bluuebunny/crossref_metadata_2025 huggingface dataset:
Food insecurity during COVID-19: A multi-state research collaborative
Authors: Niles Meredith T. , Belarmino Emily H. , Bertmann Farryl , Biehl Erin , Acciai Francesco , Josephson Anna , Ohri-Vachaspati Punam , Neff Roni
Published: December 2020

The COVID-19 pandemic has had profound impacts on the global food system, supply chain, and employment, which, in turn, has created numerous challenges to food access and food security. Early exploratory studies suggest significant increases in food insecurity in the United States. Comprehensive longitudinal research across multiple locations is needed to understand the range of impacts and responses at the household level and to improve preparedness for future events. This protocol paper outlines the formation of the National Food Access and COVID research Team (NFACT), a collaborative, interdisciplinary, multi-state research effort that will utilize common measurement tools, codebooks, code, data aggregation tools, and outreach materials to collectively examine and communicate the effect of COVID-19 on household food access and security. NFACT is led by an executive committee of researchers from four institutions, with additional NFACT collaborating institutions across more than a dozen states. A survey was developed by the NFACT executive team in March 2020, with additional refinements in May 2020, using both existing validated questions and new original questions, which were piloted and validated in Vermont. The project provides suggestive guidance for recruitment, and is designed to allow each study site to adopt recruitment strategies that meet their budget and needs. Primary outcomes of interest include food security status, employment status, food access challenges and concerns, dietary intake, and use of food assistance programs. Additional outcomes assess emotional eating, stigma, COVID-19 perceptions and experiences, and pro-environmental purchasing behaviors. This protocol and the establishment of NFACT provide important advancements in COVID-19 and food security research by generating harmonized data and assessing comparable outcomes across geographies and time. The collaborative, open-source approach makes research tools available to teams who might not have the resources to design their own tools, and can enable streamlined data collection, large-scale comparative analyses, and cost savings through reduced administrative tasks. The project has contributed to building new networks between and within states. Enabling facilitation and implementation of instruments in study sites has provided flexibility and meaningful opportunity for local stakeholder engagement and relevant outreach for informed public health decision-making.
Characterization of Structural Variation in Tibetans Reveals New Evidence of High-altitude Adaptation and Introgression
Authors: Quan Cheng , Li Yuanfeng , Wang Yahui , Ping Jie , Lu Yiming , Zhou Gangqiao
Published: December 2020

Structural variation (SV) acts as an essential mutational force shaping the evolution and function of the human genome. To investigate the role of SVs in high-altitude adaptation (HAA), we here generated a comprehensive catalog of SVs in a Chinese Tibetan (n = 15) and Han (n = 10) population using the nanopore sequencing technology. Among a total of 38,216 unique SVs in the catalog, 27% were sequence-resolved for the first time. We systemically assessed the distribution of these SVs across repeat sequences and functional genomic regions. Through genotyping in additional 189 genomes, we identified 90 Tibetan-Han stratified SVs and 124 candidate adaptive genes. Besides, we discovered 15 adaptive introgressed SV candidates and provided evidence for a deletion of 335 base pairs at 1p36.32. Overall, our results highlight the important role of SVs in the evolutionary processes of Tibetans’ adaptation to the Qinghai-Tibet Plateau and provide a valuable resource for future HAA studies.
Maternal vgll4a promotes blastoderm cohesion enabling yap1-mediated mechano-transduction during zebrafish epiboly
Authors: Camacho-Macorra Carlos , Tabanera Noemí , Bovolenta Paola , Cardozo Marcos J
Published: December 2020

Cellular cohesion provides tissue tension, which is then sensed by the cytoskeleton and decoded by the activity of mechano-transducers, such as the transcriptional cofactor Yap1, thereby enabling morphogenetic responses in multi-cellular organisms. How cell cohesion is regulated is nevertheless unclear. Here we show that, zebrafish epiboly progression, a prototypic morphogenetic event that depends on Yap activity, requires the maternal contribution of the proposed yap1 competitor vgll4a. In embryos lacking maternal/zygoticvgll4a(MZvgll4a), spreading epithelial cells are ruffled, blastopore closure is delayed and the expression of the yap1-mediatorarhgap18is decreased, impairing the actomyosin ring at the syncytial layer. Furthermore, rather than competing with Yap1, vgll4a coordinate the levels of the E-Cadherin/β-catenin adhesion complex components at the blastomere plasma membrane and hence their actin cortex distribution. Taking these results together, we propose that maternal vgll4a may act at epiboly initiation to coordinate blastomere adhesion/cohesion, which is a fundamental piece of the self-sustained bio-mechanical regulatory loop underlying morphogenetic rearrangements during gastrulation.
Using explainable machine learning to identify patients at risk of reattendance at discharge from emergency departments
Authors: Chmiel F. P. , Burns D. K. , Azor M. , Borca F. , Boniface M. J. , Zlatev Z. D. , White N. M. , Daniels T. W. V. , Kiuber M.
Published: December 2020

