bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic posttranslational modifications of cytoskeletal proteins unveil hot spots under nitroxidative stress
Authors: Griesser Eva , Vemula Venukumar , Mónico Andreia , Pérez-Sala Dolores , Fedorova Maria
Published: January 2021

The cytoskeleton is a supramolecular structure consisting of interacting protein networks that support cell dynamics in essential processes such as migration and division, as well as in responses to stress. Fast cytoskeletal remodeling is achieved with the participation of regulatory proteins and posttranslational modifications (PTMs). Redox-related PTMs are emerging as critical players in cytoskeletal regulation. Here we used a cellular model of mild nitroxidative stress in which a peroxynitrite donor induced transient changes in the organization of three key cytoskeletal proteins, i.e., vimentin, actin and tubulin. Nitroxidative stress-induced reconfiguration of intermediate filaments, microtubules and actin structures were further correlated with their PTM profiles and dynamics of the PTM landscape. Using high-resolution mass spectrometry, 62 different PTMs were identified and relatively quantified in vimentin, actin and tubulin proteins, including 12 enzymatic, 13 oxidative and 2 nitric oxide-derived modifications as well as 35 modifications by carbonylated lipid peroxidation products, thus evidencing the occurrence of a chain reaction with formation of reactive species and the activation of multiple signaling pathways. Our results unveil the presence of certain modifications under basal conditions and their modulation in response to stress in a target-, residue- and reactive species-dependent manner. Moreover, we identified protein PTM “hot spots”, such as the single cysteine residue of vimentin, supporting its role in PTM cross-talk and redox sensing. Finally, identification of novel PTMs in these proteins may pave the way for unveiling novel cytoskeleton regulatory mechanisms.
Hoxgenes regulate asexual reproductive behavior and tissue segmentation in adult animals
Authors: Arnold Christopher P. , Lozano Analí Migueles , Mann Frederick G. , Lange Jeffrey J. , Seidel Christopher , Alvarado Alejandro Sánchez
Published: January 2021

Hoxgenes are highly conserved transcription factors renowned for their roles in the segmental patterning of the embryonic anterior-posterior (A/P) axis1. Emerging evidence forHoxgene expression and function in postnatally derived structures has fueled interest in their additional roles beyond embryogenesis2,3. We report novel functions forHoxgenes in A/P adult tissue segmentation and transverse fission behavior underlying asexual reproduction in the planarian flatworm,Schmidtea mediterranea.Silencing of each of the planarianHoxfamily members identified 5Hoxgenes required for asexual reproduction. Among these, silencing ofhox3genes resulted in supernumerary segments, while silencing ofpost2beliminated segmentation altogether. The opposing roles ofhox3andpost2bin segmentation are paralleled in their respective regulation of fission behavior. Silencing ofhox3increased the frequency of fission behavior initiation, while silencing ofpost2beliminated fission behavior entirely. Furthermore, we identified a network of downstream effector genes mediatingHoxgene regulation of asexual reproduction, thereby providing insight into their respective mechanisms of action. Our study establishes postembryonic roles forHoxgenes in regulating the emergence of tissue segmentation and specific behaviors associated with asexual reproduction in adult animals.
TWO-SIGMA-G: A New Competitive Gene Set Testing Framework for scRNA-seq Data Accounting for Inter-Gene and Cell-Cell Correlation
Authors: Van Buren Eric , Hu Ming , Cheng Liang , Wrobel John , Wilhelmsen Kirk , Su Lishan , Li Yun , Wu Di
Published: January 2021

We propose TWO-SIGMA-G, a competitive gene set test for scRNA-seq data. TWO-SIGMA-G uses a mixed-effects regression model based on our previously published TWO-SIGMA to test for differential expression at the gene-level. This regression-based model provides flexibility and rigor at the gene-level in (1) handling complex experimental designs, (2) accounting for the correlation between biological replicates, and (3) accommodating the distribution of scRNA-seq data to improve statistical inference. Moreover, TWO-SIGMA-G uses a novel approach to adjust for inter-gene-correlation (IGC) at the set-level to control the set-level false positive rate. Simulations demonstrate that TWO-SIGMA-G preserves type-I error and increases power in the presence of IGC compared to other methods. Application to two datasets identified HIV-associated Interferon pathways in xenograft mice and pathways associated with Alzheimer’s disease progression in humans.
Long-term monitoring reveals topographical features and vegetation explain winter habitat use of an Arctic rodent
Authors: von Beckerath Xaver , Benadi Gita , Gilg Olivier , Sittler Benoît , Yannic Glenn , Klein Alexandra-Maria , Eitzinger Bernhard
Published: January 2021

Collapsing lemming cycles have been observed across the Arctic, presumably due to global warming creating less favorable winter conditions. The quality of wintering habitats, such as depth of snow cover, plays a key role in sustaining population dynamics of arctic lemmings. However, few studies so far investigated habitat use during the arctic winter. Here, we used a unique long-term time series to test whether lemmings are associated with topographical and vegetational habitat features for their winter refugi. We examined yearly numbers and distribution of 22,769 winter nests of the collared lemmingDicrostonyx groenlandicusfrom an ongoing long-term research on Traill Island, Northeast Greenland, collected between 1989 and 2019, and correlated this information with data on dominant vegetation types, elevation and slope. We specifically asked if lemming nests were more frequent at sites with preferred food plants such asDryas octopetala x integrifoliaand at sites with increased snow cover. We found that the number of lemming nests was highest in areas with a high proportion ofDryasheath, but also correlated with other vegetation types which suggest some flexibility in resource use of wintering lemmings. Conversely, they showed a distinct preference for sloped terrain, probably as it enhances the formation of deep snow drifts which increases the insulative characteristics of the snowpack and protection from predators. With global warming, prime lemming winter habitats may become scarce through alteration of snow physical properties, potentially resulting in negative consequence for the whole community of terrestrial vertebrates.
Dorsal color variation among subspecies of the “Oregon” Dark-eyed Junco complex
Authors: Yang Elisa T. , Unitt Philip , Mason Nicholas A.
Published: January 2021

