bluuebunny/crossref_metadata_2025 huggingface dataset:
Resilient Aspirants: Women's Candidacies and Election in Times of COVID-19
Authors: Gatto Malu A. C. , Thome Debora
Published: July 2020

The COVID-19 pandemic has gendered implications for women's time and resources. The use of informal institutions that pose obstacles to women's electoral viability may also be particularly consequential at a time of rapid change, when election dates and procedures are being amended because of health concerns. Together, these dynamics suggest that the COVID-19 pandemic may impact women's electoral participation, support, and viability in meaningful ways. The November 2020 Brazilian municipal elections provide an opportunity to explore this. Employing data from an original survey of eligible individuals and aspirant candidates, we find that the main obstacle to women's representation is not personal political ambition or efforts but women's perceptions of their access to support for their candidacies. In the face of greater challenges, resilient aspirants are choosing to work harder to compensate for potential losses in campaign support and funds.
Re-adjustments for MOM calculations of microstrip and stripline power dissipation
Authors: Huang Frederick
Published: July 2020

Microstrip and stripline losses in Method of Moments (MOM) calculations have an error arising from the large current density at the strip edges, characterized by an integration limit (W/2-d) in the equation for current density in thin strips (width W), where d is a fitting parameter. It depends primarily on the width of the MOM subsection on the edge of the strip. By comparing with the integration limit (W/2-Δ) for an actual strip with finite thickness, a correction factor is estimated. The equations incorporating d are confirmed by comparing with MOM calculations of isolated stripline, uniformly spaced parallel strips, striplines and microstrips close to ground planes, and with a strip in a uniform, externally applied magnetic field. The results are also consistent with measurements with copper. This makes the accuracy of the loss estimates commensurate with the excellence of the other aspects of MOM simulations.
Acute Stress Improves Concentration Performance
Authors: Degroote Cathy , Schwaninger Adrian , Heimgartner Nadja , Hedinger Patrik , Ehlert Ulrike , Wirtz Petra H.
Published: July 2020

Abstract. Acute stress can have both detrimental and beneficial effects on cognitive processing, but effects on concentration performance remain unclear. Here, we investigate the effects of acute psychosocial stress on concentration performance and possible underlying physiological and psychological mechanisms. The study sample comprised 47 healthy male participants who were randomly assigned either to a psychosocial stress situation (Trier Social Stress Test) or a neutral control task. Concentration performance was assessed using the d2 Test of Attention before and 30 min after the stress or control task. Salivary cortisol and alpha-amylase were repeatedly measured before and up to 1 hr after stress. We repeatedly assessed state anxiety using the State-Trait Anxiety Inventory and anticipatory cognitive stress appraisal using the Primary Appraisal Secondary Appraisal questionnaire. The stress group showed a significantly stronger improvement of concentration performance compared to the control group ( p = .042). Concentration performance improvement was predicted by increased state anxiety ( p = .020) and lower cortisol (stress) changes ( p = .043). Neither changes in alpha-amylase nor cognitive stress appraisal did relate to concentration performance. Our results show improved concentration performance after acute psychosocial stress induction that was predicted by higher state anxiety increases and lower cortisol increases. This points to a potential modulating role of specific psycho-emotional and physiological factors with opposite effects.
How Do Stress and Social Closeness Impact Prosocial Behavior?
Authors: Passarelli Thomas O. , Buchanan Tony W.
Published: July 2020

Abstract. Factors such as time pressure and psychosocial stress may increase or decrease prosocial behavior depending on a number of factors. One factor that consistently positively impacts prosocial behavior is relationship status: Prosocial behavior is more likely toward kin than toward strangers. The interactions among stress, kin relationships, and prosocial behavior were examined in two separate experiments. In Study 1, 79 university students were asked to decide how much money to donate to family members, friends, or strangers, either under time pressure or with no time constraints. Participants donated more to close kin and friends than to strangers, but time pressure did not increase prosocial behavior. In Study 2, 94 university students completed the Trier Social Stress Test for Groups (TSST-G) or a control task, followed by a similar donation task as used in Study 1. Participants donated more to close kin and friends than to strangers, but stress did not influence donation amounts. These results do not support the hypothesis that stress due to time pressure or psychosocial factors increases prosocial behavior.
The Opposite of Stress
Authors: Meier Maria , Unternaehrer Eva , Schorpp Sabine M. , Wenzel Maya , Benz Annika , Bentele Ulrike U. , Dimitroff Stephanie J. , Denk Bernadette , Prüssner Jens C.
Published: July 2020