Short-term reattendances to emergency departments are a key quality of care indicator. Identifying patients at increased risk of early reattendance could help reduce the number of missed critical illnesses and could reduce avoidable utilization of emergency departments by enabling targeted post-discharge intervention. In this manuscript we present a retrospective, single-centre study where we created and evaluated an extreme gradient boosted decision tree model trained to identify patients at risk of reattendance within 72 hours of discharge from an emergency department (University Hospitals Southampton Foundation Trust, UK). Our model was trained using 35,447 attendances by 28,945 patients and evaluated on a hold-out test set featuring 8,847 attendances by 7,237 patients. The set of attendances from a given patient appeared exclusively in either the training or the test set. Our model was trained using both visit level variables (e.g., vital signs, arrival mode, and chief complaint) and a set of variables available in a patients electronic patient record, such as age and any recorded medical conditions. On the hold-out test set, our highest performing model obtained an AUROC of 0.747 (95% CI : 0.722-0.773) and an average precision of 0.233 (95% CI : 0.194-0.277). These results demonstrate that machine-learning models can be used to classify patients, with moderate performance, into low and high-risk groups for reattendance. We explained our models predictions using SHAP values, a concept developed from coalitional game theory, capable of explaining predictions at an attendance level. We demonstrated how clustering techniques can be used to investigate the different sub-groups of explanations present in our patient cohort.
The moderating impact of the genetic predisposition to smoking behaviour on the response to tobacco excise taxes
Authors: Slob Eric A.W. , Rietveld Cornelius A.
Published: December 2020

Tobacco consumption is one of the leading causes of preventable death. While some public policies have been effective in reducing the smoking prevalence in the United States, high tobacco excise taxes do not appear to deter all individuals from starting smoking nor to affect the smoking intensity of all those who do smoke. Here, we analyse whether someone’s genetic predisposition to smoking may explain why individuals smoke despite high tobacco excise taxes. For this purpose, we interact polygenic risk scores for smoking behaviour with state-level excise tax rates on tobacco. Our analyses exploiting longitudinal data (1992-2016) from the US Health and Retirement Study show that someone’s genetic propensity to smoking moderates the effect of tobacco excise taxes on smoking behaviour along the extensive margin (smoking vs. not smoking) and the intensive margin (the amount of tobacco consumed). That is, when tobacco excise taxes are relatively low, those with a high genetic predisposition to smoking are more likely (i) to smoke, and (ii) to smoke a relatively high number of cigarettes per day. In our sample, we do not find a significant interaction effect on smoking cessation.
Model for evaluating cost-effectiveness of surveillance testing for SARS-CoV2
Authors: Silver Jonathan
Published: December 2020

Testing people without symptoms for SARS-CoV-2 followed by isolation of those who test positive could mitigate the covid-19 epidemic pending arrival of an effective vaccine. Key questions for such programs are who should be tested, how often, and when should such testing stop. Answers to these questions depend on test and population characteristics. A cost-effectiveness model that provides answers depending on user-adjustable parameter values is described. Key parameters are the value ascribed to preventing a death and the reproduction number (roughly, rate of spread) at the time surveillance testing is initiated. For current rates of spread, cost-effectiveness usually requires a value per life saved greater than $100,000 and depends critically on the extent and frequency of testing.
Clinical Evaluation of a COVID-19 Antibody Lateral Flow Assay using Point of Care Samples
Authors: Lee Won , Straube Steven , Sincic Ryan , Noble Jeanne A. , Montoy Juan Carlos , Kornblith Aaron E. , Prakash Arun , Wang Ralph , Bainton Roland J. , Kurien Philip A.
Published: December 2020

Introduction

The ongoing SARS-CoV-2 pandemic has spurred the development of numerous point of care (PoC) immunoassays. Assessments of performance of available kits are necessary to determine their clinical utility. Previous studies have mostly performed these assessments in a laboratory setting, which raises concerns of translating findings for PoC use. The aim of this study was to assess the performance of a lateral flow immunoassay for the detection of SARS-CoV-2 antibodies using samples collected at PoC.

Method

One lateral flow immunoassay (Humasis®COVID-19 IgG/IgM) was tested. In total, 50 PCR RT-PCR positive and 52 RT-PCR negative samples were collected at PoC. Fifty serum specimens from Dec 2018 to Feb 2019 were used as controls for specificity. Serum samples collected between Dec 2019 to Feb 2020 were used as additional comparators. Clinical data including symptom onset date was collected from patient history and the medical record.

Results

The overall sensitivity for the kit was 74% (95% CI: 59.7% -85.4%). The sensitivity for IgM and IgG detection >14 days after date of onset was 88% (95% CI: 68.8% -97.5%) and 84% (95% CI: 63.9% – 95.5%), with a negative predictive value (NPV) of 94% for IgM (95% CI: 83.5% - 98.8%) and 93% for IgG (95% CI: 81.8% - 97.9%). The overall specificity was 94% (95% CI: 83.5% - 98.8%). The Immunoglobulin specific specificity was 94% for IgM (95% CI: 83.5% - 98.8%) and 98% for IgG (95% CI: 89.4% - 100.0%), with a positive predictive value (PPV) of 88% for IgM (95% CI: 68.8% - 97.5%) and 95% for IgG (95% CI: 77.2% - 99.9%) respectively for samples collected from patients >14 days after date of onset. Specimen collected during early phase of COVID-19 pandemic (Dec 2019 to Feb 2020) showed 11.8% antibody positivity, and 11.3% of PCR-negative patients demonstrated antibody positivity.

