Culture

UCLA RESEARCH ALERT

FINDINGS

UCLA Jonsson Comprehensive Cancer Center researchers studying cancer evolution have created a framework to help determine which tool combinations are best for pinpointing the exact timing of DNA mutations in cancer genomes. There are currently many different algorithms that researchers have developed to help determine the timing of mutations, but until now, it has been unclear which algorithm will work best for which cancer, and what common biases influence their results.

BACKGROUND

Cancer is a disease of the genome. As a cancer develops, its DNA is constantly acquiring new mutations and the population of cancer cells is continuously evolving. Knowing the order of changes that have happened allows researchers to study the evolution of the cancer over time and see how the cancer cell population may have diversified, or became more uniform. The diversity or uniformity in the cancer cell population is related to patient response to therapy and reveals vulnerabilities that can be used to create highly targeted treatments.

METHOD

The study assessed 22 different pipelines for timing mutations in cancer genomes. Researchers tested the algorithms on a cohort of nearly 300 clinical prostate cancer samples to evaluate each pipeline and see how their results differed in various aspects. This allowed the team to see the variability across tools and have an unbiased view of how each performed.

IMPACT

Understanding when and why a tumor metastasizes, or spreads to other parts of the body, can influence how a person with cancer is treated. The framework developed in the study can help researchers decide which tool would be the most accurate for their case and generate a more personalized and targeted treatment plan for patients, minimizing the risk of cancer coming back in the future.

AUTHORS

The senior author is Paul Boutros, PhD, a professor of urology and human genetics at the David Geffen School of Medicine at UCLA who serves as associate director of cancer informatics at the UCLA Institute for Precision Health and director of cancer data science at the Jonsson Cancer Center. The first author is Lydia Liu, a PhD candidate at the University of Toronto and Visiting Graduate Researcher at UCLA, co-supervised by Dr. Thomas Kislinger at the University of Toronto and Dr. Boutros at UCLA.

JOURNAL

The study was published online in Nature Communications.

FUNDING

The work was supported in part by Prostate Cancer Canada, the Movember Foundation, the Canadian Cancer Society, the Canadian Institutes of Health Research and National Cancer Institute.

How well women with cervical cancer respond to treatment and survive correlates with the level of 10 proteins in their blood that also are associated with a "zombie" cell state called senescence, Medical College of Georgia scientists report.

They looked at pretreatment levels of these proteins in the blood of 565 Peruvian women with stage 2 and 3 cervical cancer, who received standard treatments of internal radiation, called brachytherapy, external radiation or both. They found that women with low levels of the proteins secreted by senescent cells had higher survival rates than those with high levels of these senescence-associated secreted phenotypes, or SASPs.

Additionally they found that brachytherapy, which implants a radiation source close to the cervix, greatly improved survival of patients who had high levels of these SASPs but had little impact on those with low levels.

"These results demonstrate that cellular senescence is a major determining factor for survival and therapeutic response in cervical cancer, and suggest that senescence reduction therapy may be an efficacious strategy to improve the therapeutic outcome of cervical cancer," they write in the journal Cancers.

"We want to figure out how we can treat cervical cancer better than we do. Beyond stage and treatment modality, what other factors are playing a big role in determining which patients survive and how they respond to radiation therapy," says Dr. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine, Georgia Research Alliance Eminent Scholar in Genomic Medicine and the study's corresponding author.

"The most important conclusion of our paper is you want to manage senescence to improve therapy for cervical cancer," She says.

In women with moderate to high blood levels of SASPs, use of a class of drugs called senolytics -- which target these cells for elimination and are under study to improve age-related problems and disease -- as an adjunct therapy could help, says Dr. Sharad Purohit, biochemist in the MCG Center for Biotechnology and Genomic Medicine and the study's first author.

Cervical cancer is the most common gynecological cancer, caused almost exclusively by the human papillomavirus. While it is largely preventable by regular Pap smears that can detect early, precancerous changes, or by vaccines against HPV, survival rates for those who get it have been stagnant for decades, the scientists say. In fact, survival rates of the most common cancers have improved since the mid-1970s, except for cervical and endometrial cancer, according to the American Cancer Society.

Purohit, She and their colleagues would like to change that, and have some of the first evidence that targeting senescence is one way to do it.

They looked at blood levels of a total of 19 proteins they had found secreted by cells in a pathological site like a precancerous or cancerous cervix, although why the proteins are made is a question they can't yet answer, says Purohit. This type of "liquid biopsy" can enable regular monitoring without actually doing a tissue biopsy each time, She says of the approach gaining ground in the cancer field.

They found that levels of 10 of the proteins had an impact on cervical cancer survival in the women who were an average of 49-years-old. All 10 were associated with cellular senescence, either as the largely destructive and inflammatory SASPs themselves or involved in regulating SASPs.

While cancer cells more typically are associated with rapid reproduction that enables cancer's growth, senescent cells cannot divide and reproduce. But She categorizes the proteins these senescent cancer cells are secreting as "bad stuff," which helps create an inflammatory state in which cancer thrives and helps lay the groundwork for cancer spread. It also provides some protection from radiation therapy, which like chemotherapy, works in part by killing off typically rapidly dividing cancer cells.

