Culture

WEST LAFAYETTE, Ind. -- About 50% of people who take the drug infliximab for inflammatory bowel diseases, such as Crohn's disease, end up becoming resistant or unresponsive to it.

Scientists might be able to catch problems like this one earlier in the drug development process, when drugs move from testing in animals to clinical trials, with a new computational model developed by researchers from Purdue University and Massachusetts Institute of Technology.

The researchers call the model "TransComp-R." In a study published in Science Signaling, they used the model to identify an overlooked biological mechanism possibly responsible for a patient's resistance to infliximab.

Such a mechanism is hard to catch in preclinical testing of new drugs because animal models of human diseases may have different biological processes driving disease or a response to therapy. This makes it difficult to translate observations from animal experiments to human biological contexts.

"This model could help better determine which drugs should move from animal testing to humans," said Doug Brubaker, a Purdue assistant professor of biomedical engineering, who led the development and testing of this model as a postdoctoral associate at MIT.

"If there is a reason why the drug would fail, such as a resistance mechanism that wasn't obvious from the animal studies, then this model would also potentially detect that and help guide how a clinical trial should be set up," he said.

TransComp-R consolidates thousands of measurements from an animal model to just a few data coordinates for comparing with humans. The dwindled-down data explain the most relevant sources of biological differences between the animal model and humans.

From there, scientists could train other sets of models to predict a human's response to therapy in terms of those data coordinates from an animal model.

For infliximab, data from a mouse model and human hadn't matched up because they were different types of biological measurements. The mouse model data came in the form of intestinal proteins, whereas data from patients were only available in the form of expressed genes, a discrepancy TransComp-R was able to address.

TransComp-R helped Brubaker's team to find links in the data pointing toward a resistance mechanism in humans.

The team collaborated with researchers from Vanderbilt University to test the predicted mechanism in intestinal biopsies from a Crohn's disease patient and then with experiments in human immune cells.

The researchers used single-cell sequencing of a sample from an infliximab-resistant Crohn's disease patient to identify the cell types expressing the genes related to the resistance mechanism predicted by TransComp-R.

They then treated immune cells with infliximab and an inhibitor of the receptor identified by the model to be part of the resistance mechanism. The experiment showed that inhibiting the receptor enhanced the anti-inflammatory effects of infliximab, enabling the drug to be more effective because it could better control inflammation.

With additional testing to figure out a way to more precisely measure the markers of this resistance mechanism, doctors could use information about the drug response to determine if a patient needs a different course of treatment.

Since this study, Brubaker has been working with his former research group at MIT to apply the mathematical framework behind TransComp-R to identify mouse models predictive of Alzheimer's disease biology and immune signatures of vaccine effectiveness in animal studies of COVID-19 vaccine candidates.

"The modeling framework itself can be repurposed to different kinds of animals, different disease areas and different questions," Brubaker said. "Figuring out when what we see in animals doesn't track with what's happening in humans could save a lot of time, cost and effort in the drug development process overall."

Philadelphia, August 4, 2020 - As school districts look ahead to a very different school year, pediatric infectious disease experts from across the United States convened to outline back-to-school safety guidelines for solid organ transplant (SOT) recipients. The group, led by Kevin J. Downes, MD, attending physician in the Division of Pediatric Infectious Diseases at Children's Hospital of Philadelphia (CHOP), published their recommendations today in the Journal of the Pediatric Infectious Diseases Society.

Throughout the COVID-19 pandemic, pediatric SOT patients have been categorized as high-risk due to their use of immunosuppressive medications, frequent presence of additional medical issues, and elevated risk for more severe outcomes from other viral respiratory infections. While there is no specific evidence that pediatric SOT recipients fare worse from COVID-19, parents of SOT patients are undoubtedly nervous to send their children back to school in the fall.

As a result, parents of transplant recipients need clear guidance regarding return to school decisions and what approaches, if any, they or their schools should take to protect their immunocompromised child. In addition to these health-related considerations, many are also weighing the notable academic, social, and emotional benefits of school attendance.

"We listened to the questions families brought to us, and to their transplant providers, and drafted a set of recommendations around their concerns," said Dr. Downes. "For the majority of pediatric SOT recipients, the benefits of attending school will probably outweigh the risks. However, the final decision is a matter of shared decision-making among families, transplant professionals, and educators, and depends on many factors, including the child's clinical risk, COVID-19 cases in the community, and preparedness of both the child and the school to adhere to recommended precautions to prevent viral transmission."

The consensus statements are grouped in three areas: 1) SOT patient-specific risk factors, 2) community transmission and public health responses, and 3) school-related interventions. Only questions pertaining to school attendance in kindergarten through 12th grade in U.S. schools were considered. Questions include topics related to masking, virtual learning, and infection prevention measures.

The COVID-19 pandemic has created unprecedented circumstances and unique challenges for vulnerable children around the world. While caregivers are grappling with difficult decisions regarding returning to schools, public health officials, local health departments, and school administrators are working hard to make returning to school as safe as possible. Dr. Downes and his colleagues fully support efforts to allow all children to safely return to in-person education this academic year and have provided recommendations for transplant patients, families, and providers to help meet this goal.

An early blood test could detect which babies deprived of oxygen at birth are at risk of serious neurodisabilities like cerebral palsy and epilepsy.

The prototype test looks for certain genes being switched on and off that are linked to long-term neurological issues. Further investigations of these genes may provide new targets for treating the brain damage before it becomes permanent.