Initial descriptions of avian subspecies were based on expert opinions of geographic variation in phenotypes and are inherently subjective. Although best practices for subspecies delimitation continue to be debated, reassessing subspecies limits with current, quantitative methods is important toward refining and improving taxonomic treatments. Plumage coloration is the basis of many subspecies diagnoses, but is potentially problematic because of the historical lack of quantitative methods to quantify color. Recently developed methods, such as colorimetry, provide repeatable measurements of color variation that can be used to reassess subspecies limits. In this study, we reassess color variation among subspecies of the Oregon Dark-eyed Junco (Junco hyemalis [oreganus Group]) complex, in which differences in back and hood color were established as diagnostic characters. We measured back and hood brightness and hue in 206 museum specimens among five Oregon Dark-eyed Junco subspecies using a colorimeter. We then compared mean measurements among subspecies and conducted a discriminant function analysis to assess how well dorsal color predicted subspecies. Our data correctly classified only 67.9% of males and 82.5% of females to their presumed subspecies. Furthermore, no adjacent subspecies pairs passed the “75% rule” due to extensive overlap in plumage characters. Thus, back color alone is not as effective in diagnosing Oregon Dark-eyed Junco subspecies as originally described, suggesting a possible taxonomic revision. Specifically, similarity in phenotypic and genetic data suggests that some combination ofthurberi,montanus, andshufeldtimay be lumped to recognize broad, clinal variation in dorsal color alongside clinal variation in other phenotypes and extensive gene flow.
Novel bisubstrate inhibitors for protein N-terminal acetyltransferase D
Authors: Deng Youchao , Deng Sunbin , Ho Yi-Hsun , Gardner Sarah M. , Huang Zhi , Marmorstein Ronen , Huang Rong
Published: January 2021

Protein N-terminal acetyltransferase D (NatD, NAA40) that specifically acetylates the alpha-N-terminus of histone H4 and H2A has been implicated in various diseases, but no inhibitor has been reported for this important enzyme. Based on the acetyl transfer mechanism of NatD, we designed and prepared a series of highly potent NatD bisubstrate inhibitors by covalently linking coenzyme A to different peptide substrates via an acetyl or propionyl spacer. The most potent bisubstrate inhibitor displayed an apparentKi value of 1.0 nM. Biochemical studies indicated that bisubstrate inhibitor is competitive to the peptide substrate and noncompetitive to the cofactor, suggesting NatD undergoes an ordered Bi-Bi mechanism. We also demonstrated that these inhibitors are highly specific towards NatD, displaying about 1,000-fold selectivity over other closely related acetyltransferases. High-resolution crystal structures of NatD bound to two of these inhibitors revealed the molecular basis for their selectivity and inhibition mechanism, providing a rational path for future inhibitor development.
CTP andparScoordinate ParB partition complex dynamics and ParA-ATPase activation for ParABS-mediated DNA partitioning
Authors: Taylor James A. , Seol Yeonee , Budhathoki Jagat , Neuman Keir C. , Mizuuchi Kiyoshi
Published: January 2021

ParABS partition systems, comprising the centromere-like DNA sequenceparS,theparS-binding ParB-CTPase and the nucleoid-binding ParA-ATPase, ensure faithful segregation of bacterial chromosomes and low-copy-number plasmids. F-plasmid partition complexes containing ParBFandparSFmove by generating and following a local concentration gradient of nucleoid-bound ParAF. However, the process through which ParBFactivates ParAF-ATPase has not been defined. We studied CTP- andparSF-modulated ParAF—ParBFcomplex assembly, in which DNA-bound ParAF-ATP dimers are activated for ATP hydrolysis by interacting with two ParBFN-terminal domains. CTP orparSFenhances the ATPase rate without significantly accelerating ParAF—ParBFcomplex assembly. Together,parSFand CTP accelerate ParAF—ParBFassembly without further significant increase in ATPase rate. Magnetic-tweezers experiments showed that CTP promotes multiple ParBFloading ontoparSF-containing DNA, generating condensed partition complex-like assemblies. We propose that ParBFin the partition complex adopts a conformation that enhances ParBF—ParBFand ParAF—ParBFinteractions promoting efficient partitioning.
Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling on intestinal epithelial cells
Authors: El-Naccache Darine W. , Chen Fei , Palma Mark , Lemenze Alexander , Wu Wenhui , Mishra Pankaj K. , Eltzschig Holger K. , Robson Simon C. , Di Virgilio Francesco , Haskó György , Gause William C.
Published: January 2021