"The senescent proteins really change how cancer cells may respond to therapy," She says.

They used machine learning, a form of artificial intelligence that enables computers to figure out what the data means, to make the association between high SASP level and low survival and vice versa.

In the patients included in the study, everyone with stage 2 and most with stage 3 cancer received both internal and external radiation; 86 patients with stage 3 only received external beam radiation.

Whether patients with low SASP levels could benefit from brachytherapy should be further explored, but they found no clear benefit to them, She and his colleagues write.

Organisms excrete DNA in their surroundings through metabolic waste, sloughed skin cells or gametes, and this genetic material is referred to as environmental DNA (eDNA).

As eDNA can be collected directly from water, soil or air, and analysed using molecular tools with no need to capture the organisms themselves, this genetic information can be used to report biodiversity in bulk. For instance, the presence of many fish species can be identified simultaneously by sampling and sequencing eDNA from water, while avoiding harmful capture methods, such as netting, trapping or electrofishing, currently used for fish monitoring.

While the eDNA approach has already been applied in a number of studies concerning fish diversity in different types of aquatic habitats: rivers, lakes and marine systems, its efficiency in quantifying species abundance (number of individuals per species) is yet to be determined. Even though previous studies, conducted in controlled aquatic systems, such as aquaria, experimental tanks and artificial ponds, have reported positive correlation between the DNA quantity found in the water and the species abundance, it remains unclear how the results would fare in natural environments.

However, a research team from the University of Hull together with the Environment Agency (United Kingdom), took the rare opportunity to use an invasive species eradication programme carried out in a UK fishery farm as the ultimate case study to evaluate the success rate of eDNA sampling in identifying species abundance in natural aquatic habitats. Their findings were published in the open-access, peer-reviewed journal Metabarcoding and Metagenomics.

"Investigating the quantitative power of eDNA in natural aquatic habitats is difficult, as there is no way to ascertain the real species abundance and biomass (weight) in aquatic systems, unless catching all target organisms out of water and counting/measuring them all," explains Cristina Di Muri, PhD student at the University of Hull.

During the eradication, the original fish ponds were drained and all fish, except the problematic invasive species: the topmouth gudgeon, were placed in a new pond, while the original ponds were treated with a piscicide to remove the invasive fish. After the eradication, the fish were returned to their original ponds. In the meantime, all individuals were counted, identified and weighed from experts, allowing for the precise estimation of fish abundance and biomass.

"We then carried out our water sampling and ran genetic analysis to assess the diversity and abundance of fish genetic sequences, and compared the results with the manually collected data. We found strong positive correlations between the amount of fish eDNA and the actual fish species biomass and abundance, demonstrating the existence of a strong association between the amount of fish DNA sequences in water and the actual fish abundance in natural aquatic environments", reports Di Muri.

The scientists successfully identified all fish species in the ponds: from the most abundant (i.e. 293 carps of 852 kg total weight) to the least abundant ones (i.e. one chub of 0.7 kg), indicating the high accuracy of the non-invasive approach.

"Furthermore, we used different methods of eDNA capture and eDNA storage, and found that results of the genetic analysis were comparable across different eDNA approaches. This consistency allows for a certain flexibility of eDNA protocols, which is fundamental to maintain results comparable across studies and, at the same time, choose the most suitable strategy, based on location surveyed or resources available," elaborates Di Muri.

"The opportunity of using eDNA analysis to accurately assess species diversity and abundance in natural environments will drive a step change in future species monitoring programmes, as this non-invasive, flexible tool is adaptable to all aquatic environments and it allows quantitative biodiversity surveillance without hampering the organisms' welfare."

Scientists striving to understand how and when volcanoes might erupt face a challenge: many of the processes take place deep underground in lava tubes churning with dangerous molten Earth. Upon eruption, any subterranean markers that could have offered clues leading up to a blast are often destroyed.

But by leveraging observations of tiny crystals of the mineral olivine formed during a violent eruption that took place in Hawaii more than half a century ago, Stanford University researchers have found a way to test computer models of magma flow, which they say could reveal fresh insights about past eruptions and possibly help predict future ones.

"We can actually infer quantitative attributes of the flow prior to eruption from this crystal data and learn about the processes that led to the eruption without drilling into the volcano," said Jenny Suckale, an assistant professor of geophysics at Stanford's School of Earth, Energy & Environmental Sciences (Stanford Earth). "That to me is the Holy Grail in volcanology."

The millimeter-sized crystals were discovered entombed in lava after the 1959 eruption of Kilauea Volcano in Hawaii. An analysis of the crystals revealed they were oriented in an odd, but surprisingly consistent pattern, which the Stanford researchers hypothesized was formed by a wave within the subsurface magma that affected the direction of the crystals in the flow. They simulated this physical process for the first time in a study published in Science Advances Dec. 4.

