Culture

In 2015, the first commercial nanopore DNA sequencing device was introduced by Oxford Nanopore Technologies. Based on a synthetically engineered transmembrane protein, nanopore sequencing allows long DNA strands to be channelled through the central lumen of the pore where changes in the ionic current work as a sensor of the individual bases in the DNA. This technique was a key milestone for DNA sequencing and the achievement was only made possible after decades of research.

Since then, researchers have tried to extend this principle and build larger pores to accommodate proteins for sensing purposes, but a major challenge has been the limited understanding of artificial protein design. As an alternative, a new technique based on artificial folding of DNA into complex structures, the so-called 3D-origami technique, first reported by the AU group in 2009, has emerged. Compared to proteins, DNA origami has been shown to have an unprecedented design space for constructing nanostructures that mimic and extend naturally occurring complexes.

In a new article, published in Nature Communications, the researchers now report the creation of a large synthetic nanopore made from DNA. This nanopore structure is capable of translocating large protein-sized macromolecules between compartments separated by a lipid bilayer. In addition, a functional gating system was introduced inside the pore to enable biosensing of very few molecules in solution.

With the use of powerful optical microscopes, the researchers could follow the flow of molecules through individual nanopores. By introducing a controllable plug in the pore, it was furthermore possible to size-selectively control the flow of protein-size molecules and demonstrate label-free, real time, bio-sensing of a trigger molecule.

Lastly the pore was equipped with a set of controllable flaps, allowing targeted insertion into membranes displaying particular signal molecules. In the future, this mechanism will potentially enable insertion of the sensor specifically into diseased cells and may allow diagnosis at the single cell level.

New York, NY -- Dec 12, 2019 -- Researchers at the Icahn School of Medicine at Mount Sinai have identified novel genes associated with the severity of peanut allergy, as well as ways in which these genes interact with other genes during allergic reactions.

The findings, published December 12 in the Journal of Allergy and Clinical Immunology, could lead to better treatments for peanut allergy.

Peanut allergy varies widely in severity and is the leading cause of fatal food-related anaphylaxis. The tests used to determine the existence of a peanut allergy don't offer any clues as to whether an individual ingesting a peanut could experience a minor rash, major swelling, or life-threatening issues such as difficulty breathing or cardiovascular complications.

The study's senior author, Supinda Bunyavanich, MD, MPH, Associate Professor of Genetics and Genomic Sciences, and Pediatrics, and Associate Director of the Elliot and Roslyn Jaffe Food Allergy Institute at Mount Sinai, was especially curious about why the severity of reactions varies so much, both as a clinician-scientist and as a mother of a child with a peanut allergy.

To help address this question, Dr. Bunyavanich and her team used novel multi-omic approaches (the study of the role, relationships, and actions of a system-wide measure of a given molecular type) to identify genes and networks of activity that might be driving the severity of peanut allergy reactions. The approaches included transcriptomics, the study of gene expression across the genome, and epigenomics, the study of reversible modifications to DNA that affect gene expression.

The study involved 21 children ages 7-17 with peanut allergy, who were given gradually increasing doses of peanut until they displayed an allergic response. The scientists drew blood from the participants at three times: before they ate, as they reacted, and after their reaction. The team confirmed their findings from the initial cohort by repeating the study in another 19 children.

Taking blood samples at multiple times allowed the team to analyze both the transcriptome and epigenome (which can tell scientists which genes are turned on or off through a process called methylation) as the children reacted. Using this genome-wide approach, they identified more than 300 genes and 200 CpG sites (areas where DNA can be activated or inactivated by methylation) associated with reaction severity. Combining these data using integrative networks, the team also characterized key interactions between gene expression, CpG sites, and reaction severity.

Not only did they identify novel genes associated with the severity of peanut allergy, but they also managed to characterize ways in which these genes interact with other genes and CpG sites during allergic reactions to regulate biological processes. "It was very exciting to apply multi-omics to uncover how genes and methylation sites interact to affect reaction severity in these peanut allergic kids," says Anh Do, PhD, lead author of the study and postdoctoral fellow in the Bunyavanich Lab.

Among the insights is that while the findings support recognized roles for adaptive immunity in allergy, they also suggest that neutrophil (a type of white blood cell)-mediated immunity plays a prominent role in reaction severity. "We know neutrophil-mediated immunity is part of immune responses, and this study suggests it may play a central role in the severity of peanut allergic reactions," said Dr. Bunyavanich.

Additionally, one of the reaction severity drivers the team identified, the gene ARG1, can be inhibited by arginase inhibitors, a type of drug under study for many diseases. This study's finding suggests it may be a potential target for treating peanut allergy as well.

Dr. Bunyavanich hopes future studies will identify biomarkers that can predict who is likely to have severe responses without having to expose them to peanuts first. But in the meantime, she states that this study "hopefully challenges people to think about food allergy with a broader lens."

In decades of studying how neural circuits in the brain's visual cortex adapt to experience, MIT Professor Mark Bear's lab has followed the science wherever it has led, yielding the discovery of cellular mechanisms serving visual recognition memory, in which the brain learns what sights are familiar so it can focus on what's new, and of a potential therapy for amblyopia, a disorder where children born with disrupted vision in one eye can lose visual acuity there permanently without intervention. But this time his lab's latest investigation has yielded surprising new layers of mystery.

Heading into the experiments described in a new paper in Cerebral Cortex, Bear and his team expected to confirm that key proteins called NMDA receptors act specifically in neurons in layer 4 of the visual cortex to make the circuit connection changes, or "plasticity," necessary for both visual recognition memory and amblyopia. Instead, the study has produced unexpectedly divergent results.