Multicellular intestinal nematode parasites can cross the epithelial barrier potentially causing tissue damage and release of danger associated molecular patterns (DAMPs) that may promote type 2 responses and host protective immunity. We investigated whether adenosine specifically binding the A2Badenosine receptor (A2BAR) on epithelial cells played an important role in driving intestinal immunity. Specific blockade of epithelial cell A2BAR inhibited the host protective memory response to the enteric helminth,Heligmosomoides polygyrus bakeri, including disruption of granuloma development at the host:parasite interface during the transient tissue dwelling larval stage. Memory T cell development was blocked during the primary response and transcriptional analyses revealed profound impairment of A2BAR signaling in epithelial cells and reduced type 2 markers by 24 hours after inoculation. Extracellular ATP was visualized by 24 hours after inoculation and shown in CD39 deficient mice to be critical for the adenosine production mediating initiation of type 2 immunity.
Reproducibility of protein X-ray diffuse scattering and potential utility for modeling atomic displacement parameters
Authors: Su Zhen , Dasgupta Medhanjali , Poitevin Frédéric , Mathews Irimpan I. , van den Bedem Henry , Wall Michael E. , Yoon Chun Hong , Wilson Mark A.
Published: January 2021

Protein structure and dynamics can be probed using X-ray crystallography. Whereas the Bragg peaks are only sensitive to the average unit-cell electron density, the signal between the Bragg peaks -- diffuse scattering -- is sensitive to spatial correlations in electron-density variations. Although diffuse scattering contains valuable information about protein dynamics, the diffuse signal is more difficult to isolate from the background compared to the Bragg signal, and the reproducibility of diffuse signal is not yet well understood. We present a systematic study of the reproducibility of diffuse scattering from isocyanide hydratase (ICH) in three different protein forms. Both replicate diffuse datasets and datasets obtained from different mutants were similar in pairwise comparisons (Pearson correlation coefficient (CC) ≥0.8). The data were processed in a manner inspired by previously published methods using custom software with modular design, enabling us to perform an analysis of various data processing choices to determine how to obtain the highest quality data as assessed using unbiased measures of symmetry and reproducibility. The diffuse data then were used to characterize atomic mobility using a liquid-like motions (LLM) model. This characterization was able to discriminate between distinct anisotropic atomic displacement parameter (ADP) models arising from different anisotropic scaling choices that agreed comparably with the Bragg data. Our results emphasize the importance of data reproducibility as a model-free measure of diffuse data quality, illustrate the ability of LLM analysis of diffuse scattering to select among alternative ADP models, and offer insights into the design of successful diffuse scattering experiments.
Mild impacts do not subsidize aquatic insect communities in an Atlantic Forest stream
Authors: Jonck Celio Roberto , de Oliveira Luiza Hoehne Mattos , Silva Rafael Jordão Pires , Nessimian Jorge Luiz
Published: January 2021

Odum’s perturbation theory hypothesizes that toxic pollutants cause damage to ecosystems early in the course of contamination. In contrast, organic pollutants enrich the ecosystem until it exceeds their carrying capacity, an effect known as the subsidy-stress gradient. Understanding this dynamic can improve the efficiency of river restoration programs and bring significant benefits to society by providing ecosystem services that were lost. However, the initial effects of the most common human-induced disturbances in Atlantic Forest streams are not well known, indicating the necessity to evaluate the subsidy-stress gradient in these vulnerable and diverse ecosystems.

Aim

We evaluated the composition and abundance of the community of aquatic insects from leaf litter of headwater streams in three conditions: a fully forested area (reference stream), a low-intensity urban settlement (urban stream), and a region with small farms dedicated to the cultivation of fruits and vegetables (agricultural stream).

Methods

We used alpha and beta diversity metrics and a specific biotic index to test the subsidy-stress gradient prediction.

Results

The agricultural stream showed the most degraded ecological condition. The urban stream and the reference stream showed similarity in alpha diversity metrics. According to the biotic index, the streams showed a gradient of environmental quality, with the reference stream showing the best quality and the agricultural stream the worst quality.

Conclusions

The agricultural stream showed a decrease in the environmental quality consistent with the effect predicted by the subsidy-stress gradient due to toxic pollutants’ contribution. However, the low-intensity enrichment of organic matter from the urban settlement causes a disorder in the ecosystem that reduces its environmental quality, contrary to the predicted by the subsidy-stress gradient.
Deconstruction of the retrosplenial granular cortex for social behavior in the mouse model of fragile X syndrome
Authors: Shang Hui-Fang , Cai Ruonan , Sun Hao , Sheng Tao , Lian Yan-Na , Liu Li , Chen Wei , Gao Lixia , Xu Han , Zhang Chen , Luo Jian-Hong , Li Xinjian , Li Xiang-Yao
Published: January 2021

Deficits in fragile X mental retardation 1 protein lead to fragile X syndrome (FXS) with mental retardation and social activity disorder. Until now, the neuronal circuits that mediate the social impairments of FXS were mostly unclear. Accidently, we found fewer c-fos expression in RSG of KO than WT mice after social behavior test. Inactivation of RSG neurons decreased social novelty but not the sociability of naive mice. Interestingly, although the RSG neurons of KO mice had higher background activity, fewer social contact-related Ca2+neurons were observed during social interaction testviaone-photon Ca2+imaging in freely-behaving mice. Strikingly, enhancing the activity of RSG neurons rescued the abnormal social novelty in KO mice. Further studies proved that the innervations from the subiculum and ACC to RSG contributes to the social behavior. Take together, we found that abnormal activity in the retrosplenial granular cortex (RSG) led to social novelty deficits inFmr1-knockout (KO) mice. Moreover, selective manipulation of RSG neurons may be an effective strategy to treat the social deficits in FXS.

