bluuebunny/crossref_metadata_2025 huggingface dataset:
Racial and Ethnic Disparities in COVID-19 Infection and Mortality in the United States: A state-wise update
Authors: Xian Zhaoying , Saxena Anshul , Javed Zulqarnain , Jordan John E. , Alkarawi Safa , Khan Safi U , Shah Karan , Vahidy Farhaan , Nasir Khurram , Dubey Prachi
Published: December 2020

Objectives

To evaluate COVID-19 infection and mortality in ethnic and racial sub-groups across all states in the United States.

Methods

Publicly available data from “The COVID Tracking Project at The Atlantic” was accessed between 09/09/2020 and 09/14/2020. For each state and the District of Columbia, % infection, % death, % population proportion for subgroups of race (African American (AA), Asian, American Indian or Alaska Native, (AI/AN) and White), and ethnicity (Hispanic/Latino, and non-Hispanic), were recorded. Absolute and relative excess infection (AEI and REI) and mortality (AEM and REM) were computed as absolute and relative difference between % infection or % mortality and % population proportion for each state. Median (IQR) REI is provided below.

Results

The Hispanic population had a median of 158% higher COVID-19 infection relative to their % population proportion (median REI 158%, [IQR: 100% to 200%]). This was followed by AA, with 50% higher COVID-19 infection relative to their % population proportion (median REI, 50% [IQR 25% to 100%]). The AA population had the most disproportionate mortality with a median of 46% higher mortality than % population proportion, (median REM 46% [IQR, 18% to 66%]). Disproportionate impact of COVID-19 was also seen in AI/AN and Asian population with ≥100% excess infections than % population proportion seen in 35 states for Hispanic, 14 states for AA, 9 states for AIAN, and 7 states for Asian populations. There was no disproportionate impact in the white population in any state.

Conclusions

Racial/ethnic minorities (AA, Hispanic, AIAN and Asian populations) are disproportionately affected by COVID 19 infection and mortality across the nation. These findings underscore the potential role of social determinants of health in explaining the disparate impact of SARS-CoV-2 on vulnerable demographic groups, as well as the opportunity to improve outcomes in chronically marginalized populations.
OpenSAFELY: impact of national guidance on switching from warfarin to direct oral anticoagulants (DOACs) in early phase of COVID-19 pandemic in England
Authors:   The OpenSAFELY Collaborative, Curtis Helen J , MacKenna Brian , Walker Alex J , Croker Richard , Mehrkar Amir , Morton Caroline E , Bacon Seb , Hickman George , Inglesby Peter , Bates Chris , Evans David , Ward Tom , Cockburn Jonathan , Davy Simon , Bhaskaran Krishnan , Schultze Anna , Rentsch Christopher T , Williamson Elizabeth , Hulme William , McDonald Helen I , Tomlinson Laurie , Mathur Rohini , Drysdale Henry , Eggo Rosalind M , Wing Kevin , Wong Angel YS , Forbes Harriet , Parry John , Hester Frank , Harper Sam , Evans Stephen JW , Douglas Ian J , Smeeth Liam , Goldacre Ben
Published: December 2020

Background

Early in the COVID-19 pandemic the NHS recommended that appropriate patients anticoagulated with warfarin should be switched to direct acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately co-prescribed two anticoagulants following a medication change, and associated monitoring.

Objective

To describe which people were switched from warfarin to DOACs; identify potentially unsafe co-prescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic.

Methods

Working on behalf of NHS England we conducted a population cohort based study using routine clinical data from >17 million adults in England.

Results

20,000 of 164,000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in co-prescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. INR testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420).

Conclusions

Increased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people co-prescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic.
Factors associated with decision making on COVID-19 vaccine acceptance among college students in South Carolina
Authors: Tam Cheuk Chi , Qiao Shan , Li Xiaoming
Published: December 2020

Background

COVID-19 vaccination could be a promising approach in controlling the pandemic, but its success strongly relies on the acceptance of vaccines among various populations including young adults who are especially vulnerable to COVID-19 due to their active lifestyle and perception of invulnerability. Vaccine acceptance decisions can be influenced by multiple factors and people may weigh these factors differently in their decision making. The current study aims to explore COVID-19 vaccine acceptance among college students in South Carolina and examine how they weigh these factors according to their levels of COVID-19 vaccine acceptance (i.e., acceptance, hesitance, refusal).

Methods

Online survey data were collected from 1062 college students in South Carolina between September and October 2020. Multivariate analysis of covariance was used to compare perceived importance of 12 factors affecting levels of vaccine acceptance, controlling for key demographic variables.

Results

About 60.6% of the college students reported they would definitely or likely take COVID-19 vaccine when available. Duration of vaccine protection, vaccine accessibility, and authoritative advice (e.g., if vaccination is recommended by school, government, or doctors) were considered important among the acceptance group; Negative consequences of vaccination and vaccine characteristics (i.e., ways the vaccine will be administered, and where the vaccine is made) were considered important by the refusal group; The hesitance group considered the same factors important as the refusal group did but also considered duration of vaccine protection and recommendation by school or doctors important.

