bluuebunny/crossref_metadata_2025 huggingface dataset:
Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines
Authors: Bryant Andrew , Lawrie Theresa A. , Dowswell Therese , Fordham Edmund J. , Mitchell Scott , Hill Sarah R. , Tham Tony C.
Published: June 2021

Background:

Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials.

Areas of uncertainty:

We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection.

Data sources:

We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion.

Therapeutic Advances:

Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian–Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%–91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.

Conclusions:

Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.
Comparison of Surgical Outcomes After Total Laparoscopic Hysterectomy or Total Vaginal Hysterectomy for Large Uteri
Authors: Sailofsky Sybil , Darin Christina , Alfahmy Anood , Sheyn David
Published: June 2021

(Abstracted from Obstet Gynecol 2021;137:445–453)

Laparoscopic hysterectomy is associated with less postoperative pain, shorter hospital stays, and faster recoveries when compared with abdominal hysterectomy. Because of these superior outcomes, laparoscopic hysterectomy has dramatically increased in frequency, and 1 result of this is a decrease in vaginal hysterectomy.
Inherent Mosaicism and Extensive Mutation of Human Placentas
Authors: Coorens Tim H. H. , Oliver Thomas R. W. , Sanghvi Rashesh , Sovio Ulla , Cook Emma , Vento-Tormo Roser , Haniffa Muzlifah , Young Matthew D. , Rahbari Raheleh , Sebire Neil , Campbell Peter J. , Charnock-Jones D. Stephen , Smith Gordon C. S. , Behjati Sam
Published: June 2021

(Abstracted from Nature 2021;592:80–85)

Approximately 1% to 2% of pregnancies involve chromosomal aberrations confined to the placenta. During the first few days of embryogenesis when fetal and placental lineages diverge, clonal expansion and mosaicism may occur, representing a potential pathological divergence from normal clonal dynamics of early embryogenesis.
Prediction of Stillbirth: An Umbrella Review of Evaluation of Prognostic Variables
Authors: Townsend R. , Sileo F. G. , Allotey J. , Dodds J. , Heazell A. , Jorgensen L. , Kim V. B. , Magee L. , Mol B. , Sandall J. , Smith G. C. S. , Thilaganathan B. , vonDadelszen P. , Thangaratinam S. , Khalil A.
Published: June 2021

(Abstracted from BJOG 2021;128:238–250)

The global incidence of stillbirth remains high, despite decreases in maternal and neonatal morbidity. Therefore, developing strategies to predict and prevent stillbirth is a priority.
No Increase in Kawasaki Disease–Like Illnesses During the COVID-19 Pandemic Compared With 4 Previous Years
Authors: Molin Amber , Kulenthirarajan Rajesh , Lopez-Peña Maricarmen , Knuth Emily , Barillas-Arias Liliana , Andrews Shannon L.
Published: June 2021

Background

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection produces a wide variety of inflammatory responses in children, including multisystem inflammatory syndrome in children, which has similar clinical manifestations as Kawasaki disease (KD).

Methods

We performed a chart review of all patients with KD-like illnesses from January 1, 2016, to May 31, 2020, at a tertiary care children's hospital within a larger health system. Relevant symptoms, comorbid illnesses, laboratory results, imaging studies, treatment, and outcomes were reviewed. Descriptive analyses to compare features over time were performed.

Results

We identified 81 cases of KD-like illnesses from January 1, 2016, to May 31, 2020. Few clinical features, such as gallbladder involvement, were more prevalent in 2020 than in previous years. A few patients in 2020 required more intensive treatment with interleukin 1 receptor antagonist therapy. There were no other clear differences in incidence, laboratory parameters, number of doses of intravenous immunoglobulin, or outcomes over the years of the study.

Conclusions

There was no difference in incidence, laboratory parameters, or number of doses of intravenous immunoglobulin required for treatment of KD-like illnesses during the COVID-19 pandemic when compared with previous years at our institution. Kawasaki disease–like illnesses, including multisystem inflammatory syndrome in children, may not have changed substantially during the COVID-19 pandemic.
Mammalian target of rapamycin signaling pathway is involved in synaptic plasticity of the spinal dorsal horn and neuropathic pain in rats by regulating autophagy
Authors: Hu Jijun , Chen Xueling , Cheng Jie , Kong Fanli , Xia Hui , Wu Jiang
Published: June 2021

Unveiling the etiology and the underlying mechanism of neuropathic pain, a poorly treated disease, is essential for the development of effective therapies. This study aimed to explore the role of mammalian target of rapamycin (mTOR) signaling in autophagy-mediated neuropathic pain. We established a spared nerve injury (SNI) model in adult male SD rats by ligating the common peroneal nerve and tibial, with the distal end cutoff. The paw withdrawal threshold (PWT) and C/A-fiber evoked field potentials were determined by electrophysiologic tests at day 0 (before operation), day 7 and day 14 postoperation, and SNI significantly increased field potentials (P < 0.05). Immunohistochemistry and western blots using spinal cord tissues showed that the expressions of GluR1, GluR2, Beclin-1, p62, mTOR and 4EBP1 were significantly increased after SNI (all P < 0.05), whereas the expressions of LC3 and LAMP2 were significantly decreased after SNI (all P < 0.05). Rapamycin efficiently counteracted the effect of SNI and restored the phenotypes to the level comparable to the sham control. In conclusion, rapamycin inhibits C/A-fiber-mediated long-term potentiation in the SNI rat model of neuropathic pain, which might be mediated by activation of autophagy signaling and downregulation of GluRs expression.
Investigation of clinical characteristics and genome associations in the ‘UK Lipoedema’ cohort
Authors: Grigoriadis Dionysios , Sackey Ege , Riches Katie , van Zanten Malou , Brice Glen , England Ruth , Mills Mike , Dobbins Sara E ,   Lipoedema Consortium, Genomics England Research Consortium, Jeffery Steve , Dong Liang , Savage David B. , Mortimer Peter S. , Keeley Vaughan , Pittman Alan , Gordon Kristiana , Ostergaard Pia
Published: June 2021

