bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional and chromatin-based partitioning mechanisms uncouple protein scaling from cell size
Authors: Swaffer Matthew P. , Chandler-Brown Devon , Kim Jacob , Langhinrichs Maurice , Marinov Georgi , Greenleaf William , Kundaje Anshul , Schmoller Kurt M. , Skotheim Jan M.
Published: August 2020

Biosynthesis scales with cell size such that protein concentrations generally remain constant as cells grow. As an exception, synthesis of the cell-cycle inhibitor Whi5 ‘sub-scales’ with cell size so that its concentration is lower in larger cells to promote cell-cycle entry. Here, we find that a transcriptional control uncouples Whi5 synthesis from cell size and, screening for similar genes, identify histones as the major class of sub-scaling transcripts besidesWHI5. Histone synthesis is thereby matched to genome content rather than cell size. Such sub-scaling proteins are challenged by asymmetric cell division because proteins are typically partitioned in proportion to new-born cell volume. To avoid this fate, Whi5 uses chromatin-binding to partition similar protein amounts to each new-born cell regardless of cell size. Finally, disrupting both Whi5 synthesis and chromatin-based partitioning compromises G1 size control. Thus, specific transcriptional and partitioning mechanisms determine protein sub-scaling to control cell size.
A comparative analysis of SARS-CoV-2 antivirals in human airway models characterizes 3CLproinhibitor PF-00835231 as a potential new treatment for COVID-19
Authors: de Vries Maren , Mohamed Adil S , Prescott Rachel A , Valero-Jimenez Ana M , Desvignes Ludovic , O’Connor Rebecca , Steppan Claire , Devlin Joseph C , Ivanova Ellie , Herrera Alberto , Schinlever Austin , Loose Paige , Ruggles Kelly , Koralov Sergei B , Anderson Annaliesa S. , Binder Joseph , Dittmann Meike
Published: August 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of Coronavirus Disease 2019 (COVID-19). There is a dire need for novel effective antivirals to treat COVID-19, as the only approved direct-acting antiviral to date is remdesivir, targeting the viral polymerase complex. A potential alternate target in the viral life cycle is the main SARS-CoV-2 protease 3CLpro(Mpro). The drug candidate PF-00835231 is the active compound of the first anti-3CLproregimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the pre-clinical 3CLproinhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A549+ACE2cells). We find PF-00835231 with at least similar or higher potency than remdesivir or GC-376. A time-of-drug-addition approach delineates the timing of early SARS-CoV-2 life cycle steps in A549+ACE2cells and validates PF-00835231’s early time of action. In a model of the human polarized airway epithelium, both PF-00835231 and remdesivir potently inhibit SARS-CoV-2 at low micromolar concentrations. Finally, we show that the efflux transporter P-glycoprotein, which was previously suggested to diminish PF-00835231’s efficacy based on experiments in monkey kidney Vero E6 cells, does not negatively impact PF-00835231 efficacy in either A549+ACE2cells or human polarized airway epithelial cultures. Thus, our study providesin vitroevidence for the potential of PF-00835231 as an effective SARS-CoV-2 antiviral and addresses concerns that emerged based on prior studies in non-humanin vitromodels.

Importance

The arsenal of SARS-CoV-2 specific antiviral drugs is extremely limited. Only one direct-acting antiviral drug is currently approved, the viral polymerase inhibitor remdesivir, and it has limited efficacy. Thus, there is a substantial need to develop additional antiviral compounds with minimal side effects and alternate viral targets. One such alternate target is its main protease, 3CLpro(Mpro), an essential component of the SARS-CoV-2 life cycle processing the viral polyprotein into the components of the viral polymerase complex. In this study, we characterize a novel antiviral drug, PF-00835231, which is the active component of the first-in-class 3CLpro-targeting regimen in clinical trials. Using 3Din vitromodels of the human airway epithelium, we demonstrate the antiviral potential of PF-00835231 for inhibition of SARS-CoV-2.
A Novel Factor in Olfactory Ensheathing Cell-Astrocyte Crosstalk: Anti-Inflammatory Protein α-Crystallin B
Authors: Saglam Aybike , Calof Anne L. , Wray Susan
Published: August 2020

Astrocytes are key players in CNS neuroinflammation and neuroregeneration that may help or hinder recovery, depending on the context of the injury. Although pro-inflammatory factors that promote astrocyte-mediated neurotoxicity have been shown to be secreted by reactive microglia, anti-inflammatory factors that suppress astrocyte activation are not well-characterized. Olfactory ensheathing cells (OECs), glial cells that wrap axons of olfactory sensory neurons, have been shown to moderate astrocyte reactivity, creating an environment conducive to regeneration. Similarly, astrocytes cultured in medium conditioned by cultured OECs (OEC-CM) show reduced nuclear translocation of Nuclear Factor kappa-B (NFκB), a pro-inflammatory protein that induces neurotoxic reactivity in astrocytes. In this study, we screened primary and immortalized OEC lines to identify these factors and discovered that Alpha B-crystallin (CryAB), an antiinflammatory protein, is secreted by OECs via exosomes, coordinating an intercellular immune response. Our results showed: 1) OEC exosomes block nuclear NFκB translocation in astrocytes while exosomes fromCryAB-null OECs could not; 2) OEC exosomes could be taken up by astrocytes and 3) CryAB treatment suppressed multiple neurotoxicity-associated astrocyte transcripts. Our results indicate that OEC-secreted factors are potential agents that can ameliorate, or even reverse, the growth-inhibitory environment created by neurotoxic reactive astrocytes following CNS injuries.