Conclusion

Our findings suggest relatively low vaccine acceptance among college students in South Carolina and different factors that play a role in their vaccine uptake decision according to their levels of acceptance. Tailored vaccine promotion messages should address specific concerns among the refusal and hesitancy groups. School could play a positive role in vaccine campaign since the reluctancy group considered that recommendation by their school was important in their decision making. Health educators also need to pay particular attention to the refusal group who do not value duration of protection or authoritative advice as much as their counterparts in their vaccine decision making.
The application of Hybrid deep learning Approach to evaluate chest ray images for the diagnosis of pneumonia in children
Authors: Abbasa Mohammad Ali , Bukhari Syed Usama Khalid , Arssalan Bokhari Syed Khuzaima , niazi manal
Published: December 2020

Background

Pneumonia is a leading cause of morbidity and mortality worldwide, particularly among the developing nations. Pneumonia is the most common cause of death in children due to infectious etiology. Early and accurate Pneumonia diagnosis could play a vital role in reducing morbidity and mortality associated with this ailment. In this regard, the application of a new hybrid machine learning vision-based model may be a useful adjunct tool that can predict Pneumonia from chest X-ray (CXR) images.

Aim & Objective

we aimed to assess the diagnostic accuracy of hybrid machine learning vision-based model for the diagnosis of Pneumonia by evaluating chest X-ray (CXR) images

Materials & Methods

A total of five thousand eight hundred and fifty-six digital X-ray images of children from ages one to five were obtained from the Chest X-Ray Pneumonia dataset using the Kaggle site. The dataset contains fifteen hundred and eighty-three digital X-ray images categorized as normal, where four thousand two hundred and seventy-three digital X-ray images are categorized as Pneumonia by an expert clinician. In this research project, a new hybrid machine learning vision-based model has been evaluated that can predict Pneumonia from chest X-ray (CXR) images. The proposed model is a hybrid of convolutional neural network and tree base algorithms (random forest and light gradient boosting machine). In this study, a hybrid architecture with four variations and two variations of ResNet architecture are employed, and a comparison is made between them.

Results

In the present study, the analysis of digital X-ray images by four variations of hybrid architecture RN-18 RF, RN-18 LGBM, RN-34 RF, and RN-34 LGBM, along with two variations of ResNet architecture, ResNet-18 and ResNet-30 have revealed the diagnostic accuracy of 97.78%, 96.42%, 97.1%,96.59%, 95.05%, and 95.05%, respectively.

Discussion

The analysis of the present study results revealed more than 95% diagnostic accuracy for the diagnosis of Pneumonia by evaluating chest x-ray images of children with the help of four variations of hybrid architectures and two variations of ResNet architectures. Our findings are in accordance with the other published study in which the author used the deep learning algorithm Chex-Net with 121 layers.

Conclusion

The hybrid machine learning vision-based model is a useful tool for the assessment of chest x rays of children for the diagnosis of Pneumonia.
A holistic approach for suppression of COVID-19 spread in workplaces and universities
Authors: Poole Sarah F. , Gronsbell Jessica , Winter Dale , Nickels Stefanie , Levy Roie , Fu Bin , Burq Maximilien , Saeb Sohrab , Edwards Matthew D. , Behr Michael K. , Kumaresan Vignesh , Macalalad Alexander R. , Shah Sneh , Prevost Michelle , Snoad Nigel , Brenner Michael P. , Myers Lance J. , Varghese Paul , Califf Robert M. , Washington Vindell , Lee Vivian S. , Fromer Menachem
Published: December 2020

As society has moved past the initial phase of the COVID-19 crisis that relied on broad-spectrum shutdowns as a stopgap method, industries and institutions have faced the daunting question of how to return to a stabilized state of activities and more fully reopen the economy. A core problem is how to return people to their workplaces and educational institutions in a manner that is safe, ethical, grounded in science, and takes into account the unique factors and needs of each organization and community. In this paper, we introduce an epidemiological model (the “Community-Workplace” model) that accounts for SARS-CoV-2 transmission within the workplace, within the surrounding community, and between them. We use this multi-group deterministic compartmental model to consider various testing strategies that, together with symptom screening, exposure tracking, and nonpharmaceutical interventions (NPI) such as mask wearing and social distancing, aim to reduce disease spread in the workplace. Our framework is designed to be adaptable to a variety of specific workplace environments to support planning efforts as reopenings continue.