"I always had the suspicion that these crystals are way more interesting and important than we give them credit for," said Suckale, who is senior author on the study.

Detective work

It was a chance encounter that prompted Suckale to act upon her suspicion. She had an insight while listening to a Stanford graduate student's presentation about microplastics in the ocean, where waves can cause non-spherical particles to assume a consistent misorientation pattern. Suckale recruited the speaker, then-PhD student Michelle DiBenedetto, to see if the theory could be applied to the odd crystal orientations from Kilauea.

"This is the result of the detective work of appreciating the detail as the most important piece of evidence," Suckale said.

Along with Zhipeng Qin, a research scientist in geophysics, the team analyzed crystals from scoria, a dark, porous rock that forms upon the cooling of magma containing dissolved gases. When a volcano erupts, the liquid magma - known as lava once it reaches the surface - is shocked by the cooler atmospheric temperature, quickly entrapping the naturally occurring olivine crystals and bubbles. The process happens so rapidly that the crystals cannot grow, effectively capturing what happened during eruption.

The new simulation is based on crystal orientations from Kilauea Iki, a pit crater next to the main summit caldera of Kilauea Volcano. It provides a baseline for understanding the flow of Kilauea's conduit, the tubular passage through which hot magma below ground rises to the Earth's surface. Because the scoria can be blown several hundred feet away from the volcano, these samples are relatively easy to collect. "It's exciting that we can use these really small-scale processes to understand this huge system," said DiBenedetto, the lead author of the study, now a postdoctoral scholar at the Woods Hole Oceanographic Institution.

Catching a wave

In order to remain liquid, the material within a volcano needs to be constantly moving. The team's analysis indicates the odd alignment of the crystals was caused by magma moving in two directions at once, with one flow directly atop the other, rather than pouring through the conduit in one steady stream. Researchers had previously speculated this could happen, but a lack of direct access to the molten conduit barred conclusive evidence, according to Suckale.

"This data is important for advancing our future research about these hazards because if I can measure the wave, I can constrain the magma flow - and these crystals allow me to get at that wave," Suckale said.

Monitoring Kilauea from a hazard perspective is an ongoing challenge because of the active volcano's unpredictable eruptions. Instead of leaking lava continuously, it has periodic bursts resulting in lava flows that endanger residents on the southeast side of the Big Island of Hawaii.

Tracking crystal misorientation throughout the different stages of future Kilauea eruptions could enable scientists to deduce conduit flow conditions over time, the researchers say.

"No one knows when the next episode is going to start or how bad it's going to be - and that all hinges on the details of the conduit dynamics," Suckale said.

CLEVELAND--Researchers at the Case Western Reserve University School of Medicine have identified a new target in development of Alzheimer's disease (AD) that could lead to therapies focused on treating the neurodegenerative condition early in its progression.

The discovery helps bolster a promising approach to AD research: finding and manipulating processes earlier in the disease's development with hopes of slowing its advance.

"This is a missing part of the puzzle," said Xin Qi, a professor in the Department of Physiology and Biophysics at the School of Medicine and lead researcher of the study, just published in the journal Science Advances. "We've discovered a pathway that is accessible to detection and potential treatment, prior to much of the disease's damage and well before clinical symptoms appear."

First identified more than 100 years ago, AD is an age-related neurodegenerative disorder that is associated with deposits of plaques of amyloid beta protein and tangles of tau protein in the brain, along with progressive nerve cell death. The cause of AD is not known, and the greatest risk factors for developing AD are age, genetics, and a previous traumatic brain injury.

Before the defining pathological characteristics of the disease are in place, the new pathway identified by Case Western Reserve researchers can be targeted by potential therapeutics that aim to mitigate the degeneration of white matter that impairs the normal functions of brain circuitry.

"There is a growing body of evidence in the field that AD develops much earlier than previously thought, most likely decades before our current ability to clinically diagnose the condition," said study co-author Andrew A. Pieper, the Morley-Mather Chair in Neuropsychiatry in the School of Medicine, Director of the Harrington Discovery Institute Neurotherapeutics Center at University Hospitals.

"Detecting the disease--and potentially treating it--at earlier stages will be critical to our battle against its devastating effects. The new pathway uncovered by Dr. Qi's laboratory could be targeted for therapy before the disease has progressed to the point of causing cognitive problems," said Pieper, also a psychiatrist at the Louis Stokes Cleveland VA Medical Center Geriatrics Research Education and Clinical Center (GRECC).

The Drp1 pathway

Researchers found that the pathway--known as Drp1-HK1-NLRP3--plays a key role in disrupting normal function of brain cells that produce the protective white matter sheathing for nerves, known as myelin.

The dysfunction and eventual death of these myelin-producing cells--called oligodendrocytes (OLs)--are well-established early events in AD that lead to cognitive deficits.

The new findings illuminate how OLs start to go awry: the overexpression of a certain protein (Drp1) within the recently discovered pathway.