Main Points

Astrocytes uptake OEC-secreted exosomes.

WT OEC-exosomes, but not CryAB-null OEC-exosomes, block nuclear NFκB translocation in astrocytes.

CryAB, and other factors secreted by OECs, suppresses multiple neurotoxicity-associated astrocyte transcripts.
Correct regionalisation of a tissue primordium is essential for coordinated morphogenesis
Authors: Sanchez-Corrales Yara E. , Blanchard Guy , Röper Katja
Published: August 2020

During organ development, tubular organs often form from flat epithelial primordia. In the placodes of the forming tubes of the salivary glands in theDrosophilaembryo, we previously identified spatially defined cell behaviours of cell wedging, tilting and cell intercalation that are key to the initial stages of tube formation. Here we address what the requirements are that ensure the continuous formation of a narrow symmetrical tube from an initially asymmetrical primordium whilst overall tissue geometry is constantly changing. We are using live-imaging and quantitative methods to compare wild-type and mutants that either show disrupted cell behaviours or an initial symmetrical placode organisation, with both resulting in severe impairment of the invagination. We find that early transcriptional patterning of key morphogenetic transcription factors drives the selective activation of downstream morphogenetic modules, such as GPCR signalling that activates apical-medial actomyosin activity to drive cell wedging at the future asymmetrically-placed invagination point. Over time, transcription of key factors expands across the rest of the placode and cells switch their behaviour from predominantly intercalating to predominantly apically constricting as their position approaches the invagination pit. Misplacement or enlargement of the initial invagination pit leads to early problems in cell behaviours that eventually result in a defective organ shape. Our work illustrates that the dynamic patterning of the expression of transcription factors and downstream morphogenetic effectors ensures positionally fixed areas of cell behaviour with regards to the invagination point. This patterning in combination with the asymmetric geometrical set-up ensures functional organ formation.
The spectrum of covariance matrices of randomly connected recurrent neuronal networks
Authors: Hu Yu , Sompolinsky Haim
Published: September 2020

A key question in theoretical neuroscience is the relation between the connectivity structure and the collective dynamics of a network of neurons. Here we study the connectivity-dynamics relation as reflected in the distribution of eigenvalues of the covariance matrix of the dynamic fluctuations of the neuronal activities, which is closely related to the network’s Principal Component Analysis (PCA) and the associated effective dimensionality. We consider the spontaneous fluctuations around a steady state in a randomly connected recurrent network of stochastic neurons. An exact analytical expression for the covariance eigenvalue distribution in the large-network limit can be obtained using results from random matrices. The distribution has a finitely supported smooth bulk spectrum and exhibits an approximate power-law tail for coupling matrices near the critical edge. We generalize the results to include connectivity motifs and discuss extensions to Excitatory-Inhibitory networks. The theoretical results are compared with those from finite-size networks and and the effects of temporal and spatial sampling are studied. Preliminary application to whole-brain imaging data is presented. Using simple connectivity models, our work provides theoretical predictions for the covariance spectrum, a fundamental property of recurrent neuronal dynamics, that can be compared with experimental data.
Intensive granulocyte and monocyte adsorption apheresis for generalized pustular psoriasis
Authors: Mizutani Yoko , Fujii Kento , Kawamura Miho , Inoue Madoka , Mizutani Yuki H. , Matsuyama Kanako , Doi Tomoaki , Nagaya Soichiro , Seishima Mariko
Published: August 2020

Granulocyte and monocyte adsorption apheresis (GMA) is usually performed weekly (consisting of five sessions) for refractory skin diseases, such as generalized pustular psoriasis (GPP). The time to remission of inflammatory bowel diseases has been reported to be significantly shorter in intensive GMA (twice a week) than in regular GMA (once a week). Despite several reports of GPP cases treated with intensive GMA, the efficacy of intensive GMA has not been verified in GPP. Herein, we present two GPP patients with a mutation in theIL36RNgene, who initially received regular GMA, and intensive GMA upon recurrence. There were no adverse effects during regular and intensive GMA for both patients. Because concomitant medication was only prednisolone (20 mg/day) during regular and intensive GMA, intensive GMA showed superiority to regular GMA in patient 1. Although concomitant medications were different between regular and intensive GMA in patient 2, these drugs had been used before the start of each GMA therapy. We cannot neglect the effects of concomitant drugs, but we observed a shorter time to remission in intensive GMA than that in regular GMA in both patients. More case studies will be necessary for evaluating the clinical efficacy of intensive GMA.
Longer photoperiods through range shifts and artificial light lead to a destabilizing increase in host–parasitoid interaction strength
Authors: Kehoe Rachel , Sanders Dirk , Cruse Dave , Silk Matthew , Gaston Kevin J. , Bridle Jon R. , van Veen Frank
Published: August 2020

Many organisms are experiencing changing daily light regimes due to latitudinal range shifts driven by climate change and increased artificial light at night (ALAN). Activity patterns are often driven by light cycles, which will have important consequences for species interactions.