"There are two stories here," said Bear, co-senior author and Picower Professor of Neuroscience in The Picower Institute for Learning and Memory. "One is that we have further pinpointed where to look for the root causes of amblyopia. The other is that we have now completely blown up what we thought was happening in stimulus-selective response potentiation, or SRP, the synaptic change believed to give rise to visual recognition memory."

The cortex is built like a stack of pancakes, with distinct layers of cells serving different functions. Layer 4 is considered to be the primary "input layer" that receives relatively unprocessed information that arises from each eye. Plasticity that is restricted to one eye has been assumed to occur at this early stage of cortical processing, before the information from the two eyes becomes mixed. However, while the evidence demonstrates that NMDA receptors in layer 4 neurons are indeed necessary for the degradation of vision in a deprived eye, they apparently play no role in how neural connections, or synapses, serving the uncompromised eye strengthen to compensate, and similarly don't matter for the development of SRP. That's even though NMDA receptors in visual cortex neurons have directly been shown to matter in these phenomena before, and layer 4 neurons are known to participate in these circuits via telltale changes in electrical activity.

"These findings reveal two key things," said Samuel Cooke, co-senior author and a former member of the Bear Lab who now has his own at King's College London. "First, that the neocortical circuits modified to enhance cortical responses to sensory inputs during deprivation or to stimuli that have become familiar reside elsewhere in neocortex, revealing a complexity that we had not previously appreciated. Second, the results show that effects can be clearly manifest in a region of the brain that are actually echoes of plasticity occurring elsewhere, thereby illustrating the importance of not only observing biological phenomena but also understanding their origins by locally disrupting known underlying mechanisms."

'We were stunned'

To perform the study, Bear Lab postdoc and lead author Ming-fai Fong and used a genetic technique to specifically knock out NMDA receptors in excitatory neurons in layer 4 of the visual cortex of mice. Armed with that tool, she could then investigate the consequences for visual recognition memory and "monocular deprivation," a lab model for amblyopia in which one eye is temporarily closed early in life. The hypothesis was that knocking out the NMDA receptor in these cells in layer 4 would prevent SRP from taking hold amid repeated presentations of the same stimulus, and would prevent the degradation of vision in a deprived eye as well as the commensurate strengthening of the unaffected eye.

"We were gratified to note that the amblyopia-like effect of losing cortical vision as a result of closing an eye for several days in early life was completely prevented," Cooke said. "However, we were stunned to find that the two enhancing forms of plasticity remained completely intact."

Fong said that with continued work, the lab hopes to pinpoint where in the circuit NMDA receptors are triggering SRP and the compensatory increase in strength in a non-deprived eye after monocular deprivation. Doing so, she said, could have clinical implications.

"Our study identified a crucial component in the visual cortical circuit that mediates the plasticity underlying amblyopia," she said. "This study also highlights the ongoing need to identify the distinct components in the visual cortical circuit that mediate visual enhancement, which could be important both in developing treatments for visual disability as well as developing biomarkers for neurodevelopmental disorders. These efforts are ongoing in the lab."

The search now moves to other layers, Bear said, including layer 6, which also receives unprocessed input from each eye.

"Clearly this is not the end of the story," Bear said.

A new study on wild banded mongooses reveals that females may use spontaneous abortion to cope with reproductive competition, and to save their energy for future breeding attempts in better conditions.

Researchers at the University of Exeter, UK, followed a population of wild banded mongooses (Mungos mungo) in western Uganda for 15 years, using ultrasound imaging to track which females became pregnant and which carried to full term. They discovered that there were more abortions during the dry season when food was scarce, and also when more females were competing over reproduction in the same group. Individual females were less likely to carry to term if they were young, in poor condition, or carrying smaller fetuses.

"Reproduction takes a lot of energy, and for a female whose offspring may have slim chances at survival, it makes sense to delay that investment until times are better. Spontaneous abortion may be an adaptive strategy in this species because it enables females to save energy for the next breeding attempt," says researcher, and senior author of the study, Emma Vitikainen from the University of Helsinki.

Banded mongooses are cooperative breeders that live in family groups where several females give birth at the same time to a litter that is jointly cared for by all the group members. Underneath this seemingly harmonious surface, co-breeding females compete over whose offspring do best. Pups that are born bigger have more help from their group members, grow faster and outcompete their littermates.

This study revealed that females adjust their own investment in response to the competition, and that females whose offspring would be more likely to lose out are more likely to cut their losses by aborting their fetuses mid-pregnancy. Banded mongooses also curb competition by evicting younger females. To focus on spontaneous pregnancy loss the researchers only looked at breeding events where no violent eviction events occurred.

"Female competition over reproduction is easily overlooked," explains lead author Emma Inzani from the University of Exeter, UK. "Males fight with horns and antlers over access to females, whereas female competition can be much more subtle. Our study shows that even in the absence of overt aggression, females adjust their reproductive decisions in response to competition from other females. "

All research was done under ethical permits from University of Exeter and Uganda Wildlife Authority and study methods caused no harm to pregnant mongooses.

Using new high-resolution imaging techniques, MDC researchers and colleagues have tracked titin, the body's largest protein, in real time throughout its entire lifecycle. The method and results could provide new insight into muscle development as well as treating damaged muscles and heart disease.