It's the hyperactivation of Drp1 protein that triggers inflammation and injury to OLs, culminating in a reduction of myelin--slowing communication in the brain--which leads to the degeneration of white matter and significant cognitive impairment.

What's next--targeting with therapeutics

A near total degeneration of OLs occurs before common symptoms of AD become apparent in most patients.

As such, researchers hope to target and manipulate the pathway with therapeutics that regulate the expression of Drp1, thereby slowing or reducing damage to myelin-producing OLs.

In fact, Qi's lab has patented a small molecule, known as a peptide inhibitor, that regulates the expression of Drp1--putting the brakes on degeneration of brain cells.

In the study published by Science Advances, researchers found that eliminating Drp1 expression in mouse models corrected the energy-related defect in OLs associated with the hyperexpression of that protein; this approach also reduced the activation of inflammation OLs, lessened tissue damage at those brain sites and improved cognitive performance.

"Our results show promise that targeting the Drp1-HK1-NLRP3 pathway and reducing the expression of the Drp1 protein could help reduce the downstream cascade of abnormal brain functions associated with the progression of AD," said Qi, whose lab has studied Drp1 for a decade, mostly in Parkinson's and Huntington's diseases."

"If therapies targeting this pathway can slow, stop or even reverse early stage AD progression, then possibly there can be a reduction or delay to later stage damage and impairments," Qi said.

Most AD diagnoses are in patients 65 or older, so identifying the disease in younger patients can be difficult. Many patients experience a significant loss in their brain's white matter--central to cognition, emotion and consciousness--before receiving a diagnosis.

"Identifying how AD unfolds in its earliest processes will help scientists better understand how to focus research into potential solutions for patients," said Pieper. "The Qi lab's findings may help in targeting AD earlier, potentially leading to better management of its symptoms and progression.

"There have still been only a very small number of approved medications for AD since its discovery in 1907. While these medicines augment neurotransmission to provide temporary symptomatic benefit, they do nothing to slow disease progression," said Pieper. "Identification of earlier approaches to treating AD--such as this research--is critical for society as the magnitude of AD is growing explosively with our aging population."

Researchers validated the discovery of the pathway using mouse models and post-mortem brain samples of AD patients.

What The Study Did: COVID-19 outcomes based on race and ethnicity were compared in this observational study of patients in a large health system in New York City, and the association of any disparities with coexisting medical conditions and neighborhood characteristics also was assessed.

Authors: Gbenga Ogedegbe, M.D., M.P.H., of the NYU Grossman School of Medicine in New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.26881)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: This observational study assessed the rate of appendix perforations during the COVID-19 pandemic at a children's hospital compared with 2019.

Authors: Rick Place, M.D., M.H.A., of Inova Fairfax Medical Campus in Falls Church, Virginia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.27948)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Boston, MA - Women with post-traumatic stress disorder (PTSD) and depression have an almost fourfold greater risk of early death from cardiovascular disease, respiratory disease, type 2 diabetes, accidents, suicide, and other causes than women without trauma exposure or depression, according to a large long-term study conducted by researchers at Harvard T.H. Chan School of Public Health.

"The study examines longevity--in a way, the ultimate health outcome--and the findings strengthen our understanding that mental and physical health are tightly interconnected," said Andrea Roberts, lead author of the study and a senior research scientist in the Department of Environmental Health. "This is particularly salient during the pandemic, which is exposing many Americans and others across the world to unusual stress while at the same time reducing social connections, which can be powerfully protective for our mental health."

The study, which is the first study of co-occurring PTSD and depression in a large population of civilian women, will be published online December 4, 2020 in JAMA Network Open. Previous research on PTSD and depression has primarily focused on men in the military.

Roberts and her colleagues studied more than 50,000 women at midlife (ages 43 to 64 years) and found that women with both high levels of PTSD and depression symptoms were nearly four times more likely to die from nearly every major cause of death over the following nine years than women who did not have depression and had not experienced a traumatic event.

The researchers examined whether health risk factors such as smoking, exercise, and obesity might explain the association between PTSD and depression and premature death, but these factors only explained a relatively small part. This finding suggests that other factors, such as the effect of stress hormones on the body, may account for the higher risk of early death in women with the disorders.

Treatment of PTSD and depression in women with symptoms of both disorders may reduce their substantial increased risk of mortality, the researchers said.

"These findings provide further evidence that mental health is fundamental to physical health--and to our very survival. We ignore our emotional well-being at our peril," said Karestan Koenen, senior author of the study and professor of psychiatric epidemiology in the Department of Epidemiology and Department of Social and Behavioral Sciences.

Other Harvard Chan School authors included Laura Kubzansky, Lori Chibnik, and Eric Rimm.

Tokyo Medical and Dental University (TMDU) researchers report a cross-linker for dental cement that breaks down under UV light, making treatments easier to reverse.

Tokyo - Everyone who has had tooth cavities filled knows that the best dental materials stay where the dentist puts them. The adhesion of currently available dental materials to tooth surfaces continues to improve, but what about short-term treatments that are not supposed to adhere indefinitely? TMDU researchers have developed a method of making dental materials easier to remove; their findings are published in ACS Applied Polymer Materials.