Abstract. Cognition is affected by psychophysiological states. While the influence of stress on cognition has been investigated intensively, less studies have addressed how the opposite of stress, a state of relaxation, affects cognition. We investigated whether the extent of parasympathetic activation is positively related to divergent thinking. Sixty healthy female participants were randomly allocated to a standardized vagus nerve massage ( n = 19), a standardized soft shoulder massage ( n = 22), or a resting control group ( n = 19). Subsequently, participants completed the Alternative Uses Test (AUT), a measure of divergent thinking. Respiratory sinus arrhythmia (RSA), a vagally mediated heart rate variability component, was monitored throughout the experiment. The area under the curve with respect to the increase was calculated for RSA trajectories as an indicator of vagal tone during the relaxing intervention. Regressions tested the effect of vagal tone on AUT outcomes. We found an association between vagal tone and subsequent AUT outcomes. Yet, this association was no longer significant when controlling for the effect of the creative potential of an individual, which was strongly related to AUT outcomes. Being exploratory, we found a positive association between creative potential and vagal tone. These results imply that creative potential might be related to the capacity to relax.
Working Memory Performance Under Stress
Authors: Luers Petra , Schloeffel Malgorzata , Prüssner Jens C.
Published: July 2020

Abstract. Acute stress and chronic stress change the physiology and function of the individual. As one facet, stress and its neuroendocrine correlates – with glucocorticoids in particular – modulate memory in a concerted action. With respect to working memory, impairing effects of acute stress and increased levels of glucocorticoids could be expected, but empirical evidence on moderating effects of cortisol on working memory is ambiguous in human studies. In the current study, we thus aimed to investigate cortisol stress responses and memory performance. Older men and women (32 men, 43 women, aged 61–67 years) underwent the Trier Social Stress Test (TSST) and performed the 2-back task before and after exposure to acute stress. In line with theoretical assumptions, we found that higher cortisol stress responses led to a decline of working memory performance in men. However, the opposite was evident for women, who appeared to benefit from higher stress responses. This effect was evident for accuracy, but not for reaction time. In conclusion, cortisol might mediate working memory alterations with stress in a sex-specific manner in older people. Possible mechanisms and causes for these sex differences put a focus on endocrine changes in the aging population that might lead to differential effects across the lifespan.
Association Between Work‐Related Hyperthermia Emergency Department Visits and Ambient Heat in Five Southeastern States, 2010–2012—A Case‐Crossover Study
Authors: Shire Jeffrey , Vaidyanathan Ambarish , Lackovic Michelle , Bunn Terry
Published: July 2020

The objective of this study is to assess ambient temperatures' and extreme heat events' contribution to work‐related emergency department (ED) visits for hyperthermia in the southeastern United States to inform prevention. Through a collaborative network and established data framework, work‐related ED hyperthermia visits in five participating southeastern U.S. states were analyzed using a time stratified case‐crossover design. For exposure metrics, day‐ and location‐specific measures of ambient temperatures and county‐specific identification of extreme heat events were used. From 2010 to 2012, 5,017 work‐related hyperthermia ED visits were seen; 2,298 (~46%) of these visits occurred on days when the daily maximum heat index was at temperatures the Occupational Safety and Health Administration designates as having “lower” or “moderate” heat risk. A 14% increase in risk of ED visit was seen for a 1°F increase in average daily mean temperature, modeled as linear predictor across all temperatures. A 54% increase in risk was seen for work‐related hyperthermia ED visits during extreme heat events (two or more consecutive days of unusually high temperatures) when controlling for average daily mean temperature. Despite ambient heat being a well‐known risk to workers' health, this study's findings indicate ambient heat contributed to work‐related ED hyperthermia visits in these five states. Used alone, existing OSHA heat‐risk levels for ambient temperatures did not appear to successfully communicate workers' risk for hyperthermia in this study. Findings should inform future heat‐alert communications and policies, heat prevention efforts, and heat‐illness prevention research for workers in the southeastern United States.
Global Fully Distributed Parameter Regionalization Based on Observed Streamflow From 4,229 Headwater Catchments
Authors: Beck Hylke E. , Pan Ming , Lin Peirong , Seibert Jan , van Dijk Albert I. J. M. , Wood Eric F.
Published: July 2020

All hydrological models need to be calibrated to obtain satisfactory streamflow simulations. Here we present a novel parameter regionalization approach that involves the optimization of transfer equations linking model parameters to climate and landscape characteristics. The optimization was performed in a fully spatially distributed fashion at high resolution (0.05°), instead of at lumped catchment scale, using an unprecedented database of daily observed streamflow from 4,229 headwater catchments (<5,000 km2) worldwide. The optimized equations were subsequently applied globally to produce parameter maps for the entire land surface including ungauged regions. The approach was evaluated using the Kling‐Gupta efficiency (KGE) and a gridded version of the hydrological model HBV. Tenfold cross validation was used to evaluate the generalizability of the approach and to obtain an ensemble of parameter maps. For the 4,229 independent validation catchments, the regionalized parameters yielded a median KGE of 0.46. The median KGE improvement (relative to uncalibrated parameters) was 0.29, and improvements were obtained for 88% of the independent validation catchments. These scores compare favorably to those from previous large catchment sample studies. The degree of performance improvement due to the regionalized parameters did not depend on climate or topography. Substantial improvements were obtained even for independent validation catchments located far from the catchments used for optimization, underscoring the value of the derived parameters for poorly gauged regions. The regionalized parameters—available via www.gloh2o.org/hbv—should be useful for hydrological applications requiring accurate streamflow simulations.
Transport Patterns, Size Distributions, and Depolarization Characteristics of Dust Particles in East Asia in Spring 2018
Authors: Tian Yu , Pan Xiaole , Wang Zhe , Wang Dawei , Ge Baozhu , Liu Xiaoyong , Zhang Yuting , Liu Hang , Lei Shandong , Yang Ting , Fu Pingqing , Sun Yele , Wang Zifa
Published: July 2020

