bluuebunny/crossref_metadata_2025 huggingface dataset:
Benefits of enhanced infection prophylaxis at antiretroviral therapy initiation by cryptococcal antigen status
Authors: Pett Sarah L. , Spyer Moira , Haddow Lewis J. , Nhema Ruth , Benjamin Laura A. , Najjuka Grace , Bilima Sithembile , Daud Ibrahim , Musoro Godfrey , Kitabalwa Juliet , Selemani George , Kandie Salome , Cornelius K. Magut , Katemba Chrispus , Berkley Jay A. , Hassan Amin S. , Kityo Cissy , Hakim James , Heyderman Robert S. , Gibb Diana M. , Walker Ann S.
Published: December 2020

Objectives:

To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial.

Design:

Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4+ cell count less than 100 cells/μl starting antiretroviral therapy who were randomized to receive 12-week enhanced-prophylaxis (fluconazole 100 mg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole).

Methods:

Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks, by baseline CrAg positivity.

Results:

Excluding 24 (1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781 (7.5%) participants were CrAg-positive. By 24 weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of nine standard-cotrimoxazole and three enhanced-prophylaxis cryptococcal deaths, seven and two, respectively, were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives [hazard-ratio = 0.36 (95% confidence interval 0.13–0.98), incidence 19.5 vs. 56.5/100 person-years] and CrAg-negatives [hazard-ratio = 0.33 (0.03–3.14), incidence 0.3 vs. 0.9/100 person-years; P
heterogeneity = 0.95]; nor for all deaths, cryptococcal deaths or unknown deaths (P
heterogeneity > 0.3).

Conclusion:

Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100 mg fluconazole in an enhanced-prophylaxis package at antiretroviral therapy initiation where CrAg screening is unavailable/impractical.
Homonegativity, sexual violence and condom use with women in men who have sex with men and women in West Africa
Authors: Fiorentino Marion , Eubanks August , Coulaud Pierre-Julien , Couderc Clotilde , Keita Bintou D. , Anoma Camille , Dah Elias , Mensah Ephrem , Maradan Gwenaëlle , Bourrelly Michel , Riegel Lucas , Rojas-Castro Daniela , Yaya Issifou , Spire Bruno , Laurent Christian , Sagaon-Teyssier Luis
Published: December 2020

Objective:

The study aimed to explore longitudinal interactions between homonegativity and sexual behaviors with female partners among HIV-negative West African men who have sex with men and women (MSMW).

Design and method:

The community-based cohort CohMSM ANRS 12324 – Expertise France enrolled MSM in Togo, Burkina Faso, Côte d’Ivoire and Mali. Sociobehavioral data were collected every 6 months. Using 30-month follow-up data, a multiprobit analysis was performed to investigate the relationship between psychosocial and behavioral variables ex-ante (t − 1) and ex-post (t).

Results:

MSMW (n = 326) accounted for half of all participants in CohMSM. They reported inconsistent condom use with women in 39% of visits. Perceived and internalized homonegativity at t − 1 tended to lead to sexual violence toward women at t (P < 0.1), which was associated with inconsistent condom use with them at t (P < 0.05).

Conclusion:

Given the high HIV prevalence in West African MSM, widespread condom-less sex with women in MSMW, and the aggravating effect of social and internalized homonegativity, more research in the MSMW subpopulation is needed to assess the risk of HIV bridging to women and to design support activities.
Viral suppression during COVID-19 among people with HIV experiencing homelessness in a low-barrier clinic-based program
Authors: Hickey Matthew D. , Imbert Elizabeth , Glidden David V. , Del Rosario Jan Bing , Chong Mary , Clemenzi-Allen Angelo , Oskarsson Jon , Riley Elise D. , Gandhi Monica , Havlir Diane V.
Published: December 2020

Coronavirus disease-2019 (COVID-19) threatens to further worsen HIV outcomes among people experiencing homelessness. We conducted an interrupted time-series analysis of care engagement and viral suppression among unhoused individuals in the ‘POP-UP’ low-barrier, high-intensity HIV primary care program during COVID-19. Among 85 patients, care engagement and viral suppression did not decrease in the 5 months following implementation of San Francisco's ‘shelter-in-place’ ordinance. Low-barrier, in-person HIV care for homeless individuals may be important for maintaining HIV outcomes during COVID-19.
Differential susceptibility of airway and ocular surface cell lines to FlhDC-mediated virulence factors PhlA and ShlA from Serratia marcescens
Authors: Stella Nicholas A. , Brothers Kimberly M. , Shanks Robert M. Q.
Published: December 2020

Introduction.

Serratia marcescens

is a bacterial pathogen that causes ventilator-associated pneumonia and ocular infections. The FlhD and FlhC proteins complex to form a heteromeric transcription factor whose regulon, in

S. marcescens

, regulates genes for the production of flagellum, phospholipase A and the cytolysin ShlA. The previously identified mutation, scrp-31, resulted in highly elevated expression of the flhDC operon. The scrp-31 mutant was observed to be more cytotoxic to human airway and ocular surface epithelial cells than the wild-type bacteria and the present study sought to identify the mechanism underlying the increased cytotoxicity phenotype.