Discussion

Humasis®COVID-19 IgG/IgM LFA demonstrates greater than 90% PPV and NPV for samples collected 14 days after the onset of symptoms using samples collected at PoC. While not practical for the diagnosis of acute infection, the use of the lateral flow assays with high specificity may have utility for determining seroprevalence or seroconversion in longitudinal studies.
Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction
Authors: Akbar Naveed , Forteath Calum , Hussain Muhammad S. , Reyskens Kathleen , Belch Jill J. F. , Lang Chim C. , Mordi Ify , Bhalraam U , Arthur J. Simon C. , Khan Faisel
Published: December 2020

Inflammation promotes endothelial dysfunction. Using translational vascular function testing in myocardial Infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Selective activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial function before development of significant vascular disease.

Graphical Abstract
Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Hydroxychloroquine in Healthy Volunteers
Authors: de Reus Y.A. , Hagedoorn P. , Sturkenboom M.G.G. , Grasmeijer F. , Bolhuis M.S. , Sibum I. , Kerstjens H.A.M. , Frijlink H.W. , Akkerman O.W.
Published: December 2020

Rationale

Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing for higher and therefore more effective pulmonary concentrations without dose limiting toxic effects.

Objectives

To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler.

Methods

12healthy volunteers were trained in inhaling HCQ correctly. Local tolerability and safety were assessed by pulmonary function tests, ECG and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation.

Results and discussion

Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1post inhalation. The serum HCQ concentration remained below 10 µg/L in all samples.

Conclusion

Inhaled dry powder HCQ is safe and well tolerated. Our data support further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy is warranted.
Long Covid and the role of physical activity: a qualitative study
Authors: Humphreys Helen , Kilby Laura , Kudiersky Nik , Copeland Robert
Published: December 2020

Objectives

To explore the lived experience of Long Covid with particular focus on the role of physical activity

Design

Qualitative study using semi-structured interviews

Participants

18 people living with Long Covid (9 male, 9 female; aged between 18-74; 10 White British, 3 White Other, 3 Asian, 1 Black, 1 mixed ethnicity) recruited via a UK-based research interest database for people with Long Covid

Setting

Telephone interviews with 17 participants living in the UK and 1 participant living in the US

Results

Four themes were generated. Theme one highlights the physical and social isolation experienced by people with Long Covid, compounded by a lack of support and advice from medical professionals. Theme two describes how participants sought information and validation through online sources and communities. Theme three captures the challenges associated with managing physical and cognitive effects of Long Covid including fatigue and ‘brain fog’ whilst trying to resume and maintain activities of daily living and other forms of exercise. Theme four illustrates the battle with self-concept to accept reduced function (even temporarily) and the fear of permanent reduction in physical and cognitive ability.

Conclusions

This study provides insight into the challenges of managing physical activity alongside the extended symptoms associated with Long Covid. Findings highlight the need for greater consensus around physical activity-related advice for people with Long Covid and improved support to resume activities considered important for wellbeing.

Article Summary

Strengths and limitations of this study

To our knowledge, this paper is the first to explore the role of physical activity in the lived experience of Long Covid using a qualitative approach

The study design enabled in-depth inquiry of lived experiences in a diverse sample

Inductive thematic analysis ensured descriptions and interpretations of the lived experience were tested and found to be grounded in the data

Participants were recruited from members of a Long Covid research interest database who registered via an on-line form, meaning study findings might not capture the views of digitally excluded populations

Funding statement

This work was supported by Sheffield Hallam University.

Competing interests

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Association between Participation in Government Subsidy Program for Domestic Travel and Symptoms Indicative of COVID-19 Infection
Authors: Miyawaki Atsushi , Tabuchi Takahiro , Tomata Yasutake , Tsugawa Yusuke
Published: December 2020

Importance

As countermeasures against the economic downturn caused by the coronavirus 2019 (COVID-19) pandemic, many countries have introduced or considering financial incentives for people to engage in economic activities such as travel and use restaurants. Japan has implemented a large-scale, nationwide government-funded program that subsidizes up to 50% of all travel expenses since July 2020 with the aim of reviving the travel industry. However, it remains unknown as to how such provision of government subsidies for travel impacted the COVID-19 pandemic.

Objective

To investigate the association between participation in government subsidies for domestic travel in Japan and the incidence of COVID-19 infections.

Design, Setting, and Participants

Using the data from a large internet survey conducted between August 25 and September 30, 2020, in Japan, we examined whether individuals who used subsidies experienced a higher likelihood of symptoms indicative of the COVID-19 infection.

Exposure

Participation in the government subsidy program for domestic travel.