The long‐range transport of Asian dust and its complex interaction with anthropogenic pollutants have a significant yet poorly quantified effect on the global climate. In this study, dust events were observed based on an optical particle counter with a polarization detection module at an urban site in North China. The temporal variations in the size distribution and morphological changes of dust particles were analyzed. The results demonstrate that the dust events were induced by a deep Siberian low‐pressure anomaly and/or Mongolian cyclone in the low troposphere. The morphology of dust particles, as indicated by the depolarization ratio (δ = s/(s + p), the ratio of the parallel signal to the total backscattering signal), varied significantly at different transport heights. A decreasing tendency was found when dust was trapped within the boundary layer over polluted areas, particularly when the atmospheric loading of pollutants and the relative humidity were high. During a typical polluted dust case, the δ value of mineral dust (Dp = 5 μm) decreased by 39%, as the conditions were stagnant in East China, consistent with the Cloud‐Aerosol LIDAR with Orthogonal Polarization results. The morphological variation was evaluated according to the aspect ratio, presuming that the dust particles were ellipsoidal. The interaction between dust particles and water vapor could lead to an increase of at least 6% in volume when the relative humidity increased up to 90%. An aerosol classification based on δ values and size information could be performed to estimate the contributions of different aerosol types to pollution days. The results should be helpful for evaluating satellite‐borne and ground‐based light detection and ranging data analyses.
Hydrometeor Budget of the Meiyu Frontal Rainstorms Associated With Two Different Atmospheric Circulation Patterns
Authors: Li Chao , Deng Yi , Cui Chunguang , Wang Xiaofang , Dong Xiquan , Jiang Xingwen
Published: July 2020

Characteristics of hydrometeor budget and the microphysical processes responsible for heavy precipitation are studied based on the WRF model simulations of two representative Meiyu frontal rainstorms that are associated with two distinct atmospheric circulation patterns. Case 1 is characterized by the coupling of the Eastward Propagating Mesoscale Vortex (EPMV) and Meiyu front, while Case 2 is dominated by the interaction between the Low‐Level Wind Shear (LLWS) and Meiyu front. The temporal and spatial characteristics of the hydrometeor budget are validated against observations and assimilation products including those obtained during the 2018 Integrative Monsoon Frontal Rainfall Experiment (IMFRE) campaign and discussed in the context of contrasting the precipitation intensification and dissipation stage. Specifically, the ice‐dependent cloud processes, rather than the liquid‐dependent cloud processes, are predominantly responsible for the variation of precipitation. These terms include the deposition from water vapor to the ice phase hydrometeors, the accretion from cloud liquid water to the ice phase hydrometeors in the upper troposphere, and the melting of the ice phase hydrometeors into raindrops in the mid‐lower troposphere. Then three major ice cloud conversion pathways and two minor warm cloud conversion pathways for the formation of raindrops are extracted from the overall microphysical processes active in both Case 1 and Case 2. One of the key findings is that ice‐dependent cloud processes are significantly more active in the case characterized by the coupling of EPMV and Meiyu front, and this difference is at least partly explained by the differences in dynamical and thermodynamic conditions dominated by the circulation patterns.
Hydromechanical Rock Slope Damage During Late Pleistocene and Holocene Glacial Cycles in an Alpine Valley
Authors: Grämiger Lorenz M. , Moore Jeffrey R. , Gischig Valentin S. , Loew Simon , Funk Martin , Limpach Philippe
Published: July 2020

Subglacial water pressures influence groundwater conditions in proximal alpine valley rock slopes, varying with glacier advance and retreat in parallel with changing ice thickness. Fluctuating groundwater pressures in turn increase or reduce effective joint normal stresses, affecting the yield strength of discontinuities. Here we extend simplified assumptions of glacial debuttressing to investigate how glacier loading cycles together with changing groundwater pressures generate rock slope damage and prepare future slope instabilities. Using hydromechanical coupled numerical models closely based on the Aletsch Glacier valley in Switzerland, we simulate Late Pleistocene and Holocene glacier loading cycles including long‐term and annual groundwater fluctuations. Measurements of transient subglacial water pressures from ice boreholes in the Aletsch Glacier ablation area, as well as continuous monitoring of bedrock deformation from permanent Global Navigation Satellite Systems stations, help verify our model assumptions. While purely mechanical glacier loading cycles create only limited rock slope damage in our models, introducing a fluctuating groundwater table generates substantial new fracturing. Superposed annual groundwater cycles increase predicted damage. The cumulative effects are capable of destabilizing the eastern valley flank of our model in toppling‐mode failure, similar to field observations of active landslide geometry and kinematics. We find that hydromechanical fatigue is most effective acting in combination with long‐term loading and unloading of the slope during glacial cycles. Our results demonstrate that hydromechanical stresses associated with glacial cycles are capable of generating substantial rock slope damage and represent a key preparatory factor for paraglacial slope instabilities.
Premature Deaths in Brazil Associated With Long‐Term Exposure to PM2.5 From Amazon Fires Between 2016 and 2019
Authors: Nawaz M. O. , Henze D. K.
Published: July 2020