We tested whether longer photoperiods lead to higher parasitism rates by a day‐active parasitoid on its host using a laboratory experiment in which we independently varied daylength and the presence of ALAN. We then tested whether reduced nighttime temperature tempers the effect of ALAN.

We found that parasitism rate increased with daylength, with ALAN intensifying this effect only when the temperature was not reduced at night. The impact of ALAN was more pronounced under short daylength. Increased parasitoid activity was not compensated for by reduced life span, indicating that increased daylength leads to an increase in total parasitism effects on fitness.

To test the significance of increased parasitism rate for population dynamics, we developed a host–parasitoid model. The results of the model predicted an increase in time‐to‐equilibrium with increased daylength and, crucially, a threshold daylength above which interactions are unstable, leading to local extinctions.

Here we demonstrate that ALAN impact interacts with daylength and temperature by changing the interaction strength between a common day‐active consumer species and its host in a predictable way. Our results further suggest that range expansion or ALAN‐induced changes in light regimes experienced by insects and their natural enemies will result in unstable dynamics beyond key tipping points in daylength.
Comparison of chitin‐induced natural transformation in pandemic Vibrio choleraeO1 El Tor strains
Authors: Stutzmann Sandrine , Blokesch Melanie
Published: August 2020

The human pathogen Vibrio cholerae serves as a model organism for many important processes ranging from pathogenesis to natural transformation, which has been extensively studied in this bacterium. Previous work has deciphered important regulatory circuits involved in natural competence induction as well as mechanistic details related to its DNA acquisition and uptake potential. However, since competence was first reported for V. cholerae in 2005, many researchers have struggled with reproducibility in certain strains. In this study, we therefore compare prominent seventh pandemic V. cholerae isolates, namely strains A1552, N16961, C6706, C6709, E7946, P27459, and the close relative MO10, for their natural transformability and decipher underlying defects that mask the high degree of competence conservation. Through a combination of experimental approaches and comparative genomics based on new whole‐genome sequences and de novo assemblies, we identify several strain‐specific defects, mostly in genes that encode key players in quorum sensing. Moreover, we provide evidence that most of these deficiencies might have recently occurred through laboratory domestication events or through the acquisition of mobile genetic elements. Lastly, we highlight that differing experimental approaches between research groups might explain more of the variations than strain‐specific alterations.
Transactive Teaching in a Time of Climate Crisis
Authors: Säfström Carl Anders , Östman Leif
Published: August 2020

This article discusses three problems that need to be tackled when the climate crisis becomes ‘a sustainability issue’ to be taught in schools. The article highlights, first, how knowledge concerning sustainability in schools risks being reduced and made into knowledge about ‘things’. Secondly, it also discusses how students in such a context risk being treated as instruments for ways of being in the world, rather than being subjects with ethical and political concerns for the world in which they live ‘here and now’. Thirdly, as we explore through some empirical examples, such reduction and instrumentalism objectifies both students and nature, which makes an adequate response to the crises obsolete. As an alternative, the article develops a notion of grievability and its importance for adequately responding to all living beings within a project of sustainability. To this end, it develops suggestions for a transactive teaching approach in a time of climate crisis.
Stepwise student migration: A trajectory analysis of Iranians moving from Turkey to Europe and North America
Authors: Zijlstra Judith
Published: August 2020

In the last decade, political and economic constraints have prompted many students to leave Iran. While Europe and North America have traditionally been Iranians' preferred destinations, selective entry procedures make direct access increasingly difficult. This article focuses on Iranian students' stepwise migration strategies to reach Western countries through Turkey. My research indicates that stepwise migration theory can be applied to international students, as visa restrictions and the selectivity of Western universities transformed Turkey into a stepwise migration corridor. The article also considers the advantages of the trajectory analysis method I developed. Trajectory analysis is a longitudinal and mobile method whereby migrants are followed over time and space. It enables the researcher to compare data about migrants who move stepwise and those who move crosswise by staying in Turkey. The research is based on interviews with 36 Iranians in Turkey, Europe, and the United States, of whom 15 moved in stepwise fashion. An important outcome is that students' academic capital is a crucial indicator for their ability to migrate to the West. This finding points to path dependency in students' trajectories along a hierarchy of destinations: not only in geographical terms but also in terms of the perceived level of educational institutions' reputations.
Effect of isochoric freezing on quality aspects of minimally processed potatoes
Authors: Bilbao‐Sainz Cristina , Zhao Yuanheng , Takeoka Gary , Williams Tina , Wood Delilah , Chiou Bor‐Sen , Powell‐Palm Matthew J. , Wu Vivian C.H. , Rubinsky Boris , McHugh Tara
Published: August 2020

The enhanced interest in greater convenience foods has recently led to the expansion of minimally processed potato products. This study investigated the effects of isochoric freezing on pre‐peeled potato cubes, including quality attributes (microstructure, texture, and color), nutritional value (ascorbic acid (AA) content, total phenolic content, and antioxidant capacity), and polyphenol oxidase activity. Isochoric freezing (−3 °C/30 MPa) was compared with isobaric freezing (−3 °C/0.1 MPa) and individual quick freezing followed by frozen storage at −20 °C for 4 weeks. The isochoric sample had lower drip loss and volume shrinkage as well as better preserved texture and microstructure than the other samples. All freezing methods caused an increase in total phenolic content and antioxidant capacity, but a decrease in AA content. Also, all freezing methods caused browning of the thawed potatoes, but isochoric freezing delayed its onset for more than 1 week.