The team behind the test, led by Imperial College London researchers in collaboration with groups in India, Italy and the USA, have published their findings today in the journal Scientific Reports.

The research was conducted in Indian hospitals, where there are around 0.5-1.0 million cases of birth asphyxia (oxygen deprivation) per year. Babies can suffer oxygen deprivation at birth for a number of reasons, including when the mother has too little oxygen in her blood, infection, or through complications with the umbilical cord during birth.

Following oxygen deprivation at birth, brain injury can develop over hours to months and affect different regions of the brain, resulting in a variety of potential neurodisabilities such as cerebral palsy, epilepsy, deafness or blindness.

This makes it hard to determine which babies are most at risk of complications and to design interventions that can prevent the worst outcomes.

Now, in preliminary study of 45 babies that experienced oxygen deprivation at birth, researchers have identified changes to a raft of genes in their blood that could identify those that go on to develop neurodisabilities.

The babies had their blood taken within six hours after birth and were followed up after 18 months old to see which had developed neurodisabilities. The blood was examined with next-generation sequencing to determine any difference in gene expression - the 'switching on or off' of genes - between those babies that developed neurodisabilities and those that didn't.

The team found 855 genes were expressed differently between the two groups, with two showing the most significant difference.

Examining these two genes in particular, and what processes their expression causes within cells, could lead to a deeper understanding of the causes of neurodisabilities prompted by oxygen deprivation, and potentially how to disrupt them, improving outcomes.

Lead author Dr Paolo Montaldo, from the Centre for Perinatal Neuroscience at Imperial, said: “We know that early intervention is key to preventing the worst outcomes in babies following oxygen deprivation, but knowing which babies need this help, and how best to help them, remains a challenge."

Senior author Professor Sudhin Thayyil, from the Centre for Perinatal Neuroscience at Imperial, said: “The results from these blood tests will allow us to gain more insight into disease mechanisms that are responsible for brain injury and allow us to develop new therapeutic interventions or improve those which are already available.”

The babies were part of a trial called Hypothermia for Encephalopathy in Low and middle-income countries (HELIX), which also examines the use of hypothermia (extreme cooling) on babies to prevent brain injuries developing following oxygen deprivation.

In higher-income countries this is known to reduce the chances of babies developing neurodisabilities, but in lower income settings cooling may not be feasible, and even with cooling 30 percent of babies still have adverse outcomes, so new therapies are still needed.

The team will next expand their blood testing study to a larger number of babies and examine the genes that appear to show the most difference between the groups.

Patients who suffer from thrombosis, pulmonary embolism or stroke are usually put on drugs that help their blood flow more smoothly through their body. Occupying a large section of the drug market, anticoagulants, or "blood thinners" as they are popularly known, can keep blood clots from forming or getting bigger, and can therefore help with recover from heart defects or prevent further complications.

But there is a catch: blood thinners work by blocking enzymes that help to stop bleeding after an injury. Because of this, virtually every blood thinner available today can lead to serious, and even life-threatening bleeding following an injury.

The problem remained unsolved until a few years ago, when a study was carried out on mice that had been genetically modified to be deficient in an enzyme that normally helps blood clot. The enzyme is called "coagulation factor XII" (FXII), and the mice without the enzyme had a very reduced risk of thrombosis without having bleeding side-effects. The discovery triggered a race for FXII inhibitors.

Finally, a synthetic inhibitor

Participating in the race, the Laboratory of Therapeutic Proteins and Peptides of Professor Christian Heinis at EPFL has developed the first synthetic inhibitor of FXII. The inhibitor has high potency, high selectivity, and is highly stable, with a plasma half-life of over 120 hours. Published in Nature Communications, the study is the result of an extensive collaboration with three other labs in Switzerland and the US.

"The FXII inhibitor is a variation of a cyclic peptide that we identified in a pool of more than a billion different peptides, using a technique named phage display," says Heinis. The researchers then improved the inhibitor by painstakingly replacing several of its natural amino acids with synthetic ones. "This wasn't a quick task; it took over six year and two generations of PhD students and post-docs to complete."

With a potent FXII inhibitor in hand, Heinis's group wanted to evaluate it in actual disease models. To do this, they teamed up with experts in blood and disease-modeling at the University Hospital of Bern (Inselspital) and the University of Bern.

Working with the group of Professor Anne Angellillo-Scherrer (Inselspital), they showed that the inhibitor efficiently blocks coagulation in a thrombosis model without increasing the bleeding risk. Then they assessed the inhibitor's pharmacokinetic properties with the group of Professor Robert Rieben (University of Bern). "Our collaboration found that it is possible to achieve bleeding-free anti-coagulation with a synthetic inhibitor," says Heinis.

Artificial lungs

"The new FXII inhibitor is a promising candidate for safe thromboprotection in artificial lungs, which are used to bridge the time between lung failure and lung transplantation," says Heinis. "In these devices, contact of blood proteins with artificial surfaces such as the membrane of the oxygenator or tubing can cause blood clotting." Known as 'contact activation', this can lead to severe complications or even death and limits the use of artificial lungs for longer than a few days or weeks.

To test the effectiveness of the FXII inhibitor in artificial lungs, Heinis's group turned to Professor Keith Cook at Carnegie Mellon University (US), an expert for artificial lung system engineering. Cook's group tested the inhibitor in an artificial lung model, and found that it efficiently reduced blood clotting, all without any bleeding side-effects.