Amazonian deforestation from slash‐and‐burn practices is a significant contributor to biomass burning within Brazil. Fires emit carbonaceous aerosols that negatively impact human health by increasing fine particulate matter (PM2.5) exposure. These negative effects on health compound the already detrimental climatological and ecological impacts. Despite high biomass burning emissions in Brazil and the international attention drawn by the relaxation of Amazon protections in 2019, little is known about the health impacts from PM2.5 exposure attributable to these fires. We estimate PM2.5‐related premature deaths in Brazil associated with biomass burning, focusing on temporal, interannual, and spatial trends. We find that during the fire season of 2019, 4,966 (2,427, 8,340) premature deaths were attributable to fire emissions making up 10% (5, 17) of all PM2.5‐related premature deaths in Brazil. Between the 2019 and 2018 seasons, fire emissions increased by 1.37 Tg (1.00, 2.18) or 115% (60, 201), which was responsible for an increase in health impacts of 2,109 (965, 3,623) premature deaths or 74% (54, 98). Biomass burning emissions throughout Brazil contribute significantly to premature deaths, with the largest burning events occurring in northwestern Brazil. The impact of fires on PM2.5‐related premature deaths is highest in heavily populated regions despite their fires being 1 to 2 orders of magnitude smaller than the largest burning events. Results from this study characterize the extent to which elevated PM2.5 exposure levels owing to fires affect public health in Brazil and present an additional, public health‐focused, support for increased Amazon protections.
Seismic Velocity Changes Caused by Water Table Fluctuation in the New Madrid Seismic Zone and Mississippi Embayment
Authors: Liu Chunyu , Aslam Khurram , Daub Eric
Published: July 2020

We use cross correlation of the ambient seismic field to estimate seasonal variations of seismic velocity in the Mississippi Embayment and to determine the underlying physical mechanisms. Our main observation is that the δt/t variations correlate primarily with the water table fluctuation, with the largest positive value from May to July and the largest negative value in September/October relative to the annual mean. The δv/v residuals after water level fluctuation correction correlate with air pressure in the short term and follow the trend of temperature in the long term. The δv/v residuals after water level fluctuation and air pressure correction correlate inversely with the wind speed. The correlation coefficients between water table fluctuation and δt/t are independent of the interstation distance and frequency, but high coefficients are observed more often between 0.3 and 1 Hz than between 1 and 2 Hz because high‐frequency coherent signals attenuate faster than low‐frequency ones. The δt/t variations lag behind the water table fluctuation by about 20 days, which suggests that the velocity changes can be attributed to the pore pressure diffusion effect. The seasonal variations of δt/t are azimuthally independent, and a large increase of noise amplitude only introduces a small increase to the δt/t variation. At close distances, the maximum δt/t holds a wide range of values, which is likely related to local structure. At larger distances, velocity variations sample a larger region so that it stabilizes to a more uniform value. We find that the observed changes in wave speed can be explained by a poroelastic model.
Three Years of the Lightning Imaging Sensor Onboard the International Space Station: Expanded Global Coverage and Enhanced Applications
Authors: Blakeslee Richard J. , Lang Timothy J. , Koshak William J. , Buechler Dennis , Gatlin Patrick , Mach Douglas M. , Stano Geoffrey T. , Virts Katrina S. , Walker Thomas Daniel , Cecil Daniel J. , Ellett Will , Goodman Steven J. , Harrison Sherry , Hawkins Donald L. , Heumesser Matthias , Lin Hong , Maskey Manil , Schultz Christopher J. , Stewart Michael , Bateman Monte , Chanrion Olivier , Christian Hugh
Published: July 2020