One Sentence Summary

Deletion of FMRP leads to lower social-related neuronal activity in the RSG; this causes social novelty deficits inFmr1-KO mice.
Representation and inference of size control laws by neural network aided point processes
Authors: Kamimura Atsushi , Kobayashi Tetsuya J.
Published: January 2021

The regulation and coordination of cell growth and division is a long-standing problem in cell physiology. Recent single-cell measurements using microfluidic devices provide quantitative time-series data of various physiological parameters of cells. To clarify the regulatory laws and associated relevant parameters such as cell size, mathematical models have been constructed based on physical insights over the phenomena and tested by their capabilities to reproduce the measured data. However, such a conventional model construction by abduction faces a constant risk that we may overlook important parameters and factors especially when complicated time series data is concerned. In addition, comparing a model and data for validation is not trivial when we work on noisy multi-dimensional data. Using cell size control as an example, we demonstrate that this problem can be addressed by employing a neural network (NN) method, originally developed for history-dependent temporal point processes. The NN can effectively segregate history-dependent deterministic factors and unexplainable noise from a given data by flexibly representing functional forms of the deterministic relation and noise distribution. With this method, we represent and infer birth and division cell size distributions of bacteria and fission yeast. The known size control mechanisms such as adder model are revealed as the conditional dependence of the size distributions on history and their Markovian properties are shown sufficient. In addition, the inferred NN model provides a better data representation for the abductive model searching than descriptive statistics. Thus, the NN method can work as a powerful tool to process the noisy data for uncovering hidden dynamic laws.
Design of a novel DNA Gyrase B inhibitor with a rhodanine scaffold:in silicoandin vitroapproaches
Authors: Pudipeddi Akhila , Vasudevan Sahana , Shanmugam Karthi , Stanley Alex , Pothiappan Vairaprakash , Neelakantan Prasanna , Solomon Adline Princy
Published: January 2021

Methicillin-resistantStaphylococcus aureus(MRSA) and vancomycin intermediate-resistantStaphylococcus aureus(VRSA) is one among the WHO high priority pathogens. Among these two, MRSA is the most globally documented pathogen that necessitates the pressing demand for new classes of anti-MRSA drugs. Bacterial gyrase targeted therapeutics are unique strategies to overcome cross-resistance as they are present only in bacteria and absent in higher eukaryotes. The GyrB subunit is essential for the catalytic functions of the bacterial enzyme DNA Gyrase, thereby constituting a promising druggable target. The current study performed a structure-based virtual screening to designing GyrB target-specific candidate molecules. Thede novoligand design of novel hit molecules was performed using a rhodanine scaffold. Through a systematicin silicoscreening process, the hit molecules were screened for their synthetic accessibility, drug likeliness and pharmacokinetics properties in addition to its target specific interactions. Of the total 374 hit molecules obtained throughde novoligand design, qsl-304 emerged as the most promising ligand. qsl-304 was synthesized through a one-step chemical synthesis procedure, and thein vitroactivity was proven, with an IC50of 31.23 μg/mL against the novobiocin resistant clinical isolate ofStaphylococcus aureus sa-P2003. Further studies on time-kill kinetics showed the bacteriostatic nature with the diminished recurrence of resistance.
Basis profile curve identification to understand electrical stimulation effects in human brain networks
Authors: Miller Kai J. , Müller Klaus-Robert , Hermes Dora
Published: January 2021

Brain networks can be explored by delivering brief pulses of electrical current in one area while measuring voltage responses in other areas. We propose a convergent paradigm to study brain dynamics, focusing on a single brain site to observe the average effect of stimulating each of many other brain sites. Viewed in this manner, visually-apparent motifs in the temporal response shape emerge from adjacent stimulation sites. This work constructs and illustrates a data-driven approach to determine characteristic spatiotemporal structure in these response shapes, summarized by a set of unique “basis profile curves” (BPCs). Each BPC may be mapped back to underlying anatomy in a natural way, quantifying projection strength from each stimulation site using simple metrics. Our technique is demonstrated for an array of implanted brain surface electrodes in a human patient. This framework enables straightforward interpretation of single-pulse brain stimulation data, and can be applied generically to explore the diverse milieu of interactions that comprise the connectome.

Author summary

We present a new machine learning framework to probe how brain regions interact using single-pulse electrical stimulation. Unlike previous studies, this approach does not assume a form for how one brain area will respond to stimulation in another area, but rather discovers the shape of the response in time from the data. We call the set of characteristic discovered response shapes “basis profile curves” (BPCs), and show how these can be mapped back onto the brain quantitatively. An illustrative example is included from one of our human patients to characterize inputs to the parahippocampal gyrus. A code package is downloadable fromhttps://purl.stanford.edu/rc201dv0636so the reader may explore the technique for own data, or study sample data provided to reproduce the illustrative case presented in the manuscript.
RegEnrich: An R package for gene regulator enrichment analysis reveals key role of ETS transcription factor family in interferon signaling
Authors: Tao Weiyang , Radstake Timothy R.D.J. , Pandit Aridaman
Published: January 2021

