Culture

Boston, MA (May 1, 2021) - A new study presented today at the AATS 101st Annual Meeting, found that the percentage of patients undergoing esophagectomy for cancer who suffer Venous Thromboembolism (VTE) post-operatively is much higher than previously reported, with as many as 24 percent suffering from Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE). Six-month mortality for patients with VTE was 17.6 percent compared to 2.1 percent for those without.

Venous Thromboembolism (VTE) is a common, potentially preventable post-operative complication leading to significant morbidity and mortality. Esophagectomy patients are amongst the highest risk groups for VTE due to disease burden, magnitude of surgery and high rate of perioperative morbidity. The study aimed to quantify the true incidence of VTE post esophagectomy, associated risk factors, and the impact of VTE on patients' outcomes.

Patients undergoing esophagectomy for malignancy in eight tertiary-care centers between November 2017 and March 2020 were enrolled in a prospective cohort study. All patients received guideline based VTE prophylaxis until hospital discharge and underwent bilateral lower-extremity venous-doppler ultrasonography (DUS) prior to discharge, then Computed Chest Tomography-pulmonary embolus protocol (CT-PE) as well as DUS at 30 and 90-days post-op, and DUS at 60 days. D-dimer levels were measured at each interval and patients were followed for 6 months postoperatively.

According to Yaron Shargall, M.D., FRCSC, professor and chair of the division of Thoracic Surgery at McMaster University and study leader, despite the fact that all patients were treated with VTE prophylaxis according to best practices, a high proportion would have been discharged home with VTE under standard protocols, or would have developed VTE after discharge. "When we followed this cohort of patients for six months, we saw VTE events develop mostly within one month of surgery, but also as long as six months. Even more importantly, we found that those who developed VTE had a seven-fold increase in mortality at six months, the reasons for which are yet to be determined" says Shargall. "We are yet to define if active screening for VTE in all esophagectomy patients is really justified, and if a longer duration of VTE prophylaxis, beyond the hospital stay, will improve patients' outcomes" he added.

Researchers from University of Arizona and University of Utah published a new paper in the Journal of Marketing that examines why most scholarly research is misinterpreted by the public or never escapes the ivory tower and suggests that such research gets lost in abstract, technical, and passive prose.

The study, forthcoming in the Journal of Marketing, is titled "Marketing Ideas: How to Write Research Articles that Readers Understand and Cite" and is authored by Nooshin L. Warren, Matthew Farmer, Tiany Gu, and Caleb Warren.

From developing vaccines to nudging people to eat less, scholars conduct research that could change the world, but most of their ideas either are misinterpreted by the public or never escape the ivory tower.

Why does most academic research fail to make an impact? The reason is that many ideas in scholarly research get lost in an attic of abstract, technical, and passive prose. Instead of describing "spilled coffee" and "one-star Yelp reviews," scholars discuss "expectation-disconfirmation" and "post-purchase behavior." Instead of writing "policies that let firms do what they want have increased the gap between the rich and the poor," scholars write sentences like, "The rationalization of free-market capitalism has been resultant in the exacerbation of inequality." Instead of stating, "We studied how liberal and conservative consumers respond when brands post polarizing messages on social media," they write, "The interactive effects of ideological orientation and corporate sociopolitical activism on owned media engagement were studied."

Why is writing like this unclear? Because it is too abstract, technical, and passive. Scholars need abstraction to describe theory. Thus, they write about "sociopolitical activism" rather than Starbucks posting a "Black Lives Matter" meme on Facebook. They are familiar with technical terms, such as "ideological orientation," and they rely on them rather than using more colloquial terms such as "liberal or conservative." Scholars also want to sound objective, which lulls them into the passive voice (e.g., the effects... were studied) rather than active writing (e.g., "we studied the effects..."). Scholars need to use some abstract, technical, and passive writing. The problem is that they tend to overuse these practices without realizing it.

When writing is abstract, technical, and passive, readers struggle to understand it. In one of the researchers' experiments, they asked 255 marketing professors to read the first page of research papers published in the Journal of Marketing (JM), Journal of Marketing Research (JMR), and Journal of Consumer Research (JCR). The professors understood less of the papers that used more abstract, technical, and passive writing compared to those that relied on concrete, non-technical, and active writing.

As Warren explains, "When readers do not understand an article, they are unlikely to read it, much less absorb it and be influenced by its ideas. We saw this when we analyzed the text of 1640 articles published in JM, JMR, and JCR between 2000 and 2010. We discovered that articles that relied more on abstract, technical, and passive writing accumulated fewer citations on both Google Scholar and the Web of Science." An otherwise average JM article that scored one standard deviation lower (clearer) on our measures of abstract, technical, and passive writing accumulated approximately 157 more Google Scholar citations as of May 2020 than a JM article with average writing.

Why do scholars write unclearly? There is an unlikely culprit: knowledge. Conducting good research requires authors to know a lot about their work. It takes years to create research that meaningfully advances scientific knowledge. Consequently, academic articles are written by authors who are intimately familiar with their topics, methods, and results. Authors, however, often forget or simply do not realize that potential readers (e.g., PhD students, scholars in other sub-disciplines, practicing professionals, etc.) are less familiar with the intricacies of the research, a phenomenon called the curse of knowledge.