The only problem is that the inhibitor has a relatively short retention time in the body: it's too small and the kidneys would filter it out. In the context of artificial lungs, this would mean constant infusion, since suppressing blood clotting for several days, weeks or months requires a long circulation time.

But Heinis is optimistic: "We're fixing this; we're currently engineering variants of the FXII inhibitor with a longer retention time."

LOS ANGELES (Aug. 4, 2020) - More than three years after a clinical trial was prematurely ended for failing to show progress in healing heart attack scars, a prominent peer-reviewed journal is publishing some surprising results showing that the heart cell treatment does benefit patients.

Data from the ALLSTAR study published Tuesday by the European Heart Journal showed that although infusions of allogeneic cardiac cells-called cardiosphere-derived cells or CDCs--did not appear to shrink the scar left on heart muscle after a heart attack, other data from the study show a clear benefit.

Compared with patients who received placebo treatment, patients randomized to receive CDC infusions showed a decrease in the volume of blood in the heart before and after it beats, indicating that the heart had not dilated, as it does progressively in heart failure.

"As it develops heart failure, the heart gets bigger and bigger, like a swelling balloon," said the study's lead author, Raj Makkar, MD, vice president of Cardiovascular Innovation and Intervention for Cedars-Sinai and the Stephen R. Corday, MD, chair in Interventional Cardiology. "One way we can measure the health of a heart is to measure the volume of blood it can hold. The bigger the volume, the more damaged the heart."

The newly analyzed data from the ALLSTAR study, which was sponsored by Capricor Therapeutics, showed that patients given a placebo had hearts that continued to swell, holding larger volumes of blood, while the patients who received CDC infusions had smaller hearts with lower volumes.

Results include:

The volume of blood held by the heart was essentially unchanged six months after CDC infusion, but increased by more than a teaspoonful in placebo patients.

A blood protein that measures heart failure severity was reduced in patients who had received CDCs, but not in placebo patients.

The chance that these findings were statistical flukes was only 2%.

"To me, these data are very reassuring that there really is therapeutic benefit," said Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute. "There is a growing body of evidence that this cell treatment does work."

Results from the earlier CADUCEUS trial, published in The Lancet in 2014, showed that injecting CDCs into the hearts of heart attack survivors significantly reduced their heart attack scars. In 2017, however, the multicenter ALLSTAR study was prematurely halted after six months of data showed no decrease in heart attack scar size, but later analyses revealed the beneficial findings reported here.

"We think we may have chosen the wrong endpoint," said Marbán, the Mark S. Siegel Family Foundation Distinguished Professor, whose discoveries and technologies resulted in CDCs. "This happens in science because you have to design the trial a year or more before you begin, and sometimes you bet on the wrong horse ... but that doesn't necessarily mean the therapy is ineffective."

The cells used in the study were CAP-1002, Capricor Therapeutic's off-the-shelf, cardiosphere-derived cell (CDC) product candidate. Other clinical trials and case series, in which CDCs were used to treat advanced heart failure, Duchenne Muscular Dystrophy, and COVID-19, also demonstrated positive results. And new studies using CDCs are in the planning stages.

"California is known as the stem cell state, but few technologies being tested in California actually were developed here," said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs, dean of the Medical Faculty and professor of Medicine. "Increasing evidence-including the results of the large multicenter ALLSTAR trial-validates the potential utility of a cell product which was conceived by a faculty member at Cedars-Sinai, and first tested clinically here."

LA JOLLA--Your immune system's "memory" T cells keep track of the viruses they have seen before. This immune cell memory gives the cells a headstart in recognizing and fighting off repeat invaders.

Now, a new study led by scientists at La Jolla Institute for Immunology (LJI) shows that memory helper T cells that recognize common cold coronaviruses also recognize matching sites on SARS-CoV-2, the virus that causes COVID-19.

The research, published Aug. 4, 2020 in Science, may explain why some people have milder COVID-19 cases than others--though the researchers emphasize that this is speculation and much more data is needed.

"We have now proven that, in some people, pre-existing T cell memory against common cold coronaviruses can cross-recognize SARS-CoV-2, down to the exact molecular structures," says LJI Research Assistant Professor Daniela Weiskopf, Ph.D., who co-led the new study with LJI Professor Alessandro Sette, Dr. Biol. Sci. "This could help explain why some people show milder symptoms of disease while others get severely sick."

"Immune reactivity may translate to different degrees of protection," adds Sette. "Having a strong T cell response, or a better T cell response may give you the opportunity to mount a much quicker and stronger response."

The new work builds on a recent Cell paper from the Sette Lab and the lab of LJI Professor Shane Crotty, Ph.D., which showed that 40 to 60 percent of people never exposed to SARS-CoV-2 had T cells that reacted to the virus. Their immune systems recognized fragments of the virus it had never seen before. This finding turned out to be a global phenomenon and was reported in people from the Netherlands, Germany, the United Kingdom and Singapore.

Scientists wondered if these T cells came from people who had previously been exposed to common cold coronaviruses--what Sette calls SARS-CoV-2's "less dangerous cousins." If so, was exposure to these cold viruses leading to immune memory against SARS-CoV-2?

For the new study, the researchers relied on a set of samples collected from study participants who had never been exposed to SARS-CoV-2. They defined the exact sites of the virus that are responsible for the cross-reactive T cell response. Their analysis showed that unexposed individuals can produce a range of memory T cells that are equally reactive against SARS-CoV-2 and four types of common cold coronaviruses.