Changes in a few key transcriptional regulators can lead to different biological states, including cell activation and differentiation, and diseases. Extracting the key gene regulators governing a biological state allows us to gain mechanistic insights and can further help in translational research. Most current tools perform pathway/GO enrichment analysis to identify key genes and regulators but tend to overlook the regulatory interactions between genes and proteins. Here we presentRegEnrich, an open-source Bioconductor R package, which combines differential expression analysis, data-driven gene regulatory network inference, enrichment analysis, and gene regulator ranking to identify key regulators using gene/protein expression profiling data. By benchmarking using multiple gene expression datasets of gene silencing studies, we found thatRegEnrichusing the GSEA method to rank the regulators performed the best to retrieve the key regulators. Further,RegEnrichwas applied to 21 publicly available datasets onin vitrointerferon-stimulation of different cell types. We found that not only IRF and STAT transcription factor families played an important role in cells responding to IFN, but also several ETS transcription factor family members, such as ELF1 and ETV7, are highly associated with IFN stimulations. Collectively,RegEnrichcan accurately identify key gene regulators from the cells under different biological states in a data-driven manner, which can be valuable in mechanistically studying cell differentiation, cell response to drug stimulation, disease development, and ultimately drug development.
Ultrasensitive measurement of both SARS-CoV2 RNA and serology from saliva
Authors: Ter-Ovanesyan Dmitry , Gilboa Tal , Lazarovits Roey , Rosenthal Alexandra , Yu Xu G. , Li Jonathan Z. , Church George M. , Walt David R.
Published: January 2021

Tests for COVID-19 generally measure SARS-CoV2 viral RNA from nasal swabs or antibodies against the virus from blood. It has been shown, however, that both viral particles and antibodies against those particles are present in saliva, which is more accessible than both swabs and blood. We present methods for highly sensitive measurements of both viral RNA and serology from the same saliva sample. We developed an efficient saliva RNA extraction method and combined it with an ultrasensitive serology test based on Single Molecule Array (Simoa) technology. We apply our test to the saliva of patients who presented to the hospital with COVID-19 symptoms, some of whom tested positive with a conventional RT-qPCR nasopharyngeal swab test. We demonstrate that combining viral RNA detection by RT-qPCR with serology identifies more patients as infected than either method alone. Our results suggest the utility of combining viral RNA and serology testing from saliva, a single easily accessible biofluid.
Disentangling sex differences in the shared genetic architecture of posttraumatic stress disorder, traumatic experiences, and social support with body size and composition
Authors: Carvalho Carolina Muniz , Wendt Frank R. , Pathak Gita A. , Maihofer Adam X. , Stein Dan J. , Sumner Jennifer A. , Hemmings Sian M. J. , Nievergelt Caroline M. , Koenen Karestan C. , Gelernter Joel , Belangero Sintia I. , Polimanti Renato
Published: January 2021

There is a well-known association of posttraumatic stress disorder (PTSD) and traumatic experiences with body size and composition, including consistent differences between sexes. However, the biology underlying these associations is unclear. To understand this complex relationship, we investigated large-scale datasets from the Psychiatric Genomic Consortium (12 823 cases and 35 648 controls), the UK Biobank (up to 360 000 individuals), and the GIANT (Genetic Investigation of Anthropometric Traits) Consortium (up to 339 224 individuals). We used genome-wide association statistics to estimate sex-specific genetic correlations (rg) among PTSD, traumatic experiences, social support, and multiple anthropometric traits. After multiple testing corrections (false discovery rate, FDR q<0.05), we observed 58 significant rg relationships in females (e.g., childhood physical abuse and body mass index, BMI rg=0.245, p=3.88×10−10) and 21 significant rg relationships in males (e.g., been involved in combat or exposed to warzone and leg fat percentage; rg=0.405, p=4.42×10−10). We performed causal inference analyses of these genetic overlaps using Mendelian randomization and latent causal variable approaches. Multiple female-specific putative causal relationships were observed linking body composition/size with PTSD (e.g., leg fat percentage➔PTSD; beta=0.319, p=3.13×10−9), traumatic experiences (e.g., childhood physical abuse➔waist circumference; beta=0.055, p=5.07×10−4), and childhood neglect (e.g., “someone to take you to doctor when needed as a child”➔BMI; beta=-0.594, p=1.09×10−5). In males, we observed putative causal effects linking anthropometric-trait genetic liabilities to traumatic experiences (e.g., BMI➔childhood physical abuse; beta=0.028, p=8.19×10−3). In conclusion, our findings provide insights regarding sex-specific causal networks linking anthropometric traits to PTSD, traumatic experiences, and social support.
SARS-CoV-2 RNA screening in routine pathology specimens
Authors: Stillfried Saskia von , Villwock Sophia , Bülow Roman D. , Djudjaj Sonja , Buhl Eva M. , Maurer Angela , Ortiz-Brüchle Nadina , Celec Peter , Klinkhammer Barbara M. , Wong Dickson W.L. , Cacchi Claudio , Braunschweig Till , Knüchel-Clarke Ruth , Dahl Edgar , Boor Peter
Published: January 2021

Virus detection methods are important to cope with the SARS-CoV-2 pandemics. Apart from the lung, SARS-CoV-2 was detected in multiple organs in severe cases. Less is known on organ tropism in patients developing mild or no symptoms, and some of such patients might be missed in symptom-indicated swab testing.