The research team explores whether the curse of knowledge might be enabling unclear writing by asking PhD students to write about two research projects. The students wrote about one project on which they were the lead researcher and another project led by one of their colleagues. The students reported that they were more familiar with their own research than their colleague's research. They also thought that they wrote more clearly about their own research, but they were mistaken. In fact, the students used more abstraction, technical language, and passive voice when they wrote about their own research than when they wrote about their colleague's research.

"To make a greater impact, scholars need to overcome the curse of knowledge so they can package their ideas with concrete, technical, and active writing. Clear writing gives ideas the wings needed to escape the attics, towers, and increasingly narrow halls of their academic niches so that they can reduce infection, curb obesity, or otherwise make the world a better place," says Farmer.

WHAT:

In a mouse study, National Institutes of Health researchers have identified and mapped a diverse spectrum of motor neurons along the spinal cord. These neurons, which send and receive messages throughout the body, include a subset that is susceptible to neurodegenerative diseases. Created with a genetic sequencing technique, the atlas reveals 21 subtypes of neurons in discrete areas throughout the spinal cord and offers insight into how these neurons control movement, how they contribute to the functioning of organ systems and why some are disproportionately affected in neurodegenerative diseases.

The study was led by Claire Le Pichon, Ph.D., head of the Unit on the Development of Neurodegeneration at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). It appears in Nature Communications.

Spinal cord neurons are responsible for all types of movement in the body, ranging from voluntary movements like walking to the involuntary constriction and relaxation of the stomach as it processes its contents. Traditionally, scientists categorize these neurons into three main types: skeletal motor neurons, visceral motor neurons and interneurons. Previous research suggests there are additional subtypes within these three categories and that some of these subtypes may be more vulnerable to neurodegenerative diseases than others. For example, diseases like spinal muscular atrophy and amyotrophic lateral sclerosis, or ALS, affect only certain types of skeletal muscle neurons.

In the current study, the team used a technique called single nucleus RNA sequencing to identify 21 subtypes of spinal cord neurons in mice. The findings reveal highly distinct subtypes, especially among motor neurons that control the glands and internal organs. The team also discovered that visceral motor neurons extend higher up along the spinal column than previously known. The authors believe these motor neurons may be newly discovered subtypes with unknown functions.

Boston, MA (April 30, 2021) - A new study, presented today at the AATS 101st Annual Meeting, shows that non-invasive cell-free DNA tests can reduce the need for regular surveillance biopsies to detect early rejection in heart transplant patients. The study was the first of its kind to be performed on both adult and pediatric patients.

Pediatric and adult heart transplant recipients were recruited prospectively from eight participating sites and followed longitudinally for at least 12 months with serial plasma samples collected immediately prior to all endomyocardial biopsies. Structured biopsy results and clinical data were collected and monitored by an independent clinical research organization (CRO).

For all patients taken together in comparison to the composite biopsy outcome using repeated measures, donor fraction (DF) cfDNA at a pre-defined cut point of 0.14 had a sensitivity of 67%, a specificity of 79%, a PPV of 34% and a NPV of 94% with an area under the curve (AUC) of 0.78 (p

"Our multicenter group has demonstrated the utility of a clinically viable test for the donor-derived fraction of cell-free DNA, which can vastly reduce the need for routine surveillance biopsies," explained Marc Richmond, MD, MS, Associate Professor of Pediatrics at Columbia University Medical Center, and the Associate Medical Director of the Program for Pediatric Cardiomyopathy, Heart Failure and Transplantation. "Our consortium of eight centers is continuing to analyze additional data and put forth new studies using this technology." This assay is clinically usable at any time point after seven days post-transplant and can have a turnaround time of as little as 24 hours. Future studies will include clinical protocols that further assess how this method compares to current practice standards.

Boston, MA (April 30, 2021) - A new study, presented today at the AATS 101st Annual Meeting, found that severely ill COVID-19 patients treated with ECMO did not suffer worse long-term outcomes than other mechanically-ventilated patients. The multidisciplinary team included cardio thoracic surgeons, critical care doctors, medical staff at long-term care facilities, physical therapists and other specialists, and followed patients at five academic centers: University of Colorado; University of Virginia; University of Kentucky; Johns Hopkins University; and Vanderbilt University.

Survivors of critical illness are at high risk for long-term physical, psychological, and cognitive deficits. Extracorporeal membrane oxygenation (ECMO) shows promising survival benefit for select patients with COVID-19. However, its impact on long-term recovery was unknown. The study measured physical, psychological, and cognitive deficits in in 46 patients who were canulated for ECMO compared to a control group of 262 mechanically ventilated patients who did not receive ECMO.

The multi-disciplinary team conducted a retrospective analysis of mechanically ventilated patients with COVID-19 admitted between March and May 2020. Data were available for all mechanically ventilated patients from three sites, while all five sites provided ECMO patient data. Survivors had access to a multi-disciplinary post-intensive care unit recovery clinic for long-term care. Physical, psychological, and cognitive deficits were measured using validated instruments during follow up. Patient characteristics and long-term outcomes were compared based on ECMO status.

The study found no significant difference in survival at discharge (69.6 percent ECMO vs. 69.9 percent non-ECMO.) Of the 215 survivors across both groups, 93.9 percent were residing at home, 16.1 percent had returned to work or usual activity and 26.2 percent were still using supplemental oxygen; these rates did not differ significantly based on ECMO status. Rates of physical, psychological and cognitive deficits did not differ significantly.