Hypothesis/Gap Statement. Although FlhC and FlhD have been implicated as virulence determinants, the mechanisms by which these proteins regulate bacterial cytotoxicity to different cell types remains unclear.

Aim. This study aimed to evaluate the mechanisms of FlhDC-mediated cytotoxicity to human epithelial cells by

S. marcescens

.

Methodology. Wild-type and mutant bacteria and bacterial secretomes were used to challenge airway and ocular surface cell lines as evaluated by resazurin and calcein AM staining. Pathogenesis was further tested using a Galleria mellonella infection model.

Results. The increased cytotoxicity of scrp-31 bacteria and secretomes to both cell lines was eliminated by mutation of flhD and shlA. Mutation of the flagellin gene had no impact on cytotoxicity under any tested condition. Elimination of the phospholipase gene, phlA, had no effect on bacteria-induced cytotoxicity to either cell line, but reduced cytotoxicity caused by secretomes to airway epithelial cells. Mutation of flhD and shlA, but not phlA, reduced bacterial killing of G. mellonella larvae.

Conclusion. This study indicates that the

S. marcescens

FlhDC-regulated secreted proteins PhlA and ShlA, but not flagellin, are cytotoxic to airway and ocular surface cells and demonstrates differences in human epithelial cell susceptibility to PhlA.
Neighborhood-level Racial/Ethnic and Economic Inequities in COVID-19 Burden Within Urban Areas in the US and Canada
Authors: Saha Sudipta , Feldman Justin M.
Published: December 2020

The COVID-19 pandemic exhibits stark social inequities in infection and mortality outcomes. We investigated neighborhood-level inequities across cities in the US and Canada for COVID-19 cumulative case rates (46 cities), death rates (12 cities), testing rates and test positivity (12 cities), using measures that characterize social gradients by race/ethnicity, socioeconomic composition, or both jointly. We found consistent evidence of social gradients for case, death and positivity rates, with the most privileged neighborhoods having the lowest rates, but no meaningful variation in the magnitude of inequities between cities. Gradients were not apparent in testing rates, suggesting inadequate testing in the most deprived neighborhoods. Health agencies should monitor and compare inequities as part of their COVID-19 reporting practices and to guide pandemic response efforts.

HIGHLIGHTS

Within urban regions with available data in the US and Canada, there were strong social gradients for case, death and positivity rates

The most racially and/or economically privileged neighborhoods had the lowest rates

Social gradients were similar for neighborhood-level measures of racial/ethnic composition, income, racialized economic segregation, and racialized occupational segregation

Testing rates did not show consistent social gradients, which suggests that the most deprived neighborhoods have inadequate access to testing relative to their higher disease burden
Health Signatures During COVID-19: A Precision Fitness Case Study
Authors: Pollet Erin P. , Sathish Aishwarya , Maloney Zacharie , Long Byron L. , Brethen Jennifer , Qutub Amina Ann
Published: December 2020

BACKGROUND

Stay-at-home orders have proven a controversial, while effective, method of SARS-CoV-2 containment. However objective measures of how the pandemic and stay-at-home orders are affecting the daily health of uninfected individuals have been lacking.

METHODS

We investigated the effect of pandemic-related events on 61 individuals in San Antonio, Texas whose daily activity and sleep data were recorded via wearable activity trackers from April 2019 to August 2020. We assessed changes in six fitness metrics (steps walked, resting heart rate, sedentary minutes, wake duration after sleep onset, rapid eye movement (REM) duration, total sleep duration). Cluster analysis and time-course analysis identified trends in activity before, after and during stay-at-home orders. Quantitative measures of activities were compared to survey responses.

RESULTS

Four behavior patterns during stay-at-home orders were identified. Most individuals suffered declines in healthy habits compared to their daily activity in 2019 and early 2020 (e.g., up to −60% steps walked). Inflection points corresponded with key dates relevant to SARS-CoV-2 including the first reported case in the U.S. (Feb 29) and city-wide stay-at-home orders (Mar 23). Pre-existing conditions (diabetes, asthma) were associated with a steeper than average decline in sleep quality during stay-at-home orders. Unexpectedly, we also identified a group of predominately male individuals who improved their daily fitness during stay-at-home orders.

CONCLUSIONS

Objective measures of daily activity indicated most individuals’ fitness suffered at the onset of stay-at-home orders and slowly returned towards baseline. For a subset of individuals, fitness quantitatively improved – better sleep, more exercise, lower resting heart rate – during stay-at-home orders.
Smoking, distress and COVID-19 in England: cross-sectional population surveys from 2016 to 2020
Authors: Kock Loren , Shahab Lion , Brown Jamie , Moore Graham , Horton Marie , Brose Leonie
Published: December 2020

Background: Changes in the prevalence of mental health problems among smokers due to the COVID-19 pandemic in England have important implications for existing health inequalities. This study examined the prevalence of psychological distress among smokers following the onset of the pandemic compared with previous years.