The Lightning Imaging Sensor (LIS) was launched to the International Space Station (ISS) in February 2017, detecting optical signatures of lightning with storm‐scale horizontal resolution during both day and night. ISS LIS data are available beginning 1 March 2017. Millisecond timing allows detailed intercalibration and validation with other spaceborne and ground‐based lightning sensors. Initial comparisons with those other sensors suggest flash detection efficiency around 60% (diurnal variability of 51–75%), false alarm rate under 5%, timing accuracy better than 2 ms, and horizontal location accuracy around 3 km. The spatially uniform flash detection capability of ISS LIS from low‐Earth orbit allows assessment of spatially varying flash detection efficiency for other sensors and networks, particularly the Geostationary Lightning Mappers. ISS LIS provides research data suitable for investigations of lightning physics, climatology, thunderstorm processes, and atmospheric composition, as well as real‐time lightning data for operational forecasting and aviation weather interests. ISS LIS enables enrichment and extension of the long‐term global climatology of lightning from space and is the only recent platform that extends the global record to higher latitudes (±55°). The global spatial distribution of lightning from ISS LIS is broadly similar to previous data sets, with globally averaged seasonal/annual flash rates about 5–10% lower. This difference is likely due to reduced flash detection efficiency that will be mitigated in future ISS LIS data processing, as well as the shorter ISS LIS period of record. The expected land/ocean contrast in the diurnal variability of global lightning is also observed.
National Travel Assistance Entitlements Are Inaccessible to Whānau Māori
Authors: Masters-Awatere Bridgette , Murphy Sarah , Helmhout Toni Bailey , Flavell Kahurimu , Cormack Donna
Published: July 2020

New Zealand’s National Travel Assistance scheme is intended to provide financial support for people who need to either travel frequently or over long distances for specialist health care treatment. Taking an Indigenous Psychology orientation to “away-from-home” hospital admissions, we broaden the focus beyond an individual’s physical experience of hospitalization to the wider social and political context. Based on our research, we recommend a whānau-centered approach to travel assistance that will offer better coordination and remove factors negatively impacting whānau Māori (Indigenous families in New Zealand) health outcomes and contribute to United Nations Sustainable Development Goal 10 of reducing inequality. Our research is congruent with the community psychology value of “accountability” and the World Health Organisation value of “better health for everyone, everywhere.”
A Qualitative Analysis of Gendered Experiences of Schizophrenia in an Outpatient Psychiatric Hospital in Mexico
Authors: Ponting Carolyn , Delgadillo Desiree , Rivera-Olmedo Noemi , Yarris Kristin E.
Published: July 2020

Individuals living with a major mental illness experience socioemotional impairments, including difficulties achieving gendered social role expectations. In Mexico, though gender roles are dynamic, men remain highly valued for their ability to provide economic security, whereas women are valued for expressions of family nurturance. Though failure to achieve gendered expectations has been associated with stigmatization and family conflict for individuals with schizophrenia, these relationships remain largely unexplored in Mexico. In this article, we examine the impact of gendered social roles for men and women living with a diagnosis of schizophrenia in Mexico. Drawing on qualitative content analysis of semistructured interviews conducted with 19 individuals seeking outpatient services from a psychiatric clinic in Mexico, we explore how gendered expectations and social roles shape understandings of, and responses to, the illness experience of schizophrenia. Underlying themes for men and women with schizophrenia included the following: (a) Role Changes and (b) Expected Prognosis. Subthemes within Role Changes revealed that participants encountered difficulties with employment, changes in family roles and relationships, and familial stigma following their diagnosis. Subthemes within Expected Prognosis revealed that participants’ symptoms made it difficult to start a family, and that generally, those interviewed believed women had an easier time coping with their illness. Our findings suggest that assessing gendered expectations provides a more nuanced understanding of an individual’s lived experience of schizophrenia and may be leveraged to tailor clinical goals most important to a client’s social function.
RNA editing contributes to epitranscriptome diversity in chronic lymphocytic leukemia
Authors: Gassner Franz J. , Zaborsky Nadja , Buchumenski Ilana , Levanon Erez Y. , Gatterbauer Matthias , Schubert Maria , Rauscher Stefanie , Hebenstreit Daniel , Nadeu Ferran , Campo Elias , Egle Alexander , Greil Richard , Geisberger Roland
Published: July 2020

RNA editing—primarily conversion of adenosine to inosine (A > I)—is a widespread posttranscriptional mechanism, mediated by Adenosine Deaminases acting on RNA (ADAR) enzymes to alter the RNA sequence of primary transcripts. Hence, in addition to somatic mutations and alternative RNA splicing, RNA editing can be a further source for recoding events. Although RNA editing has been detected in many solid cancers and normal tissue, RNA editing in chronic lymphocytic leukemia (CLL) has not been addressed so far. We determined global RNA editing and recurrent, recoding RNA editing events from matched RNA-sequencing and whole exome sequencing data in CLL samples from 45 untreated patients. RNA editing was verified in a validation cohort of 98 CLL patients and revealed substantially altered RNA editing profiles in CLL compared with normal B cells. We further found that RNA editing patterns were prognostically relevant. Finally, we showed that ADAR knockout decreased steady state viability of MEC1 cells and made them more susceptible to treatment with fludarabine and ibrutinib in vitro. We propose that RNA editing contributes to the pathophysiology of CLL and targeting the RNA editing machinery could be a future strategy to maximize treatment efficacy.
Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results
Authors: Heuser Michael , Palmisiano Neil , Mantzaris Ioannis , Mims Alice , DiNardo Courtney , Silverman Lewis R. , Wang Eunice S. , Fiedler Walter , Baldus Claudia , Schwind Sebastian , Pardee Timothy , Perl Alexander E. , Cai Charles , Kaulfuss Stefan , Lagkadinou Eleni , Rentzsch Christine , Wagner Markus , Wilkinson Gary , Wu Bingyan , Jeffers Michael , Genvresse Isabelle , Krämer Alwin
Published: July 2020