"The initial guidance for ECMO in COVID was helpful and saved a lot of lives, and not to their detriment, which is very encouraging," explained Dr. Jessica Rove, Assistant Professor, Cardiothoracic Surgery at University of Colorado Anschutz Medical Campus, and Section Chief, Cardiac Surgery, Rocky Mountain Regional VA Medical Center. "This multidisciplinary collaboration is committed to examining long-term outcomes beyond survival, and early results look promising. This may help to further refine who should receive ECMO and may increase the rate of positive outcomes."

Further research will continue to follow patients and measure outcomes over the longer term. Dr. Lauren Taylor, fellow at University of Colorado Anschutz Medical Campus explained, "It is exciting that we now have the long term outcomes of these patients and that they are so promising. Further study of these patients over the long term can help to further refine who we are canulating for ECMO, leading to better outcomes for all."

A new study finds Black patients are more likely to die after their heart bypass surgery if they're at a hospital where some care teams see mostly white patients and others see mostly Black patients. On the other hand, mortality rates are comparable between Black and white patients after heart bypass surgery when the teams of health care providers at their hospitals all care for patients of all races.

Some level of care team segregation within hospitals was very common, and the findings bring up another angle to better understand racial inequities in surgical outcomes, says co-first author John Hollingsworth, M.D., M.Sc., a professor of urology at Michigan Medicine and of health management and policy at the University of Michigan School of Public Health.

Previous studies have already shown that mortality after heart bypass surgery is higher overall in Black patients than white patients, but known factors such as access to care and use of lower resourced hospitals don't fully explain the disparities.

Hollingsworth and colleagues' new paper reviewed Medicare claims from more than 12,000 heart bypass procedures between 2008 and 2014. The data included claims from 72 hospitals across the country where at least 10 Black patients and at least 10 white patients underwent heart bypass surgery over the study interval.

Researchers used social network analysis to see where provider overlap happened--or didn't happen--between Black and white heart bypass patients and create a provider care team segregation score for each hospital.

"In the Medicare population, there is a lack of overlap in the composition of the provider care teams that treat Black and white patients undergoing heart bypass surgery in the same hospital," Hollingsworth says. "Such provider care team segregation is associated with higher operative mortality for this procedure among Black patients."

Researchers say the reasons for this segregation may include patient preference, in which people prefer to have a care provider who looks like them; admission priority, in which Black patients are more likely to come from the emergency room for their heart bypass than schedule it in advance as an elective surgery; and effects of structural racism on the process of assigning patients to provider care teams, which includes a variety of decisions that don't always get shared or explained.

Co-senior author Brahmajee Nallamothu, M.D., M.P.H., a professor of internal medicine and an interventional cardiologist at the Michigan Medicine Frankel Cardiovascular Center, says the findings point to the need for in-depth study of provider care team segregation as part of the effort to reduce health care inequities.

LA JOLLA--(April 30, 2021) Scientists have known for a while that SARS-CoV-2's distinctive "spike" proteins help the virus infect its host by latching on to healthy cells. Now, a major new study shows that the virus spike proteins (which behave very differently from those safely encoded by vaccines) also play a key role in the disease itself.

The paper, published on April 30, 2021, in Circulation Research, also shows conclusively that COVID-19 is a vascular disease, demonstrating exactly how the SARS-CoV-2 virus damages and attacks the vascular system on a cellular level. The findings help explain COVID-19's wide variety of seemingly unconnected complications, and could open the door for new research into more effective therapies.

"A lot of people think of it as a respiratory disease, but it's really a vascular disease," says Assistant Research Professor Uri Manor, who is co-senior author of the study. "That could explain why some people have strokes, and why some people have issues in other parts of the body. The commonality between them is that they all have vascular underpinnings."

Salk researchers collaborated with scientists at the University of California San Diego on the paper, including co-first author Jiao Zhang and co-senior author John Shyy, among others.

While the findings themselves aren't entirely a surprise, the paper provides clear confirmation and a detailed explanation of the mechanism through which the protein damages vascular cells for the first time. There's been a growing consensus that SARS-CoV-2 affects the vascular system, but exactly how it did so was not understood. Similarly, scientists studying other coronaviruses have long suspected that the spike protein contributed to damaging vascular endothelial cells, but this is the first time the process has been documented.

In the new study, the researchers created a "pseudovirus" that was surrounded by SARS-CoV-2 classic crown of spike proteins, but did not contain any actual virus. Exposure to this pseudovirus resulted in damage to the lungs and arteries of an animal model--proving that the spike protein alone was enough to cause disease. Tissue samples showed inflammation in endothelial cells lining the pulmonary artery walls.

The team then replicated this process in the lab, exposing healthy endothelial cells (which line arteries) to the spike protein. They showed that the spike protein damaged the cells by binding ACE2. This binding disrupted ACE2's molecular signaling to mitochondria (organelles that generate energy for cells), causing the mitochondria to become damaged and fragmented.

Previous studies have shown a similar effect when cells were exposed to the SARS-CoV-2 virus, but this is the first study to show that the damage occurs when cells are exposed to the spike protein on its own.