Using this model, we consider a number of case studies, including an office workplace, a factory floor, and a university campus. Analysis of these cases illustrates that continuous testing can help a workplace avoid an outbreak by reducing undetected infectiousness even in high-contact environments. We find that a university setting, where individuals spend more time on campus and have a higher contact load, requires more testing to remain safe, compared to a factory or office setting. Under the modeling assumptions, we find that maintaining a prevalence below 3% can be achieved in an office setting by testing its workforce every two weeks, whereas achieving this same goal for a university could require as much as fourfold more testing (i.e., testing the entire campus population twice a week). Our model also simulates the dynamics of reduced spread that result from the introduction of mitigation measures when test results reveal the early stages of a workplace outbreak. We use this to show that a vigilant university that has the ability to quickly react to outbreaks can be justified in implementing testing at the same rate as a lower-risk office workplace. Finally, we quantify the devastating impact that an outbreak in a small-town college could have on the surrounding community, which supports the notion that communities can be better protected by supporting their local places of business in preventing onsite spread of disease.
Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility
Authors: Kho Pik-Fang , Partida Gabriel Cuellar , Dörk Thilo , Goode Ellen L. , Lambrechts Diether , Scott Rodney J. ,   Endometrial Cancer Association Consortium, Spurdle Amanda B. , O’Mara Tracy A. , Glubb Dylan M.
Published: December 2020

Genome-wide association studies (GWAS) of endometrial cancer have identified 16 genetic susceptibility loci. To identify candidate endometrial cancer susceptibility genes, we have performed the first transcriptome-wide association study (TWAS) of endometrial cancer. For this analysis, we have used the largest endometrial cancer GWAS and gene expression from 48 tissues to maximise statistical power. We used colocalisation analysis to prioritise seven candidate susceptibility genes, including CYP19A1, which wes previously established as an endometrial cancer susceptibility gene. Notably, one of the candidate susceptibility genes was located at 17q24.2, a potentially novel risk locus for endometrial cancer. Using phenome-wide association analysis, candidate susceptibility genes were found to associate with traits related to endometrial cancer risk factors, in addition to other clinical phenotypes that may provide novel risk factors. TWAS data were also used to perform drug repurposing analysis and identified 14 compounds; two of these are tubulin inhibitors, a drug class used to treat advanced endometrial cancer. In summary, this study has revealed biologically relevant endometrial cancer susceptibility genes, providing insights into endometrial cancer aetiology and avenues for the development of new treatments.
A-to-I mRNA editing in a ferric siderophore receptor improves competition for iron inXanthomonas oryzae
Authors: Nie Wenhan , Wang Sai , Huang Jin , Xu Qin , Wang Peihong , Wu Yan , Yiming Ayizekeranmu , Ahmad Iftikhar , Zhu Bo , Chen Gongyou
Published: December 2020

Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by the adenosine deaminase RNA-specific family of enzymes, is a frequent post-transcriptional modification in metazoans. Research on A-to-I editing in bacteria is limited, and the importance is underestimated. In this study, we show that bacteria may use A-to-I editing as an alternative strategy to promote uptake of metabolic iron. The T408A editing event ofxfeAinXanthomonas oryzaepv.oryzicola(Xoc) senses extracytoplasmic iron and changes the hydrogen bonding network of ligand channel domains. The frequency of A-to-I RNA editing during iron-deficient conditions increased by 76.87%, which facilitated the passage of iron through the XfeA outer membrane channel. When bacteria were subjected to high iron concentrations, the percentage of A-to-I editing inxfeAdecreased, which reduced iron transport via XfeA. Furthermore, A-to-I RNA editing increased expression of multiple genes in the chemotaxis pathway, including methyl-accepting chemotaxis proteins (MCPs) that sense concentrations of exogenous ferric enterobactin (Fe-Ent) at the cytoplasmic membrane. A-to-I RNA editing helpsXocmove towards an iron-rich environment and supports our contention that editing inxfeAfacilitates entry of a ferric siderophore. Overall, our results reveal a new signaling mechanism that bacteria use to facilitate iron uptake and improve their competitiveness.
Neuroanatomical correlates of social intelligence measured by the Guilford test
Authors: Myznikov A , Zheltyakova M , Korotkov A , Kireev M , Masharipov R , Jagmurov O.Dz. , Habel U , Votinov M
Published: December 2020

Social interactions are a crucial aspect of human behaviour. Numerous neurophysiological studies have focused on socio-cognitive processes associated with the so-called theory of mind – the ability to attribute mental states to oneself and others. Theory of mind is closely related to social intelligence defined as a set of abilities that facilitate effective social interactions. Social intelligence encompasses multiple theory of mind components and can be measured by the Four Factor Test of Social Intelligence (the Guilford-Sullivan test). However, it is unclear whether the differences in social intelligence are reflected in structural brain differences. During the experiment, 48 healthy right-handed individuals completed the Guilford-Sullivan test. T1-weighted structural MRI images were obtained for all participants. Voxel-based morphometry analysis was performed to reveal grey matter volume differences between the two groups (24 subjects in each) – with high social intelligence scores and with low social intelligence scores, respectively. Participants with high social intelligence scores had larger grey matter volumes of the bilateral caudate, left insula, left inferior parietal lobule, inferior temporal gyrus, and middle occipital gyrus. Only the cluster in the caudate nuclei survived a cluster-level FWE correction for multiple comparisons. The obtained results suggest caudate nucleus involvement in the neural system of socio-cognitive processes, reflected by its structural characteristics.
Tolerance of an acute warming challenge declines with body mass in Nile tilapia: evidence of a link to capacity for oxygen uptake
Authors: Blasco F.R. , Taylor E.W. , Leite C.A.C. , Monteiro D.A. , Rantin F.T. , McKenzie D.J.
Published: December 2020