As twinkling lights brighten the holiday season, Max Delbrueck Center for Molecular Medicine researchers are cheered by red and green lights for an entirely different reason. Using colorful probes, a team has tracked the full lifecycle of titin, the body's largest protein known to play a key role in muscle tissue. Observing titin from synthesis to degradation has provided novel insight into the formation of sarcomeres, the main contractile units of heart and skeletal muscle. The results were reported in the journal Proceedings of the National Academy of Sciences (PNAS).

Titin is such a large molecule that its analysis provides unique challenges. The team attached red and green fluorescent tags to opposite ends of the protein, enabling them to observe titin's precise movements in muscle cells derived from the mouse heart, called cardiomyocytes.

"Cardiomyocytes are highly specialized and cannot skip a beat," said Michael Gotthardt, who heads MDC's Neuromuscular and Cardiovascular Cell Biology Lab and spearheaded the research. "We can watch how titin is made and inserted into the myofilament while everything is still working. It's beautiful to see."

Not just a pretty picture

The insight gained from being able to watch titin in real time is significant. Titin has long been assumed to be the rigid backbone of sarcomeres, the basic functional segments of heart and skeletal muscles that expand and contract. It turns out that titin is much more dynamic than previously thought, Gotthardt said.

Heart muscle cells appear to have a pool of soluble titin spread throughout the sarcomere, ready to replace proteins damaged in the repetitive process of muscle expansion and contraction. Overextended proteins are moved out of the cells and then degraded. All of this happens over the course of a few hours, which sounds fast, but is actually much longer than for any other sarcomeric protein.

The large amount of titin located outside the sarcomere was as surprise, seen for the first time thanks to the new genetic mouse model and imaging technique, Gotthardt said. Another unexpected finding was the diversity of titin molecules, called isoforms, that were observed. Faster moving proteins are likely different isoforms than slower moving ones.

"This is a look at the real life of the sarcomere," Gotthardt said. "We can understand the formation and remodeling of the myofilament structure, which has relevance to human disease and development."

Potential applications

The fluorescent probes can help researchers study how muscles rebuild themselves after exercise, or how heart muscles remodel after a heart attack. They might also help to better understand heart diseases associated with mutations in other sarcomeric proteins, said Franziska Rudolph, first author of the paper.

"This is amazing, to follow endogenous titin variants in real time from start to finish," Rudolph said. "So many experiments are possible with these mouse models and different imaging techniques."

For example, the technique could potentially be used to track implanted cells to see how well they are integrating with the native muscle fiber, and if they properly connect with their new neighbors to work as a unit or not. Such insight could show if cell based therapies are effective.

Validating the novel tools and establishing methods for image analysis was a challenge and required the collaboration with colleagues from MDC's Berlin Institute for Medical Systems Biology, University Medical Center Goettingen, and the University of Arizona. The team worked hard to show how the fluorescent proteins, which are genetically generated, had no unexpected side effects on muscle or titin development and function.

MDC researchers are continuing to investigate titin with the new tools, including how skeletal muscles respond to exercise.

INFORMS journal Manufacturing & Service Operations Management New Study Takeaways:

Shoppers' decisions are increasingly shaped by their experience and the desire for better service.

Brick-and-mortar stores that work together to provide waiting area entertainment options can obtain higher profits than they would by providing their own entertainment.

CATONSVILLE, MD, December 13, 2019 - With the popularity of online shopping, it's no secret brick-and-mortar stores are fighting to stay relevant. Waiting area entertainment is one way they are standing out, because no one likes to wait. New research in the INFORMS journal Manufacturing & Service Operations Management says funding entertainment is no easy task, but one way to offset the price and increase customer experience and revenue is to work with, not against competitors.

"A service provider can improve its bottom line by working with other stores or businesses to split the cost of providing entertainment options. This allows everyone to keep customers rolling in, then they can compete on other service dimensions such as prices," said Tinglong Dai of Johns Hopkins University.

Shoppers decisions are increasingly shaped by their experience and the desire for better service. No one likes to wait. By entertaining customers, with Wi-Fi, television, and other amenities, their experience is better and they tend to come back.

An example of businesses that share space and can benefit from this plan are boardwalks, malls or airport car rental facilities, to name a few. Disney Parks, Experiences and Products famously pioneered the practice of providing diversions for customers waiting for rides. Now it's being widely mimicked across several other industries.

Occupied waiting feels shorter than unoccupied waiting, however, waiting area entertainment can represent a significant portion of companies' operational costs.

This study, "Co-opetition in Service Clusters with Waiting-Area Entertainment," conducted by Dai and fellow co-authors Yuan Xuchuan of Singapore University of Social Sciences, Lucy Gongtao Chen of the National University of Singapore and Srinagesh Gavirneni of Cornell University, looks at case studies in Singapore, Taiwan and here in the United States. The authors found that if businesses work together to create an entertainment space, they can save money and likely increase revenue with more customers flooding their stores.

"We looked at the case of two businesses in the same service cluster competing for customers and independently making price, capacity and entertainment decisions. We saw that with intense competition, service providers had to make heavy investments in entertainment options and it eroded profits," said Dai, a professor in the Carey Business School at Hopkins.

"We then looked at two service providers who were competing for customers but cooperated in providing entertainment options. We saw that co-opetition helped obtain higher profits than under a monopoly."

One key insight for co-opetition: it's important to be fair in the shared resource funding, but a narrow focus on fairness may backfire and completely eliminate the benefit from resource sharing.

Dec. 13, 2019--The number of people newly infected each year and the number of people living with nontuberculous mycobacterial lung disease appears to be increasing, especially among women and those 65 and older, according to new research published online in the Annals of the American Thoracic Society.