This discovery suggests that fighting off a common cold coronavirus can indeed teach the T cell compartment to recognize some parts of SARS-CoV-2 and provides evidence for the hypothesis that common cold viruses can, in fact, induce cross-reactive T cell memory against SARS-CoV-2.

"We knew there was pre-existing reactivity, and this study provides very strong direct molecular evidence that memory T cells can 'see' sequences that are very similar between common cold coronaviruses and SARS-CoV-2," says Sette.

Looking closer, the researchers found that while some cross-reactive T cells targeted the SARS-CoV-2's spike protein, the region of the virus that recognizes and binds to human cells, pre-existing immune memory was also directed to other SARS-CoV-2 proteins. This finding is relevant, Sette explains, since most vaccine candidates target mostly the spike protein. These findings suggest the hypothesis that inclusion of additional SARS-CoV-2 targets might enhance the potential to take advantage of this cross reactivity and could further enhance vaccine potency.

Article #22: "Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans," by Jose Mateus et al. Please see paper PDF for full author and institution list.

Contact: Alessandro Sette at alex@lji.org (email). Daniela Weiskopf at daniela@lji.org (email).

DOI Information: Reporters wishing to link to this paper's abstract on sciencemag.org can use the following URL: https://science.sciencemag.org/lookup/doi/10.1126/science.abd3871

Note: This paper will be available for free when the embargo lifts at https://www.sciencemag.org.

News Release: A related news release is available from La Jolla Institute for Immunology in La Jolla, CA.

For Immediate Release: The paper, "Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans," by Jose Mateus and colleagues, has been added to the current Science Press Package, for immediate release (with no embargo).

Journal

Science

DOI

10.1126/science.abd3871

Researchers in China identified four key population categories useful in guiding COVID-19 public health policies aimed at minimizing the spread of the disease and reducing fatalities. The team, led by Dr. Baoguo Jiang of the Department of Orthopedics & Traumatology at Peking University People's Hospital, published their findings in the journal Precision Clinical Medicine on May 28.

"Our research develops a decision-making support model to describe SARS-COV-2 infection, and can be adjusted to reflect local transmission characteristics and public health capabilities," Dr. Jiang said. "This model will be instrumental for local authorities to determine the optimal disease suppression strategy in a data-driven and science-driven manner.

The study divided subjects into four main categories: "Isolated" (via quarantine or hospitalization), "not infected," "infected and not isolated," and "removed" (recovered or deceased). Within those broad categories, they analyzed the effectiveness of the three main things public health policy can control - whether face masks and other heightened hygiene measures are required in public, mandatory lockdowns, and mandatory social distancing.

Data collected were from Wuhan, China, where the COVID-19 outbreak began last year. In designing the study, the researchers calibrated the model based on 32,583 confirmed COVID-19 cases in Wuhan between December 2019 and March 2020. The "infected and not isolated" category presented an extra challenge, because not all infected persons displayed symptoms, yet had the potential to infect many others. To control for this, their model allows for a predetermined number of subjects presumed infected but not showing symptoms to progress to the "removed" (and recovered) category.

Public health officials in Wuhan estimated the probability of having close contact with someone infected with COVID-19 was reduced by about 75 percent amid stringent quarantine conditions. Implementing mandatory face masks and hygiene practices in public was estimated to reduce the likelihood of transmitting the infection by 50 percent.

"Our research demonstrates that implementation of case isolation and mass quarantine is the most effective measure to the complete suppression of COVID-19 outbreak," Dr. Jiang said.

The research team found that their study model could be applied in the U.S., U.K., and Italy, with only minor adjustments in likelihood of person-to-person transmission within each of the four main population categories. Population density accounted for most of those differences, explaining why cities like Wuhan and New York saw the disease spread more rapidly.

One of the study's key findings was that face masks and social distancing were not enough to reverse upward trend of the disease. Wuhan only saw reversal in COVID-19 infection rates after adding contact tracing and strict quarantines to their containment policy. Further, they found that if no quarantine was implemented and the disease was allowed to spread unchecked, over 10 million people in Wuhan alone - or about 91 percent of the population - would become infected before the population would achieve herd immunity. "Starting mass quarantine and case isolation earlier greatly improves the effectiveness of disease suppression and also demands fewer health care resources," Dr. Baoguo said.

Another important finding was that quarantine must be implemented at a rate of at least 50 percent, and a maximum of 10 weeks after the start of a COVID-19 outbreak to have a chance at reversing the infection rate. If less that 40 percent of the population remains quarantined or the quarantine begins more than 11 weeks after onset of the outbreak, it is too late, the study says.

Dr. Jiang said his team plans to further investigate how to optimally allocate prevention and control measures.

"On the one hand, through arduous efforts, our fight against COVID-19 has achieved major results with strategic significance," Dr. Jiang said. "The prevention and control measures have been normalized. On the other hand, an increasing number of asymptomatic COVID-19 carriers have been reported recently. More study on transmission characteristics of the disease among asymptomatic persons is necessary to better control the epidemic."

Researchers reported a novel technology enhancing the high transparency of refractive polymer film via a one-step vapor deposition process. The sulfur-containing polymer (SCP) film produced by Professor Sung Gap Im's research team at KAIST's Department of Chemical and Biomolecular Engineering has exhibited excellent environmental stability and chemical resistance, which is highly desirable for its application in long-term optical device applications. The high refractive index exceeding 1.9 while being fully transparent in the entire visible range will help expand the applications of optoelectronic devices.