It is proposed that larger individuals within fish species may be more sensitive to global warming, due to limitations in their capacity to provide oxygen for aerobic metabolic activities. This could affect size distributions of populations in a warmer world but evidence is lacking. In Nile tilapiaOreochromis niloticus(n=18, mass range 21-313g), capacity to provide oxygen for aerobic activities (aerobic scope) was independent of mass at acclimation temperature (26°C). Tolerance of acute warming, however, declined significantly with mass when evaluated as critical temperature for fatigue from aerobic swimming (CTswim). The CTswimprotocol challenges a fish to meet the oxygen demands of constant intense aerobic exercise while their demands for basal metabolism are accelerated by incremental warming, culminating in fatigue. CTswimelicited pronounced increases in oxygen uptake but maximum rates achieved prior to fatigue declined very significantly with mass. Mass-related variation in CTswimand maximum oxygen uptake rates were positively correlated, which may indicate a causal relationship. When faced with acute thermal stress, larger fishes within populations may become constrained in their ability to swim at lower temperatures than smaller con-specifics. This could affect survival and fitness of larger fish in a world with more frequent and extreme heatwaves, with consequences for population productivity.
A thermodynamic scaling law for electrically perturbed lipid membranes: validation with the steepest-entropy-ascent framework
Authors: Goswami I. , Bielitz R. , Verbridge S.S. , von Spakovsky M.R.
Published: December 2020

Experimental evidence has demonstrated the potential of transient pulses of electric fields to alter mammalian cell phenotypes. Strategies with these pulsed electric fields (PEFs) have been developed for clinical applications in cancer therapeutics, in-vivo decellularization, and tissue regeneration. Successful implementation of these strategies involves understanding how PEFs impact the cellular structures and, hence, cell behavior. The caveat, however, is that the PEF parameter space comprised of different pulse widths, amplitudes, and the number of pulses is very large, and design of experiments to explore all possible combinations of PEF parameters is prohibitive from a cost and time standpoint. In this study, a scaling law based on the Ising model is introduced to understand the impact of PEFs on the outer cell lipid membrane so that an understanding developed in one PEF pulse regime may be extended to another. Experimental study is used to argue for the scaling model. Next, the validity of this scaling model to predict the behavior of both thermally quenched and electrically perturbed lipid membranes is demonstrated via computational predictions made by the steepest-entropy-ascent quantum thermodynamic (SEAQT) framework. Based on the simulation results, a form of scaled PEF parameters is thus proposed for lipid membrane.
EccDNA formation is dependent on MMEJ, repressed by c-NHEJ pathway, and stimulated by DNA double-strand break
Authors: Paulsen Teressa , Malapati Pumoli , Eki Rebeka , Abbas Tarek , Dutta Anindya
Published: December 2020

Extrachromosomal circular DNAs (eccDNA) are widespread in normal and cancer cells and are known to amplify oncogenic genes. However, the mechanisms that form eccDNA have never been fully elucidated due to the complex interactions of DNA repair pathways and lack of a method to quantify eccDNA abundance. Through the development of a sensitive and quantitative assay for eccDNA we show that the formation of eccDNA is through resection dependent repair of double-strand DNA breaks, especially micro-homology mediated end joining, and through mismatch repair. The most significant decreases in eccDNA levels occurred in cells lacking PARP1, POLQ, NBS1, RAD54, and FAN1. Further, a significant increase in eccDNA occurred in cells lacking c-NHEJ proteins DNA-PKcs, XRCC4, XLF, LIG4 and 53BP1. This suggests that when alt-NHEJ pathways are utilized to repair DNA breaks by necessity, the formation of eccDNA is increased. Induced and site-directed double-strand DNA breaks increase eccDNA formation, even from a single break. Additionally, we find that eccDNA levels accumulate as cells undergo replication in S-phase and that levels of eccDNA are decreased if DNA synthesis is prevented. Together, these results show that the bulk of eccDNA form by resection based alt-NHEJ pathways, especially during DNA replication and the repair of double-strand breaks.
Inhibition of HIV infection by structural proteins of the inner nuclear membrane is associated with reduced chromatin dynamics
Authors: Bhargava Anvita , Maurin Mathieu , Davidson Patricia M. , Jouve Mabel , Lahaye Xavier , Manel Nicolas
Published: December 2020