Methods: Cross-sectional data were used from a representative survey of smokers (18+) in England (n = 2,927) during four months (April to July) in 2016, 2017 and 2020. Adjusted logistic regressions estimated the associations between past-month psychological distress across two time periods (2016/17 and 2020), and age. Weighted proportions, chi-squared statistics and stratified logistic regression models were used to compare the distributions of minimal, moderate and severe distress, respectively, within socio-demographic and smoking characteristic categories in 2016/17 and 2020.

Results: The prevalence of moderate and severe distress among past-year smokers was higher in 2020 (moderate: 28.79%, 95%CI 26.11-31.60; OR=2.08, 95%CI 1.34-3.25; severe: 11.04%, 9.30-13.12; OR=2.16, 1.13-4.07) than in 2016/17 (moderate: 20.66%, 19.02-22.43; severe: 8.23%, 7.16-9.47). While there was no overall evidence of an interaction between time period and age, young (16-24 years) and middle-age groups (45-54 years) may have experienced greater increases in moderate and older age groups (65+ years) in severe distress from 2016/17 to 2020. There were also increases in 2020 of moderate distress among those from more disadvantaged social grades and of both moderate and severe distress among women and those with low cigarette addiction.

Conclusions: Between April-July 2016/17 and April-July 2020 in England there were increases in both moderate and severe distress among smokers. The distribution of distress differed between 2016/17 and 2020 and represents a widening of established inequalities, with increases in distress among socio-economically disadvantaged groups, women and diverging age groups.
The Impacts of Testing Cadence, Mode of Instruction, and Student Density on Fall 2020 COVID-19 Rates On Campus
Authors: Stubbs Christopher W. , Springer Michael , Thomas Tasha S.
Published: December 2020

We analyzed the COVID-19 infection rate among undergraduate students at 9 colleges and Universities in the greater Boston area and 4 comparison schools elsewhere, from Fall 2020. We assessed whether the cumulative rate of infection is dependent on the mode of instruction (in-person, hybrid, or remote), on the number and density of dorm-resident undergraduates, and/or on COVID-19 testing cadence. We limited our analysis to institutions that have implemented at least weekly PCR testing of dormitory-resident undergraduates. Our primary conclusions are that (i) the fraction of students that succumbed to a COVID-19 infection up through Nov 22, 2020 shows no correlation with either the total number of students on campus, or the fractional occupancy of dormitories, (ii) remote instruction vs. hybrid instruction has no significant measurable impact on cumulative infection rate, and (iii) there is evidence that testing 2 or 3 times per week is correlated with lower infection rates than weekly testing. These data are consistent with a hypothesis of students predominantly acquiring infection off-campus, with little community transmission within dormitory housing. This implies good student compliance with face mask and social distancing protocols.

Significance Statement

We review the incidence of COVID-19 infection among under-graduate students for selected colleges and universities that conducted at least weekly COVID-19 testing during the Fall of 2020. We analyzed the infection-rate dependence on number of students on campus, dormitory residential density, instructional methodology (remote vs. hybrid), and testing cadence. This compilation of outcomes can help inform policy decisions for congregate settings.
A novel multi-omics-based identification of symptoms, comorbid conditions, and possible long-term complications in COVID-19
Authors: Barh Debmalya , Tiwari Sandeep , Andrade Bruno Silva , Weener Marianna E. , Góes-Neto Aristóteles , Azevedo Vasco , Ghosh Preetam , Ganguly Nirmal Kumar
Published: December 2020

Till date the comprehensive clinical pictures, comorbid conditions, and long-term complications of COVID-19 are not known. Recently using a multi-omics-based strategy, we have predicted the drugs for COVID-19 management with ∼70% accuracy. Here, using a similar multi-omics-based bioinformatics approach and three-ways of analysis, we identified the symptoms, comorbid conditions, and short, mid and possible long-term complications of COVID-19 with ∼90% precision. In our analysis (i) we identified 27 parent, 170 child, and 403 specific conditions associated with COVID-19. (ii) Among the specific conditions, 36 are viral and 53 short-term, 62 short to mid to long-term, 194 mid to long-term, and 57 are congenital conditions. (iii) At a cut off “count of occurrence” of 4, we found ∼ 90% of the enriched conditions are associated with COVID-19. (iv) Except the dry cough and loss of taste, all other COVID-19 associated mild and severe symptoms are enriched. (v) Cardiovascular, pulmonary, metabolic, musculoskeletal, neuropsychiatric, kidney, liver, and immune system disorders are found as top comorbid conditions. (vi) Specific diseases such as myocardial infarction, hypertension, COPD, lung injury, diabetes, cirrhosis, mood disorders, dementia, macular degeneration, chronic kidney disease, lupus, arthritis etc. along with several other diseases are also enriched as top candidates. (vii) Interestingly, many cancers and congenital disorders associated with COVID-19 severity are also identified. (viii) Arthritis, dermatomyositis, glioma, diabetes, psychiatric disorder, cardiovascular diseases having bidirectional relationship with COVID-19 are also found as top ranked conditions. Based on the accuracy (∼90%) of this analysis, long presence of SARS-CoV-2 RNA in human, and our previously proposed “genetic remittance” assumption, we hypothesize that all the identified comorbid conditions including the short-long-mid and mid-long non-communicable diseases (NCDs) could also be long-term consequences in COVID-19 survivors and warrants long-term observational studies.
Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature
Authors: Brydges Christopher R , Fiehn Oliver , Mayberg Helen S , Schreiber Henry , Dehkordi Siamak Mahmoudian , Bhattacharyya Sudeepa , Cha Jungho , Choi Ki Sueng , Craighead W Edward , Krishnan Ranga R , Rush A John , Dunlop Boadie W , Kaddurah-Daouk Rima ,   for the Mood Disorders Precision Medicine Consortium
Published: December 2020