In "Incidence and Prevalence of Nontuberculous Mycobacterial Lung Disease in a Large United States Managed Care Health Plan, 2008-2015," Kevin L. Winthrop, MD, MPH, and colleagues report on their analysis of NTM diagnoses among approximately 27 million participants in a national health care plan (Optum) during the eight-year study period.

"Our findings add to other recent studies from North America and other regions of the world that show NTM disease is increasing," said Dr. Winthrop, professor of infectious diseases and public health at the Oregon Health and Science University.

Nontuberculous mycobacteria (NTM) are found naturally in the environment, and everyone inhales them. The most common NTM is Mycobacterium avium complex, though altogether there are more than 160 different species.

While only a tiny fraction of people develops NTM disease, those with chronic lung diseases such as COPD and cystic fibrosis and those who are immunocompromised are at greater risk for the disease, which can be debilitating and even cause death. Unlike the bacterium that causes tuberculosis, NTM is not contagious.

The researchers reported incidence, the number of new infections reported each year per 100,000 person-years (the number of participants × eight years) and prevalence, the total number of those living with NTM in a given year per 100,000 persons.

The study found from 2008 to 2015:

The annual incidence of NTM lung disease increased from 3.13 to 4.73 per 100,000 person-years.

The annual prevalence increased from 6.78 to 11.70 per 100,000 persons.

For women, the annual incidence increased from 4.16 to 6.69 per 100,000 person-years, while the prevalence increased from 9.63 to 16.78 per 100,000 persons.

For those aged 65 and older, the annual incidence increased from 12.70 to 18.37 per 100,000 person-years, while the annual prevalence increased from 30.27 to 47.48 per 100,000 persons.

The incidence of NTM increased by at least 10 percent in 29 states.

The prevalence of NTM increased by at least 10 percent in 39 states.

"There are likely multiple reasons for these increases," Dr. Winthrop said. "The number of people at risk is increasing because the population is aging and more people are living with chronic lung diseases. Increasing environmental exposure is also likely a factor, as is greater awareness of NTM disease among physicians."

He added that the high rates of NTM among women may be explained by the fact that they live longer and may be more likely to seek medical care. There may also be as yet unidentified biologic and genetic factors that contribute to greater incidence and prevalence among women.
Study limitations include inaccuracies in diagnostic coding and unequal distribution of participants in the health plan across the country.

SAN ANTONIO -- Researchers from The University of Texas MD Anderson Cancer Center today reported results from a pooled analysis of more than 5,100 breast cancer patients that found residual cancer burden (RCB) continuous index and classification were independently and strongly prognostic for all breast cancer phenotypes.

The study's results were presented by W. Fraser Symmans, M.D., professor of Pathology, during the 2019 San Antonio Breast Cancer Symposium.

"This meta-analysis indicates that continuous RCB index is an accurate and reliable tool to assess patient prognosis," said Symmans. "Furthermore, we found that these results were consistently generalizable and could help determine the most appropriate treatment plans for patients with all breast cancer subtypes."

Pathological complete response (pCR), defined by the exclusion of any residual cancer, is a known strong prognostic indicator that is useful for communication of residual risk and subsequent treatment plans for breast cancer patients. Similarly, smaller studies have indicated that the extent of residual disease after neoadjuvant chemotherapy is associated with risk of the cancer returning in the future.

In this pooled subject-level analysis, Symmans worked with a team of researchers from the I-SPY Clinical Trials Consortium to analyze data from 12 institutes or clinical trials representing more than 5,100 breast cancer patients from six countries. MD Anderson has hosted a freely available website to calculate RCB since 2007. This is widely used as a resource with educational materials and calculator for RCB index and category. RCB is determined by factors including the dimensions of the primary tumor bed area; the percentage of cancer that is invasive versus in situ; the number of involved lymph nodes and size of the largest metastasis. RCB index was classified as: RCB-I (minimal burden), RCB-II (moderate burden) or RCB-III (extensive burden).

Symmans and colleagues evaluated associations between the continuous RCB index and both event-free survival (EFS) and distant recurrence-free survival (DRFS), adjusting for differences between studies. They also evaluated the association between RCB index and prognosis within each HR/HER2 subtype. Kaplan Meier estimates of EFS and DRFS at five and 10 years were calculated for each RCB class within each phenotype.

Results from the analysis indicated RCB index and classification was an accurate and consistent indicator of prognosis for all four breast cancer subtypes. RCB index also was tightly associated with prognosis over long-term follow-up.

"This pooled analysis confirms and expands upon prior findings that RCB index can predict risk of breast cancer recurrence," said Symmans. "This assessment of prognostic risk can be used to accurately determine disease progression and inform treatment choice for breast cancer patients inclusive of all subtypes."

Analysis

Prognostic differences by RCB class occurred within five years in HR- breast cancer but extended to 10 years in HR+ breast cancer.

For HR+/HER2-, 11% of patients were classified as having a pathological complete response (pCR): 11% as RCB-I, 53% as RCB-II, and 25% as RCB-III. At the 10-year follow-up, 19% of the pCR group had a recurrence or had died, compared with 14% of the RCB-I group, 31% of the RCB-II group, and 48% of the RCB-III group.

For HR+/HER2+, 38% of patients were classified as having a pCR: 20% as RCB-I, 33% as RCB-II, and 8% as RCB-III. At the 10-year follow-up, 9% of the pCR group had had a recurrence or had died, compared with 17% of the RCB-I group, 36% of the RCB-II group, and 55% of the RCB-III group.