The Human Immunodeficiency Virus (HIV) enters the nucleus to establish infection. HIV interacts with nuclear pore components to cross the nuclear envelope. In contrast, the role of other proteins of the nuclear envelope in HIV infection is not yet understood. The inner nuclear transmembrane proteins SUN1 and SUN2 connect lamins in the interior of the nucleus to the cytoskeleton in the cytoplasm. Increased levels of SUN1 or SUN2 potently restrict HIV infection through an unresolved mechanism. Here, we find that SUN1 and SUN2 exhibit a differential and viral strain-specific antiviral activity HIV-1 and HIV-2. In macrophages and HeLa cells, HIV-1 and HIV-2 are respectively preferentially inhibited by SUN1 and SUN2. This specificity maps to the nucleoplasmic domain of SUN proteins, which associates with Lamin A/C and participates to the DNA damage response. We find that etoposide, a DNA-damaging drug, stimulates infection. Inhibition of the DNA damage signaling kinase ATR, which induces a DNA damage response, also enhances HIV-1 infection. The proviral effect of ATR inhibition on infection requires the HIV-1 Vpr gene. Depletion of endogenous Lamin A/C, which sensitizes cells to DNA damage, also enhances HIV-1 infection in HeLa cells. SUN1 overexpression neutralizes these proviral effects, while the antiviral effect of SUN2 is rescued by etoposide treatment. Finally, we show that inhibition of HIV-1 infection by overexpressed SUN proteins and endogenous Lamin A/C is associated with reduced internal movements of chromatin and reduced rotations of the nucleus. Altogether, these results highlight distinct antiviral activities of SUN1 and SUN2 and reveal an emerging role of nuclear movements and the DNA damage response in the control of HIV infection by structural components of the nuclear envelope.
Evolution of the Codling Moth Pheromone Through the Member of an Ancient Desaturase Expansion
Authors: Lassance Jean-Marc , Ding Bao-Jian , Löfstedt Christer
Published: December 2020

Defining the origin of genetic novelty is central to our understanding of the evolution of novel traits. Diversification among fatty acid desaturase (FAD) genes has played a fundamental role in the introduction of structural variation in fatty acyl derivatives. Because of its central role in generating diversity in insect semiochemicals, the FAD gene family has become a model to study how gene family expansions can contribute to the evolution of lineage-specific innovations. Here we used the codling moth (Cydia pomonella) as a study system to decipher the proximate mechanism underlying the production of the Δ8Δ10 signature structure of Olethreutine moths. Biosynthesis of the codling moth sex pheromone, (E8,E10)-dodecadienol (codlemone), involves two consecutive desaturation steps, the first of which is unusual in that it generates anE9 unsaturation. The second step is also atypical: it generates a conjugated diene system from theE9 monoene C12intermediate via 1,4-desaturation. Here we describe the characterization of the FAD gene acting in codlemone biosynthesis. We identify 27 FAD genes corresponding to the various functional classes identified in Insects and Lepidoptera. These genes are distributed across theC. pomonellagenome in tandem arrays or isolated genes, indicating that the FAD repertoire consists of both ancient and recent duplications and expansions. Using transcriptomics, we show large divergence in expression domains: some genes appear ubiquitously expressed across tissue and developmental stages; others appear more restricted in their expression pattern. Functional assays using heterologous expression systems reveal that one gene, Cpo_CPRQ, which is prominently and exclusively expressed in the female pheromone gland, encodes an FAD that possesses bothE9 and Δ8Δ10-desaturation activities. Phylogenetically, Cpo_CPRQ clusters within the Lepidoptera-specific Δ10/Δ11 clade of FADs, a classic reservoir of unusual desaturase activities in moths. Our integrative approach shows that the evolution of the signature pheromone structure of Olethreutine moths relied on a gene belonging to an ancient gene expansion. Members of other expanded FAD subfamilies do not appear to play a role in chemical communication. This advises for caution when postulating the consequences of lineage-specific expansions based on genomics alone.
Integration of Magnetic Tweezers and Traction Force Microscopy for the Exploration of Matrix Rheology and Keratinocyte Mechanobiology: Model Force- and Displacement-Controlled Experiments
Authors: Moghram Waddah I. , Singh Pratibha , VandeLune Christian A. , Sander Edward A. , Selby John C.
Published: December 2020

In this work we demonstrate the integration of magnetic tweezers (MT) with substrate deformation tracking microscopy (DTM) and traction force microscopy (TFM) for the investigation of extracellular matrix rheology and human epidermal keratinocyte mechanobiology in the context of human blistering skin diseases. Two model bead-on-gel experiments are described in which an MT device is used to apply a prescribed force or displacement waveform to a fibronectin-coated superparamagnetic bead attached to a type I collagen gel containing a layer of covalently attached red-fluorescent microspheres. Serial fast time-lapse DIC and epifluorescence image acquisitions are used to capture displacements of the bead and microspheres, respectively, in response to the applied force or displacement. Due to the large number of acquired images and the dynamic behavior of substrate microspheres observed during the experiment, new quantitative methods are developed for the tracking and filtering of microsphere displacement data, the selection of L2 regularization parameters used for TFM analysis, and the identification of time intervals within the overall image set that can be approximated as being subject to elastostatic conditions. Two major proof-of-concept applications are described in which integrated MT-DTM/TFM experiments are used to (i) estimate the elastic properties of a fibrillar type I collagen gel substrate and (ii) demonstrate how a force applied to a focal adhesion contact on the apical surface of a living keratinocyte is directly transmitted to basal cell-matrix anchoring junctions as observed by substrate deformations and incremental traction stresses that develop within the collagen subjacent to the cell.
Differential impact of maternal overnutrition and undernutrition on offspring glucose homeostasis
Authors: Adekunbi Praise B. , Ogunsola Abimbola O. , Adekunbi Daniel A.
Published: December 2020