Here we tested and validated several approaches and selected the most reliable RT-PCR protocol for the detection of SARS-CoV-2 RNA in patients’ routine diagnostic formalin-fixed and paraffin-embedded (FFPE) specimens available in pathology, to assess a) organ tropism in samples from COVID-19-positive patients, b) unrecognized cases in selected tissues from negative or not-tested patients during a pandemic peak, and c) retrospectively, pre-pandemic lung samples.

We identified SARS-CoV-2 RNA in four samples from confirmed COVID-19 patients, in two gastric biopsies, one colon resection, and one pleural effusion specimen, while all other specimens, particularly from patients with mild COVID-19 disease course, were negative. In the pandemic peak cohort, we identified one previously unrecognized COVID-19 case in tonsillectomy samples. All pre-pandemic lung samples were negative.

In conclusion, SARS-CoV-2 RNA detection in FFPE pathology specimens can potentially improve surveillance of COVID-19, allow retrospective studies, and advance our understanding of SARS-CoV-2 organ tropism and effects.
Hepatitis E virus seroprevalence and associated risk factors in high-risk groups: A cross-sectional study from Turkey
Authors: Balaban H. Yasemin , Aslan Abdullah Tarık , Akdoğan Kittana Fatma Nur , Alp Alpaslan , Dağ Osman , Ayar Şefika Nur , Vahabov Cavanşir , Şimşek Cem , Yıldırım Tolga , Göker Hakan , Ergünay Koray , Erdem Yunus , Büyükaşık Yahya , Şimşek Halis
Published: January 2021

Background

The renal transplant recipients (RT), allogeneic hematopoietic stem cell transplant recipients (allo-HSCT), patients with acute hepatitis (AH), and chronic hepatitis C patients (CHC) are at risk of hepatitis E virus (HEV) infection. However, seroepidemiology, risk factors to HEV exposure, and the prevalence of HEV viremia has not yet been investigated among these patients in Turkey.

Materials&Methods

In this cross-sectional study, 292 consecutive serum samples were tested for HEV immunoglobulin IgG/IgM and HEV RNA using commercial ELISA and in-house nested PCR with Sanger sequencing, respectively. Sociodemographic, clinical, laboratory data, and risk factors were collected using a questionnaire and hospital database. Multiple logistic regression analysis was employed to identify independent predictors for anti-HEV seropositivity.

Results

Among all patients (n=292) tested for HEV RNA reactivity, only 2 patients (one RT recipient and one patient with AH) were identified as having HEV3 viremia. HEV viremia rate was 0.6% in whole group. These patients had shown no signs of chronic HEV infection for 6 months and was found to spontaneously seroconverted 6 months after enrollment. Anti-HEV IgG was positive in 29 patients yielding an HEV seroprevalence of 9.9%. Older age (aOR:1.03, 95% CI, 1.00-1.06; p:0.022) and eating undercooked meat (aOR:3.11, 95% CI, 1.08-8.92; p:0.034) were independent risk factors to anti-HEV seropositivity in all patients. Similarly, multiple logistic regression analysis demonstrated that age (aOR:1.03, 95% CI, 0.99-1.07, p:0.058) and eating undercooked meat (aOR:5.77, 95% CI, 1.49-22.25, p:0.011) were independent risk factors for anti-HEV IgG positivity in the non-immunosuppressive subgroup consisting of AH and CHC patients.

Conclusion

The HEV seroprevalence rate was high (9.9%), despite low viremia rate (0.6%) in high-risk patients. The emergence of HEV3 might indicate a serious problem for these patients. Future investigations are needed to elucidate foodborne transmission routes of HEV in Turkey.
Effects of stricter management guidelines on return-to-play timeframes following concussion in professional Australian Rules football
Authors: Pearce Alan J , King Doug A , White Adam J , Suter Catherine M
Published: January 2021

Background

Management of concussion remains a serious issue for professional sports, particularly with the growing knowledge on the consequences of repetitive concussion. One primary concern is the subjective assessment of recovery that dictates the time until a concussed athlete is returned to competition. In response to this concern, the Australian Football League (AFL) changed its policy in 2020 such that clearance for return-to-play was extended from one day, to a minimum of five days, prior to the next scheduled match.

Objective

We sought to examine the impact of the AFL policy change by asking whether the time to return-to-play after concussion was increased in the 2020 season relative to previous years.

Methods

Retrospective data on injury and return-to-play were sourced from publicly available tables published on the AFL website. We compared the number of matches missed and the number of days missed in concussed players across 2017 to 2020 inclusive.

Results

Analysis of data from 166 concussed players revealed no increase in the number of matches missed in 2020 relative to previous years as would have been expected from an extend recovery protocol. Considering the number of days missed in 2020 relative to 2017-19 we found, paradoxically, that there was an overall reduction in the average time to return-to-play in 2020 (11.2 vs 16.2 days).

Conclusion

This study demonstrates that any policy change around concussion management requires ongoing auditing to ensure clearance meets policy objectives and highlights the need for objective measures for return-to-play after concussion.
The epidemiology of herpes simplex virus type 2 in sub-Saharan Africa: systematic review, meta-analyses, and meta-regressions
Authors: Harfouche Manale , Abu-Hijleh Farah M. , James Charlotte , Looker Katharine J. , Abu-Raddad Laith J.
Published: January 2021

Background

Herpes simplex virus type 2 (HSV-2) infection is a prevalent sexually transmitted infection with a sizable disease burden that is highest in sub-Saharan Africa. This study aimed to characterize HSV-2 epidemiology in this region.