Background

It is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety.

Methods

Serum samples (baseline, 12 weeks) were drawn from participants (n=196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder.

Results

Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite’s effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, which suggests that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to gut microbiota.

Conclusions

A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches.
Factors affecting germination and establishment success of an endemic cactus of the Chihuahuan Desert
Authors: Ortiz-Martínez Eder , Golubov Jordan , Mandujano María C. , Arroyo-Cosultchi Gabriel
Published: December 2020

Seed and seedling are the most critical stages of cacti life cycle. From the thousands of seeds produced in a reproductive season, only a small fraction gets to germinate, the rest gets lost due to predation or gets potentially buried in the seed bank. These early stages depend on facilitation by nurse plants for germination and seedling recruitment. In this paper, we aim to describe some aspects of the recruitment ofCephalocereus polylophus. We tested the viability of seeds with different storage times as an indicator of their potential to form a short-term seed bank. Through the analysis of seed germination and seedlings survival under the canopy of two nurse plant species and open areas, we aimed to assess the importance of facilitation for recruitment. A predator exclusion experiment was used to evaluate the intensity of herbivory on seeds and seedlings of different developmental stages. Seeds had germination rates above 90%, even after two years of storage. Seed germination was only registered under one of the two nurses. After two years, up to 19% of the seedlings planted under both nurse plants survived. Protection against herbivores increased survival chances from 30 to 52 % for all age-group seedlings. Considering that facilitation is a crucial interaction forC. polylophus, future conservation programs should include the protection of plant communities.
Rapid assembly of a polar network architecture drives efficient actomyosin contractility
Authors: Costache Vlad , Garcia Serena Prigent , Plancke Camille N. , Li Jing , Begnaud Simon , Suman Shashi Kumar , Reymann Anne-Cécile , Kim Taeyoon , Robin François B.
Published: December 2020

Summary

Actin network architecture and dynamics play a central role in cell contractility and tissue morphogenesis. Pulsed contractions driven by RhoA represent a generic mode of actomyosin contractility, but the mechanisms underlying (1) how their specific architecture emerges, and (2) how this architecture supports the contractile function of the network, remain unclear. Here, we combine quantitative microscopy, single-molecule imaging, numerical simulations and simple mathematical modelling, to explore the dynamic network architecture underlying pulsed contraction. We show that during pulsed contractions, two subpopulations of formins are recruited by RhoA from the cytoplasm and bind to the cell surface in the earlyC. elegansembryo:recruitedformins, a functionally inactive population, andelongatingformins, which actively participate in actin filaments elongation. Focusing on formin dynamics during pulses, we show that minority elongating formins precede recruited formins, a kinetic dynamics compatible with formins capturing and rapidly saturating barbed ends available for filament elongation. We then show that these elongating formins assemble a polar network of actin, with barbed ends pointing out of the pulse, pointing to a kinetic rather than mechanical control of network architecture. Finally, our numerical simulations demonstrate that this geometry favors rapid network contraction. Our results thus show that formins saturate available actin filaments barbed ends and convert a local, biochemical gradient of RhoA activity into a polar network architecture, thereby driving rapid and efficient network contractility, an important evolutionary feature in a metazoan with a rapid embryonic cell cycles.

Highlights

The formin CYK-1 drives actin network assembly during RhoA-driven pulses

The process is extremely rapid, with a formin-based actin elongation rate higher than 1.3 μm·s-1

A barbed-end saturation mechanism allows for responsive F-actin assembly

Rapid and responsive F-actin elongation results in the assembly of aster-like polar actin networks

Numerical simulations show network polarity drives very efficient network contractility
Genetic toolkit for sociality predicts castes across the spectrum of social complexity in wasps
Authors: Wyatt Christopher D. R. , Bentley Michael , Taylor Daisy , Brock Ryan E. , Taylor Benjamin A. , Bell Emily , Leadbeater Ellouise , Sumner Seirian
Published: December 2020