For HR-/HER2+, 69% of patients were classified as having a pCR: 11% as RCB-I, 16% as RCB-II, and 4% as RCB-III. At the 10-year follow-up, 7% of the pCR group had had a recurrence or had died, compared with 15% of the RCB-I group, 37% of the RCB-II group, and 40% of the RCB-III group.

For HR-/HER2-, 43% of patients were classified as having a pCR: 12% as RCB-I, 33% as RCB-II, and 11% as RCB-III. At the 10-year follow-up, 14% of the pCR group had had a recurrence or had died, compared with 25% of the RCB-I group, 39% of the RCB-II group, and 75% of the RCB-III group.

After five years, RCB-I patients had slightly worse EFS than pCR in HR- breast cancer and HR+/HER2+ breast cancer, but the same EFS as pCR in HR+/HER2- breast cancer. On the other hand, the large numbers of patients in this study made it possible to observe that a precise estimate of future risk could be calibrated from the actual value of RCB index calculated from a person's surgical resection specimen. That finding could facilitate another step forward in precision in the assessment of treatment, communication of residual risk and treatment planning for patients with breast cancer.

The authors note several limitations to the study, including data collection from multiple institutions which may introduce some variation in clinical methods, the handling of specimens and other factors. Some data were collected prospectively and some retrospectively, another variable factor.

Cancer centers do not all routinely collect data on RCB; this analysis indicates that RCB is a potential predictor of recurrence across breast cancer subtypes. "These findings indicate the importance of implementing residual cancer burden screening as a standard tool during cancer treatment. Routinizing RCB can give a more accurate sense of each patient's prognosis, recurrence and best course of treatment while building an even more robust data set to improve understanding of the relationship between RCB index and long-term prognosis," Symmans said.

Philadelphia, December 13, 2019 - Unfortunately, cancers that occur in the back of the mouth and upper throat are often not diagnosed until they become advanced, partly because their location makes them difficult to see during routine clinical exams. A report in the Journal of Molecular Diagnostics, published by Elsevier, describes the use of acoustofluidics, a new non-invasive method that analyzes saliva for the presence of human papilloma virus (HPV)-16, the pathogenic strain associated with oropharyngeal cancers (OPCs). This novel technique detected OPC in whole saliva in 40 percent of patients tested and 80 percent of confirmed OPC patients.

"OPC has an approximate incidence of 115,000 cases per year worldwide and is one of the fastest-rising cancers in Western countries due to increasing HPV-related incidence, especially in younger patients. It is paramount that surveillance methods are developed to improve early detection and outcomes," explained co-lead investigator Tony Jun Huang, PhD, Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA.

"Considering these factors, the successful detection of HPV from salivary exosomes isolated by our acoustofluidic platform offers distinct advantages, including early detection, risk assessment, and screening," added Dr. Huang. This technique may also help physicians predict which patients will respond well to radiation therapy or achieve longer progression-free survival.

Exosomes are tiny microvesicles originating within cells that are secreted into body fluids. They are believed to play a role in intercellular communication and their numbers are elevated in association with several types of cancers. Acoustofluidics is an advanced technology that fuses acoustics and microfluidics. Fluid samples are analyzed using a tiny acoustofluidic chip developed to isolate salivary exosomes by removing unwanted particles based on size, leaving exosome-rich concentrated samples that make it easier to detect tumor-specific biomarkers.

In this study investigators analyzed saliva samples from 10 patients diagnosed with HPV-OPC using traditional methods. They found that the technique identified the tumor biomarker HPV-16 DNA in 80 percent of the cases when coupled with droplet digit PCR. Since this method is independent of sample variability that arises due to changes in saliva viscosity and collection methods used, it may prove ideal for use in clinical settings.

Dr. Huang highlighted some of the technique's features, including automated and fast exosome isolation (less than five minutes of processing time compared to approximately eight hours of processing time using benchmark technologies). Analyses can be performed at relatively low cost and at points of care. Also, it is suitable for repeated and continuous monitoring of tumor progression and treatment, unlike traditional biopsy.

"With these features, the acoustofluidic technology has the potential to significantly exceed current industry standards, address unmet needs in the field, help expedite exosome-related biomedical research, and aid in the discovery of new exosomal biomarkers," commented Dr. Huang.

"The saliva exosome liquid biopsy is an effective early detection and risk assessment approach for OPC," said co-lead investigator David T.W. Wong, DMD, DMSc, of the Center for Oral/Head and Neck Oncology Research, School of Dentistry at the University of California Los Angeles, CA, USA. "The acoustofluidic separation technique provides a fast, biocompatible, high-yield, high-purity, label-free method for exosome isolation from saliva." According to the researchers, this technology can also be used to analyze other biofluids such as blood, urine, and plasma.

The study was an international collaboration between Duke University, UCLA, and University of Birmingham (UK). Prof Hisham Mehanna, Director of the Institute of Head and Neck Studies and Education, University of Birmingham, Birmingham, UK, said 'The results are a testament to the power of interdisciplinary research and international collaboration.'

Should germline genetic testing be offered to all patients with breast cancer? The American College of Medical Genetics and Genomics (ACMG) addresses this important question in a new statement published in Genetics in Medicine, "Points to Consider: Is There Evidence to Support BRCA1/2 and Other Inherited Breast Cancer Genetic Testing for All Breast Cancer Patients? A Statement of the American College of Medical Genetics and Genomics."