"If you remove the replicating capabilities of the virus, it still has a major damaging effect on the vascular cells, simply by virtue of its ability to bind to this ACE2 receptor, the S protein receptor, now famous thanks to COVID," Manor explains. "Further studies with mutant spike proteins will also provide new insight towards the infectivity and severity of mutant SARS CoV-2 viruses."

The researchers next hope to take a closer look at the mechanism by which the disrupted ACE2 protein damages mitochondria and causes them to change shape.

While the CRISPR-Cas9 gene editing system has become the poster child for innovation in synthetic biology, it has some major limitations. CRISPR-Cas9 can be programmed to find and cut specific pieces of DNA, but editing the DNA to create desired mutations requires tricking the cell into using a new piece of DNA to repair the break. This bait-and-switch can be complicated to orchestrate, and can even be toxic to cells because Cas9 often cuts unintended, off-target sites as well.

Alternative gene editing techniques called recombineering instead perform this bait-and-switch by introducing an alternate piece of DNA while a cell is replicating its genome, efficiently creating genetic mutations without breaking DNA. These methods are simple enough that they can be used in many cells at once to create complex pools of mutations for researchers to study. Figuring out what the effects of those mutations are, however, requires that each mutant be isolated, sequenced, and characterized: a time-consuming and impractical task.

Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School (HMS) have created a new gene editing tool called Retron Library Recombineering (RLR) that makes this task easier. RLR generates up to millions of mutations simultaneously, and "barcodes" mutant cells so that the entire pool can be screened at once, enabling massive amounts of data to be easily generated and analyzed. The achievement, which has been accomplished in bacterial cells, is described in a recent paper in PNAS.

"RLR enabled us to do something that's impossible to do with CRISPR: we randomly chopped up a bacterial genome, turned those genetic fragments into single-stranded DNA in situ, and used them to screen millions of sequences simultaneously," said co-first author Max Schubert, Ph.D., a postdoc in the lab of Wyss Core Faculty member George Church, Ph.D. "RLR is a simpler, more flexible gene editing tool that can be used for highly multiplexed experiments, which eliminates the toxicity often observed with CRISPR and improves researchers' ability to explore mutations at the genome level."

Retrons: from enigma to engineering tool

Retrons are segments of bacterial DNA that undergo reverse transcription to produce fragments of single-stranded DNA (ssDNA). Retrons' existence has been known for decades, but the function of the ssDNA they produce flummoxed scientists from the 1980s until June 2020, when a team finally figured out that retron ssDNA detects whether a virus has infected the cell, forming part of the bacterial immune system.

While retrons were originally seen as simply a mysterious quirk of bacteria, researchers have become more interested in them over the last few years because they, like CRISPR, could be used for precise and flexible gene editing in bacteria, yeast, and even human cells.

"For a long time, CRISPR was just considered a weird thing that bacteria did, and figuring out how to harness it for genome engineering changed the world. Retrons are another bacterial innovation that might also provide some important advances," said Schubert. His interest in retrons was piqued several years ago because of their ability to produce ssDNA in bacteria - an attractive feature for use in a gene editing process called oligonucleotide recombineering.

Recombination-based gene editing techniques require integrating ssDNA containing a desired mutation into an organism's DNA, which can be done in one of two ways. Double-stranded DNA can be physically cut (with CRISPR-Cas9, for example) to induce the cell to incorporate the mutant sequence into its genome during the repair process, or the mutant DNA strand and a single-stranded annealing protein (SSAP) can be introduced into a cell that is replicating so that the SSAP incorporates the mutant strand into the daughter cells' DNA.

"We figured that retrons should give us the ability to produce ssDNA within the cells we want to edit rather than trying to force them into the cell from the outside, and without damaging the native DNA, which were both very compelling qualities," said co-first author Daniel Goodman, Ph.D., a former Graduate Research Fellow at the Wyss Institute who is now a Jane Coffin Childs Postdoctoral Fellow at UCSF.

Another attraction of retrons is that their sequences themselves can serve as "barcodes" that identify which individuals within a pool of bacteria have received each retron sequence, enabling dramatically faster, pooled screens of precisely-created mutant strains.

To see if they could actually use retrons to achieve efficient recombineering with retrons, Schubert and his colleagues first created circular plasmids of bacterial DNA that contained antibiotic resistance genes placed within retron sequences, as well as an SSAP gene to enable integration of the retron sequence into the bacterial genome. They inserted these retron plasmids into E. coli bacteria to see if the genes were successfully integrated into their genomes after 20 generations of cell replication. Initially, less than 0.1% of E. coli bearing the retron recombineering system incorporated the desired mutation.

To improve this disappointing initial performance, the team made several genetic tweaks to the bacteria. First, they inactivated the cells' natural mismatch repair machinery, which corrects DNA replication errors and could therefore be "fixing" the desired mutations before they were able to be passed on to the next generation. They also inactivated two bacterial genes that code for exonucleases - enzymes that destroy free-floating ssDNA. These changes dramatically increased the proportion of bacteria that incorporated the retron sequence, to more than 90% of the population.

Name tags for mutants

Now that they were confident that their retron ssDNA was incorporated into their bacteria's genomes, the team tested whether they could use the retrons as a genetic sequencing "shortcut," enabling many experiments to be performed in a mixture. Because each plasmid had its own unique retron sequence that can function as a "name tag", they reasoned that they should be able to sequence the much shorter retron rather than the whole bacterial genome to determine which mutation the cells had received.