The continual improvement of long-lasting caries treatments can be regarded a triumph of dental material research. However, there are dental procedures that require non-permanent adhesion to the tooth surface, such as the fixing of orthodontic brackets. Removing adhered materials after such procedures generally requires mechanical detachment that can damage tooth enamel.

Efforts to improve removal processes have produced materials that are weakened by triggers, such as heat or electric currents. However, approved sources of these stimuli are not readily available in standard dental clinics. The researchers therefore focused on UV light-responsive materials that can be triggered by the UV sources widely used by dentists to cure resin cements and composites.

The toughness of many dental cements is a result of mixing them with a cross-linker that locks the cement molecules to each other to form a stable network. The researchers have introduced a chemical 'switch' into a new cross-linker that opens when UV light is shined on it.

"The cross-linker structure resembles rings threaded onto a piece of string with bulky stoppers at each end," study lead author Atsushi Tamura explains. "We have added a section to the string--an o-nitrobenzyl ester group--that breaks under UV light causing the rings to slide off. This has a significant effect on the stability of the cement material the cross-linker is holding in place."

The researchers used their cross-linker to stabilize a commercially available resin cement that was used to stick two polymer blocks together, or to attach a polymer block to a bovine tooth. After shining UV light on the cross-linked cement for just 2 minutes, the cement showed a significant reduction in adhesion strength in both tests, meaning separation of the bonded materials was easier following UV treatment.

"We are very encouraged by the initial findings using our cross-linker," study corresponding author Nobuhiko Yui explains. "Although the UV wavelength used to disrupt the material was not clinically appropriate in this case, we intend to develop the chemistry of our internal switch so that it can provide a facile and readily accessible method of removing adhesives in the clinic."

The article, "Light-Embrittled Dental Resin Cements Containing Photodegradable Polyrotaxane Cross-Linkers for Attenuating Debonding Strength", was published in ACS Applied Polymer Materials (DOI: https://doi.org/10.1021/acsapm.0c01024).

At the same time, the article was selected to be featured as ACS (American Chemical Society) Editors' Choice (on 25th November, 2020) based on recommendations by ca. 70 ACS journals' editors due to its potential for broad public interest, an honor given to only one article from the entire ACS portfolio each day of the year.

News at a Glance:

Analysis of Victorian data by the Murdoch Children's Research Institute suggests that COVID-19 cases in schools and childcare were mainly driven by community transmission

373 students possibly acquired COVID-19 via a school or early childhood education centre

The COVID-19 in Victorian Schools Report recommends prioritising opening schools and childcare for onsite learning as soon as community transmission levels fall and provides detailed mitigation plans for outbreaks

COVID-19 cases in schools, early childhood education centres and childcare are mainly driven by community transmission. Off-site learning should therefore be a last resort, a new Australian report has found.

The Murdoch Children's Research Institute (MCRI) prepared the COVID-19 in Victorian Schools Report at the request of the Victorian State Government. The report recommends schools and childcare centres should re-open as soon as community transmission of coronavirus falls and stays low.

Professor Fiona Russell, from MCRI and The University of Melbourne, who led the analysis team said, "School and childcare COVID-19 outbreaks were far more likely in those areas that also had high community levels, suggesting community transmission drives COVID-19 spread in schools."

"The single best policy to support school reopening prior to the development of a vaccine or treatment is suppression of COVID-19," she said.

The report analysed government data which included reported COVID-19 cases and outbreaks across all early childhood and primary and secondary educational settings in Victoria from 25 January to 31 August.

At the start of August 2020, Victoria and the United Kingdom were reporting similar numbers of new daily cases. By mid-November, Victoria had recorded 14 days of no new cases while the UK was experiencing 25,000 new cases every day.

Cases associated with schools accounted for eight per cent of all cases in Victoria. Of 373 students and 139 staff who were infected and linked to a childcare or school event, four students and four staff were admitted to hospital, all of whom subsequently recovered.

The report's senior co-author MCRI Professor Sharon Goldfeld said, "Childcare and schools play a critical role not only in providing education, but also offer critical support, especially for the most vulnerable of students, which makes them a priority for opening and remaining open."

"Closing schools should be a last resort, especially for childcare and primary school children as cases in this age group are less likely to transmit and be associated with an outbreak."

The report also provided detailed scenario plans for possible outbreaks following the staged easing of lockdown restrictions which would follow a traffic light system. These plans have drawn on experiences from international settings, designed to reduce day-to-day disruptions as far as possible, while ensuring that teachers, students and the wider community is kept as safe as possible.

Key findings:

373 students had an infection likely acquired at an ECEC or school event

There were 1,635 infections linked with ECECs and schools, out of a total of 19,109 infections in Victoria. Cases associated with schools accounted for nine per cent of all infections in Victoria.