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49–8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9–8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1–7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.
Sex specific effects of “junk-food” diet on calcium permeable AMPA receptors and silent synapses in the nucleus accumbens core
Authors: Alonso-Caraballo Yanaira , Fetterly Tracy L. , Jorgensen Emily T. , Nieto Allison M. , Brown Travis E. , Ferrario Carrie R.
Published: July 2020

CP-AMPARs in the nucleus accumbens (NAc) mediate cue-triggered motivation for food and cocaine. In addition, increases in NAc CP-AMPAR expression and function can be induced by cocaine or sugary, fatty junk-foods. However, the precise nature of these alterations and the degree to which they rely on the same underlying mechanisms is not well understood. This has important implications for understanding adaptive vs. maladaptive plasticity that drives food- and drug-seeking behaviors. Furthermore, effects of junk-foods on glutamatergic plasticity in females are unknown. Here, we use a combination of protein biochemistry and whole-cell patch clamping to determine effects of diet manipulation on glutamatergic plasticity within the NAc of males and females. We found that junk-food consumption increases silent synapses and subsequently increases CP-AMPAR levels in males in the NAc of male rats. In addition, a brief period of junk-food deprivation is needed for the synaptic insertion of CP-AMPARs and the maturation of silent synapses in males. In contrast, junk-food did not induce AMPAR plasticity in females but may instead alter NMDAR-mediated transmission. Thus, these studies reveal sex differences in the effects of junk-food on NAc synaptic plasticity. In addition, they provide novel insights into how essential food rewards alter NAc function.
Psychiatric face of COVID-19
Authors: Steardo Luca , Steardo Luca , Verkhratsky Alexei
Published: July 2020

The Coronavirus Disease 2019 (COVID-19) represents a severe multiorgan pathology which, besides cardio-respiratory manifestations, affects the function of the central nervous system (CNS). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similarly to other coronaviruses demonstrate neurotropism; the viral infection of the brain stem may complicate the course of the disease through damaging central cardio-respiratory control. The systemic inflammation as well as neuroinflammatory changes are associated with massive increase of the brain pro-inflammatory molecules, neuroglial reactivity, altered neurochemical landscape and pathological remodelling of neuronal networks. These organic changes, emerging in concert with environmental stress caused by experiences of intensive therapy wards, pandemic fears and social restrictions, promote neuropsychiatric pathologies including major depressive disorder, bipolar disorder (BD), various psychoses, obsessive-compulsive disorder and post-traumatic stress disorder. The neuropsychiatric sequelae of COVID-19 represent serious clinical challenge that has to be considered for future complex therapies.
Acid-suppressive medications and risk of colorectal cancer: results from three large prospective cohort studies
Authors: Babic Ana , Zhang Xuehong , Morales-Oyarvide Vicente , Yuan Chen , Khalaf Natalia , Khalili Hamed , Lochhead Paul , Chan Andrew T. , Ogino Shuji , Wolpin Brian M. , Wu Kana , Fuchs Charles S. , Giovannucci Edward L. , Stampfer Meir J. , Ng Kimmie
Published: July 2020

Background

Despite several plausible biological mechanisms linking proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) with colorectal tumorigenesis, their association with risk of colorectal cancer (CRC) has not been adequately assessed in prospective epidemiological studies.

Methods

We evaluated the association of acid-suppressive medication use with CRC risk among 175,871 (PPI) and 208,831 (H2RA) participants from three large prospective cohort studies. Medication use was assessed at baseline and updated biennially. The association was evaluated using multivariate Cox proportional hazards regression models.

Results

There was no significant association between baseline PPI use (hazard ratio (HR) = 0.89, 95% confidence interval (CI), 0.71–1.12) or PPI use after a lag of 8–10 years (HR = 1.12, 95% CI, 0.78–1.59) with CRC risk. We observed no significant association between H2RA use after a lag of 8–10 years and CRC risk (HR = 1.02, 95% CI, 0.81–1.28), while risk was lower for participants with baseline H2RA use (HR = 0.76, 95% CI, 0.60–0.95). Duration of PPI use or H2RA use was not associated with CRC risk (P-trend = 0.21 and 0.95, respectively).