Of all cancers that develop in women in the United States (US), breast cancer has the highest incidence, regardless of race or ethnicity. Approximately 5-10% of breast cancers are estimated to result from hereditary causes, the majority of which are attributed to pathogenic or likely pathogenic (P/LP) variants in the BRCA1 and BRCA2 (BRCA1/2) genes, although variants in other genes such as PALB2, TP53, PTEN, CDH1, CHEK2 and ATM also contribute.

Identification of inherited cancer risk empowers individuals and their families to prevent cancers or detect them early. Furthermore, incorporating genetic testing results into patients' care plans has the potential to guide treatment and improve outcomes. But testing alone will not improve outcomes. Implementation of appropriate care following testing is required and data are needed to generate evidence that informs clinical practice.

As progress in precision medicine continues, it is important that patients receive accurate information to ensure the implementation of risk reducing strategies and evidence-based cancer genomics best practices. The purpose of this new ACMG points-to-consider document is to outline the rationale for ongoing support of existing evidence-based guidelines built on a risk stratification approach while data related to broader testing strategies continues to emerge.

"Medical geneticists play an important role in facilitating the best care and practices of patients with cancer or a predisposition to develop cancer," said ACMG President Anthony R. Gregg, MD, MBA, FACOG, FACMG. "This Points to Consider document acknowledges the complexity of professional organization guidelines in the cancer space. Medical geneticists are uniquely qualified to analyze the literature that informs professional organizations and their guidelines. Implementation of cancer genetic testing guidelines is best when carried out with input and in many cases under the direction of a medical geneticist with cancer expertise."

The new ACMG document provides points for clinicians to consider in the context of testing breast cancer patients for inherited cancer predisposition, including:

All patients with breast cancer should be evaluated to determine the need for germline genetic testing for hereditary breast cancer. According to national practice guidelines, genetic testing for breast cancer patients is indicated based on patient characteristics including age at diagnosis, family cancer history, expression of estrogen progesterone receptors and HER2 expression and disease stage.

When discussing genetic testing for breast cancer patients, clinicians should be aware of the current insufficient evidence to support genetic testing for all patients with breast cancer, especially with multi-gene panels that include genes without evidence to support follow-up care.

When discussing management after identification of a P/LP in moderately penetrant breast cancer genes:

recognize that guidance is based on consensus recommendations; and

enhanced screening has not, to date, been associated with enhanced survival or identification of disease at an earlier stage.

Whenever genetic testing for inherited breast cancer is performed on a clinical basis, testing should include full gene sequencing, deletion/duplication analysis and detection of known P/LP intronic variants in a Clinical Laboratory Improvement Amendments (CLIA)-certified and/or College of American Pathologists (CAP)-accredited genetic testing laboratory.

The implications of genetic testing should be reviewed with patients in the context of genetic counseling as genetic testing is ordered. This counseling should include the expertise of trained genetics professional or healthcare provider with special expertise in cancer genetics principles.

Patients who have a P/LP variant in an established breast cancer-associated gene in which evidenced-based follow-up recommendations exist should be educated about the importance of cascade testing of family members.

The points-to-consider document concludes by stating, "With the advances in sequencing technologies and increasing access to and expanding indications for genetic testing, it remains critical to ensure that implementation of testing is based on evidence. Currently, there is insufficient evidence to recommend genetic testing for BRCA1/2 alone or in combination with multi-gene panels for all breast cancer patients.... Ideally, professional societies should work together to weigh data, formulate and harmonize evidence-based recommendations, and seek to reduce barriers to care...Moreover...the implementation of precision medicine approaches across oncology must also consider a means by which the promise of genetic testing for inherited cancer predisposition may be realized by all populations, regardless of race, ethnicity and ability to pay."

PHOENIX - Women with bacterial vaginosis exhibit elevated levels of the pro-inflammatory protein, IL-36y, according to a new collaborative study led by the University of Arizona College of Medicine-Phoenix.

Bacterial vaginosis (BV) is the most common bacterial infection in females, affecting more than 21 million U.S. women. BV is a complicated disease to study and understand, because it involves multiple, complex infectious agents. Having BV makes women more susceptible to sexually transmitted infections and other diseases, according to the Centers for Disease Control and Prevention (CDC).

Melissa Herbst-Kralovetz, PhD, an associate professor in the Department of Basic Medical Sciences at the College of Medicine-Phoenix, led the study with Emory University and the CDC. The group analyzed cervicovaginal epithelial cells collected from women with and without bacterial vaginosis. The study, published in October in the Journal of Infectious Diseases, included a team of UArizona College of Medicine - Phoenix investigators, including Pawel Laniewski, PhD, a research scientist, and Jameson Gardner, a graduate research student, both members of Dr. Herbst-Kralovetz's lab.

"These new findings, coupled with our other recent reports, are incredibly exciting as we build our understanding of this novel cytokine in terms of health and disease in the genital tract," Dr. Herbst-Kralovetz said. In this study, we learned that this novel protein is elevated in the most common vaginal disorder -- BV, and may be playing a key role in susceptibility to other diseases."

"BV is a type of vaginal infection caused by the overgrowth of diverse vaginal anaerobes bacteria that require no oxygen to survive or grow," Dr. Laniewski said. "The cause and manifestation of this common disorder still remains controversial."

Researchers profiled the microbiome in women with and without BV and determined if the novel cytokine (IL-36y) was elevated in women with BV. They then selected several bacteria highly associated with BV and prevalent in clinical studies to infect in a human 3D cervical epithelial cell model, which allowed them to use a reductionist approach to better understand the potential contributions of specific bacteria to changes in immune activity, such as measuring IL-36y levels. A reductionist approach starts from the simplest level and works upward in complexity, with the idea that isolated molecules, or in this case bacteria, have the power to provide understanding of the entire system.

