers seek to develop strategies for the treatment of cancer using immunotherapies or for resource-conserving crops production, among other things. Maximilian Hörner and Wolfgang Schamel are group leader in the Cluster of Excellence, Wilfried Weber is a member of the speaker team.
Story Source:
Materials provided by University of Freiburg. Note: Content may be edited for style and length.

Mark King is campaigning for better access to defibrillators, after his 12-year-old son died having suffered a sudden cardiac arrest.Mr King showed BBC Breakfast’s Charlie Stayt and Naga Munchetty how to use life-saving equipment saying: “You cannot misuse a defibrillator.”

A team of scientists headed by SANKEN (The Institute of Scientific and Industrial Research) at Osaka University demonstrated that single virus particles passing through a nanopore could be accurately identified using machine learning. The test platform they created was so sensitive that the coronaviruses responsible for the common cold, SARS, MERS, and COVID could be distinguished from each other. This work may lead to rapid, portable, and accurate screening tests for COVID and other viral diseases.
The global coronavirus pandemic has revealed the crucial need for rapid pathogen screening. However, the current gold-standard for detecting RNA viruses — including SARS-CoV-2, the virus that causes COVID — is reverse transcription-polymerase chain reaction (RT-PCR) testing. While accurate, this method is relatively slow, which hinders the timely interventions required to control an outbreak.
Now, scientists led by Osaka University have developed an intelligent nanopore system that can be used for the detection of SARS-CoV-2 virus particles. Using machine-learning methods, the platform can accurately discriminate between similarly sized coronaviruses responsible for different respiratory diseases. “Our innovative technology has high sensitivity and can even electrically identify single virus particles,” first author Professor Masateru Taniguchi says. Using this platform, the researchers were able to achieve a sensitivity of 90% and a specificity of 96% for SARS-CoV-2 detection in just five minutes using clinical saliva samples.
To fabricate the device, nanopores just 300 nanometers in diameter were bored into a silicon nitride membrane. When a virus was pulled through a nanopore by the electrophoretic force, the opening became partially blocked. This temporarily decreased the ionic flow inside the nanopore, which was detected as a change in the electrical current. The current as a function of time provided information on the volume, structure, and surface charge of the target being analyzed. However, to interpret the subtle signals, which could be as small as a few nanoamps, machine learning was needed. The team used 40 PCR-positive and 40 PCR-negative saliva samples to train the algorithm.
“We expect that this research will enable rapid point-of-care and screening tests for SARS-CoV-2 without the need for RNA extraction,” Professor Masateru Taniguchi explains. “A user-friendly and non-invasive method such as this is more amenable to immediate diagnosis in hospitals and screening in places where large crowds are gathered.” The complete test platform consists of machine learning software on a server, a portable high-precision current measuring instrument, and cost-effective semiconducting nanopore modules. By using a machine-learning method, the researchers expect that this system can be adapted for use in the detection of emerging infectious diseases in the future. The team hopes that this approach will revolutionize public health and disease control.
Story Source:
Materials provided by Osaka University. Note: Content may be edited for style and length.

Researchers at the National Institutes of Health have developed a prototype device that could potentially diagnose pregnancy complications by monitoring the oxygen level of the placenta. The device sends near-infrared light through the pregnant person’s abdomen to measure oxygen levels in the arterial and venous network in the placenta. The method was used to study anterior placenta, which is attached to the front wall of the uterus. The researchers described their results as promising but added that further study is needed before the device could be used routinely.
The small study was conducted by Amir Gandjbakhche, Ph.D., of the Section on Translational Biophotonics at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and colleagues. It appears in Biomedical Optics Express.
The researchers devised mathematical methods to study the passage of light through the skin, abdominal wall and uterine tissue to reach the placenta and calculate its oxygen levels. Currently, the device cannot monitor oxygen in women with a posterior placenta, which is attached to the back wall of the uterus, because the distance is too far for the light to travel. However, anterior placenta is associated with a higher rate of complications than posterior placenta, such as postpartum hemorrhage and an increased need for labor induction or cesarean delivery.
The researchers enrolled 12 pregnant women with an anterior placenta in the study. Of these, five had a pregnancy complication, including hypertension, a short cervix and polyhydramnios (excess amniotic fluid). On average, the women with complications had a placental oxygen level of 69.6%, a difference statistically significant from the 75.3% seen in the healthy pregnancies in the study. The authors see their results as a first step in continuously monitoring placental oxygen levels to assess maternal and fetal health.
Story Source:
Materials provided by NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development. Note: Content may be edited for style and length.