Practical Application

Results showed that isochoric freezing of pre‐peeled and cut potatoes caused less freeze damage than isobaric and individual quick freezing, which might find application in the commercial preservation of minimally processed food products.
A protocol for the large‐scale analysis of reefs using Structure from Motion photogrammetry
Authors: Bayley Daniel T. I. , Mogg Andrew O. M.
Published: August 2020

Substrate complexity is an essential metric of reef health and a strong predictor of several ecological processes connected to the reef, including disturbance, resilience, and associated community abundance and diversity.

Underwater Structure from Motion (SfM) photogrammetry has been growing rapidly in use over the last 5 years due to advances in computing power, reduced costs of underwater digital cameras and a push for reproducible data. This has led to the adaptation of an originally terrestrial survey technique into the marine realm, which can now be applied at the habitat scale.

This technique allows researchers to make detailed 3D reconstructions of reef surfaces for morphometric analysis of reef physical structure and perform large‐scale image‐mosaic mapping. SfM is useful for both reef‐scale and colony‐scale assessments, where visual or acoustic methods are impractical or not sufficiently detailed.

Here we provide a protocol for the collection, analysis and display of 3D reef data, focussing on large‐scale habitat assessments of coral reefs using primarily open‐source software. We further suggest applications for other underwater environments and scales of assessment, and hope this standardized protocol will help researchers apply this technology and inspire new avenues of ecological research.
The dawn of a new synthetic opioid era: the need for innovative interventions
Authors: Pardo Bryce , Taylor Jirka , Caulkins Jon , Reuter Peter , Kilmer Beau
Published: September 2020

Background

Overdose deaths related to illegal drugs in North American markets are now dominated by potent synthetic opioids such as fentanyl, a circumstance foreshadowed by often‐overlooked events in Estonia since the turn of the century. Market transitions generate important and far‐reaching implications for drug policy.

Argument and analysis

The supplier‐driven introduction of illegally manufactured synthetic opioids into street opioids is elevating the risk of fatal overdose. Using the most recent overdose mortality and drug seizure data in North America, we find that overdose deaths and seizures involving synthetic opioids are geographically concentrated, but this might be changing. Examination here suggests that in some places fentanyl and its analogues have virtually displaced traditional opioids, such as heroin. The concealing of synthetic opioids in powders sold as heroin or pressed into counterfeit medications substantially increases harms. The nature and scale of the challenge posed by synthetic opioids is unprecedented in recent drug policy history.

Conclusions

There is urgent need for policy and technological innovation to meet the challenges posed by illegally produced synthetic opioids. Novel interventions worth examining include supervising drug use, proactively deterring on‐line distribution and new technologies aimed at improving transparency, such as point‐of‐use drug content testing. Continuing to approach this problem only with existing policies and available methods, such as naloxone, is unlikely to be enough and will result in many premature deaths.
From bench to bedside: Impact of left ventricular assist device outflow conduit anastomosis position on outcome
Authors: Tarzia Vincenzo , Di Giammarco Gabriele , Bagozzi Lorenzo , Bortolussi Giacomo , Maccherini Massimo , Marinelli Daniele , Bernazzali Sonia , Maiani Massimo , Gregori Dario , Scuri Silvia , Tessari Chiara , Fabozzo Assunta , Bottio Tomaso , Livi Ugolino , Gerosa Gino
Published: August 2020

Continuous flow left ventricular assist devices (LVADs) have become a valuable therapy for end‐stage heart failure. In vitro research highlighted a role of outflow cannula position on the pattern of blood flow in the aorta. However, the clinical effects of the alterations of flow remain unclear. We investigate short‐ and long‐term outcomes of patients implanted with Jarvik 2000 LVAD, according to the ascending (Group 1) versus descending (Group 2) outflow graft connection to the aorta in a multicenter study. From May 2008 to October 2014, 140 consecutive end‐stage heart failure patients underwent Jarvik 2000 LVAD implantation in 17 Italian centers. According with a preliminary multivariate analysis, we selected the 90 patients implanted in the four high‐volume centers to avoid bias (Group 1 n = 39, Group 2 n = 51). Among the groups, no differences were recorded in the hospital mortality and the main complications occurring after LVAD implantation were similar. In multivariable analysis, the ascending aorta outflow cannula position and higher creatinine at discharge were significant predictors for long‐term survival. Postimplant hemolysis was more pronounced in descending aorta outflow graft anastomosis. Outflow graft anastomosis to the ascending aorta is associated with better long‐term survival, independent of age and perfusion techniques, reflecting the previous in vitro results.
Characterization of a pulsatile rotary total artificial heart
Authors: Jurney Patrick L. , Glynn Jeremy J. , Dykan Igor V. , Hagen Matthew W. , Kaul Sanjiv , Wampler Richard K. , Hinds Monica T. , Giraud George D.
Published: August 2020