First, the team tested whether RLR could detect known antibiotic resistance mutations in E coli. They found that it could - retron sequences containing these mutations were present in much greater proportions in their sequencing data compared with other mutations. The team also determined that RLR was sensitive and precise enough to measure small differences in resistance that result from very similar mutations. Crucially, gathering these data by sequencing barcodes from the entire pool of bacteria rather than isolating and sequencing individual mutants, dramatically speeds up the process.

Then, the researchers took RLR one step further to see if it could be used on randomly-fragmented DNA, and find out how many retrons they could use at once. They chopped up the genome of a strain of E. coli highly resistant to another antibiotic, and used those fragments to build a library of tens of millions of genetic sequences contained within retron sequences in plasmids. "The simplicity of RLR really shone in this experiment, because it allowed us to build a much bigger library than what we can currently use with CRISPR, in which we have to synthesize both a guide and a donor DNA sequence to induce each mutation," said Schubert.

This library was then introduced into the RLR-optimized E coli strain for analysis. Once again, the researchers found that retrons conferring antibiotic resistance could be easily identified by the fact that they were enriched relative to others when the pool of bacteria was sequenced.

"Being able to analyze pooled, barcoded mutant libraries with RLR enables millions of experiments to be performed simultaneously, allowing us to observe the effects of mutations across the genome, as well as how those mutations might interact with each other," said senior author George Church, who leads the Wyss Institute's Synthetic Biology Focus Area and is also a Professor of Genetics at HMS. "This work helps establish a road map toward using RLR in other genetic systems, which opens up many exciting possibilities for future genetic research."

Another feature that distinguishes RLR from CRISPR is that the proportion of bacteria that successfully integrate a desired mutation into their genome increases over time as the bacteria replicate, whereas CRISPR's "one shot" method tends to either succeed or fail on the first try. RLR could potentially be combined with CRISPR to improve its editing performance, or could be used as an alternative in the many systems in which CRISPR is toxic.

More work remains to be done on RLR to improve and standardize editing rate, but excitement is growing about this new tool. RLR's simple, streamlined nature could enable the study of how multiple mutations interact with each other, and the generation of a large number of data points that could enable the use of machine learning to predict further mutational effects.

"This new synthetic biology tool brings genome engineering to an even higher levels of throughput, which will undoubtedly lead to new, exciting, and unexpected innovations," said Don Ingber, M.D., Ph.D., the Wyss Institute's Founding Director. Ingber is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children's Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

Mitochondria are the energy suppliers of our body cells. These tiny cell components have their own genetic material, which triggers an inflammatory response when released into the interior of the cell. The reasons for the release are not yet known, but some cardiac and neurodegenerative diseases as well as the ageing process are linked to the mitochondrial genome. Researchers at the Max Planck Institute for Biology of Ageing and the CECAD Cluster of Excellence in Ageing research have investigated the reasons for the release of mitochondrial genetic material and found a direct link to cellular metabolism: when the cell's DNA building blocks are in short supply, mitochondria release their genetic material and trigger inflammation. The researchers hope to find new therapeutic approaches by influencing this metabolic pathway.

Our body needs energy - for every metabolic process, every movement and for breathing. This energy is produced in tiny components of our body cells, the so-called mitochondria. Unlike other cell components, mitochondria have their own genetic material, mitochondrial DNA. However, in certain situations, mitochondria release their DNA into the interior of the cell, causing a reaction from the cell's own immune system and being associated with various diseases as well as the ageing process. The reasons for the release of mitochondrial DNA are not yet known.

Shortage of DNA building blocks triggers inflammatory reaction

To answer the question of when mitochondria release their DNA, researchers at the Max Planck Institute for Biology of Ageing have focused on the mitochondrial protein YME1L, which owes its name to yeast mutants that release their mitochondrial DNA - yeast mitochondrial escape 1. "In cells lacking YME1L, we observed the release of mitochondrial DNA into the cell interior and a related immune response in the cells", said Thomas MacVicar, one of the study's two first authors. Closer examination revealed a direct link to the building blocks of DNA. "If the cells lack YME1L, there is a deficiency of DNA building blocks inside the cell", Thomas MacVicar describes. "This deficiency triggers the release of mitochondrial DNA, which in turn causes an inflammatory response in the cell: the cell stimulates similar inflammatory reactions as it does during a bacterial or viral infection. If we add DNA building blocks to the cells from the outside, that also stops the inflammation."

New therapeutic approaches based on the metabolism of DNA building blocks

The discovered link between the cellular inflammatory response and the metabolism of DNA building blocks could have far-reaching consequences, explains Thomas MacVicar: "Some viral inhibitors stop the production of certain DNA building blocks, thereby triggering an inflammatory response. The release of mitochondrial DNA could be a crucial factor in this, contributing to the effect of these inhibitors." Several ageing-associated inflammatory diseases, including cardiac and neurodegenerative diseases, as well as obesity and cancer, are linked to mitochondrial DNA. The authors hope that modulating the metabolism of DNA building blocks will offer new therapeutic opportunities in such diseases.