Methods

Cochrane and PRISMA guidelines were followed to systematically review, synthesize, and report HSV-2 related findings. Meta-analyses and meta-regressions were conducted.

Findings

From 218 relevant publications, 451 overall outcome measures and 869 stratified measures were extracted. Pooled incidence rates ranged between 2.4-19.4 per 100 person-years across populations. Pooled seroprevalence was lowest at 37.3% (95% confidence interval (CI): 34.9-39.7%) in general populations and high in female sex workers and HIV positive individuals at 62.5% (95% CI: 54.8-70.0%) and 71.3% (95% CI: 66.5-75.9%), respectively. In general populations, pooled seroprevalence increased steadily with age. Compared to women, men had a lower seroprevalence with an adjusted risk ratio (ARR) of 0.61 (95% CI: 0.56-0.67).

Seroprevalence decreased in recent decades with an ARR of 0.98 (95% CI: 0.97-0.99) per year. Seroprevalence was highest in Eastern and Southern Africa. Pooled HSV-2 proportion in genital ulcer disease was 50.7% (95% CI: 44.7-56.8%) and in genital herpes it was 97.3% (95% CI: 84.4-100%).

Interpretation

Seroprevalence is declining by 2% per year, but a third of the population is infected. Age and geography play profound roles in HSV-2 epidemiology. Temporal declines and geographic distribution of HSV-2 seroprevalence mirror that of HIV prevalence, suggesting sexual risk behavior has been declining for three decades. HSV-2 is the etiological cause of half of GUD and nearly all genital herpes cases.

Funding

This work was supported by pilot funding from the Biomedical Research Program at Weill Cornell Medicine in Qatar and by the Qatar National Research Fund [NPRP 9-040-3-008].
A Mathematical Model of Platelet Antiparasitic Action in Erythrocytes and Merozoites During Malaria Infection
Authors: Rubio Felipe Alves , Yang Hyun Mo
Published: January 2021

Platelets have been seen traditionally as fragments of blood mediating coagulation. However, evidence during malaria infection suggests that platelets also act against merozoites, an infectious form of malaria in the bloodstream, and megakaryocytes can release giant platelets with a larger volume than normal platelets. We propose a mathematical model to study the interaction between red blood cells, merozoites, and platelets during malaria infection. We analyzed two cases of the interaction of platelets with malaria infection. In the first one, we considered the isolated action of normal platelets and, in the second one, the joint antiparasitic action of both normal and giant platelets. Numerical simulations were performed to evaluate the stability of the equilibrium points of the system of equations. The model showed that the isolated antiparasitic action of normal platelets corroborates malaria infection control. However, the system can converge to a presence-merozoite equilibrium point, or an oscillatory behavior may appear. The joint antiparasitic action of both normal and giant platelets eliminated the oscillatory behavior and drove the dynamics to converge to lower parasitic concentration than the case of isolated action of normal platelets. Moreover, the joint antiparasitic action of platelets proved more easily capable of eliminating the infection.
SARS-CoV-2 infection in pregnancy is associated with robust inflammatory response at the maternal-fetal interface
Authors: Lu-Culligan Alice , Chavan Arun R. , Vijayakumar Pavithra , Irshaid Lina , Courchaine Edward M. , Milano Kristin M. , Tang Zhonghua , Pope Scott D. , Song Eric , Vogels Chantal B.F. , Lu-Culligan William J. , Campbell Katherine H. , Casanovas-Massana Arnau , Bermejo Santos , Toothaker Jessica M. , Lee Hannah J. , Liu Feimei , Schulz Wade , Fournier John , Muenker M. Catherine , Moore Adam J. ,   Yale IMPACT Team, Konnikova Liza , Neugebauer Karla M. , Ring Aaron , Grubaugh Nathan D. , Ko Albert I. , Morotti Raffaella , Guller Seth , Kliman Harvey J. , Iwasaki Akiko , Farhadian Shelli F.
Published: January 2021

Pregnant women appear to be at increased risk for severe outcomes associated with COVID-19, but the pathophysiology underlying this increased morbidity and its potential impact on the developing fetus is not well understood. In this study of pregnant women with and without COVID-19, we assessed viral and immune dynamics at the placenta during maternal SARS-CoV-2 infection. Amongst uninfected women, ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term. Term placentas from women infected with SARS-CoV-2, however, displayed a significant increase in ACE2 levels. Using immortalized cell lines and primary isolated placental cells, we determined the vulnerability of various placental cell types to direct infection by SARS-CoV-2in vitro. Yet, despite the susceptibility of placental cells to SARS-CoV-2 infection, viral RNA was detected in the placentas of only a subset (∼13%) of women in this cohort. Through single cell transcriptomic analyses, we found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited markers associated with pregnancy complications, such as preeclampsia, and robust immune responses, including increased activation of placental NK and T cells and increased expression of interferon-related genes. Overall, this study suggests that SARS-CoV-2 is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion. While this likely represents a protective mechanism shielding the placenta from infection, inflammatory changes in the placenta may also contribute to poor pregnancy outcomes and thus warrant further investigation.
Covid-19 in end-stage renal disease patients with renal replacement therapies: a systematic review and meta-analysis
Authors: Nopsopon Tanawin , Kittrakulrat Jathurong , Takkavatakarn Kullaya , Eiamsitrakoon Thanee , Kanjanabuch Talerngsak , Pongpirul Krit
Published: January 2021

Introduction

The novel coronavirus (COVID-19), caused by SARS-CoV-2, showed various prevalence and case-fatality rates (CFR) among patients with different pre-existing chronic conditions. End-stage renal disease (ESRD) patients with renal replacement therapy (RRT) might have a higher prevalence and CFR due to reduced immune function from uremia and kidney tropism of SARS-CoV-2, but there was no systematic study on the infection and mortality of the SARS-CoV-2 infection in ESRD patients who are on RRT.