This article describes the properties and performance of a rotary total artificial heart (TAH) that produces inherently pulsatile flow. The hydraulic performance of the TAH was characterized using a mock circulatory loop to simulate four physiologically relevant conditions: baseline flow, increased flow, systemic hypertension, and pulmonary hypertension. The pump has a variable shuttle rate (beats per minute), percentage dwell time, and angular velocity on either side (revolutions per minute), which allows for full control of the flow rate and pulsatility over a range of healthy and pathologic pressures and flow rates. The end‐to‐end length and displacement volume of the TAH are 9.8 cm and 130 mL, respectively, allowing it to fit in smaller chest cavities including those of smaller adults and juvenile humans.
Identifying language disorder in bilingual children aged 2.5 years requires screening in both languages
Authors: Nayeb Laleh , Lagerberg Dagmar , Sarkadi Anna , Salameh Eva‐Kristina , Eriksson Mårten
Published: September 2020

Aim

Bilingual children are at risk of being overlooked for early identification of language difficulties. We investigated the accuracy of four screening models for children aged 2.5. The first model screened the child using their mother tongue, the second screened in Swedish, and the third screened in both languages used by the child. The fourth model consisted of direct screening in Swedish and using parental information about the child's language development in their mother tongue.

Methods

Overall, 111 bilingual children (51% girls), 29‐33 months, were recruited from three child health centres in Gävle, Sweden, from November 2015 to June 2017. All children were consecutively assessed by a speech and language pathologist, blinded to the screening outcomes.

Results

Developmental language disorder was confirmed in 32 children (29%). Only the third model, based on direct assessment using the two languages used by the child, attained adequate accuracy; 88% sensitivity, 82% specificity, 67% positive and 94% negative predictive values.

Conclusion

Bilingual children should be screened directly in both their languages in order to achieve adequate accuracy. Such screening procedure is particularly important for children from families with low socio‐economic status living in complex linguistic environments.
Understanding pregnant women’s adherence‐related beliefs about Nicotine Replacement Therapy for smoking cessation: A qualitative study
Authors: McDaid Lisa , Thomson Ross , Emery Joanne , Coleman Tim , Cooper Sue , Phillips Lucy , Bauld Linda , Naughton Felix
Published: August 2020

Introduction

Reducing smoking during pregnancy is a public health priority. Nicotine replacement therapy (NRT) is offered routinely to pregnant women who smoke in the United Kingdom. However, evidence of treatment efficacy in this population is weak, most likely due to poor adherence. Guided by the Necessity‐Concerns Framework, we conducted a qualitative study to better understand pregnant women’s perceived needs and concerns regarding NRT use, with consideration of combination NRT.

Methods

Semi‐structured interviews were conducted by telephone with 18 pregnant or recently pregnant women in England and Wales, purposively sampled for different NRT‐related experiences. Participants were recruited online via Facebook adverts and through a Stop Smoking Service. A hybrid approach of deductive and inductive thematic coding was used for analysis.

Results

Findings were organized around three themes: 1) the role of motivation to stop smoking; 2) necessity beliefs about using NRT; and 3) concerns about NRT. Some women reported fluctuating motivation for stopping smoking which undermined their NRT use. Others used NRT to cut down the number of cigarettes they smoked. Reasons for low NRT necessity beliefs included a preference for quitting unassisted, low or unrealistic expectations of efficacy, and overconfidence in achieving cessation (necessity testing). Concerns included safety, particularly around increased nicotine exposure with combination NRT, addictiveness, side effects, and capability to use.

Conclusion

Pregnant women have multiple necessity beliefs and concerns that influence their use of NRT. Targeting these, alongside increasing and maintaining motivation to quit smoking, will likely help optimize NRT use in pregnancy and improve quit rates.
Demographic and health factors associated with pandemic anxiety in the context of COVID‐19
Authors: McElroy Eoin , Patalay Praveetha , Moltrecht Bettina , Shevlin Mark , Shum Adrienne , Creswell Cathy , Waite Polly
Published: August 2020

Objectives

The mental health consequences of COVID‐19 are predicted to have a disproportionate impact on certain groups. We aimed to develop a brief measure, the Pandemic Anxiety Scale, to capture the specific aspects of the pandemic that are provoking anxiety, and explore how these vary by health and demographic factors.

Design

Data were from a convenience sample of parents (N = 4,793) and adolescents (N = 698) recruited in the first 6 weeks of lockdown.

Methods

Factor analytic and IRT methods were used to validate the new measure in both parent and adolescent samples. Associations between scores on the new measure and age, gender, household income, and physical health status were explored using structural equation modelling (SEM).

Results

Two factors were identified in both samples: disease anxiety (e.g., catching, transmitting the virus) and consequence anxiety (e.g., impact on economic prospects); and unique associations with health and demographic factors were observed.