Testing, Tracing and Isolation within 48 hours of a notification is the most important strategy to prevent an outbreak. In Victoria, the average time between confirmation of the first case in an ECEC or school and school closure was 1 day. This timely response prevented outbreaks from occurring as 66 percent of events in schools involved just a single infection in a staff member or student and 92 percent involved fewer than 10 cases.

Of 139 staff & 373 students who likely acquired COVID-19 at an ECEC or school event, 8 (4 staff and 4 students) admitted to hospital and all recovered

Infections in ECEC and schools were rarely linked to the most vulnerable population, the elderly

If the first case was aged 12 years or younger, an outbreak (2 or more cases) was very uncommon.

A group of researchers developed a promising fix to CRISPR-Cas9's problem with unwanted genetic changes using a method that allows them to turn off gene-editing until it reaches key cell cycle phases where more accurate repairs are likely to happen.

Researchers from Hiroshima University and Tokyo Medical and Dental University published on Communications Biology the results of their study which successfully demonstrated a more precise gene-editing and suppressed unintended genetic deletions, insertions, or mutations called off-target effects.

Although previous methods were developed that reported fewer off-target effects associated with the CRISPR technology, the researchers said these often exhibited lower editing efficiency.

"We aimed to develop the method to avoid the side effect called off-target effect which is one of the most challenging problems in the genome-editing field," said Wataru Nomura, one of the study's authors and a professor at HU's Graduate School of Biomedical and Health Sciences.

"Our method is like hitting two birds with one stone. We can improve the preciseness of genome editing and suppression of off-target effects at the same time."

More control in gene-editing

CRISPR-Cas9 has ushered in a new frontier in gene editing as a simpler and less expensive tool. Acting like scissors, it can snip genetic material you want to alter. The process, however, can also create off-target effects that limit its use in the field of therapeutics.

The newest method developed to eliminate off-target effects works by using the anti-CRISPR protein AcrIIA4 which works like an "off switch" that stops the genome editing activity of SpyCas9. The researchers fused AcrIIA4 with the N terminal region of human Cdt1 -- a gene that helps ensure DNA replication happens only once per cell division -- intending to deactivate gene editing until S and G2, phases of the cell cycle when homology-directed repair (HDR) is dominant.

HDR is one of the two DNA repair processes used by organisms along with non-homologous end joining (NHEJ). Of the two, however, HDR is the preferred method as the repair relies on the existence of two chromosome copies in each cell. HDR's use of the duplicate chromosome as a template for repair makes gene editing more precise as opposed to NHEJ which just tends to connect the broken ends of the DNA. HDR occurs during the S and G2 phases of the cell cycle while NHEJ operates in all phases, especially in G1 -- the first phase of the cycle's interphase stage where the cell grows in preparation for DNA replication.

The researchers found that the amount of ArIIA4-Cdt1 fusion is dependent on the cell cycle. It increases during the G1 phase which stops gene-editing from happening and, consequently, halts repairs through NHEJ. Meanwhile, it decreases during the S, G2, and M phases that follow.

"The efficiency of HDR using AcrIIA4-Cdt1 was increased approximately by 4.0-fold compared to that using SpyCas9 alone. At target or off-target site 1 (HCN1 gene), the mutation ratio was decreased by 86.5%. Moreover, the mutation ratio at off-target site 2 (MFAP1 gene) was decreased from 8.5% to 0.6% using AcrIIA4-Cdt1," the researchers said in the study.

"Co-expression of SpyCas9 and AcrIIA4-Cdt1 not only increases the frequency of HDR but also suppresses off-target effects. Thus, the combination of SpyCas9 and AcrIIA4-Cdt1 is a cell cycle-dependent Cas9 activation system for accurate and efficient genome editing."

Nomura said they want to further improve the preciseness of the system so it could be used safely in the therapeutic field.

"We envision to apply our system to other CRISPR/anti-CRISPR combinations as well as other CRISPR based gene editor such as base editors and targeted transcription mediators," he said.

"Our ultimate goal is to develop a genome editing system which can be used safely in the medical therapeutic field."

Reactive oxygen molecules, also known as "free radicals", are generally considered harmful. However as it now turns out, they control cellular processes, which are important for the brain's ability to adapt - at least in mice. Researchers from the German Center for Neurodegenerative Diseases (DZNE) and the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden published the findings in the journal Cell Stem Cell.

The researchers focused on the "hippocampus", a brain area that is regarded as the control center for learning and memory. New nerve cells are created lifelong, even in adulthood. "This so-called adult neurogenesis helps the brain to adapt and change throughout life. It happens not only in mice, but also in humans," explains Prof. Gerd Kempermann, speaker of the DZNE's Dresden site and research group leader at the CRTD.

A trigger for neurogenesis

New nerve cells emerge from stem cells. "These precursor cells are an important basis for neuroplasticity, which is how we call the brain's ability to adapt," says the Dresden scientist. Together with colleagues he has now gained new insights into the processes underlying the formation of new nerve cells. The team was able to show in mice that neural stem cells, in comparison to adult nerve cells, contain a high degree of free radicals. "This is especially true when the stem cells are in a dormant state, which means that they do not divide and do not develop into nerve cells," says Prof. Kempermann. Current study shows that an increase in the concentration of the radicals makes the stem cells ready to divide. "The oxygen molecules act like a switch that sets neurogenesis in motion."