Conclusions

Among participants from three large prospective cohorts, use of PPI or H2RA was not associated with higher risk of colorectal cancer.
Synaptic RTP801 contributes to motor-learning dysfunction in Huntington’s disease
Authors: Martín-Flores Núria , Pérez-Sisqués Leticia , Creus-Muncunill Jordi , Masana Mercè , Ginés Sílvia , Alberch Jordi , Pérez-Navarro Esther , Malagelada Cristina
Published: July 2020

RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington’s disease (HD) patients’ putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Moreover, the protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Finally, striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor-learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.
Activating PIK3CA mutation promotes adipogenesis of adipose-derived stem cells in macrodactyly via up-regulation of E2F1
Authors: Sun Bin , Jiang Yongkang , Cui Hengqing , Fang Xia , Han Gang , Dai Xinyi , Zhou Shengbo , Mao Hailei , Wang Bin
Published: July 2020

Macrodactyly is a congenital malformation characterized by enlargement of bone and soft tissues in limbs, typically with excessive accumulation of adipose tissues. Although gain-of-function mutation of PIK3CA has been identified in macrodactyly, the mechanism of PIK3CA mutation in adipose accumulation is poorly understood. In this study, we found that adipocytes from macrodactyly were more hypertrophic than those observed in polydactyly. PIK3CA (H1047R) activating mutation and enhanced activity of PI3K/AKT pathway were detected in macrodactylous adipose-derived stem cells (Mac-ADSCs). Compared to polydactyly-derived ADSCs (Pol-ADSCs), Mac-ADSCs had higher potential in adipogenic differentiation. Knockdown of PIK3CA or inhibition by BYL-719, a potent inhibitor of PIK3CA, impaired adipogenesis of Mac-ADSCs in vitro. In vivo study, either transient treatment of ADSCs or intragastrical gavage with BYL-719 inhibited the adipose formation in patient-derived xenograft (PDX). Furthermore, RNA-seq revealed that E2F1 was up-regulated in Mac-ADSCs and its knockdown blocked the PIK3CA-promoted adipogenesis. Our findings demonstrated that PIK3CA activating mutation promoted adipogenesis of ADSCs in macrodactyly, and that this effect was exerted by the up-regulation of E2F1. This study revealed a possible mechanism for adipose accumulation in macrodactyly and suggested BYL-719 as a potential therapeutic agent for macrodactyly treatment.
Hybrid Fourier-domain mode-locked laser for ultra-wideband linearly chirped microwave waveform generation
Authors: Tang Jian , Zhu Beibei , Zhang Weifeng , Li Ming , Pan Shilong , Yao Jianping
Published: July 2020

We show the generation of a tunable linearly chirped microwave waveform (LCMW) with an ultra-large time-bandwidth product (TBWP) based on a hybrid Fourier-domain mode-locked (FDML) laser. The key device in the hybrid FDML laser is a silicon photonic integrated micro-disk resonator (MDR) which functions as an optical bandpass filter, to have strong wavelength selectivity and fast frequency tunability. By incorporating the integrated MDR in the fiber-based ring cavity to perform frequency-domain mode locking, an FDML laser is realized and a broadband frequency-chirped optical pulse is generated. By beating the frequency-chirped optical pulse with an optical carrier from a laser diode (LD) at a photodetector (PD), an LCMW is generated. The bandwidth of the LCMW is over 50 GHz and the temporal duration is over 30 µs, with an ultra-large TBWP of 1.5 × 106. Thanks to the strong tunability of the MDR in the FDML laser, the generated LCMW is fully tunable in terms of bandwidth, temporal duration, chirp rate, and center frequency.
Targeting QKI-7 in vivo restores endothelial cell function in diabetes
Authors: Yang Chunbo , Eleftheriadou Magdalini , Kelaini Sophia , Morrison Thomas , González Marta Vilà , Caines Rachel , Edwards Nicola , Yacoub Andrew , Edgar Kevin , Moez Arya , Ivetic Aleksandar , Zampetaki Anna , Zeng Lingfang , Wilkinson Fiona L. , Lois Noemi , Stitt Alan W. , Grieve David J. , Margariti Andriana
Published: July 2020

Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications.
Emerging heterogeneous compartments by viruses in single bacterial cells
Authors: Trinh Jimmy T. , Shao Qiuyan , Guan Jingwen , Zeng Lanying
Published: July 2020

Spatial organization of biological processes allows for variability in molecular outcomes and coordinated development. Here, we investigate how organization underpins phage lambda development and decision-making by characterizing viral components and processes in subcellular space. We use live-cell and in situ fluorescence imaging at the single-molecule level to examine lambda DNA replication, transcription, virion assembly, and resource recruitment in single-cell infections, uniting key processes of the infection cycle into a coherent model of phage development encompassing space and time. We find that different viral DNAs establish separate subcellular compartments within cells, which sustains heterogeneous viral development in single cells. These individual phage compartments are physically separated by the E. coli nucleoid. Our results provide mechanistic details describing how separate viruses develop heterogeneously to resemble single-cell phenotypes.
Escape from nonsense-mediated decay associates with anti-tumor immunogenicity
Authors: Litchfield Kevin , Reading James L. , Lim Emilia L. , Xu Hang , Liu Po , Al-Bakir Maise , Wong Yien Ning Sophia , Rowan Andrew , Funt Samuel A. , Merghoub Taha , Perkins David , Lauss Martin , Svane Inge Marie , Jönsson Göran , Herrero Javier , Larkin James , Quezada Sergio A. , Hellmann Matthew D. , Turajlic Samra , Swanton Charles
Published: July 2020