Conclusions

Anxieties due to the COVID‐19 are multifaceted, and the PAS is a short, reliable, and valid measure of these concerns. These anxieties are differentially associated with demographic, social, and health factors, which should be considered when developing strategies to mitigate the mental health impact of the pandemic.
UDP‐glucuronosyltransferase polymorphisms affect diethylnitrosamine‐induced carcinogenesis in humanized transgenic mice
Authors: Landerer Steffen , Kalthoff Sandra , Paulusch Stefan , Strassburg Christian P.
Published: August 2020

UDP‐glucuronosyltransferase (UGT) 1A enzymes detoxify a broad array of exogenous compounds including environmental toxins and carcinogens. Case‐control studies identified genetic variations in UGT1A genes leading to reduced glucuronidation activity, which were associated with hepatocellular carcinoma (HCC) formation and progression. The aim of the study was therefore to examine the direct effect of common UGT1A polymorphisms (SNPs) on HCC development and outcome in a diethylnitrosamine (DEN)‐induced mouse model. Therefore, a single intraperitoneal DEN injection (20 mg/kg) was administered to 15‐day‐old htgUGT1A‐WT and htgUGT1A‐SNP mice (containing a human haplotype of 10 common UGT1A SNPs) either receiving water or coffee cotreatment for the following 39 weeks. After this time, tumor incidence, size (>1 mm), histology, liver‐body ratio, serum aminotransferase activities, and UGT1A regulation and activity levels were determined. In DEN‐treated htgUGT1A‐SNP mice, a markedly higher number of tumors with a bigger cumulative diameter were detected. The relative liver weight and aminotransferase activity levels were also significantly higher in mice carrying UGT1A SNPs. After coffee + DEN cotreatment, susceptibility for tumor development and growth considerably decreased in both mouse lines, but was still higher in htgUGT1A‐SNP mice. In conclusion, our study provides experimental evidence for the protective role of UGT1A enzymes in neoplastic transformation. These data confirm case‐control studies implicating impaired UGT1A‐mediated carcinogen detoxification as a risk factor for individual cancer disposition. Coffee treatment, which is able to activate UGT1A expression and activity, reduced HCC development and provides an explanation for the protective properties of coffee on liver diseases including liver cancer.
Determinants of population persistence and abundance of terrestrial and arboreal vertebrates stranded in tropical forest land‐bridge islands
Authors: Benchimol Maíra , Peres Carlos A.
Published: September 2020

Megadams are among the key modern drivers of habitat and biodiversity loss in emerging economies. The Balbina Hydroelectric Dam of Central Brazilian Amazonia inundated 312,900 ha of primary forests and created approximately 3500 variable‐sized islands that still harbor vertebrate populations after nearly 3 decades after isolation. We estimated the species richness, abundance, biomass, composition, and group size of medium‐ to large‐bodied forest vertebrates in response to patch, landscape, and habitat‐quality metrics across 37 islands and 3 continuous forest sites throughout the Balbina archipelago. We conducted 1168 km of diurnal censuses and had 12,420 camera‐trapping days along 81 transects with 207 camera stations. We determined the number of individuals (or groups) detected per 10 km walked and the number of independent photographs per 10 camera‐trapping days, respectively, for each species. We recorded 34 species, and patch area was the most significant predictor of vertebrate population relative abundance and aggregate biomass. The maximum group size of several group‐living species was consistently larger on large islands and in continuous patches than on small islands. Most vertebrate populations were extirpated after inundation. Remaining populations are unlikely to survive further ecological disruptions. If all vertebrate species were once widely distributed before inundation, we estimated that approximately 75% of all individual vertebrates were lost from all 3546 islands and 7.4% of the animals in all persisting insular populations are highly likely to be extirpated. Our results demonstrate that population abundance estimates should be factored into predictions of community disassembly on small islands to robustly predict biodiversity outcomes. Given the rapidly escalating hydropower infrastructure projects in developing counties, we suggest that faunal abundance and biomass estimates be considered in environmental impact assessments and large strictly protected reserves be established to minimize detrimental effects of dams on biodiversity. Conserving large tracts of continuous forests represents the most critical conservation measure to ensure that animal populations can persist at natural densities in Amazonian forests.
Correlations of forced oscillometric bronchodilator response with airway inflammation and disease duration in asthma
Authors: Higaki Naoko , Iwamoto Hiroshi , Yamaguchi Kakuhiro , Sakamoto Shinjiro , Horimasu Yasushi , Masuda Takeshi , Miyamoto Shintaro , Nakashima Taku , Ohshimo Shinichiro , Fujitaka Kazunori , Hamada Hironobu , Hattori Noboru
Published: August 2020

Introduction

Airway resistance and reactance, measured by forced oscillometry, are used to measure the airway obstruction in patients with asthma.

Objectives

This study aimed to investigate the oscillometric bronchodilator responses in treated and untreated asthma and evaluate its association with airway inflammation and disease duration.

Materials and methods

This study included 30 nonsmoking patients with mild to moderate treated asthma, 25 patients with newly diagnosed untreated asthma and 29 control subjects. Spirometric and oscillometric measurements were performed before and after inhalation of 400 µg salbutamol. Disease duration was defined as the number of years since asthma diagnosis.

Results

At airway resistance of 5 Hz (R5) and 20 Hz (R20), bronchodilator responses in patients with untreated and treated asthma were greater than those in control subjects. In patients with untreated asthma, higher fractional exhaled nitric oxide concentration (FeNO) levels were strongly correlated with greater reversibility of R20 (rs = −0.621, P < 0.001). In patients with treated asthma, there was no significant association between FeNO and oscillometric reversibility, whereas longer disease duration was significantly associated with lesser bronchodilator response at R20 (rs = 0.441, P < 0.05). Treated asthma patients with longer disease duration (≥10 years) showed significantly higher post‐bronchodilator R5 and R20 than the treated asthma patients with shorter disease duration (<10 years).