Free radicals are waste products of normal metabolism. Cellular mechanisms are usually in place to make sure they do not pile up. This is because the reactive oxygen molecules cause oxidative stress. "Too much of oxidative stress is known to be unfavorable. It can cause nerve damage and trigger aging processes," explains Prof. Kempermann. "But obviously this is only one aspect and there is also a good side to free radicals. There are indications of this in other contexts. However, what is new and surprising is the fact that the stem cells in our brains not only tolerate such extremely high levels of radicals, but also use them for their function."

Healthy aging

Radical scavengers, also known as "antioxidants", counteract oxidative stress. Such substances are therefore considered important components of a healthy diet. They can be found in fruits and vegetables. "The positive effect of antioxidants has been proven and is not questioned by our study. We should also be careful with drawing conclusions for humans based on purely laboratory studies," emphasizes Kempermann. "And yet our results at least suggest that free radicals are not fundamentally bad for the brain. In fact, they are most likely important for the brain to remain adaptable throughout life and to age in a healthy way."

A combined research team from the Universities of Portsmouth and Bournemouth and Portsmouth Hospitals University NHS Trust has shown that an assessment score used to measure a patient's severity of illness can be applied to patients with Covid-19 without modification.

The Portsmouth Academic ConsortIum For Investigating COVID-19 (PACIFIC-19) team has shown that the National Early Warning Score (NEWS) is equally good at predicting certain adverse clinical outcomes in patients with Covid-19 and other groups of patients admitted to hospital.

These results are important because they show that different techniques are not required for monitoring the severity of illness of patients with Covid-19. Developing new ways of working would require investment, take time and lead to extra demands on staff training, at a time when these are in short supply.

NEWS is used across the NHS to measure a patient's severity of illness. It takes commonly measured vital sign readings (pulse, blood pressure, temperature, breathing rate, etc) and converts them to a single value from 0 to 20. The higher the NEWS value the greater the patient's risk of developing certain adverse clinical outcomes.

The original work underpinning NEWS started in Portsmouth about 14 years ago. Since then, NEWS has been recommended by the Royal College of Physicians and NHS England. More recently, the World Health Organisation (WHO) has recommended its use for the close monitoring of clinical deterioration in patients with Covid-19.

In a separate study, the PACIFIC-19 team was also able to show that the Covid-19 outbreak, and the processes required to respond to it, did not adversely affect the ability of healthcare staff to monitor the vital signs of patients under their care.

Dr Ina Kostakis, Research Fellow at the University of Portsmouth's Centre for Healthcare Modelling and Informatics and the lead author of both studies, said: "We all know about the immense extra burdens that the Covid-19 outbreak has imposed on hospital staff, but we have shown that the tools and processes they already use to monitor deteriorating patients have stood up to the task."

Professor Anoop Chauhan, Executive Director of Research and Innovation at Portsmouth Hospitals University Trust and a senior author on the studies, said: "I'm immensely proud of the way the team came together rapidly at the start of the crisis and has now produced this important work. We look forward to producing even more insights that help us to look after our patients during this pandemic and beyond."

A new study from Karolinska Institutet and the Helmholtz Diabetes Research Center shows that primary cilia, hair-like protrusions on endothelial cells inside vessels, play an important role in the blood supply and delivery of glucose to the insulin-producing beta cells in the pancreatic islets. The findings are published in eLife and may be relevant for transplantation therapies in diabetes, as formation of functional blood vessels is important for the treatment to be successful.

When blood glucose levels rise, beta cells in pancreatic islets release insulin into the blood stream. Insulin triggers glucose uptake in a variety of tissues including fat and muscle. Glucose and other nutrients must cross the vascular barrier to reach beta cells inside pancreatic islets. Similarly, newly released insulin must cross the blood vessels into the blood stream to reach its target tissues.

Endothelial cells can be found on the inside of blood vessels. Vessels in the pancreatic islets form a dense network with many small pores in the endothelial cell membrane, facilitating the exchange of molecules across the vessel wall.

Now, researchers have investigated how pancreatic islet vessel formation and function are affected by primary cilia, small hair-like structures found on beta cells and endothelial cells. Professor Per-Olof Berggren's research group at The Rolf Luft Research Center for Diabetes and Endocrinology, the Department of Molecular Medicine and Surgery, Karolinska Institutet in Sweden and Dr. Jantje Gerdes' research group at the Helmholtz Diabetes Research Center in Munich, Germany, have previously shown that insulin secretion is modulated by cilia on beta cells.

In the new study, the researchers examined a mouse model of Bardet-Biedl Syndrome, a disease caused by cilia dysfunction. They were able to show that when endothelial cilia are dysfunctional, the blood supply to the pancreatic islets is less efficient. Newly formed vessels have larger diameters and fewer pores that allow nutrients to pass through the vessel wall.