To test the hypothesis that maternal undernutrition exerts a greater effect on offspring metabolic function compared to maternal overnutrition, female rats (n=10 per group) were subjected to a high calorie diet or 50 % global nutrient restriction relative to control rats on standard rat chow, for 8 weeks prior to pregnancy and during pregnancy. Birth weight was determined on the day dams were found with pups. At 3 months of age, offspring’s fasting blood glucose, serum insulin and triglyceride levels as well as glucose tolerance and insulin sensitivity were determined. A 50 % calorie restriction caused a significant weight loss in the under-nourished dams but those on high calorie diet had similar body weight as control rats. Maternal overnutrition and undernutrition significantly lowered birth weight, indicating intra-uterine growth restriction in these animals. Fasting blood glucose was significantly higher in female offspring of over-nourished dams, but neither maternal overnutrition nor undernutrition affected offspring’s glucose tolerance. Male offspring of dams exposed to maternal overnutrition or undernutrition had a significantly higher insulin level compared to control, whereas female offspring were unaffected. The development of hyperinsulinaemia in male offspring of undernourished dams was accompanied by reduced insulin sensitivity. This study demonstrates that early-life exposure to two extreme ends of the nutritional plane is associated with similar birth weight outcome but different metabolic phenotype in adulthood. Evidence of insulin resistance only in male offspring of under-nourished dams indicates differences in sex-specific metabolic effect of maternal undernutrition compared to overnutrition.
V-NeuroStack: 3D Time Stacks for Identifying Patterns in Calcium Imaging Data
Authors: Naik Ashwini G. , Kenyon Robert V. , Taheri Aynaz , Berger-Wolf Tanya , Ibrahim Baher , Llano Daniel A.
Published: December 2020

Background

Understanding functional correlations between the activities of neuron populations is vital for the analysis of neuronal networks. Analyzing large-scale neuroimaging data obtained from hundreds of neurons simultaneously poses significant visualization challenges. We developed V-NeuroStack, a novel network visualization tool to visualize data obtained using calcium imaging of spontaneous activity of cortical neurons in a mouse brain slice.

New Method

V-NeuroStack creates 3D time stacks by stacking 2D time frames for a period of 600 seconds. It provides a web interface that enables exploration and analysis of data using a combination of 3D and 2D visualization techniques.

Comparison with existing Methods

Previous attempts to analyze such data have been limited by the tools available to visualize large numbers of correlated activity traces. V-NeuroStack can scale data sets with at least a few thousand temporal snapshots.

Results

V-NeuroStack’s 3D view is used to explore patterns in the dynamic large-scale correlations between neurons over time. The 2D view is used to examine any timestep of interest in greater detail. Furthermore, a dual-line graph provides the ability to explore the raw and first-derivative values of a single neuron or a functional cluster of neurons.

Conclusions

V-NeuroStack enables easy exploration and analysis of large spatio-temporal datasets using two visualization paradigms: (a) Space-Time cube (b)Two-dimensional networks, via web interface. It will support future advancements in in vitro and in vivo data capturing techniques and can bring forth novel hypotheses by permitting unambiguous visualization of large-scale patterns in the neuronal activity data.
Concept Recognition as a Machine Translation Problem
Authors: Boguslav Mayla R , Hailu Negacy D , Bada Michael , Baumgartner William A , Hunter Lawrence E
Published: December 2020

Background

Automated assignment of specific ontology concepts to mentions in text is a critical task in biomedical natural language processing, and the subject of many open shared tasks. Although the current state of the art involves the use of neural network language models as a post-processing step, the very large number of ontology classes to be recognized and the limited amount of gold-standard training data has impeded the creation of end-to-end systems based entirely on machine learning. Recently, Hailu et al. recast the concept recognition problem as a type of machine translation and demonstrated that sequence-to-sequence machine learning models had the potential to outperform multi-class classification approaches. Here we systematically characterize the factors that contribute to the accuracy and efficiency of several approaches to sequence-to-sequence machine learning.

Results

We report on our extensive studies of alternative methods and hyperparameter selections. The results not only identify the best-performing systems and parameters across a wide variety of ontologies but also illuminate about the widely varying resource requirements and hyperparameter robustness of alternative approaches. Analysis of the strengths and weaknesses of such systems suggest promising avenues for future improvements as well as design choices that can increase computational efficiency with small costs in performance. Bidirectional Encoder Representations from Transformers for Biomedical Text Mining (BioBERT) for span detection (as previously found) along with the Open-source Toolkit for Neural Machine Translation (OpenNMT) for concept normalization achieve state-of-the-art performance for most ontologies in CRAFT Corpus. This approach uses substantially fewer computational resources, including hardware, memory, and time than several alternative approaches.