The refractive index is a ratio of the speed of light in a vacuum to the phase velocity of light in a material, used as a measure of how much the path of light is bent when passing through a material. With the miniaturization of various optical parts used in mobile devices and imaging, demand has been rapidly growing for high refractive index transparent materials that induce more light refraction with a thin film.

As polymers have outstanding physical properties and can be easily processed in various forms, they are widely used in a variety of applications such as plastic eyeglass lenses. However, there have been very few polymers developed so far with a refractive index exceeding 1.75, and existing high refractive index polymers require costly materials and complicated manufacturing processes.

Above all, core technologies for producing such materials have been dominated by Japanese companies, causing long-standing challenges for Korean manufacturers. Securing a stable supply of high-performance, high refractive index materials is crucial for the production of optical devices that are lighter, more affordable, and can be freely manipulated.

The research team successfully manufactured a whole new polymer thin film material with a refractive index exceeding 1.9 and excellent transparency, using just a one-step chemical reaction. The SCP film showed outstanding optical transparency across the entire visible light region, presumably due to the uniformly dispersed, short-segment polysulfide chains, which is a distinct feature unachievable in polymerizations with molten sulfur.

The team focused on the fact that elemental sulfur is easily sublimated to produce a high refractive index polymer by polymerizing the vaporized sulfur with a variety of substances. This method suppresses the formation of overly long S-S chains while achieving outstanding thermal stability in high sulfur concentrations and generating transparent non-crystalline polymers across the entire visible spectrum.

Due to the characteristics of the vapor phase process, the high refractive index thin film can be coated not just on silicon wafers or glass substrates, but on a wide range of textured surfaces as well. We believe this thin film polymer is the first to have achieved an ultrahigh refractive index exceeding 1.9.

Professor Im said, "This high-performance polymer film can be created in a simple one-step manner, which is highly advantageous in the synthesis of SCPs with a high refractive index. This will serve as a platform material for future high-end optical device applications."

Hypermutation is an unusual occurence that can lead to many nearby mutations at once, severely damaging our genetic material and potentially causing cancer. The best known type of local hypermutation, called a mutation shower or thunderstorm, is quite uncommon and it leads to many mutations accumulated in a small area, e.g. a single gene.

Researchers from IRB Barcelona's Genome Data Science Lab, led by the ICREA researcher Fran Supek, have discovered a new type of hypermutation called mutation fog, which can generate hundreds of mutations in every cell. Such mutations are widely distributed, but accumulate in the most important regions of the genome, where genes reside (the so-called euchromatin). The fact that these mutations are spread around explains why they have remained undetected until now.

Surprisingly, the scientists have also identified that the newly discovered hypermutation type is related to a normal DNA repair process. When cells sense a mismatch in their DNA, they undergo a DNA repair reaction, in order to preserve genetic information. Remarkably, this reaction can become coupled to the APOBEC enzyme-typically used by human cells to defend against viruses and having an important role in fighting hepatitis and HIV. The work by the Genome Data Science Lab indicates that, in some cases, when both the APOBEC enzymes and the DNA repair process are active at the same time, APOBEC hijacks the DNA repair, generating the mutation fog.

"We think that this APOBEC-driven mutation fog has a mutagenic potential that matches or even exceeds that of well-known strong carcinogens, such as tobacco smoke or ultraviolet radiation," Fran Supek explains. Recent work by other research groups suggests that the process appears to be more active in late-stage metastatic cancers: it helps the cancer evolve, enabling it to resist drugs and radiation. "This finding makes APOBEC an attractive target for treating cancer, removing its ability to evolve and to become more aggressive," adds Supek.

The origin of a half of the mutations in some lung and breast cancers

A thorough analysis of more than 6,000 human cancer genomes, including lung tumours, breast tumours and melanomas, among others, led to the finding that the mutation fog is a common phenomenon. "More than half of all APOBEC mutations in some lung or breast cancers are generated by the hypermutation mechanism that we have found," says David Mas-Ponte, first author of the study and PhD student in the Genome Data Lab.

Some types of cancer, such as cervical or some head-and-neck cancers, are known to be due to viruses. However, this study has found mutations caused by this APOBEC system not only in these tumours but also in cancers that are not currently known to be virus-related. Further work should clarify what triggers the APOBEC system. "Understanding APOBEC better could have broad implications for cancer treatment," adds Mas-Ponte.

The HyperClust statistical method

Mas-Ponte and Supek designed a statistical method, called HyperClust, that can rapidly analyse large amounts of human genomic data to find unusual mutational processes that can lead to simultaneous mutations, such as these cases of mutation fog. This statistical method is described in the article, which has been published in Nature Genetics, and is also available as an open-source software in a Github repository.

This work has been funded by the ERC Starting Grant "HYPER-INSIGHT" awarded to Fran Supek; ICREA reaearcher and EMBO Young Investigator; and the Severo Ochoa grant awarded to IRB Barcelona. David Mas-Ponte was the recipient of an FPI-SO fellowship.

Scientists from Nanyang Technological University, Singapore (NTU Singapore) and the Agency for Science, Technology and Research (A*STAR) have showed that applying "temporal pressure" to the skin of mice can create a new way to deliver drugs.

In a paper published in Science Advances, the researchers showed that bringing together two magnets so that they pinch and apply pressure to a fold of skin, led to short term changes in the skin barrier and specifically the formation of "micropores" underneath its surface.