Since 2005, the guidelines for the care of unconscious cardiac arrest patients have been to cool the body temperature down to 33 degrees Celsius. A large, randomised clinical trial led by Lund University and Region Skåne in Sweden has shown that this treatment does not improve survival. The study is published in the New England Journal of Medicine.
“These results will affect the current guidelines,” says Niklas Nielsen, researcher at Lund University and consultant in anaesthesiology and intensive care at Helsingborg Hospital, who led the study.
In the early 2000s, two studies in the New England Journal of Medicine showed that induced hypothermia in unconscious cardiac arrest patients greatly improved patient survival. The studies changed existing treatment practices, and led to the introduction of new guidelines around the world. However, the evidence for the guidelines was considered by many to be weak. As a result, a large international randomised clinical trial was initiated, and led by researchers at Lund University and Helsingborg Hospital.
The results of the comprehensive study, which has now been published in the same journal, show that hypothermia does not reduce mortality in unconscious patients with suspected cardiac arrest.
“It is important to set high standards for clinical studies, partly to determine what should be introduced in healthcare, partly to challenge the practices that are already in use — to ensure that we have got it right and that healthcare is evidence-based. The results produced strongly indicate that normal temperature should be recommended, not hypothermia,” says Niklas Nielsen.
In total, 1900 adult patients who suffered cardiac arrest and were unconscious when admitted to hospital were included in the study. Between November 2017 and January 2020, a total of 61 hospitals around the world participated in the study which has now been published. The patients included in the study had suffered unexpected out-of-hospital cardiac arrest.

Research shows that inhibiting necroptosis, a form of cell death, could be a novel therapeutic approach for treating chronic obstructive pulmonary disease (COPD), an inflammatory lung condition, also known as emphysema, that makes it difficult to breathe.
Published in the American Journal of Respiratory and Critical Care Medicine, the study by a team of Australian and Belgian researchers, revealed elevated levels of necroptosis in patients with COPD.
By inhibiting necroptosis activity, both in the lung tissue of COPD patients as well as in specialised COPD mouse models, the researchers found a significant reduction in chronic airway inflammation as well as damage to the lung.
Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation who led the research team, said that necroptosis was a form of cell death known to drive tissue inflammation and destruction.
“Necroptosis, apoptosis and necrosis are all forms of cell death but they operate in distinctly different ways. Significantly, in necroptosis, a cell bursts, dispersing its contents into nearby tissues resulting in an immune and inflammation response.”
“Our research suggests that inhibiting necroptosis and preventing this inflammation response may be a new therapeutic approach to treating COPD,” said Professor Hansbro.
Joint first author on the study, Dr Zhe Lu, a researcher at the University of Newcastle, said that their study was the first of its type to be able to distinguish between the roles of necroptosis and apoptosis in COPD.
“Necroptosis is generally pro-inflammatory. Apoptosis, however, tends to be non-inflammatory as it’s a more ordered form of cell death-a cell self-degrades as opposed to bursting and there’s no leakage of cell contents. This may explain why, in our study, it’s the inhibition of necroptosis and not apoptosis that reduces lung damage and COPD associated inflammation,” said Dr Lu.
A debilitating respiratory condition and a leading cause of death worldwide, there are currently no treatments that halt or reverse the progression of COPD.
“Our research suggests that it is the type of cell death associated with COPD that is important and that the development of new drugs that can interfere or intervene in the necroptosis process could be a new targeted therapy for this common lung disease,” said Professor Hansbro.
The study was led by researchers from the Centenary Institute, University of Technology Sydney, University of Newcastle and Ghent University Hospital, Belgium.
Story Source:
Materials provided by University of Technology Sydney. Note: Content may be edited for style and length.