Frameshift insertion/deletions (fs-indels) are an infrequent but highly immunogenic mutation subtype. Although fs-indels are degraded through the nonsense-mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and elicit anti-tumor immune responses. Using allele-specific expression analysis, expressed fs-indels are enriched in genomic positions predicted to escape NMD, and associated with higher protein expression, consistent with degradation escape (NMD-escape). Across four independent melanoma cohorts, NMD-escape mutations are significantly associated with clinical-benefit to checkpoint inhibitor (CPI) therapy (Pmeta = 0.0039). NMD-escape mutations are additionally found to associate with clinical-benefit in the low-TMB setting. Furthermore, in an adoptive cell therapy treated melanoma cohort, NMD-escape mutation count is the most significant biomarker associated with clinical-benefit. Analysis of functional T cell reactivity screens from personalized vaccine studies shows direct evidence of fs-indel derived neoantigens eliciting immune response, particularly those with highly elongated neo open reading frames. NMD-escape fs-indels represent an attractive target for biomarker optimisation and immunotherapy design.
Collective cell mechanics of epithelial shells with organoid-like morphologies
Authors: Rozman Jan , Krajnc Matej , Ziherl Primož
Published: July 2020

The study of organoids, artificially grown cell aggregates with the functionality and small-scale anatomy of real organs, is one of the most active areas of research in biology and biophysics, yet the basic physical origins of their different morphologies remain poorly understood. Here, we propose a mechanistic theory of epithelial shells which resemble small-organoid morphologies. Using a 3D surface tension-based vertex model, we reproduce the characteristic shapes from branched and budded to invaginated structures. We find that the formation of branched morphologies relies strongly on junctional activity, enabling temporary aggregations of topological defects in cell packing. To elucidate our numerical results, we develop an effective elasticity theory, which allows one to estimate the apico-basal polarity from the tissue-scale modulation of cell height. Our work provides a generic interpretation of the observed epithelial shell morphologies, highlighting the role of physical factors such as differential surface tension, cell rearrangements, and tissue growth.
Structural signatures in EPR3 define a unique class of plant carbohydrate receptors
Authors: Wong Jaslyn E. M. M. , Gysel Kira , Birkefeldt Thea G. , Vinther Maria , Muszyński Artur , Azadi Parastoo , Laursen Nick S. , Sullivan John T. , Ronson Clive W. , Stougaard Jens , Andersen Kasper R.
Published: July 2020

Receptor-mediated perception of surface-exposed carbohydrates like lipo- and exo-polysaccharides (EPS) is important for non-self recognition and responses to microbial associated molecular patterns in mammals and plants. In legumes, EPS are monitored and can either block or promote symbiosis with rhizobia depending on their molecular composition. To establish a deeper understanding of receptors involved in EPS recognition, we determined the structure of the Lotus japonicus (Lotus) exopolysaccharide receptor 3 (EPR3) ectodomain. EPR3 forms a compact structure built of three putative carbohydrate-binding modules (M1, M2 and LysM3). M1 and M2 have unique βαββ and βαβ folds that have not previously been observed in carbohydrate binding proteins, while LysM3 has a canonical βααβ fold. We demonstrate that this configuration is a structural signature for a ubiquitous class of receptors in the plant kingdom. We show that EPR3 is promiscuous, suggesting that plants can monitor complex microbial communities though this class of receptors.
Cosmogenic exposure dating reveals limited long-term variability in erosion of a rocky coastline
Authors: Swirad Zuzanna M. , Rosser Nick J. , Brain Matthew J. , Rood Dylan H. , Hurst Martin D. , Wilcken Klaus M. , Barlow John
Published: July 2020

Predicted sea-level rise and increased storminess are anticipated to lead to increases in coastal erosion. However, assessing if and how rocky coasts will respond to changes in marine conditions is difficult due to current limitations of monitoring and modelling. Here, we measured cosmogenic 10Be concentrations across a sandstone shore platform in North Yorkshire, UK, to model the changes in coastal erosion within the last 7 kyr and for the first time quantify the relative long-term erosive contribution of landward cliff retreat, and down-wearing and stripping of rock from the shore platform. The results suggest that the cliff has been retreating at a steady rate of 4.5 ± 0.63 cm yr−1, whilst maintaining a similar profile form. Our results imply a lack of a direct relationship between relative sea level over centennial to millennial timescales and the erosion response of the coast, highlighting a need to more fully characterise the spatial variability in, and controls on, rocky coast erosion under changing conditions.