Conclusions

Machine translation is a promising avenue for fully machine-learning-based concept recognition that achieves state-of-the-art results on the CRAFT Corpus, evaluated via a direct comparison to previous results from the 2019 CRAFT Shared Task. Experiments illuminating the reasons for the surprisingly good performance of sequence-to-sequence methods targeting ontology identifiers suggest that further progress may be possible by mapping to alternative target concept representations. All code and models can be found at:https://github.com/UCDenver-ccp/Concept-Recognition-as-Translation.
Activation of Kiss1 neurons in the preoptic hypothalamus stimulates testosterone synthesis in adult male mice
Authors: Sanz Elisenda , Bean Jonathan C. , Palmiter Richard D. , Quintana Albert , McKnight G. Stanley
Published: December 2020

Kisspeptin-expressing neurons in the rostral periventricular region of the third ventricle (RP3V) play an essential role in female reproduction. However, adult male mice were reported to have very few Kisspeptin-expressing neurons in the RP3V compared to females. This led to the hypothesis that Kiss1RP3Vneurons are responsible for the ability of females, but not males, to generate a surge of LH, triggering ovulation and steroid synthesis in the female. Using mouse genetics and cell type-specific gene expression analysis, we show that male mice harbor almost as many Kiss1RP3Vneurons as the female and that gene expression in these neurons is very similar. Specific activation of male Kiss1RP3Vneurons expressing viral-encoded hM3Dq caused a surge in serum testosterone levels. These results demonstrate that Kiss1RP3Vneurons are present in the adult male and fully capable of regulating the hypothalamic/pituitary/gonadal axis. We suggest that these neurons may continue to play a role in reproductive behavior in adult male mice.
Design of smart antibody mimetics with photosensitive switches
Authors: He Lian , Tan Peng , Huang Yun , Zhou Yubin
Published: December 2020

As two prominent examples of intracellular single-domain antibodies or antibody mimetics derived from synthetic protein scaffolds, monobodies and nanobodies are gaining wide applications in cell biology, structural biology, synthetic immunology, and theranostics. We introduce herein a generally-applicable method to engineer light-controllable monobodies and nanobodies, designated as moonbody and sunbody, respectively. These engineered antibody-like modular domains enable rapid and reversible antibody-antigen recognition by utilizing light. By paralleled insertion of two LOV2 modules into a single sunbody and the use of bivalent sunbodies, we substantially enhance the range of dynamic changes of photo-switchable sunbodies. Furthermore, we demonstrate the use of moonbodies or sunbodies to precisely control protein degradation, gene transcription, and base editing by harnessing the power of light.
SIX2 and SIX3 coordinately regulate functional maturity and fate of human pancreatic β cells
Authors: Bevacqua Romina J. , Lam Jonathan Y. , Peiris Heshan , Whitener Robert L. , Kim Seokho , Gu Xueying , Friedlander Mollie S.H. , Kim Seung K.
Published: December 2020

The physiological functions of many vital tissues and organs continue to mature after birth, but the genetic mechanisms governing this postnatal maturation remain an unsolved mystery. Human pancreatic β-cells produce and secrete insulin in response to physiological cues like glucose, and these hallmark functions improve in the years after birth. This coincides with expression of the transcription factors SIX2 and SIX3, whose functions in native human β-cells remain unknown. Here, we show that shRNA-mediatedSIX2orSIX3suppression in human pancreatic adult islets impairs insulin secretion. However, transcriptome studies revealed thatSIX2andSIX3regulate distinct targets. Loss ofSIX2markedly impaired expression of genes governing β-cell insulin processing and output, glucose sensing, and electrophysiology, whileSIX3loss led to inappropriate expression of genes normally expressed in fetal β-cells, adult a-cells and other non-β-cells. Chromatin accessibility studies identified genes directly regulated by SIX2. Moreover, β-cells from diabetic humans with impaired insulin secretion also had reducedSIX2transcript levels. Revealing howSIX2andSIX3govern functional maturation and maintain developmental fate in native human β-cells should advance β-cell replacement and other therapeutic strategies for diabetes.
Escape from mitotic catastrophe by actin-dependent nuclear displacement in fission yeast
Authors: Yukawa Masashi , Teratani Yasuhiro , Toda Takashi
Published: December 2020

Proper nuclear positioning is essential for the execution of a wide variety of cellular processes in eukaryotic cells (Gundersen and Worman, 2013; Kopf et al., 2020; Lele et al., 2018). In proliferating mitotic cells, nuclear positioning is crucial for successful cell division. The bipolar spindle, which pulls sister chromatids towards two opposite poles, needs to assemble in the geometrical center of the cell. This ensures symmetrical positioning of the two nuclei that are reformed upon mitotic exit, by which two daughter cells inherit the identical set of the chromosomes upon cytokinesis. In fission yeast, the nucleus is positioned in the cell center during interphase; cytoplasmic microtubules interact with both the nucleus and the cell tips, thereby retaining the nucleus in the medial position of the cell (Daga et al., 2006; Tran et al., 2001). By contrast, how the nucleus is positioned during mitosis remains elusive. Here we show that several cell-cycle mutants that arrest in mitosis all displace the nucleus towards one end of the cell axis. Intriguingly, the actin cytoskeleton, not the microtubule counterpart, is responsible for the asymmetric movement of the nucleus. Time-lapse live imaging indicates that mitosis-specific F-actin cables interact with the nuclear membrane, thereby possibly generating an asymmetrical pushing force. In addition, constriction of the actomyosin ring further promotes nuclear displacement. This nuclear movement is beneficial, because if the nuclei were retained in the cell center, subsequent cell division would impose the lethal cut phenotype (Hirano et al., 1986; Yanagida, 1998), in which chromosomes are intersected by the contractile actin ring and the septum. Thus, fission yeast escapes from mitotic catastrophe by means of actin-dependent nuclear movement.
A meta-analysis on uncertainty monitoring in four non-primate animal species: Pigeons, rats, large-billed crows, and bees
Authors: Qu Zhizhen , Kwok Sze Chai
Published: December 2020