"We found that infection with BV-associated bacteria induced IL-36y in a species-specific manner, and that infection with a polymicrobial mixture of the BV-associated bacteria induced IL-36y at a level greater than infection with any single bacterial species alone," Gardner said.

Dr. Laniewski said the study brings researchers "closer to better understanding how different microbes commonly found in women with BV contribute to the activation of specific components of our immune system, which can relate to disease incidence and recurrence."

The laboratory of Dr. Herbst-Kralovetz has shown that IL-36y is an important regulator of inflammation in the female reproductive tract. In addition to this study, researchers investigated the role of IL-36y in the immune response to the herpes infection. They demonstrated that IL-36y is elevated in cervical cancer. Collectively, they hypothesize this research can have broad implications with other bacterial and viral sexually transmitted infections and gynecologic diseases, including cancer.

Researchers say they don't necessarily know the role IL-36y may play in these diseases, but many of them cause, or are driven by and exacerbated by, the inflammatory response. Therefore, IL-36y could be an important mediator of the response to disease.

"This is just the beginning and these data further highlight this emerging cytokine (IL-36y) as a key player in the female reproductive tract and women's health," Dr. Herbst-Kralovetz said.

Institutional investors tend to put their money largely in public companies, persuaded that market discipline makes their accounts more reliable than private ones' and most financial literature confirms their beliefs.

A new study by scholars from University of Bolzano, Bocconi University, and Stern School of Business concludes on the contrary that, if you circumscribe the comparison to public and private companies with similar organizational structures, private firms display a higher accounting (earnings) quality.

«Our result implies that investors would better raise the share of private companies in their portfolios», Bocconi University's Antonio Marra says.

In considering a sample of 397,386 firm-year observations spanning 2005-2014 in 11 European countries (Belgium, Denmark, Finland, France, Germany, Italy, the Netherlands, Norway, Spain, Sweden, and the UK), the scholars note that all the public companies are business groups, while more than two thirds of the private companies are standalone firms. While, in standalone firms, individual financial statements are used for both tax and financial reporting, business groups' consolidated statements are used only for financial reporting, implying that standalone firms have an incentive to underreport earnings in order to save taxes and business groups don't. Among private companies, thus, standalone firms' earnings quality results lower than business groups'.

Less expected is the second result: when comparing only business groups, private companies display more reliable accounts, i.e. their accruals valuation (the valuation of non-cash-based quantities) is more in line with international accounting standards.

Public companies, the authors explain, have a strong incentive to over report earnings to improve their short-term market performance and in the European Union this incentive outweighs market discipline in determining earnings quality.

A notable exception to the rule is the UK, where public companies exhibit more reliable accounts than private ones. «The UK market is the most developed in Europe», Prof. Marra comments, «with the best protection for investors. When rules are effectively enforced, earnings quality improves».

Ancient air samples from one of Antarctica's snowiest ice core sites may add a new molecule to the record of changes to Earth's atmosphere over the past century and a half, since the Industrial Revolution began burning fossil fuels on a massive scale.

While carbon dioxide and methane are well known, researchers at the University of Washington and the University of Rochester are part of a team working to trace a much rarer gas, present at less than one in a trillion molecules. Though rare, the atmospheric detergent known as hydroxyl can scrub the atmosphere and determine the fate of more plentiful gases that affect Earth's climate.

An Antarctic field campaign last winter led by the U.S. and Australia has successfully extracted some of the largest samples of air dating from the 1870s until today. These samples are a first step to learning the changes in hydroxyl concentration over the past 150 years. Early results from the fieldwork were shared this week at the American Geophysical Union's annual fall meeting in San Francisco.

"It's probably the most extreme atmospheric chemistry you can do from ice core samples, and the logistics were also extreme," said Peter Neff, a postdoctoral researcher with dual appointments at the UW and at the University of Rochester.

But the months the team spent camped on the ice at the snowy Law Dome site paid off.

"This is, to my knowledge, the largest air sample from the 1870s that anyone's ever gotten," Neff said. His 10 weeks camped on the ice included minus-20 degrees Fahrenheit temperatures and several snowstorms, some of which he shared from Antarctica via Twitter.

Air from deeper ice cores drilled in Antarctica and Greenland has provided a record of carbon dioxide and methane, two greenhouse gases, going back thousands of years. While carbon dioxide has a lifetime of decades to centuries, an even more potent gas, methane, has a lifetime of just nine or 10 years.

Pinpointing the exact lifetime of methane, and how it has changed over the years, depends on the concentration of hydroxyl. That number is important for the global climate models used to study past and future climate.

To trace the history of hydroxyl, a fleeting molecule with a lifetime of less than a millionth of a second, a field campaign in late 2018 and early 2019 drilled ice to study this very reactive gas by examining its slightly more plentiful companion, carbon with 14 neutrons bonded to an oxygen atom, or "carbon-14 monoxide," which is chemically destroyed by hydroxyl and so tracks hydroxyl's concentrations.

Researchers get the carbon-14 monoxide gas from bubbles in the ice that form when snow is compressed.

"The special thing about glacier ice is that it always has these air bubbles," Neff said. "Any glacier in the world is going to have that bubbly texture, because it started as a pile of six-fingered snowflakes, and between those fingers is air."

One or several decades after hitting the ground, bubbles become completely sealed off from their surroundings due to compression under layers of snow. The heavy snow accumulation at Law Dome means plenty of air bubbles per year, and provides a thick enough shield to protect the carbon-14 monoxide from solar radiation.