Main Outcomes and Measures

Five symptoms indicative of the COVID-19 infection (high fever, sore throat, cough, headache, and smell and taste disorder) within the past one month of the survey.

Results

Of the 25,482 respondents (50.3% [12,809] women; mean [SD] age, 48.4 [17.4] years), 3,289 (12.9%) participated in the subsidy program at the time of survey. After adjusting for potential confounders, we found that participants in the subsidy program exhibited higher incidence of high fever (adjusted rate, 4.8% for participants vs. 3.7% for non-participants; adjusted odds ratio [aOR], 1.90; 95%CI, 1.42-2.54; p<0.001), sore throat (19.8% vs. 11.3%; aOR, 2.09; 95%CI, 1.37-3.20; p=0.002), cough (19.1% vs. 11.2%; aOR 1.96; 95%CI, 1.27-3.02; p=0.007), headache (29.1% vs. 25.5%; aOR, 1.24; 95%CI, 1.07-1.43; p=0.007), and smell and taste disorder (2.6% vs. 1.8%; aOR 1.98; 95%CI; 1.15-3.40; p=0.01) compared with non-participants.

Conclusion and Relevance

The participants of government subsidies for domestic travel experienced a higher incidence of symptoms indicative of the COVID-19 infection.
Opportunities to catalyze improved healthcare access in pluralistic systems: a cross-sectional study in Haiti
Authors: Klarman Molly B , Schon Justin , Cajusma Youseline , Maples Stace , Beau de Rochars Valery M , Baril Chantale , Nelson Eric J
Published: December 2020

Introduction

Gains to ensure global healthcare access are at risk of stalling because some old resilient challenges require new solutions. Our objective was to study a pluralistic healthcare system that is reliant on both conventional and non-conventional providers to discover opportunities to catalyze renewed progress.

Methods

A cross-sectional study was conducted among households with children less than 5 years of age in Haiti. Households were randomly sampled geographically with stratifications for population density. Household questionnaires with standardized cases (intentions) were compared to self-recall of health events (behaviors). The connectedness of households and their providers was determined by network analysis.

Results

A total of 568 households (incorporating 2900 members) and 65 providers were enrolled. Households reported 636 health events in the prior month. Households sought care for 35% (n=220) and treated with home remedies for 44% (n=277). The odds of seeking care increased 217% for severe events (aOR=3.17; 95%CI 1.99-5.05; p< 0.001). The odds of seeking care from a conventional provider increased by 37% with increasing distance (aOR=1.37; 95%CI 1.06-1.79; p=0.016). Despite stating an intention to seek care from conventional providers, there was a lack of congruence in practice that favored non-conventional providers (McNemar’s Chi-squared Test p<0.001). Care was sought from primary providers for 68% (n=150) of cases within a three-tiered network; 25% (n=38/150) were non-conventional.

Conclusion

Addressing geographic barriers, possibly with technology solutions, should be prioritized to meet healthcare seeking intentions while developing approaches to connect non-conventional providers into healthcare networks when geographic barriers cannot be overcome.

Article Summary

The study is inclusive of both conventional and non-conventional healthcare providers, reflecting Haiti’s pluralistic healthcare system.

The study utilized randomized geospatial sampling method to ensure participants were geographically representative of all families in the study area.

Employed an unique application of network analysis to observe relationships between families and healthcare providers to identify approaches to increase healthcare access in seemingly change resilient pluralistic systems.

A limitation of the approach to compare healthcare seeking intentions and behaviors was that the standardized case scenarios did not cover all health event scenarios.

A limitation on enrollment was that non-conventional healthcare providers were more difficult to locate than conventional providers.
Risk factors for severe illness and death in COVID-19: a systematic review and meta-analysis
Authors: Degarege Abraham , Naveed Zaeema , Kabayundo Josiane , Brett-Major David
Published: December 2020

Objectives

This systematic review and meta-analysis synthesized the evidence on the impact of demographics and comorbidities with clinical outcomes of COVID-19, including severe illness, admission to the intensive care unit (ICU), and death.

Methods

The PRISMA guidelines were followed to conduct and report this meta-analysis. The protocol is registered in PROSPERO International prospective register of systematic reviews (ID=CRD42020184440). Two authors independently searched literature from PubMed, Embase, Cochrane library and CINHAL on May 6, 2020; removed duplicates; screened titles, abstracts and full text using criteria; and extracted data from eligible articles. A random-effects model was used to estimate the summary odds ratio (OR). Variations among studies were examined using Cochrane Q and I2.