Humans have the metacognitive capacity to be aware of what they do and do not know. While uncertainty monitoring has long been regarded as uniquely human, researchers in search of the polygenetic root of this ability have gathered evidence that primate species possess functional features parallel to humans. However, there were no systematic studies that quantitively take into account of extant data for these non-primate animals. Through a meta-analysis, we collected published data reported in 11 articles from 55 individual non-primate animals spanning over four species on the “opt-out” paradigm, the most prevailing paradigms used to test nonhuman animals’ uncertainty monitoring. We used chosen-forced advantage and opt-out rate to quantify animals’ performance results for computing the aggregated effect size for this literature. We found that these four NPA species process a significantly positive effect size for both scores and identified the moderators that have contributed to the inconsistencies across these studies. Implications for theories on metacognition are discussed.
Identification of hippocampal volume as a mediator of the association between APOE4 and dementia
Authors: Brenek Sixtine , Debette Stéphanie , Auriacombe Sophie , Amouyel Philippe , Chouraki Vincent , Meirhaeghe Aline , Damotte Vincent
Published: December 2020

Objective

To identify any mediating effect of vascular and neurodegenerative risk factors of dementia in the association existing between APOE4 and dementia.

Methods

1,240 participants from the French Three City Dijon Study without prevalent tumor or dementia were included. Among these participants, 76 developed dementia during the 12 years of follow-up. Using regression and mediation analyses, we studied whether known risk factors for dementia i.e smoking status, body mass index, diabetes mellitus, hypercholesterolemia, hypertension, hippocampal volume, rate of hippocampal volume loss or white matter hyperintensities could mediate the association between APOE4 and dementia. Regression models were adjusted for age, sex, education level (and total intracranial volume when imaging metrics were considered).

Results

Hippocampal volume was a partial mediator of the association between APOE4 and dementia (mediation ratio = 6.7%, p=0.03). No mediation effect was found for hypercholesterolemia. No mediation analyses could be undertaken for the others factors due to the lack of their association with APOE4 in our sample.

Conclusions

In this study, the association between APOE4 and dementia was partially mediated by hippocampal volume, confirming a deleterious role of APOE4 in the hippocampus. This result warrants further replication in other cohorts, with higher sample sizes.
Bridging neuronal correlations and dimensionality reduction
Authors: Umakantha Akash , Morina Rudina , Cowley Benjamin R. , Snyder Adam C. , Smith Matthew A. , Yu Byron M.
Published: December 2020

Two commonly used approaches to study interactions among neurons are spike count correlation, which describes pairs of neurons, and dimensionality reduction, applied to a population of neurons. While both approaches have been used to study trial-to-trial correlated neuronal variability, they are often used in isolation and have not been directly related. We first established concrete mathematical and empirical relationships between pairwise correlation and metrics of population-wide covariability based on dimensionality reduction. Applying these insights to macaque V4 population recordings, we found that the previously reported decrease in mean pairwise correlation associated with attention stemmed from three distinct changes in population-wide covariability. Overall, our work builds the intuition and formalism to bridge between pairwise correlation and population-wide covariability and presents a cautionary tale about the inferences one can make about population activity by using a single statistic, whether it be mean pairwise correlation or dimensionality.
Direct activation of RA signaling in cardiomyocytes protects hearts from apoptosis after myocardial infarction in mice
Authors: Da Silva Fabio , Motamedi Fariba Jian , Tison Amelie , Arachchige Lahiru Chamara Weerasinghe , Bradford Stephen T. , Lefebvre Jonathan , Dollé Pascal , Ghyselinck Norbert B. , Wagner Kay Dietrich , Schedl Andreas
Published: December 2020

Retinoic acid (RA) is an essential signaling molecule for cardiac development and plays a protective role in the heart after myocardial infarction (MI). In both cases, the effect of RA signaling on cardiomyocytes, the principle cell type of the heart, has been reported to be indirect. Here we have developed an inducible murine transgenic RA-reporter line usingCreERT2technology that permits lineage tracing of RA-responsive cells and faithfully recapitulates endogenous RA activity in multiple organs during embryonic development. Strikingly, we have observed a direct RA response in cardiomyocytes during mid-late gestation and after MI. Ablation of RA signaling through deletion of theAldh1a1/a2/a3genes encoding RA-synthesizing enzymes leads to increased cardiomyocyte apoptosis in adults subjected to MI. RNA sequencing analysis revealsTgm2andAce1, two genes with well-established links to cardiac repair, as potential targets of RA signaling in primary cardiomyocytes, thereby providing novel links between the RA pathway and heart disease.