Major evolutionary transitions describe how biological complexity arises; e.g. in evolution of complex multicellular bodies, and superorganismal insect societies. Such transitions involve the evolution of division of labour, e.g. as queen and worker castes in insect societies. Castes across different evolutionary lineages are thought to be regulated by a conserved genetic toolkit. However, this hypothesis has not been tested thoroughly across the complexity spectrum of the major transition. Here we reveal, using machine learning analyses of brain transcription, evidence of a shared genetic toolkit across the spectrum of social complexity in Vespid wasps. Whilst molecular processes underpinning the simpler societies (which likely represent the origins of social living) are conserved throughout the major transition, additional processes appear to come into play in more complex societies. Such fundamental shifts in regulatory processes with complexity may typify other major evolutionary transitions, such as the evolution of multicellularity.
The variant Senescence-Associated-Secretory-Phenotype induced by centrosome amplification constitutes a pathway that activates Hypoxia-Inducible-Factor-1α
Authors: Wu Selwin K. , Ariffin Juliana , Picone Remigio
Published: December 2020

The Senescence-Associated-Secretory Phenotype (SASP) promote paracrine invasion however may also suppress tumour growth, thus generating complex phenotypic outcomes. Although centrosome amplification can induce proliferation arrest, the subsequent fate of cells with centrosome amplification remains elusive. Here, we report that centrosome amplification induces a variant SASP, constituting a pathway activating paracrine invasion. The centrosome amplification SASP is non-canonical as it lacks detectable DNA damage or prominent NF-κB activation. Instead, involving Rac activation and reactive oxygen species production. Consequently, inducing hypoxia-inducible factor 1α and associated genes, which includes pro-migratory factors such as ANGPTL4. Since senescent cells also have poor fitness, it is tempting to speculate that centrosome amplification induced SASP is one explanation for why extra centrosomes promote malignancy in some experimental models but are neutral or inhibitory in others.
Memory-like B cells emerging from germinal centres recycle through the subcapsular sinus
Authors: Zhang Yang , Garcia-Ibanez Laura , Ulbricht Carolin , Lok Laurence S C , Dennison Thomas W , Ferdinand John R , Mueller-Winkler Jennifer , Burnett Cameron J M , Yam-Puc Juan C , Zhang Lingling , Brown Geoffrey , Tybulewicz Victor L J , Rot Antal , Hauser Anja E , Clatworthy Menna R , Toellner Kai-Michael
Published: December 2020

Infection or vaccination leads to the development of germinal centers (GCs) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. We followed the migratory pathways of B cells emerging from germinal centers (BEM) and found that many migrated into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From there, B cells may exit the lymph node to enter distant tissues. Some BEMcells interacted with and took up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibited the recycling of BEMcells and resulted in less efficient adaption to antigenic variation. Our findings suggest that the recycling of BEMcells, that transport antigen and that contain the genetic code for B cell receptor variants, may support affinity maturation to antigenic drift.
Mechanisms underlying neonate specific metabolic effects of volatile anesthetics
Authors: Stokes Julia , Freed Arielle , Pan Amanda , Sun Grace X , Bornstein Rebecca , Snell John , Park Kyung Yeon , Morgan Philip G , Sedensky Margaret M , Johnson Simon C
Published: December 2020

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well-documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood ß-hydroxybutarate (ß-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. ß-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of ß-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.
A predictive model of fractional land use
Authors: Kapitza Simon , Golding Nick , Wintle Brendan A.
Published: December 2020

Land use change leads to shifts in species ranges and declines in biodiversity across the world. By mapping likely future land use under projections of socio-economic change, these ecological changes can be predicted to inform conservation decision-making.

We present a land use modelling approach that enables ecologists to map changes in land use under various socio-economic scenarios at fine spatial resolutions. Its predictions can be used as a direct input to virtually all existing spatially-explicit ecological models.

The most commonly used land use modelling approaches provide binary predictions of land use. However, continuous representations of land use have been shown to improve ecological models. Our approach maps the fractional cover of land use within each grid cell, providing higher information content than discrete classes at the same spatial resolution.

When parametrized using data from 1990, the method accurately reproduced land use patterns observed in the Amazon from 1990 until 2018. Predictions were accurate in terms of the fractional amounts allocated across the landscape and the correct identification of areas with declines and increases in different land uses. A small case study showcases the successful application of our model to reproduce patterns of agricultural expansion and habitat decline.

The model source code is provided as an open-source R package, making this new, open method available to ecologists to bridge the gap between socio-economic, land use and biodiversity modelling.
Wild red wolfCanis rufuspoaching risk
Authors: Agan Suzanne W. , Treves Adrian , Willey Lisabeth
Published: December 2020