Scientists at the University of Nottingham have developed an ultrasonic imaging system, which can be deployed on the tip of a hair-thin optical fibre, and will be insertable into the human body to visualise cell abnormalities in 3D.

The new technology produces microscopic and nanoscopic resolution images that will one day help clinicians to examine cells inhabiting hard-to-reach parts of the body, such as the gastrointestinal tract, and offer more effective diagnoses for diseases ranging from gastric cancer to bacterial meningitis.

The high level of performance the technology delivers is currently only possible in state-of-the-art research labs with large, scientific instruments - whereas this compact system has the potential to bring it into clinical settings to improve patient care.

The Engineering and Physical Sciences Research Council (EPSRC)-funded innovation also reduces the need for conventional fluorescent labels - chemicals used to examine cell biology under a microscope - which can be harmful to human cells in large doses.

The findings are being reported in a new paper, entitled 'Phonon imaging in 3D with a fibre probe' published in the Nature journal, Light: Science & Applications.

Paper author, Salvatore La Cavera, an EPSRC Doctoral Prize Fellow from the University of Nottingham Optics and Photonics Research Group, said of the ultrasonic imaging system: "We believe its ability to measure the stiffness of a specimen, its bio-compatibility, and its endoscopic-potential, all while accessing the nanoscale, are what set it apart. These features set the technology up for future measurements inside the body; towards the ultimate goal of minimally invasive point-of-care diagnostics."

Currently at prototype stage, the non-invasive imaging tool, described by the researchers as a "phonon probe", is capable of being inserted into a standard optical endoscope, which is a thin tube with a powerful light and camera at the end that is navigated into the body to find, analyse, and operate on cancerous lesions, among many other diseases. Combining optical and phonon technologies could be advantageous; speeding up the clinical workflow process and reducing the number of invasive test procedures for patients.

3D mapping capabilities

Just as a physician might conduct a physical examination to feel for abnormal 'stiffness' in tissue under the skin that could indicate tumours, the phonon probe will take this '3D mapping' concept to a cellular level.

By scanning the ultrasonic probe in space, it can reproduce a three-dimensional map of stiffness and spatial features of microscopic structures at, and below, the surface of a specimen (e.g. tissue); it does this with the power to image small objects like a large-scale microscope, and the contrast to differentiate objects like an ultrasonic probe.

"Techniques capable of measuring if a tumour cell is stiff have been realised with laboratory microscopes, but these powerful tools are cumbersome, immobile, and unadaptable to patient-facing clinical settings. Nanoscale ultrasonic technology in an endoscopic capacity is poised to make that leap," adds Salvatore La Cavera.

How it works

The new ultrasonic imaging system uses two lasers that emit short pulses of energy to stimulate and detect vibrations in a specimen. One of the laser pulses is absorbed by a layer of metal - a nano-transducer (which works by converting energy from one form to another) - fabricated on the tip of the fibre; a process which results in high-frequency phonons (sound particles) getting pumped into the specimen. Then a second laser pulse collides with the sound waves, a process known as Brillouin scattering. By detecting these "collided" laser pulses, the shape of the travelling sound wave can be recreated and displayed visually.

The detected sound wave encodes information about the stiffness of a material, and even its geometry. The Nottingham team was the first to demonstrate this dual-capability using pulsed lasers and optical fibres.

The power of an imaging device is typically measured by the smallest object that can be seen by the system, i.e. the resolution. In two dimensions the phonon probe can "resolve" objects on the order of 1 micrometre, similar to a microscope; but in the third dimension (height) it provides measurements on the scale of nanometres, which is unprecedented for a fibre-optic imaging system.

Future applications

In the paper, the researchers demonstrate that the technology is compatible with both a single optical fibre and the 10-20,000 fibres of an imaging bundle (1mm in diameter), as used in conventional endoscopes.

Consequently, superior spatial resolution and wide fields of view could routinely be achieved by collecting stiffness and spatial information from multiple different points on a sample, without needing to move the device - bringing a new class of phonon endoscopes within reach.

Beyond clinical healthcare, fields such as precision manufacturing and metrology could use this high-resolution tool for surface inspections and material characterisation; a complementary or replacement measurement for existing scientific instruments. Burgeoning technologies such as 3D bio-printing and tissue engineering could also use the phonon probe as an inline inspection tool by integrating it directly to the outer diameter of the print-needle.

Next, the team will be developing a series of biological cell and tissue imaging applications in collaboration with the Nottingham Digestive Diseases Centre and the Institute of Biophysics, Imaging and Optical Science at the University of Nottingham; with the aim to create a viable clinical tool in the coming years.

Successful navigation requires the ability to separate memories in a context-dependent manner. For example, to find lost keys, one must first remember whether the keys were left in the kitchen or the office. How does the human brain retrieve the contextual memories that drive behavior? J.B. Julian of the Princeton Neuroscience Institute at Princeton University, USA, and Christian F. Doeller of the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, Germany, found in a recent study that modulation of map-like representations in our brain's hippocampal formation can predict contextual memory retrieval in an ambiguous environment.

The researchers developed a novel virtual reality navigation task in which human participants learned object positions in two different virtual environments and then had their memory tested during a functional MRI scan. Memory for object locations was also tested in a third ambiguous context, which the researchers defined as a "squircle" - a cross between a square and a circle. There were no "correct" object positions there; instead, study participants had to rely solely on their memory. "The result of our study confirms the theory, long held by several neuroscientists, that a critical function of the hippocampal formation is to represent the contextual information that guides behavior. Cognitive maps in the brain help us to act according to a specific situation. ", explains Christian Doeller.