In tests, they showed that these micropores, of about 3 micrometres in area, allowed drugs applied on the surface of the skin to diffuse through it more easily. Six times greater quantity of drug diffused through the skin of mice with the micropores compared to the skin of mice which did not receive the temporal pressure treatment.

Lead author of the paper, Dr Daniel Lio, who did this research as part of his doctoral thesis at NTU's School of Chemical and Biomedical Engineering, Interdisciplinary Graduate Programme, said that while needles and microneedle injections damage the skin, micropores could pave the way towards painless transdermal delivery of drugs such as insulin.

"Our research project was first inspired by the traditional Chinese medicine 'tuina' therapy where physicians rub and apply pressure on skin and muscle tissue and apply a topical ointment," explained Dr Lio, who is now working at A*STAR's Enterprise Group.

Going a step further, the joint team which included Prof David Laurence Becker from NTU Lee Kong Chian School of Medicine and Skin Research Institute of Singapore; Assoc Prof Wang Xiaomeng from the NTU Lee Kong Chian School of Medicine, and Assistant Prof Xu Chenjie from the School of Chemical and Biomedical Engineering, tested the delivery of insulin through the skin of mice using the new method.

Reducing skin damage and pain from delivering drugs through skin

Experimental results showed that nanoparticles and insulin were effectively delivered through the skin of mice, at molecular masses up to 20,000 daltons.

This mass is 40 times the largest currently reported in the scientific literature for transdermal drug delivery (i.e. via patches), which is 500 daltons.

The amount of drug delivered via the temporal pressure method was also comparable to the amount delivered by a microneedle patch - dozens of needles smaller than the width of a human hair made from biocompatible compounds, commonly used to deliver small amounts of drugs through the skin over time.

Compared to conventional injection where the skin has to be penetrated and there is a risk of a hypoglycaemia effect - when the injected insulin acts too fast and the patient gets dizzy - the new method is able to slowly deliver drugs over time without breaking the skin, thus causing less pain.

In experiments, the team also found that with their method, cells in the skin layer (epidermis) were observed to have an increase in the number of "gap junctions" and a reduction in "tight junctions". These junctions control the amount of molecules being delivered between the cells: if there is an increased expression of gap junctions, more molecules can be delivered across the cell barrier, while tight junctions restrict the extracellular movement of molecules.

In the animal experiments, two magnets were used to apply pressure on the mouse dorsal skin for 1 or 5 minutes, depending on how fast the drug delivery is needed, before being removed and the drug is then topically applied like a cream.

The team hypothesised that for drugs that need to be delivered more slowly or in smaller doses - 1 minute would be sufficient, while for drugs to be delivered faster, more micropores would be needed, therefore 5 minutes would be required.

The drug was then left for 12 hours before the skin was imaged with fluorescent microscopy to see to what extent the drug had penetrated through the skin.

The team compared three types of skin: skin that received pressure treatment, skin which had not, and skin which had drugs delivered through microneedles.

Skin that received pressure treatment had similar amounts of drug delivered through the skin to that found with a microneedle patch, while skin that did not receive the pressure treatment had significantly less drug delivered.

Micropores were also observed to disappear a day after they were formed, which suggests that the skin cells have filled up the gaps.

Prof Becker, whose research expertise is in tissue repair and regeneration, said their paper highlighted the potential to use this method which could alleviate the need for diabetes patients to inject insulin multiple times daily using conventional needles and syringes.

"Patients who have to inject drugs daily, such as insulin, are constantly asking whether there is another way to deliver their medicines that doesn't involve hurting or penetrating the skin. Our new findings hold promise for them and we hope that we can refine this method so that one day it may be possible to deliver enough drugs through the skin via a patch and to rid them of their daily injections," Prof Becker added.

This multidisciplinary project, supported by the Skin Research Institute of Singapore (SRIS) - a collaboration between A*STAR, National Skin Center (NSC) and NTU, took two years and is continuing.

It is also supported by multiple grants from various agencies, which include A*STAR, SRIS, and the National Medical Research Council.

The team has since filed a patent for a pressure device, which looks like a vice-like clamp for the skin, through NTU's innovation and enterprise company, NTUtive, and is currently carrying out further experiments to refine the drug delivery mechanism.

Solar activity varies in 11-year cycles. As the activity cycle switches to a new one, the Sun is usually very calm for several years.

For a long time, researchers have believed that there is not much of interest going on in the Sun during the passive period, therefore not worth studying. Now this assumption is showed to be false by Juha Kallunki, Merja Tornikoski and Irene Björklund, researchers at Metsähovi Radio Observatory, in their peer-reviewed research article published in Solar Physics. This is the first time that astronomers are systematically studying the phenomena of the solar minimum.

Not all phenomena could be explained - yet

The researchers reached their conclusion by examining the solar radio maps detected by the Metsähovi Radio Observatory and comparing them with the data collected by a satellite observing the Sun in the ultraviolet range. The solar maps showed active areas, or radio brightenings, which can be observed on the maps as hotter areas than the rest of the solar surface. According to researchers, there are three explanations for radio brightenings.

First, some brightenings were observed in the polar areas on the solar maps that could be identified as coronal holes. Particle flows, or solar winds, ejected by coronal holes can cause auroras when they reach the Earth's atmosphere. The corona is the outer atmosphere of the Sun.

Second, the researchers observed brightenings from which, based on other observations, ejections of hot material from the surface of the sun could be detected.

Third, radio brightenings were found in areas where, based on satellite observations, strong magnetic fields were detected.