Results

Out of 4,275 articles obtained from the databases and screened, 71 studies that involved 216,843 patients were abstracted and then, where appropriate, analyzed by meta-analysis. The COVID-19 related outcomes reported were death in 26 studies, severe illness in 41 studies, and admission to ICU in 11 studies. Death was significantly correlated with hypertension (OR 2.60, 95% CI 1.95–3.25, I2 = 52.6%, n= 13 studies), cardiovascular disease (5.16, 4.10–6.22, 0.0%, 6), diabetes (2.11, 1.35–2.87, 67.4%, 12), chronic respiratory disease (2.83, 2.14–3.51, 0.0%, 9), cerebrovascular diseases (5.14, 1.08–9.19, 0.0%, 2), male sex (1.34, 1.18 1.50, 38.7%, 16), age older than 60 (6.09, 3.53 8.66, 95.5%, 6) or 65 years (3.56, 1.21 5.90, 18.2%, 6). Severe illness was also significantly associated with hypertension (1.70, 1.30 –2.10, 47.8%, 21), cardiovascular diseases (2.04, 1.01–3.08, 30.6%, 10), diabetes (1.65, 1.23–2.08, 24.9%, 18), male sex (1.35, 1.23 1.47, 0.0%, 32) and age at least 60 (4.91, 1.35 8.47, 0.0%, 4) or 65 (2.55,1.94 3.17, 24.5%, 9) years. Among hospitalized patients, the odds of admission to ICU was greater in individuals who had cardiovascular diseases (1.36,1.04–1.69, 0.0%, 4), diabetes (1.55, 1.20–1.90, 0.0%, 5) and chronic respiratory disease (1.52, 1.09–1.94, 0.0%, 5) than those who were not having these comorbidities.

Conclusions

Older age and chronic diseases increase the risk of developing severe illness, admission to ICU and death among COVID-19 patients. Special strategies are warranted to prevent SARS-CoV-2 infection and manage COVID-19 cases in those with vulnerabilities.
MACE2K: A Text-Mining Tool to Extract Literature-based Evidence for Variant Interpretation using Machine Learning
Authors: Gupta Samir , Rao Shruti , Miglani Trisha , Iyer Yasaswini , Lin Junxia , Saiyed Ahson M. , Ikwuemesi Ifeoma , McNulty Shannon , Thaxton Courtney , Madhavan Subha
Published: December 2020

Interpretation of a given variant’s pathogenicity is one of the most profound challenges to realizing the promise of genomic medicine. A large amount of information about associations between variants and diseases used by curators and researchers for interpreting variant pathogenicity is buried in biomedical literature. The development of text-mining tools that can extract relevant information from the literature will speed up and assist the variant interpretation curation process. In this work, we present a text-mining tool, MACE2k that extracts evidence sentences containing associations between variants and diseases from full-length PMC Open Access articles. We use different machine learning models (classical and deep learning) to identify evidence sentences with variant-disease associations. Evaluation shows promising results with the best F1-score of 82.9% and AUC-ROC of 73.9%. Classical ML models had a better recall (96.6% for Random Forest) compared to deep learning models. The deep learning model, Convolutional Neural Network had the best precision (75.6%), which is essential for any curation task.
Serine Palmitoyltransferase Controls Stemness of Intestinal Progenitors
Authors: Li Ying , Chaurasia Bhagirath , Kaddai Vincent , Wilkerson Joseph L. , Alan Maschek J. , Cox James , Wei Peng , Bensard Claire , Meikle Peter J , Clevers Hans , Shayman James A , Hirabayashi Yoshio , Holland William L. , Rutter Jared , Summers Scott A.
Published: December 2020

Cancers of the gastrointestinal tract including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia are common comorbidities of obesity. Excessive delivery of macronutrients to the cells lining the gut can increase one’s risk for these cancer by inducing imbalances in the rate of intestinal stem cell proliferation vs. differentiation, which can produce polyps and other aberrant growths. We demonstrate that serine palmitoyltransferase (SPT), which diverts dietary fatty and amino acids into the sphingolipid biosynthesis pathway, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the biosynthetic pathway are upregulated in human colon tumors. These enzymes produce sphingolipids that serve as pro-stemness signals that stimulate peroxisome-proliferator activated receptor alpha (PPARα)-mediated induction of fatty acid binding protein-1. This increases fatty acid uptake and oxidation and enhances the stemness program. Serine palmitoyltransferase thus serves as a critical link between dietary macronutrients, epithelial regeneration, and cancer risk.
Efferent control of hearing sensitivity and protection via inner ear supporting cells
Authors: Zhao Hong-Bo , Liu Li-Man , Yu Ning , Zhu Yan , Mei Ling , Chen Jin , Liang Chun
Published: December 2020

It is well-known that medial olivocochlear (MOC) efferent nerves innervate outer hair cells (OHCs) and inhibit OHC electromotility to control hearing sensitivity. Here, we report that the MOC nerve fibers associated with MOC neurotransmitter acetylcholine (ACh) receptors and presynaptic vesicular acetylcholine transporters (VAChT) also innervated the cochlear supporting cells (SCs). Application of ACh could evoke inward currents in SCs and reduced gap junctions (GJs) between them with long-lasting effect. We further found that uncoupling of GJs between SCs shifted OHC electromotility to the left hyperpolarization direction and enhanced the direct effect of ACh on OHC electromotility. Diminution of this control by deficiency of GJs between SCs compromised the regulation of active cochlear amplification and increased susceptibility to noise. These data suggest that the MOC efferent system has functional innervations with SCs. Such efferent innervation may have an important role in the protection of hearing from noise and slow efferent effect.
Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, while the Alzheimer’s R47H mutant does the opposite
Authors: Vilalta Anna , Zhou Ye , Sevalle Jean , Griffin Jennifer K. , Satoh Kanayo , Allendorf David H. , De Suman , Puigdellívol Mar , Bruzas Arturas , Burguillos Miguel A. , Dodd Roger B. , Chen Fusheng , Zhang Yalun , Flagmeier Patrick , Needham Lisa-Maria , Enomoto Masahiro , Qamar Seema , Henderson James , Walter Jochen , Fraser Paul E. , Klenerman David , Lee Steven F. , St George-Hyslop Peter , Brown Guy C.
Published: December 2020