Although decades of research indicate that the human hippocampus is critical for contextual memory, no previous studies have linked context-specific signals in this formation of the brain to spatial behavior in a way that clearly separates memory from non-memory factors. This research was performed in collaboration with the Kavli Institute for Systems Neuroscience, NTNU, Trondheim, Norway and supported by the European Research Council (ERC-CoG GEOCOG).

The human immune system comprises functionally specialised cellular defence mechanisms that protect the body against disease. These include the dendritic cells. Their main function is to present antigens to other immune cells, especially T cells, thereby activating a primary immune response. Dendritic cells are divided into Type 1 (DC1) and Type 2 (DC2) dendritic cells. Each type fulfils different functions: DC1 provide an immune response to bacteria and viruses, DC2 protect against fungal or parasitic infections. In a recent study conducted at MedUni Vienna's Institute of Cancer Research, researchers found that a particular group of proteins plays a major role in the development of Type 1 dendritic cells. This could open up new therapeutic options in the defence against viruses or bacteria but also for cancer immunity.

Dendritic cells are formed from multipotent progenitor cells in the bone marrow. However, it was hitherto unclear which proteins are responsible for this transition from stem cells to differentiated cells. The study, which has now been published in Cell Death and Differentiation, used animal models and molecular biology techniques such as RNA sequencing to show that a combination of two proteins known as "c-Jun" and "JunB" are essential factors in the development of Type 1 dendritic cells. "Both proteins are transcription factors, DNA-binding molecules belonging to the Activator-Protein-1 (AP-1) family," explains study author Philipp Novoszel, who is also associated with the Comprehensive Cancer Center (CCC) of MedUni Vienna and Vienna General Hospital.

In order to analyse the role of these proteins, the c-Jun- and/or JunB gene was deleted in dendritic cells. "This showed that c-Jun and JunB are jointly, but not individually, essential for DC1 development," says second study author, Barbara Drobits from the Institute of Cancer Research and CCC. The mechanism in detail: working in a never previously described synergy, the c-Jun/JunB transcription factor pair together controls the development of DC1. "An expression analysis of DC1 lacking c-Jun/JunB, showed changes in the cellular identity, and a shift towards DC2." At the same time, the immunological functions of DC1 were greatly reduced when c-Jun/JunB were lacking. Differences were also found in an infection model. In the animal model, deactivation of c-Jun/JunB protected against infection with the bacterium Listeria monocytogenes.

"The results describe a previously unknown function of c-Jun/JunB in the development of dendritic cells. It has already been shown in previous studies that another member of the

AP-1 family known as Batf3 is necessary for DC1 development, in that it regulates the expression of the transcription factor IRF8. However, it was not clear with which AP-1 protein Batf3 interacts to perform this function. Our data now provide this "missing link", in that they point to c-Jun/JunB as being Batf3's tango partner," summarise the study authors.

DC1 are essential for defending against bacteria and viruses as well as for immunity to cancers - a better understanding of the underlying biology could therefore provide new, promising therapeutic approaches for future clinical application.

CHICAGO --- Itch torments its sufferers and can be as debilitating as chronic pain.

But it's a hard symptom to measure -- particularly for the 10 million U.S. children with atopic dermatitis, also known as eczema. They can't always verbalize or quantify their suffering via a survey or scale.

It can also be difficult to objectively measure itch for adults with liver disease, kidney disease and certain cancers who experience its symptoms.

So, it's hard to track how well treatments and drugs are working.

But now there is a soft, wearable sensor that actually quantifies itch by measuring scratching when placed on the hand developed by Northwestern University scientists. While it was tested in patients with atopic dermatitis, it can be used in any condition that causes itch. The novel sensor can support clinical trials for new treatments, track treatment response and monitor for disease worsening -- all in the home setting.

This is the first sensor able to capture all forms of scratching -- finger, wrist and elbow motion related. It also is the first validated in a pediatric population where conditions like atopic dermatitis are the most common.

"Itch torments so many patients across so many conditions. It can be as debilitating as chronic pain," said lead author Dr. Shuai "Steve" Xu, assistant professor of dermatology and of pediatrics at Northwestern University Feinberg School of Medicine. "If we're able to quantify scratching accurately, then we have the ability to objectively quantify itching. This is really important in patients -- like children -- who can't always verbalize or quantify their suffering."

The paper will be published April 30 in Science Advances.

Xu also is an assistant professor of biomedical engineering at McCormick School of Engineering and Applied Science and medical director of the Querrey Simpson Institute for Bioelectronics, both at Northwestern.

About 10 million U.S. children have atopic dermatitis. The hallmark symptom is itch leading to sleep disturbance, poor neurocognitive development and, on average, a full night of sleep lost per week.

"Atopic dermatitis is so much more than just itchy skin," Xu said. "It is a devastating disease that causes tremendous suffering worldwide. The quality of life of severe atopic dermatitis (not only for the child but also the parent) is equivalent to many life-threatening diseases.