Methods

We searched five electronic databases and performed a systematic review and meta-analysis up to June 30, 2020, to evaluate the prevalence and case fatality rate (CFR) of the COVID-19 infection among ESRD patients with RRT. The global COVID-19 data were retrieved from the international database on June 30, 2020, for estimating the prevalence and CFR of the general population as referencing points.

Results

Of 3,272 potential studies, 34 were eligible studies consisted of 1,944 COVID-19 confirmed cases in 21,873 ESRD patients with RRT from 12 countries in four WHO regions. The overall pooled prevalence in ESRD patients with RRT was 3.10% [95% confidence interval (CI) 1.25–5.72] which was higher than referencing 0.14% global average prevalence. The overall estimated CFR of COVID-19 in ESRD patients with RRT was 18.06% (95%CI 14.09– 22.32) which was higher than the global average at 4.98%.

Conclusions

This meta-analysis suggested high COVID-19 prevalence and CFR in ESRD patients with RRT. ESRD patients with RRT should have their specific protocol of COVID-19 prevention and treatment to mitigate excess cases and deaths.

Author summary

Chronic kidney disease (CKD) was associated with increasing severity and mortality of COVID-19. End-stage renal disease (ESRD) patients were at the terminal stage of CKD and had reduced immune function due to uremia. Additionally, ESRD patients with kidney transplantation had a diminished immune system from immunosuppressive agents. Kidneys might be the secondary target of SARS-CoV-2 after the respiratory tract regardless of the previous history of kidney disease, preferably the glomerulus, which was associated with the richness of some specific protein-coding genes in the kidney. The overall pooled prevalence in ESRD patients with renal replacement therapy was approximately 22 times of the referencing global average prevalence. The overall estimated case fatality rate of COVID-19 in ESRD patients with renal replacement therapy was approximately 3.6 times the global average. ESRD patients with renal replacement therapy had high COVID-19 prevalence and case fatality rate. We suggested that ESRD patients with renal replacement therapy should have their specific protocol of COVID-19 prevention and treatment to mitigate excess cases and deaths.
PREVALENCE OF ABDOMINAL OBESITY AND ITS ASSOCIATION WITH CARDIOVASCULAR RISK AMONG THE ADULT POPULATION IN BURKINA FASO
Authors: Cisse Kadari , Samadoulougou Sékou , Ouedraogo Mady , Kouanda Seni , Kirakoya-Samadoulougou et Fati
Published: January 2021

Objective

The objective of this study is to determine the prevalence of abdominal obesity and its associated factors in Burkina Faso. We hypothesize that there is a high burden of abdominal obesity and it is significantly associated with sociodemographic and cardiovascular risk factors.

Design

We performed secondary analysis of the survey conducted in Burkina Faso using the World Health Organization (WHO) STEPwise approach.

Setting

The study was conducted in Burkina Faso with all 13 regions of the country included.

Participants

Our study involved 4308 adults of both sexes aged 25 to 64 years.

Main outcome

Our primary outcome was the abdominal obesity which was could defined using a cut-off point of waist circumference (WC) of ≥94 cm for men and ≥80 cm for women.

Results

The overall age-standardized prevalence of abdominal obesity was 22.5% (95% CI: 21.3–23.7). This age-standardized prevalence was 35.9% (95% CI: 33.9–37.9) among women and 5.2% (95% CI: 4.3–6.2) among men (p < 0.001). In urban areas, the age-standardized prevalence of abdominal obesity was 42.8% (95% CI: 39.9–45.7) and 17.0% (95%CI: 15.7–18.2) in rural areas (p < 0.001). The overall age-standardized prevalence of very high WC (WC ≥102 cm for men and ≥88 cm for women) was 10.2% (95%CI: 9.3–11.1). According to the National Institute for Health and Clinical Excellence (NICE) BMI–WC matrix, which combines the body mass index (BMI) and WC to define different levels of cardiovascular health risk, 14.6% of adult Burkinabè had an increased cardiovascular health risk.

Conclusion

Our study shows a high prevalence of abdominal obesity among the adult population in Burkina Faso. These findings suggest that the measurement of WC should be systematically incorporated in Burkina Faso primary healthcare centers for the early detection of high cardiovascular risk in order to reduce levels of premature death.

STRENGTHS AND LIMITATIONS OF THIS STUDY

➢

This is the first national representative study on abdominal obesity in the context of an emerging epidemiological transition in Burkina Faso.

➢

A recommended cut-off point was used to define abdominal obesity among the adult population in Burkina Faso, which we found to be associated with “intermediate” cardiovascular risk factors.

➢

The waist circumference and risk factors used in this study were measured using the standard approach proposed by the WHO [1]. However, some risk factors such as physical inactivity, alcohol consumption, and type of fat were self-reported and may therefore be affected by information bias.

➢

This study was a cross-sectional study and must not be considered to make causal inference.

Target journal

https://bmjopen.bmj.com/