Conclusion

The present study provides further evidence of an association between airway inflammation and variable airway obstruction in asthma patients and indicates that long‐term disease duration could be related to poorly reversible airway resistance in patients with mild to moderate asthma.
Effects of Bardoxolone Methyl on Hepatic Enzymes in Patients with Type 2 Diabetes Mellitus and Stage 4 CKD
Authors: Lewis James H. , Jadoul Michel , Block Geoffrey A. , Chin Melanie P. , Ferguson Deborah A. , Goldsberry Angie , Meyer Colin J. , O’Grady Megan , Pergola Pablo E. , Reisman Scott A. , Wigley W. Christian , Chertow Glenn M.
Published: August 2020

In a multinational placebo‐controlled phase III clinical trial in 2,185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, treatment with the Nrf2 activator bardoxolone methyl increased estimated glomerular filtration rate, a measure of kidney function, but also resulted in increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase. These increases in liver enzyme level(s) were maximal after 4 weeks of treatment and reversible, trending back toward baseline through week 48. Total bilirubin concentrations did not increase, and no cases met Hy’s Law criteria, although two subjects had ALT concentrations that exceeded 10 × the upper limit of the population reference range leading to discontinuation of treatment. Animal and cell culture experiments suggested that the increases in ALT and AST induced by bardoxolone methyl may be related to its pharmacological activity. Bardoxolone methyl significantly induced the mRNA expression of ALT and AST isoforms in cultured cells. Expression of ALT and AST isoforms in liver and kidney also positively correlated with Nrf2 status in mice. Overall, these data suggest that the increases in ALT and AST observed clinically were, at least in part, related to the pharmacological induction of aminotransferases via Nrf2 activation, rather than to any intrinsic form of hepatotoxicity.
Pharmacokinetics and Pharmacodynamics of Cenerimod, A Selective S1P1R Modulator, Are Not Affected by Ethnicity in Healthy Asian and White Subjects
Authors: Juif Pierre‐Eric , Dingemanse Jasper , Winkle Peter , Ufer Mike
Published: August 2020

Cenerimod is a sphingosine‐1‐phosphate 1 receptor (S1P1R) modulator in phase II development for treatment of systemic lupus erythematosus. Its pharmacokinetics (PKs), pharmacodynamics (PDs), as well as safety and tolerability were investigated in white and Asian subjects to allow for recruitment of Asian patients in future studies. A randomized, double‐blind, placebo‐controlled parallel‐group study was performed in 20 healthy male subjects (n = 10 per ethnicity). A single, oral dose of 4 mg cenerimod or placebo (ratio 8:2) was administered under fasted conditions. The PKs of cenerimod were similar in white and Asian subjects indicated by geometric mean ratios (90% confidence interval) of 0.99 (0.80–1.21) for maximum plasma concentration, 0.96 (0.75–1.24) for area under the plasma concentration‐time curve from 0 to infinity, and 1.04 (0.86–1.25) for terminal half‐life. Accordingly, the extent and time course of reduction in lymphocyte count (as PD biomarker) were also similar in white and Asian subjects as compared with placebo. As observed for other S1PR modulators, a transient mean (SD) heart rate reduction in white (15.1 (14.8) bpm) and Asian (11.8 (6.16) bpm) subjects was observed following administration of cenerimod. The drug was safe and well‐tolerated indicated by occurrence of a single adverse event of chemical conjunctivitis in a white subject that was not suspected as study drug related. In conclusion, the determined absence of any relevant PK or PD differences supports using the same doses of cenerimod in white and Asian patients in upcoming late‐phase studies.
Integrating dispersal along freshwater ecosystems into species distribution models
Authors: Perrin Sam Wenaas , Englund Göran , Blumentrath Stefan , Brian O’Hara Robert , Amundsen Per‐Arne , Gravbrøt Finstad Anders
Published: August 2020

Aim

Our ability to model species distributions and abundances is a valuable ecological tool in predicting future distributions of species. Effectively incorporating connectivity into these predictions is crucial; however, many connectivity measures utilize metrics which may not have a direct relation to the dispersal capacity of the species they are attempting to model. The identification of more relevant metrics is therefore a vital step forward in species distribution modelling.

Location

85 freshwater lakes across a latitudinal gradient in Sweden, and an additional 282 freshwater lakes in one drainage basin in northern Norway.

Methods

To investigate the effect of different connectivity measures, we first record recolonization of fish into lakes previously treated with the piscicide rotenone. Two invasive fish species, the northern pike (Esox lucius) and the European perch (Perca fluviatilis), were used as focal study species. We model the distributions of these species in a drainage basin with snapshot data of present‐day distributions to see how well the effects of the different connectivity measures correspond to the effects seen in our recolonization study. Connectivity is quantified using slope and distance along streams connecting lacustrine populations.

Results

The effects of connectivity variables were similar in both the recolonization study and the species distribution modelling. Incorporation of connectivity improved species distribution models significantly. There was little evidence for the inclusion of distance between populations, while there was strong evidence for the inclusion of different slope parameters for both species.