Researchers also found radio brightenings in some areas where no explanatory factor was found on the basis of satellite observations.

'The other sources used did not explain the cause of the brightening. We don't know what causes those phenomena. We must continue our research', Kallunki says.

Additional observations and research are also needed to predict whether the phenomena of the solar minimum indicate something about the next active period, about its onset and intensity, for example. Each one of the last four cycles has been weaker than the previous one. Researchers do not know why the activity curves do not rise as high as during the previous cycles.

'Solar activity cycles do not always last exactly 11 years, either', explains Docent Merja Tornikoski.

'A new activity period will not be identified until it is already ongoing. In any case, these observations of the quiet phase we are now analysing are clearly during a period when activity is at its lowest. Now we are waiting for a new rise in activity.'

Solar storms can cause danger

On the Earth, solar activity can be seen as auroras, for example. Solar activity can even cause major damage, as solar storms caused by solar flares can damage satellites, electricity networks and radio frequency communications. Research helps to prepare for such damage.

'In solar storms, it takes 2 to 3 days before the particles hit the Earth. They reach satellites higher up in orbit much faster, which would leave us even less time to prepare for damage', Kallunki points out.

Located in Kirkkonummi, Aalto University Metsähovi is the only astronomical radio observatory and continuously operational astronomical observation station in Finland. Metsähovi is internationally known for its unique, continuous datasets, including a solar monitoring programme spanning over 40 years that has collected data from scientifically very interesting high radio frequencies. This is possible thanks to the exceptionally precise mirror surface of the Metsähovi radio telescope.

Researchers have demonstrated the use of tinted, semi-transparent solar panels to generate electricity and produce nutritionally-superior crops simultaneously, bringing the prospect of higher incomes for farmers and maximising use of agricultural land.

By allowing farmers to diversify their portfolio, this novel system could offer financial protection from fluctuations in market prices or changes in demand, and mitigate risks associated with an unreliable climate. On a larger scale it could vastly increase capacity for solar-powered electricity generation without compromising agricultural production.

This is not the first time that crops and electricity have been produced simultaneously using semi-transparent solar panels - a technique called 'agrivoltaics'. But in a novel adaptation, the researchers used orange-tinted panels to make best use of the wavelengths - or colours - of light that could pass through them.

The tinted solar panels absorb blue and green wavelengths to generate electricity. Orange and red wavelengths pass through, allowing plants underneath to grow. While the crop receives less than half the total amount of light it would get if grown in a standard agricultural system, the colours passing through the panels are the ones most suitable for its growth.

"For high value crops like basil, the value of the electricity generated just compensates for the loss in biomass production caused by the tinted solar panels. But when the value of the crop was lower, like spinach, there was a significant financial advantage to this novel agrivoltaic technique," said Dr Paolo Bombelli, a researcher in the University of Cambridge's Department of Biochemistry, who led the study.

The combined value of the spinach and electricity produced using the tinted agrivoltaic system was 35% higher than growing spinach alone under normal growing conditions. By contrast, the gross financial gain for basil grown in this way was only 2.5%. The calculations used current market prices: basil sells for around five times more than spinach. The value of the electricity produced was calculated by assuming it would be sold to the Italian national grid, where the study was conducted.

"Our calculations are a fairly conservative estimate of the overall financial value of this system. In reality if a farmer were buying electricity from the national grid to run their premises then the benefit would be much greater," said Professor Christopher Howe in the University of Cambridge's Department of Biochemistry, who was also involved in the research.

The study found the saleable yield of basil grown under the tinted solar panels reduced by 15%, and spinach reduced by around 26%, compared to under normal growing conditions. However, the spinach roots grew far less than their stems and leaves: with less light available, the plants were putting their energy into growing their 'biological solar panels' to capture the light.

Laboratory analysis of the spinach and basil leaves grown under the panels revealed both had a higher concentration of protein. The researchers think the plants could be producing extra protein to boost their ability to photosynthesise under reduced light conditions. In an additional adaptation to the reduced light, longer stems produced by spinach could make harvesting easier by lifting the leaves further from the soil.

"From a farmer's perspective, it's beneficial if your leafy greens grow larger leaves - this is the edible part of the plant that can be sold. And as global demand for protein continues to grow, techniques that can increase the amount of protein from plant crops will also be very beneficial," said Bombelli.

"With so many crops currently grown under transparent covers of some sort, there is no loss of land to the extra energy production using tinted solar panels," said Dr Elinor Thompson at the University of Greenwich, and lead author of the study.

All green plants use the process of photosynthesis to convert light from the sun into chemical energy that fuels their growth. The experiments were carried out in Italy using two trial crops. Spinach (Spinacia oleracea) represented a winter season crop: it can grow with fewer daylight hours and can tolerate colder weather. Basil (Ocimum basilicum) represented a summer season crop, requiring lots of light and higher temperatures.

The researchers are currently discussing further trials of the system to understand how well it would work for other crops, and how growth under predominantly red and orange light affects the crops at the molecular level.

Computer systems that emulate key aspects of human problem solving are commonly referred to as artificial intelligence (AI). This field has seen massive progress over the last years. Most notably, deep learning enabled groundbreaking progress in areas such as self-driving cars, computers beating the best human players in strategy games (Go, chess), computer games, and in poker, and initial applications in diagnostic medicine. Deep learning is based on artificial neural networks - networks of mathematical functions that are iteratively reorganized until they accurately map the data describing a given problem to its solution.