"Consequently, the smallest blood vessels, the capillaries, become less efficient at delivering glucose to the beta cells," says Yan Xiong, assistant professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet and first author of the study.

Signalling via the growth factor VEGF-A was identified as a key player in this process. Endothelial cells that lack functional cilia are less sensitive to VEGF-A compared to normal endothelial cells, resulting in impaired signalling via the VEGFR2 receptor.

"In summary, we have demonstrated that primary cilia, specifically those on endothelial cells, regulate pancreatic islet vascularisation and vascular barrier function via the VEGF-A/VEGFR2 signalling pathway," says Dr Gerdes, one of the senior authors of the study.

The formation of functional blood vessels is an important factor in transplantation therapies. Beta cell replacement therapy could potentially treat and cure type 1 diabetes, and the formation of a functional interface between beta cells and blood vessels is an important step towards longer graft survival and diabetes remission.

"This study improves the understanding of how primary cilia facilitate efficient blood vessel formation, and potentially offers novel therapeutic avenues to enable effective pancreatic islet transplantation in diabetes and possibly transplantation of other organs as well," says Dr Berggren, the other senior author of the study.

Emotions are complex phenomena that influence our minds, bodies and behaviour. A number of studies have sought to connect given emotions, such as fear or pleasure, to specific areas of the brain, but without success. Some theoretical models suggest that emotions emerge through the coordination of multiple mental processes triggered by an event. These models involve the brain orchestrating adapted emotional responses via the synchronisation of motivational, expressive and visceral mechanisms. To investigate this hypothesis, a research team from the University of Geneva (UNIGE) studied brain activity using functional MRI. They analysed the feelings, expressions and physiological responses of volunteers while they were playing a video game that had been specially developed to arouse different emotions depending on the progress of the game. The results, published in the journal PLOS Biology, show that different emotional components recruit several neural networks in parallel distributed throughout the brain, and that their transient synchronisation generates an emotional state. The somatosensory and motor pathways are two of the areas involved in this synchronisation, thereby validating the idea that emotion is grounded in action-oriented functions in order to allow an adapted response to events.

Most studies use passive stimulation to understand the emergence of emotions: they typically present volunteers with photos, videos or images evoking fear, anger, joy or sadness while recording the cerebral response using electroencephalography or imaging. The goal is to pinpoint the specific neural networks for each emotion. &laquoThe problem is, these regions overlap for different emotions, so they're not specific», begins Joana Leitão, a post-doctoral fellow in the Department of Fundamental Neurosciences (NEUFO) in UNIGE's Faculty of Medicine and at the Swiss Centre for Affective Sciences (CISA). &laquoWhat's more, it's likely that, although these images represent emotions well, they don't evoke them».

A question of perspective

Several neuroscientific theories have attempted to model the emergence of an emotion, although none has so far been proven experimentally. The UNIGE research team subscribe to the postulate that emotions are &laquosubjective»: two individuals faced with the same situation may experience a different emotion. &laquoA given event is not assessed in the same way by each person because the perspectives are different,» continues Dr Leitão.

In a theoretical model known as the component process model (CPM) - devised by Professor Klaus Scherer, the retired founding director of CISA- an event will generate multiple responses in the organism. These relate to components of cognitive assessment (novelty or concordance with a goal or norms), motivation, physiological processes (sweating or heart rate), and expression (smiling or shouting). In a situation that sets off an emotional response, these different components influence each other dynamically. It is their transitory synchronisation that might correspond to an emotional state.

Emotional about Pacman

The Geneva neuroscientists devised a video game to evaluate the applicability of this model. &laquoThe aim is to evoke emotions that correspond to different forms of evaluation», explains Dr Leitão. &laquoRather than viewing simple images, participants play a video game that puts them in situations they'll have to evaluate so they can advance and win rewards». The game is an arcade game that is similar to the famous Pacman. Players have to grab coins, touch the &laquonice monsters», ignore the &laquoneutral monsters» and avoid the &laquobad guys» to win points and pass to the next level.

The scenario involves situations that trigger the four components of the CPM model differently. At the same time, the researchers were able to measure brain activity via imaging; facial expression by analysing the zygomatic muscles; feelings via questions; and physiology by skin and cardiorespiratory measurements. &laquoAll of these components involve different circuits distributed throughout the brain», says the Geneva-based researcher. &laquoBy cross-referencing the imagery data with computational modelling, we were able to determine how these components interact over time and at what point they synchronise to generate an emotion».

A made-to-measure emotional response

The results also indicate that a region deep in the brain called the basal ganglia is involved in this synchronisation. This structure is known as a convergence point between multiple cortical regions, each of which is equipped with specialised affective, cognitive or sensorimotor processes. The other regions involve the sensorimotor network, the posterior insula and the prefrontal cortex. &laquoThe involvement of the somatosensory and motor zones accords with the postulate of theories that consider emotion as a preparatory mechanism for action that enables the body to promote an adaptive response to events», concludes Patrik Vuilleumier, full professor at NEUFO and senior author of the study.