The reintroduced red wolf population in northeastern North Carolina declined to 7 known wolves by October 2020. Poaching (illegal killing) is the major component of verified anthropogenic mortality in this and many other carnivore populations, but it is still not well understood. Poaching is often underestimated, partly as a result of cryptic poaching, when poachers conceal evidence. Cryptic poaching inhibits our understanding of the causes and consequences of anthropogenic mortality which is important to conservation as it can inform us about future population patterns within changing political and human landscapes. We estimate risk for marked adult red wolves of 5 causes of death (COD: legal, nonhuman, unknown, vehicle and poached) and disappearance, describe variation in COD in relation to hunting season, and compare time to disappearance or death. We include unknown fates in our risk estimates. We found that anthropogenic COD accounted for 0.724 – 0.787, including cryptic and reported poaching estimated at 0.510 – 0.635 of 508 marked animals. Risk of poaching and disappearance was significantly higher during hunting season. Mean time from collaring until nonhuman COD averaged 376 days longer than time until reported poached and 642 days longer than time until disappearance. Our estimates of risk differed from prior published estimates, as expected by accounting for unknown fates explicitly. We quantify the effects on risk for three scenarios for disappearances, which span conservative to most likely COD. Implementing proven practices that prevent poaching or hasten successful reintroduction may reverse the decline to extinction in the wild of this critically endangered population. Our findings add to a growing literature on endangered species protections and enhancing the science used to measure poaching worldwide.
Decoding Study-Independent Mind-Wandering from EEG using Convolutional Neural Networks
Authors: Jin Christina Yi , Borst Jelmer P. , van Vugt Marieke K.
Published: December 2020

Objective

Mind-wandering is a mental phenomenon where the internal thought process disengages from the external environment periodically. In the current study, we trained EEG classifiers using convolutional neural networks (CNN) to track mind-wandering across studies.

Approach

We transformed the input from raw EEG to band-frequency information (power), singletrial ERP (stERP) patterns, and connectivity matrices between channels (based on inter-site phase clustering, ISPC). We trained CNN models for each input type from each EEG channel as the input model for the meta-learner. To verify the generalizability, we used leave-N-participant-out crossvalidations (N=6) and tested the meta-learner on the data from an independent study for across-study predictions.

Main results

The current results show limited generalizability across participants and tasks. Nevertheless, our meta-learned trained with the stERPs performed the best among the state-of-theart neural networks. The mapping of each input model to the output of the meta-learner indicates the importance of each EEG channel.

Significance

Our study makes the first attempt to train study-independent mind-wandering classifiers. The results indicate that this remains challenging. The current proposed stacking neural network design allows an easy inspection of channel importance and feature maps.
Disentangling the shark and ray trade in Indonesia to reconcile conservation with food security
Authors: Prasetyo Andhika P. , McDevitt Allan D. , Murray Joanna M. , Barry Jon , Agung Firdaus , Muttaqin Efin , Mariani Stefano
Published: December 2020

Indonesian marine resources are among the richest on the planet, sustaining highly diverse fisheries and includes the largest elasmobranch landings in the world, making Indonesia one of the world’s largest exporters of shark and ray products. Socio-economic and food security considerations pertaining to Indonesian communities add further layers of complexity to the management and conservation of these vulnerable species. This study investigates how shark and ray trade flows in and out of Indonesia and attempts to examine patterns and drivers of the current scenario. We identify substantial discrepancies between reported landings and declared exports, and between Indonesian exports in shark fin and meat products and the corresponding figures reported by importing countries. These mismatches are estimated to amount to over $43.6M and $20.9M for fins and meat, respectively, for the period between 2012 and 2018. Although the declared exports are likely to be an underestimation because of significant unreported or illegal trading activities, we find that domestic consumption of shark and ray products plays a significant role in explaining these discrepancies due to the increasing local demand for meat. The study also unearths a general scenario of unsystematic data collection and lack of granularity of product terminology, which is inadequate to meet the challenges of over-exploitation, illegal trade and food security in Indonesia. We discuss how to improve data transparency to support trade regulations and governance actions, by improving inspection measures, and conserving elasmobranch populations without neglecting the socio-economic dimension of this complex system.
Complete Protection of Nasal and Lung Airways Against SARS-CoV-2 Challenge by Antibody Plus Th1 Dominant N- and S-Specific T-Cell Responses to Subcutaneous Prime and Thermally-Stable Oral Boost Bivalent hAd5 Vaccination in an NHP Study
Authors: Gabitzsch Elizabeth , Safrit Jeffrey T. , Verma Mohit , Rice Adrian , Sieling Peter , Zakin Lise , Shin Annie , Morimoto Brett , Adisetiyo Helty , Wong Raymond , Bezawada Ashish , Dinkins Kyle , Balint Joseph , Peykov Victor , Garban Hermes , Liu Philip , Bone Pete , Bacon Andrew , Drew Jeff , Sanford Daniel C. , Spilman Patricia , Sender Lennie , Rabizadeh Shahrooz , Niazi Kayvan , Soon-Shiong Patrick
Published: December 2020

We have developed a dual-antigen COVID-19 vaccine incorporating genes for a modified SARS-CoV-2 spike (S-Fusion) protein and the viral nucleocapsid (N) protein with an Enhanced T-cell Stimulation Domain (N-ETSD) with the potential to increase MHC class I/II responses. The adenovirus serotype 5 platform used, hAd5 [E1-, E2b-, E3-], previously demonstrated to be effective in the presence of Ad immunity, can be delivered in an oral formulation that overcomes cold-chain limitations. The hAd5 S-Fusion + N-ETSD vaccine was evaluated in rhesus macaques showing that a subcutaneous prime followed by oral boosts elicited both humoral and Th1 dominant T-cell responses to both S and N that protected the upper and lower respiratory tracts from high titer (1 x 106TCID50) SARS-CoV-2 challenge. Notably, viral replication was inhibited within 24 hours of challenge in both lung and nasal passages, becoming undetectable within 7 days post-challenge.