Missense mutations (e.g. R47H) of the microglial receptor TREM2 increase risk of Alzheimer’s disease (AD), and the soluble ectodomain of wild-type TREM2 (sTREM2) appears to protect in vivo, but the underlying mechanisms are unclear. We show that Aβ oligomers bind to TREM2, inducing shedding of sTREM2. Wild-type sTREM2 inhibits Aβ oligomerization, fibrillization and neurotoxicity, and disaggregates preformed Aβ oligomers and protofibrils. In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aβ, but rather promotes Aβ protofibril formation and neurotoxicity. Thus, in addition to mediating phagocytosis, wild-type TREM2 may protect against amyloid pathology by Aβ-induced release of sTREM2 that blocks Aβ aggregation and neurotoxicity; while R47H sTREM2 promotes Aβ aggregation into neurotoxic forms, which may explain why the R47H variant gene increases AD risk several fold.
CRISPR-mediated deletion of the Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) improves human T cell function for adoptive T cell therapy
Authors: Prade Sonja , Wright David , Logan Nicola , Teagle Alexandra R. , Stauss Hans , Zamoyska Rose
Published: December 2020

Adoptive T cell transfer has improved the treatment of cancer patients. However, treatment of solid tumors is still challenging and new strategies that optimize T cell function and response duration in the tumor could be beneficial additions to cancer therapy. In this study, we deleted the intracellular phosphatase PTPN22 and the endogenous TCR α chain from human PBMC-derived T cells using CRISPR/Cas9 and transduced them with TCRs specific for a defined antigen. Deletion of PTPN22 in human T cells increased the secretion of IFNγ and GM-CSF in multiple donors. The cells retained a polyfunctional cytokine expression after re-stimulation and greater numbers of PTPN22KOT cells expressed inflammatory cytokines compared to unmutated control cells. PTPN22KOT cells seemed to be more polyfunctional at low antigen concentrations. Additionally, we were able to show that that PTPN22KOT cells were more effective in controlling tumor cell growth. This suggests that they might be more functional within the suppressive tumor microenvironment thereby overcoming the limitations of immunotherapy for solid tumors.
Investigating mechanisms underlying genetic resistance to Salmon Rickettsial Syndrome in Atlantic salmon using RNA sequencing
Authors: Moraleda Carolina P. , Robledo Diego , Gutiérrez Alejandro P. , del-Pozo Jorge , Yáñez José M. , Houston Ross D.
Published: December 2020

Background

Salmon Rickettsial Syndrome (SRS), caused byPiscirickettsia salmonis,is one of the primary causes of morbidity and mortality in Atlantic salmon aquaculture, particularly in Chile. Host resistance is a heritable trait, and functional genomic studies have highlighted genes and pathways important in the response of salmon to the bacteria. However, the functional mechanisms underpinning genetic resistance are not yet well understood. In the current study, a large population of salmon pre-smolts were challenged withP. salmonis, with mortality levels recorded and samples taken for genotyping. In parallel, head kidney and liver samples were taken from animals of the same population with high and low genomic breeding values for resistance, and used for RNA-Sequencing to compare their transcriptome profile both pre and post infection.

Results

A significant and moderate heritability (h2= 0.43) was shown for the trait of binary survival. Genome-wide association analyses using 38K imputed SNP genotypes across 2,251 animals highlighted that resistance is a polygenic trait. Several thousand genes were identified as differentially expressed between controls and infected samples, and enriched pathways related to the host immune response were highlighted. In addition, several networks with significant correlation with SRS resistance breeding values were identified, suggesting their involvement in mediating genetic resistance. These included apoptosis, cytoskeletal organisation, and the inflammasome.