Main conclusions

Our study demonstrates the need to ensure the relevance of connectivity measures when accounting for dispersal limitation in distribution models. The correspondence of estimated connectivity measures from recolonization studies to those estimated from species distribution models demonstrates a link between species dispersal capacity and the connectivity measures employed, and is likely to improve our ability to predict species future distributions.
Infant Spontaneous Motor Tempo
Authors: Rocha Sinead , Southgate Victoria , Mareschal Denis
Published: August 2020

Spontaneous Motor Tempo (SMT) is influenced by individual differences in age and body size. We present the first data documenting the SMT of infants from 5 to 37 months of age using a simple drumming task. As in late childhood and adulthood, we predicted that infant SMT would slow across the first years of life. However, we find that older infants drum more quickly than younger infants. Furthermore, studies of adults suggest larger bodies prefer slower rhythms. This relationship may be the product of biomechanical resonance, or effects may be driven by rhythmic experience, such as of locomotion. We used infants, whose body size is dissociated from their predominant experience of locomotion as their parent often carries them, to test this argument. We reveal that infant SMT is predicted by parent, but not own, body size, supporting a passive experience‐based argument, and propose that early rhythm may be set by repetitive vestibular stimulation when carried by the caregiver.
Semiquantitative assessment of the relative apical sparing pattern of longitudinal strain for cardiac amyloidosis identification
Authors: Saito Makoto , Imai Misaki , Wake Daisuke , Higaki Rieko , Nakao Yasuhisa , Sumimoto Takumi , Yokomoto Yuki , Ogimoto Akiyoshi , Suzuki Moeko , Kawakami Hideo , Hiasa Go , Okayama Hideki , Inoue Katsuji , Ikeda Shuntaro , Yamaguchi Osamu
Published: August 2020

Backgrounds

The relative apical sparing pattern (RASP) of left ventricular (LV) longitudinal strain (LS) is frequently associated with cardiac amyloidosis (CA). However, the visual assessment of RASP is inconsistent, and the quantitative assessment of RASP is time‐consuming. This study aimed to compare assessments of RASP for the identification of CA with conventional assessments and investigate their reproducibility and relevance on the assessments.

Methods

Forty patients with biopsy‐proven CA were compared with 80 hypertrophied patients matched for mean LV wall thickness. We compared the discriminative abilities of three assessments of RASP to identify CA (visual, quantitative, and semiquantitative). Nine patterns of semiquantitative RASP were investigated; finally, it was defined as “reduction of LS” (≥ −10%) in ≥5 (of 6) basal segments, relative to “preserved LS” (< −15%) in at least one apical segment.

Results

The concordance between the two observers for visual RASP was modest (κ = 0.65). On the other hand, the consistency for semiquantitative RASP was perfect (κ = 1.00). The discriminative ability of semiquantitative RASP (area under the curve [AUC]  = 0.74) was significantly better than that of visual RASP (AUC = 0.65) and equivalent to that of binary quantitative RASP.

Conclusion

Semiquantitative RASP assessment is reproducible and accurately discriminates CA. This simple assessment may help readily refine the risk stratification of patients with diffuse LV hypertrophy.
Trends in lobectomy/amygdalohippocampectomy over time and the impact of hospital surgical volume on hospitalization outcomes: A population‐based study
Authors: Kwon Churl‐Su , Blank Leah , Mu Lan , Jetté Nathalie
Published: August 2020

Objective

Despite national guidelines supporting surgical referral in drug‐resistant epilepsy, it is hypothesized that surgery is underutilized. We investigated the volumes of lobectomy/amygdalohippocampectomy surgeries over time and examined differences in outcomes between (1) high‐volume (HV), middle‐volume (MV), and low‐volume (LV) hospitals and (2) Level 4 Centers versus non–Level 4 Centers.

Methods

The 2003‐2014 National Inpatient Sample (the largest all‐payer hospitalization database, representative of the US population) was utilized. Epilepsy was identified using a previously validated International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) case definition and surgeries using ICD‐9‐CM procedure codes. A hospital was considered a Level 4 Center if it performed intracranial electroencephalographic (EEG) monitoring. Tumor surgeries were excluded. Linear regression was used to perform trend tests. Weighted multivariate logistic regression was used to summarize association of surgery with outcomes.

Results

A total of 4,487 lobectomy/amygdalohippocampectomy surgeries were performed in children and adults with epilepsy. Lobectomy/amygdalohippocampectomy surgeries significantly decreased over time (slope: −0.24, P < .001). This declining surgical trend was greater for all resective/disconnective surgery (slope: −0.45, P < .001), and greatest when compared to all types of epilepsy surgery, for example, resection/disconnection/radiosurgery/laser interstitial thermal therapy/vagus nerve stimulation/deep brain stimulation/responsive neurostimulation/intracranial EEG (slope: −0.95, P < .001). LV compared to HV hospitals had higher odds of transfer to other facilities (13.60% vs 4.24%, odds ratio [OR] = 2.76, 95% confidence interval [CI] = 1.11‐6.82). LV hospitals had higher odds of surgical complications versus MV (12.69% vs 6.80%, OR = 2.20, 95% CI = 1.01‐5.09). HV hospitals incurred the least total charges. There were no differences in discharge status, adverse events, length of stay, or cost between Level 4 Centers versus non–Level 4 Centers.

Significance

Lobectomies/amygdalohippocampectomies are decreasing over time, suggesting ongoing underutilization. LV centers are associated with greater complication and transfer rates. Future studies are required to understand the reason for worse outcomes in LV centers and to determine whether a minimum number of surgeries must be performed to meet necessary standards.