ONE SENTENCE SUMMARY

hAd5 spike + nucleocapsid SC prime/oral boost vaccine elicits humoral and T-cell responses and protects rhesus macaques from SARS-CoV-2 challenge.
Biologically informed deep neural network for prostate cancer classification and discovery
Authors: Elmarakeby Haitham A. , Hwang Justin , Liu David , AlDubayan Saud H. , Salari Keyan , Richter Camden , Arnoff Taylor E , Park Jihye , Hahn William C. , Van Allen Eliezer
Published: December 2020

Determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer (PrCa) remains a major biological and clinical challenge. Here, we developed a biologically informed deep learning model (P-NET) to stratify PrCa patients by treatment resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. Using a molecular cohort of 1,238 prostate cancers, we demonstrated that P-NET can predict cancer state using molecular data that is superior to other modeling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such asMDM4andFGFR1, that were implicated in predicting advanced disease and validatedin vitro. Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.
Host response to cholestyramine can be mediated by the gut microbiota
Authors: Newman Nolan K. , Monnier Philip M. , Rodrigues Richard R. , Gurung Manoj , Vasquez-Perez Stephany , Hioki Kaito A. , Greer Renee L. , Brown Kevin , Morgun Andrey , Shulzhenko Natalia
Published: December 2020

The gut microbiome has been implicated as a major factor contributing to metabolic diseases as well as being contributors to the response to drugs used for the treatment of such diseases. In this study, using a diet-induced obesity mouse model, we tested the effect of cholestyramine, a bile acid sequestrant, on the murine gut microbiome and mammalian metabolism. We also explored the hypothesis that some beneficial effects of this drug on systemic metabolism can be attributed to alterations in gut microbiota. First, we demonstrated that cholestyramine can decrease glucose and epidydimal fat levels. Next, while investigating gut microbiota we found increased alpha diversity of the gut microbiome of cholestyramine-treated mice, with fourteen taxa showing restoration of abundance to levels resembling those in mice fed with a control diet. Analyzing expression of genes known to be regulated by cholestyramine (including Cyp7a1), we confirmed the expected effect of this drug in the liver and ileum. Finally, using a transkingdom network analysis we inferredAcetatifactor murisandMuribaculum intestinaleas potential mediators/modifiers of cholestyramine effects on the mammalian host. In addition,A. muriscorrelated positively with glucagon (Gcg) expression in the ileum and negatively correlated with small heterodimer partner (Shp) expression in the liver. Interestingly,A. murisalso correlated negatively with glucose levels, further indicating the potential probiotic role forA. muris. In conclusion, our results indicate the gut microbiome has a role in the beneficial effects of cholestyramine and suggest specific microbes as targets of future investigations.
Non-Vertical Cultural Transmission, Assortment, and the Evolution of Cooperation
Authors: Cohen Dor , Lewin-Epstein Ohad , Feldman Marcus W. , Ram Yoav
Published: December 2020

Cultural evolution of cooperation under vertical and non-vertical cultural transmission is studied, and conditions are found for fixation and coexistence of cooperation and defection. The evolution of cooperation is facilitated by its horizontal transmission and by an association between social interactions and horizontal transmission. The effect of oblique transmission depends on the horizontal transmission bias. Stable polymorphism of cooperation and defection can occur, and when it does, reduced association between social interactions and horizontal transmission evolves, which leads to a decreased frequency of cooperation and lower population mean fitness. The deterministic conditions are compared to outcomes of stochastic simulations of structured populations. Parallels are drawn with Hamilton’s rule incorporating assortment and effective relatedness.
RAS specific protease Induces Irreversible Growth Arrest via p27 in several KRAS Mutant Colorectal Cancer cell lines
Authors: Stubbs Caleb K. , Biancucci Marco , Vidimar Vania , Satchell Karla J. F.
Published: December 2020