Conclusions

While resistance to SRS is a polygenic trait, this study has highlighted several relevant networks and genes that are likely to play a role in mediating genetic resistance. These genes may be future targets for functional studies, including genome editing, to further elucidate their role underpinning genetic variation in host resistance.
A Quadratic Model Captures the Human V1 Response to Variations in Chromatic Direction and Contrast
Authors: Barnett Michael A. , Aguirre Geoffrey K. , Brainard David H.
Published: December 2020

An important goal for vision science is to develop quantitative models for the representation of visual signals at post-receptoral sites. To this end, we develop the quadratic color model (QCM) and examine its ability to account for the BOLD fMRI response in human V1 to spatially-uniform temporal chromatic modulations, systematically varying in their chromatic directions and contrasts. We find that the QCM explains the same, cross-validated variance as a conventional GLM, with far fewer free parameters. The QCM generalizes to allow prediction of V1 responses to a large range of modulations. We replicated the results for each subject and find good agreement across both replications and subjects. We find that within the LM cone contrast plane, V1 is most sensitive to L-M contrast modulations and least sensitive to L+M contrast modulations. Within V1, we observe little to no change in chromatic sensitivity as a function of eccentricity.
Leveraging Affinity Interactions to Prolong Drug Delivery of Protein Therapeutics
Authors: Dogan Alan , Dabkowski Katherine , von Recum Horst
Published: December 2020

While peptide and protein therapeutics have made tremendous advances in clinical treatments over the past few decades, they have been largely hindered by their ability to be effectively delivered to patients. While bolus parenteral injections have become standard clinical practice, they are insufficient to treat diseases that require sustained, local release of therapeutics. Cyclodextrin-based polymers (pCD) have been utilized as a platform to extend the local delivery of small-molecule hydrophobic drugs by leveraging hydrophobic-driven thermodynamic interactions between pCD and payload to extend its release, which has seen success bothin vitroandin vivo.Herein, we proposed the novel synthesis of protein-polymer conjugates that are capped with a “high affinity” adamantane. Using bovine serum albumin as a model protein, and anti-interleukin 10 monoclonal antibodies as a functional example, we outline the synthesis of novel protein-polymer conjugates that, when coupled with cyclodextrin delivery platforms, can maintain a sustained release of up to 65 days without largely sacrificing protein structure/function which has significant clinical applications in local antibody-based treatments for immune diseases, cancers, and diabetes.

Graphical Abstract
Magnetic Tweezers with Magnetic Flux Density Feedback Control
Authors: Moghram Waddah I. , Kruger Anton , Sander Edward A. , Selby John C.
Published: December 2020

In this work, we present a single-pole magnetic tweezers (MT) device designed for integration with substrate deformation tracking microscopy (DTM) and/or traction force microscopy (TFM) experiments intended to explore extracellular matrix rheology and human epidermal keratinocyte mechanobiology. Assembled from commercially available off-the-shelf electronics hardware and software, the MT device is amenable to replication in the basic biology laboratory. In contrast to conventional solenoid current-controlled MT devices, operation of this instrument is based on real-time feedback control of the magnetic flux density emanating from the blunt end of the needle core using a cascade control scheme and a digital proportional-integral-derivative (PID) controller. Algorithms that compensate for an apparent spatially non-uniform remnant magnetization of the needle core that develops during actuation are implemented into the feedback control scheme. Through optimization of PID gain scheduling, the MT device exhibits magnetization and demagnetization response times of less than 100 ms without overshoot over a wide range of magnetic flux density setpoints. Compared to current-based control, magnetic flux density-based control allows for more accurate and precise magnetic actuation forces by compensating for temperature increases within the needle core due to heat generated by the applied solenoid currents. Near field calibrations validate the ability of the MT device to actuate 4.5 μm-diameter superparamagnetic beads with forces up to 25 nN with maximum relative uncertainties of ±30% for beads positioned between 2.5 and 40 μm from the needle tip.
Automated Machine Learning for High-Throughput Image-Based Plant Phenotyping
Authors: Koh Joshua C.O. , Spangenberg German , Kant Surya
Published: December 2020

Automated machine learning (AutoML) has been heralded as the next wave in artificial intelligence with its promise to deliver high performance end-to-end machine learning pipelines with minimal effort from the user. AutoML with neural architecture search which searches for the best neural network architectures in deep learning has delivered state-of-the-art performance in computer vision tasks such as image classification and object detection. Using wheat lodging assessment with UAV imagery as an example, we compared the performance of an open-source AutoML framework, AutoKeras in image classification and regression tasks to transfer learning using modern convolutional neural network (CNN) architectures pretrained on the ImageNet dataset. For image classification, transfer learning with Xception and DenseNet-201 achieved best classification accuracy of 93.2%, whereas Autokeras had 92.4% accuracy. For image regression, transfer learning with DenseNet-201 had the best performance (R2=0.8303, RMSE=9.55, MAE=7.03, MAPE=12.54%), followed closely by AutoKeras (R2=0.8273, RMSE=10.65, MAE=8.24, MAPE=13.87%). Interestingly, in both tasks, AutoKeras generated compact CNN models with up to 40-fold faster inference times compared to the pretrained CNNs. The merits and drawbacks of AutoML compared to transfer learning for image-based plant phenotyping are discussed.
De novomacrocyclic peptides for inhibiting, stabilising and probing the function of the Retromer endosomal trafficking complex
Authors: Chen Kai-En , Guo Qian , Cui Yi , Kendall Amy K. , Hill Timothy A. , Hall Ryan J. , Sacharz Joanna , Norwood Suzanne J. , Xie Boyang , Leneva Natalya , Yang Zhe , Ghai Rajesh , Stroud David A. , Fairlie David , Suga Hiroaki , Jackson Lauren P. , Teasdale Rohan D. , Passioura Toby , Collins Brett M.
Published: December 2020

The Retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signalling. Mutations in Retromer cause late-onset Parkinson’s disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its function we have created a novel series of macrocyclic peptides that bind Retromer with high affinity and specificity. Crystal structures show the majority of cyclic peptides bind to Vps29 via a Pro-Leu-containing sequence, structurally mimicking known interactors such as TBC1D5, and blocking their interaction with Retromerin vitroand in cells. By contrast, macrocyclic peptide RT-L4 binds Retromer at the Vps35-Vps26 interface and is a more effective molecular chaperone than reported small molecules, suggesting a new therapeutic avenue for targeting Retromer. Finally, tagged peptides can be used to probe the cellular localisation of Retromer and its functional interactions in cells, providing novel tools for studying Retromer function.
Modulation of motor cortex plasticity by repetitive paired-pulse TMS at late I-wave intervals is influenced by intracortical excitability
Authors: Opie George M , Sasaki Ryoki , Hand Brodie J , Semmler John G
Published: December 2020

The late indirect (I) waves recruited by transcranial magnetic stimulation (TMS) over primary motor cortex (M1) can be modulated using I-wave periodicity repetitive TMS (iTMS). The purpose of this study was to determine if the response to iTMS is influenced by different interstimulus intervals (ISIs) targeting late I-waves, and whether these responses were associated with individual variations in intracortical excitability. 17 young (27.2 ± 6.4 years, 12 females) healthy adults received iTMS at late I-wave intervals (4.0, 4.5 & 5.0 ms) in three separate sessions. Changes due to each intervention were examined with motor evoked potential (MEP) amplitudes and short-interval intracortical facilitation (SICF) using both posterior-anterior (PA) and anterior-posterior (AP) TMS current directions. Changes in MEP amplitude and SICF were influenced by iTMS ISI, with the greatest facilitation for ISIs at 4 and 5 ms with PA TMS, and 4 ms with AP TMS. Maximum SICF at baseline (irrespective of ISI) was associated with increased iTMS response, but only for PA stimulation. These results suggest that modifying iTMS parameters targeting late I-waves can influence M1 plasticity. They also suggest that maximum SICF may be a means by which responders to iTMS targeting the late I-waves could be identified.
SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2
Authors: Lei Yuyang , Zhang Jiao , Schiavon Cara R. , He Ming , Chen Lili , Shen Hui , Zhang Yichi , Yin Qian , Cho Yoshitake , Andrade Leonardo , Shadel Gerry S. , Hepokoski Mark , Lei Ting , Wang Hongliang , Zhang Jin , Yuan Jason X.-J. , Malhotra Atul , Manor Uri , Wang Shengpeng , Yuan Zu-Yi , Shyy John Y-J.
Published: December 2020

Coronavirus disease 2019 (COVID-19) includes the cardiovascular complications in addition to respiratory disease. SARS-CoV-2 infection impairs endothelial function and induces vascular inflammation, leading to endotheliitis. SARS-CoV-2 infection relies on the binding of Spike glycoprotein (S protein) to angiotensin converting enzyme 2 (ACE2) in the host cells. We show here that S protein alone can damage vascular endothelial cells (ECs) in vitro and in vivo, manifested by impaired mitochondrial function, decreased ACE2 expression and eNOS activity, and increased glycolysis. The underlying mechanism involves S protein downregulation of AMPK and upregulation of MDM2, causing ACE2 destabilization. Thus, the S protein-exerted vascular endothelial damage via ACE2 downregulation overrides the decreased virus infectivity.
Inhibition of the occipital face area modulates the electrophysiological signals of face familiarity positively: a combined cTBS-EEG study
Authors: Eick Charlotta Marina , Ambrus Géza Gergely , Kovács Gyula
Published: December 2020

The occipital face area (OFA) is hierarchically one of the first stages of the face processing network. It has originally been thought to be involved in early, structural processing steps, but currently more and more studies challenge this view and propose that it also takes part in higher face processing, such as identification and recognition. Here we tested whether the OFA is involved in the initial steps of recognition memory and plays a causal role in the differential processing of familiar and unfamiliar faces. We used an offline, inhibitory continuous theta-burst stimulation (cTBS) protocol over the right OFA and the vertex as control site. An electroencephalographic (EEG) recording of event-related potentials (ERPs), elicited by visually presented familiar (famous) and unfamiliar faces was performed before and after stimulation. We observed a difference in ERPs for famous and unfamiliar faces in a time-window corresponding to the N250 component. Importantly, this difference was significantly increased by cTBS of the right OFA, suggesting its causal role in the differential processing of familiar and unfamiliar faces. The enhancement occurred focally, at electrodes close to the right hemispheric cTBS site, as well as over similar occipito-temporal sites of the contralateral hemisphere. To the best of our knowledge, this is the first study showing the causal role of the rOFA in the differential processing of familiar and unfamiliar faces, using combined cTBS and EEG recording methods. These results are discussed with respect to the nature of familiar face representations, supported by an extensive, bilateral network.