In biology, deep learning has established itself as a powerful method to predict phenotypes (i.e., observable characteristics of cells or individuals) from genome data (for example gene expression profiles). Deep learning is usually a "black box" method: Neural networks are very powerful predictors when provided with enough training data. For example, they have been used to predict cell type from gene expression profiles, and protein structures from DNA sequence data. But standard neural networks cannot explain the learnt relationship of inputs to outputs in a human-understandable way. For this reason, deep learning has so far contributed little to advancing our mechanistic understanding of molecular functions within cells.

To address this lack of interpretability, CeMM Postdoctoral Fellow Nikolaus Fortelny and CeMM Principal Investigator Christoph Bock pursued the idea of performing deep learning directly on biological networks, instead of the generic, fully connected artificial neural networks used in conventional deep learning. They established "knowledge-primed neural networks" (KPNNs) that are based on signaling pathways and gene-regulatory networks. In KPNNs, each node corresponds to a protein or a gene, and each edge has a mechanistic biological interpretation (e.g., protein A regulates the expression of gene B).

The CeMM researchers show in their new study published in Genome Biology that deep learning on biological networks is technically feasible and practically useful. By forcing the deep learning algorithm to stay close to gene-regulatory processes that are encoded in the biological network, KPNNs create a bridge between the power of deep learning and our rapidly growing knowledge and understanding of complex biological systems. As a result, the approach provides concrete insights into the investigated biological systems, while maintaining high prediction performance. This powerful new methodology uses an optimized approach for deep learning, which stabilizes node weights in the presence of redundancy, enhances the quantitative interpretability of node weights, and controls for the uneven connectivity inherent to biological networks.

CeMM researchers demonstrated their new KPNN method on large single-cell datasets, including a compendium of 483,084 single-cell transcriptomes for immune cells established by the Human Cell Atlas consortium. In this dataset, the scientists discovered unexpected diversity in the cell-type-defining regulatory networks between immune cells from bone marrow and cord blood.

The KPNN method combines the predictive power of deep learning and its ability to infer activity levels across multiple hidden layers with the functional interpretability of biological networks. KPNNs are particularly useful for the single-cell RNA-seq data, which are generated at massive scale using single-cell sequencing assays. Moreover, KPNNs are broadly applicable to other areas of biology and biomedicine where relevant prior knowledge can be represented as networks.

The predictions and biological insights obtained by KPNNs will be useful for dissecting cell signaling and gene regulation in health and disease, for identifying novel drug targets, and for deriving testable biological hypotheses from single-cell sequencing data. More generally, the study illustrates the future impact that artificial intelligence and deep learning, will have on mechanistic biology as the scientific community learns how to make AI results biologically interpretable.

Plastic from used personal protective equipment (PPE) can, and should, be transformed into renewable liquid fuels - according to a new study, published in the peer-reviewed Taylor & Francis journal Biofuels.

Experts from The University of Petroleum and Energy Studies have suggested a strategy that could help to mitigate the problem of dumped PPE - currently being disposed of at unprecedented levels due to the current COVID-19 pandemic - becoming a significant threat to the environment.

Out today, the research show how billions of items of disposable PPE can be converted from its polypropylene (plastic) state into biofuels - which is known to be at par with standard fossil fuels.

Lead author Dr Sapna Jain explains that the transformation into biocrude, a type of synthetic fuel, "will not just prevent the severe after-effects to humankind and the environment but also produce a source of energy".

"Presently, the world is focusing to combat COVID-19, however, we can foresee the issues of economic crisis and ecological imbalance also," she explains.

"We have to prepare ourselves to meet the challenges which are forcefully imposed by the COVID-19 pandemic, so as to maintain sustainability.

"There is a high production and utilization of PPE to protect the community of health workers and other frontline workers of COVID-19. The disposal of PPE is a concern owing to its material i.e. non-woven polypropylene.

"The proposed strategy is a suggestive measure addressing the anticipated problem of disposal of PPE."

During the current COVID-19 pandemic specifically, PPE is being designed for single use followed by disposal. Once these plastic materials are discharged into the environment they end up in landfill or oceans, as their natural degradation is difficult at ambient temperature. They need decades to decompose. Recycling these polymers requires both physical methods and chemical methods. Reduction, reuse and recycling are the three pillars of sustainable development that can help to prevent the disposal of plastic to the environment.

The research team reviewed many related research articles as they looked to explore the current policies around PPE disposal, the polypropylene content in PPE, and the feasibility of converting PPE into biofuel.

In particular, they focused on the structure of polypropylene, its suitability for PPE, why it poses an environmental threat and methods of recycling this polymer.

Their conclusive findings call for the PPE waste to be converted into fuel using pyrolysis. This a chemical process for breaking down plastic at high temperature - between 300-400 degree centigrade for an hour - without oxygen.

Co-author Dr Bhawna Yadav Lamba says this process is among the most promising and sustainable methods of recycling compared with incineration and landfill.

"Pyrolysis is the most commonly used chemical method whose benefits include the ability to produce high quantities of bio-oil which is easily biodegradable," she states.

"There is always a need for alternative fuels or energy resources to meet our energy demands. The pyrolysis of plastics is one of the methods to mitigate our energy crisis."

She concludes: "The challenges of PPE waste management and increasing energy demand could be addressed simultaneously by the production of liquid fuel from PPE kits. The liquid fuel produced from plastics is clean and have fuel properties similar to fossil fuels."