Ras-specific proteases to degrade RAS within cancer cells are under active development as an innovative strategy to treat tumorigenesis. The naturally occurring biological toxin effector called RAS/RAP1-specific endopeptidase (RRSP) is known to cleave all RAS within a cell, including HRAS, KRAS, NRAS and mutant KRAS G13D. In the course of studies developing RRSP as an anti-cancer therapeutic, it was shown that cleavage of total RAS by RRSP results in a range of cell fates from cytotoxicity to moderate growth inhibition. Despite the considerable amount of evidence demonstrating RRSP anti-tumor effectsin vivo,our understanding of the mechanisms involved are unknown. Here, we first demonstrate, using isogenic mouse fibroblasts expressing a single isoform of RAS or mutant KRAS, that RRSP equally inactivates all isoforms of RAS as well as the major oncogenic KRAS mutants. The cleavage of RAS inhibited phosphorylation of ERK and cell proliferation regardless of the RAS isoform. To investigate further how RAS processing might lead to varying outcomes in cell fate within cancer cells, we tested RRSP against four colorectal cancer cell lines with a range of cell fates. While cell lines highly susceptible to RRSP (HCT116 and SW1463) undergo cytotoxic death, RRSP treatment of GP5d cells induces G1 cell cycle arrest, and SW620 cells instead induces growth inhibition through cell senescence. In three of four cell lines tested, growth effects were dictated by rescued expression of the tumor suppressor protein p27 (Kip1). The ability of RRSP to inactivate all RAS and inhibit cancer cell growth through a variety of mechanisms highlights the antitumor potential of RRSP, and further warrants investigation as a potential anti-tumor therapeutic.
Design of a radial multi-offset detection pattern forin vivophase contrast imaging of the retinal ganglion cells in humans
Authors: Gofas-Salas Elena , Rui Yuhua , Mecê Pedro , Zhang Min , Snyder Valerie C. , Vienola Kari V. , Lee Daniel , Sahel José-Alain , Grieve Kate , Rossi Ethan A.
Published: December 2020

Previous work has shown that multi-offset detection in adaptive optics scanning laser ophthalmoscopy (AOSLO) can be used to image retinal ganglion cells (RGCs) in monkeys and humans. However, though images of RGCs in anesthetized monkeys with high light levels produced high contrast images of RGCs, images from humans failed to reach the same contrast due to several drawbacks in the previous dual-wavelength multi-offset approach. Our aim here was to design and build a multi-offset detection pattern for humans at safe light levels that could reveal the retinal ganglion cell layer neurons with a contrast, robustness and acquisition time approaching results only previously obtained in monkeys. Here, we present a new imaging system using only one light source, compared to the previous dual-wavelength used on monkeys. Our single-wavelength solution allows for increased light power and eliminates problematic chromatic aberrations. Then, we demonstrate that a radial multi-offset detection pattern with an offset distance of 8-10 Airy Disk Diameter (ADD) is optimal to detect photons multiply scattered in all directions from RGCs thereby enhancing their contrast. This new setup and image processing pipeline led to improved imaging of retinal ganglion cells using multi-offset imaging in AOSLO.
Archaeal chromatin ‘slinkies’ are inherently dynamic complexes with deflected DNA wrapping pathways
Authors: Bowerman Samuel , Wereszczynski Jeff , Luger Karolin
Published: December 2020

Eukaryotes and many archaea package their DNA with histones. While the four eukaryotic histones wrap ∼147 DNA base pairs into nucleosomes, archaeal histones form “nucleosome-like” complexes that continuously wind between 60 - 500 base pairs of DNA (“archaeasomes”), suggested by crystal contacts and analysis of cellular chromatin. Solution structures of large archaeasomes (>90 DNA base pairs) have never been directly observed. Here, we utilize molecular dynamics simulations, analytical ultracentrifugation, and cryoEM to structurally characterize the solution state of archaeasomes on longer DNA. Simulations reveal dynamics of increased accessibility without disruption of DNA-binding or tetramerization interfaces. Mg2+concentration influences compaction, and cryoEM densities illustrate that DNA is wrapped in consecutive substates arranged 90°out-of-plane with one another. Without ATP-dependent remodelers, archaea may leverage these inherent dynamics to balance chromatin packing and accessibility.
Construction of a liquid-liquid phase separation system from the gel-sol transition of elongated protein microgels in a crowding agent
Authors: Xu Yufan , Qi Runzhang , Zhu Hongjia , Li Bing , Shen Yi , Krainer Georg , Klenerman David , Knowles Tuomas P. J.
Published: December 2020

Liquid proteinaceous materials have been frequently found in cells or tissues and are crucial for various biological processes. Unlike their solid-state counterparts, liquid-state protein compartments are challenging to engineer and control at the microscale. Conventionally, gelation (sol-gel transition) of biological molecules has been thought to be the intermediate step between liquid-liquid phase separation (LLPS) states and insoluble aggregates that are related to protein functions, malfunctions and even diseases. However, the opposite process, i.e., the gel-sol transition of materials, has not been broadly explored. Here we describe a thermoresponsive gel-sol transition of a protein in a crowded environment that results in a demixed LLPS state, contradicting the common consequence of a one-phase protein solution by the end of such transition at elevated temperature without crowding agents. We also demonstrate a simple method to monitor the gel-sol transition by showing that elongated gelatin microgels can evolve towards a spherical morphology in the crowding agents because of interfacial tension. The LLPS system was explored for the diffusion of small particles for drug-release application scenarios. Our results demonstrate a route for the rapid construction of LLPS models, where the gel-sol transition of the protein-rich phase is monitorable. The models are featured with tunable size and dimensional monodispersity of dispersed condensates. The present study can be employed in biophysics and bioengineering with practices such as 3D printing and temperature sensing.