"Patients with atopic dermatitis are 44% more likely to report suicidal thoughts as a result of the itch compared to controls. Thus, the ability to quantify their symptoms is really important to help new drugs get approved, but also support their day to day lives. In some ways -- it's like measuring glucose for diabetes...measuring itching in an atopic dermatitis patient may be just as important."

"This is an exciting time for children and adults with atopic dermatitis -- or eczema -- because of the flurry of activity in developing new therapeutics," said Dr. Amy Paller, chair of dermatology at Northwestern. "Nothing is more important to measure a medication's effectiveness for eczema than itch, the symptom that both defines eczema and has the greatest impact on quality of life. This sensor could play a critical role in this regard, especially for children."

In addition, clinicians and parents have the ability to track how well itch is being controlled in patients at home to monitor for treatment response, as well as early signs of worsening disease, Xu said.

This sensor marries advances in soft, flexible electronics that wrap seamlessly around the hand with machine learning algorithms that specifically identifies scratching without being tricked by similar motion-related movements (e.g. hand waving). The sensor measures both low-frequency motion and high-frequency vibrations from the hand to significantly improve accuracy compared to wrist-watch tools.

The sensor was accepted into the Food and Drug Administration's Drug Discovery Tool program. This program allows novel devices like this sensor to be qualified to aid in the approval of new drugs.

The study was conducted in two parts. The first part involved training the sensor to pick up scratching in healthy adults doing voluntary scratching behaviors. The second part tested the sensors on pediatric patients with atopic dermatitis. Parents set up an infrared camera to serve as the "gold standard". The algorithm and sensor were then used to count scratches in this pediatric patient population. More than 300 hours of sleep data was manually reviewed and scored for scratching and linked to the sensors.

eNeuro is publishing a special collection of commentaries on April 30, 2021 on the neuroscience documentary In Silico. The collection, titled "Epistemological Lessons from the Blue and Human Brain Projects," features reactions to the documentary from leading neuroscientists as well as a discussion on brain modelling and massive research collaborations in general.

Noah Hutton's In Silico follows neuroscientist Henry Markram and his attempt to develop a computer model of the brain. The collaboration, called The Human Brain Project, received €1 billion in funding and pledged to build a full model within ten years. The documentary chronicles Markram and his team as the project stirs up controversy and fails to meet its deadline.

The special collection from eNeuro discusses the documentary and the larger issues surrounding brain modelling. The commentaries include:

What In Silico got wrong, from the perspective of Human Brain Project scientists

Next steps for large-scale, collaborative neuroscience initiatives

How charismatic leaders shape the field

The history and science of building brain models

"The movie is an excuse to think more broadly about how to approach the study of brain function," said Christophe Bernard, editor-in-chief of eNeuro, "and what modelling the brain means." The eNeuro special collection and In Silico will be available online on April 30, 2021.

Boston, MA (April 30, 2021) - Research presented today at the AATS 101st Annual Meeting, shows that the six year Integrated Cardiothoracic (CT I-6) residency continues to be the most challenging to match, while the pool of applicants has become more diverse. The study, which aimed to identify applicant characteristics associated with a successful match, used data from the National Residency Matching Program (NRMP), Electronic Residency Application Service (ERAS), and Association of American Medical Colleges (AAMC) for Thoracic Surgery, Orthopaedic Surgery, Neurological Surgery, Otolaryngology (ENT), Plastic Surgery, and Vascular Surgery for 2010-2020.

Data compared number of applicants and residency positions, gender, race, and qualifications among CT I-6 applicants with those of other competitive surgical subspecialties, including Orthopaedic Surgery, Neurological Surgery, Otolaryngology, Plastic Surgery, and Vascular Surgery. Competitive subspecialties analyzed included those that had (1) more United States (US) senior applicants than positions offered; (2) ? 5 positions available in the Supplemental Offer and Acceptance Program (SOAP); and (3) United States Medical Licensing Examination (USMLE) Step 1 score average of ?235 in the 2020 NRMP Match.

Number of applicants, number of positions, match rates, gender, race, and objective metrics including Alpha Omega Alpha (AOA) membership, USMLE Step 1 and 2 CK scores, research productivity, and graduation from a top-40 NIH-funded US medical school were recorded. Descriptive statistics and Student t tests were calculated to compare applicant gender and race between surgical subspecialties.

Despite growth of 280 percent in PGY-1 positions over the ten-year period, CT I-6 continued to be the most difficult to match among all competitive surgical subspecialties, with the lowest match rates among total applicants. The number of female applicants has risen from 16 percent in 2015 to 28 percent in 2020. Furthermore, the diversity among I-6 program applicants has increased in all race and ethnicity categories from 2015 to 2019: White (+0.2 percent), Black (+2.1 percent), Asian (+2.1 percent), and Hispanic (+0.9 percent).

For all applicants, the greatest predictors of a successful match appear to be Step-2 CK, AOA membership, and graduation from a top-40 NIH-funded US medical school.

"Over the last 10 years, trends in the CT I-6 match have been very exciting," explained Lead Author Lauren Bougioukas, medical student at the University of Vermont Larner College of Medicine. "I-6 has been recruiting very competitive, talented applicants. In particular, I am thrilled to see increased numbers of racially diverse and female applicants. I hope this study serves as a springboard for future research regarding the I-6 match, and also better informs aspiring cardiothoracic surgeons looking to pursue an I-6 residency."