The international team extracted about two dozen 3-foot-long sections of ice per day, then put the tubes of ice in a snow cave to protect them from cosmic rays that are stronger near the poles. Those rays can zap other molecules and distort the historic record.

"Once the samples are at the surface, they're hot potatoes," Neff said.

The day after extracting a core, the team would clean the ice and place it in a device of Neff and his University of Rochester postdoctoral supervisor Vasilii Petrenko's design: a 335-liter vacuum chamber in a warm bath to melt the ice and process the samples at their source, to avoid contamination and collect the biggest air samples.

"A single sample size was about 400 or 500 kilograms of ice, about the same weight as a grand piano, to get enough of that carbon-14 monoxide molecule," Neff said. "At the field camp we turned 500 kilos of ice into one 50-liter canister of air."

The team retrieved 20 barrel-shaped canisters of air from various time periods.

Analysis over the coming months will aim to produce a concentration curve for carbon-14 monoxide and hydroxyl over the decades, similar to the now-famous curves for carbon dioxide and methane. The curves show how gas concentrations have changed in the atmosphere since the industrial era.

Throughout the effort, Neff has also explored more lighthearted combinations of ice and air. During a trip in early 2016 to prepare for this effort, Neff did an unofficial experiment that went viral on social media when he posted it in February 2018. The video captures the sound a piece of ice makes when dropped down the tunnel created by an ice core drill.

He shared more photos and videos during this past winter's expedition to Antarctica, sometimes within hours of returning from a remote camp to an internet-connected research station.

"It's great to be able to share something about Antarctica, from Antarctica," Neff said. "It's a way that we as geoscientists can share with people the work that they help to support."

In an era when digital technology allows people to stay connected to work, friends and commerce 24/7, life can feel overly busy for many people and time is often considered a scarce resource.

The way people track the passage of time may seem somewhat arbitrary, but findings from new study suggest that when people sense that the valuable resource of time is running out to take advantage of opportunities--such as flash sales, online payment windows, video
games or online movies--their desire to consume high-calorie foods increases. In other words, if time in shown moving downwards, such as 60...59...58...57...seconds remaining, then consumers sense an impending exhaustion of a resource, and this triggers a desire to compensate for this deficiency by consuming a different resource: calories. The study abstract is available online in the Journal of Consumer Psychology.

Researchers from the Indian Institutes of Management Udaipur/Indore discovered this pattern in one study in which participants were asked to cross out the letter "e" in a passage while a timer counted either from 1 second to 60 seconds, or from 60 to 1. After this task, the participants indicated their likelihood of purchasing chocolate cake or fruit salad. The results showed that participants preferred the high-calorie chocolate cake when time was ticking down, but this was not the case when time was ticking up.

"Our research highlights that the common and innocuous practice of timekeeping can produce unwanted and undesirable consequences in the domain of calorie consumption," according to study author Ankur Kapoor, an assistant professor in the marketing department at the Indian Institute of Management Udaipur.

Then the researchers explored whether they could change this pattern in another experiment in which participants were asked to complete a word search puzzle. One group saw the timer counting down the seconds, while the other group saw the number of elapsed seconds. Then half the participants in each group were asked to remember instances when they felt like they had sufficient resources, while the other half recalled mundane, everyday events in their lives.

Finally, all the participants were invited to take candies as a token of thanks for their participation. The participants who were exposed to the downward time took more candy than those who saw time moving upward--but only when they recalled mundane events. The effect was not found when people recalled an abundance of resources.

Although this study focused on how the direction of time keeping can influence food choices, the findings suggest that consumers who see time counting down may experience other consequences. People who feel that resources are deficient may become less open to taking risks or participating in pro-social behaviors like volunteering or donating resources. When time is viewed as a resource, downward time-keeping devices may also create a sense of artificial urgency that could affect an individual's attitude in other situations, like meals and conversations.

The investigators hope this study will spur further research to explore other implications of their findings, such as the psychological effects of monitoring other finite resources, such as money left in pre-paid accounts or battery indicators on smartphones.

"Today, there is an increased ability to monitor things like time, health, sleep and food," according to the authors. "We hope that this research provides initial insights into the subtle effects of direction of resource monitoring,"

A model that uses genetic markers to accurately estimate the lifespans of different vertebrate species is presented in a study in Scientific Reports this week. The 'lifespan clock' screens 42 selected genes for CpG sites, short pieces of DNA whose density is correlated with lifespan, to predict how long members of a given vertebrate species may live.

Maximum lifespan for a species is difficult to define and can differ greatly between species. Previous research has suggested that it is controlled by genes but so far, no gene variants have been found that account for these differences.

To build their model, Benjamin Mayne and colleagues used reference genomes of 252 vertebrate species with known lifespans to identify 42 genes that may be predictive of lifespan. The authors found that CpG density in the identified genes is highly predictive of lifespan in vertebrates, including extinct species.

Using the genome of the African elephant and its average lifespan of 65 years as a reference, the authors used their model to estimate that both the woolly mammoth and the straight-tusked elephant had a lifespan of 60 years. Using the genomes of modern and early humans and chimpanzees as references resulted in estimates for the lifespans of Denisovans and Neanderthals of around 38 years. The authors also showed that their model was able to estimate the lifespans of long-lived species such as the Pinta Island Tortoise and the bowhead whale, which can be challenging because these species often outlive their observers.

The findings may inform research into the ecology and evolution of living and extinct species, the protection of threatened species, and sustainable fishing, the authors suggest.