Lipoedema is a chronic adipose tissue disorder mainly affecting women, causing excess subcutaneous fat deposition on the lower limbs with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is currently unclear. A tightly phenotyped cohort of 200 lipoedema patients was recruited from two UK specialist clinics. Objective clinical characteristics and measures of quality of life data were obtained. In an attempt to understand the genetic architecture of the disease better, genome-wide single nucleotide polymorphism (SNP) genotype data were obtained, and a genome wide association study (GWAS) performed on 130 of the recruits. The analysis revealed genetic loci suggestively associated with the lipoedema phenotype, with further support provided by an independent cohort taken from the 100,000 Genomes Project. Top SNPs included loci associated with lipoma formation, biosynthesis of hormones and lipid hydroxylation. Exactly how these SNPs relate to a lipoedema disease mechanism is not yet understood but the findings are consistent with existing fat and hormone hypotheses. This first GWAS of a UK lipoedema cohort has identified genetic regions of suggestive association with the disease. Further replication of these findings in different populations is warranted.
Integrated Analysis of the Association Between Alzheimer’s Disease (AD) and Cardiovascular Disease (CVD)
Authors: Wei Katherine , Delprato Anna
Published: June 2021

Alzheimer’s Disease (AD), the sixth leading cause of death in the US, and cardiovascular disease (CVD), the first leading cause of death in the US, are frequently associated. Past studies hypothesize that amyloid deposits damage organs, causing this association. Examining how vascular factors can influence AD pathogenesis can help in understanding the link between the blood to the brain, which can provide alternative paths of exploration for disease treatment. This study analyzes gene expression and shared biological processes between AD and CVD, specifically myocardial infarction and heart failure, via bioinformatic approaches and published datasets from the Gene Expression Omnibus (GEO). First, 73 differentially expressed genes (DEGs) were identified among four datasets using blood samples from AD and CVD patients. Panther’s Gene Ontology Analysis validated several biological processes such as xylulose biosynthetic process and toll-like receptor TLR1:TLR2 signaling pathway along with molecular functions, cellular components, and pathways to be significantly enriched in the list of 73 DEGs. Analysis of protein-protein interactions and the associated gene network indicated that from the list of 73 DEGs, only six (MAPK14, TLR2, HCK, GRB2, PRKCD, PTPN6) had eight or more degrees. Next, those six genes were identified in a normalized dataset containing different brain regions of AD and non-AD patients. Two-sample t-tests for differences in mean showed statistically significant differences in GRB2 and PRKCD, supporting a blood-brain relationship in the association between AD and CVD. This study can help in developing new medications to target AD and CVD susceptible genes.
Broad Clinical Manifestations of Polygenic Risk for Coronary Artery Disease in the Women’s Health Initiative
Authors: Clarke Shoa L. , Parham Matthew , Lankester Joanna , Shadyab Aladdin H. , Liu Simin , Kooperberg Charles , Manson JoAnn E. , Tcheandjieu Catherine , Assimes Themistocles L.
Published: June 2021

Background

The genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized.

Methods

We measured polygenic risk for CAD using the metaGRS, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women’s Health Initiative (WHI) and applied a phenome-wide association study framework to assess associations between the PRS and broad range of blood biomarkers, clinical measurements, and outcomes.

Results

Polygenic risk for CAD was associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors. Analysis of adjudicated outcomes showed a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. We identified novel associations between increased polygenic risk for CAD and decreased risk for incident breast and lung cancer, with replication of the breast cancer finding in an external cohort. Genetic correlation and two-sample Mendelian randomization suggest that breast cancer association is likely due to horizontal pleiotropy, while the association with lung cancer may be causal.

Conclusion

Polygenic risk for CAD has broad clinical manifestations, reflected in biomarkers, clinical measurements, behaviors, and diagnoses. Some of these associations may represent direct pathways between genetic risk and CAD while others may reflect pleiotropic effects independent of CAD risk.
A cross-sectional study of the relationship between exercise, physical activity, and health-related quality of life among Japanese workers during the COVID-19 pandemic
Authors: Sugano Ryosuke , Ikegami Kazunori , Eguchi Hisashi , Tsuji Mayumi , Tateishi Seiichiro , Nagata Tomohisa , Matsuda Shinya , Fujino Yoshihisa , Ogami Akira ,   for the CORoNaWork Project
Published: June 2021

Background

Exercise and physical activity positively affect physical and mental health, and healthy workers contribute to increased work productivity. This study aimed to investigate time spent on exercise during leisure time and physical activity, including time at work, in relation to health-related quality of life (HRQOL) among Japanese workers.

Methods

An Internet-based national health survey –Collaborative Online Research on Novel-coronavirus and Work study (CoRoNaWork study) – was conducted among 33,087 Japanese workers in December 2020. After excluding invalid responses, 27,036 participants were categorized into four and five groups according to exercise time and physical activity time, respectively. Each group’s scores were compared on each of the four questions on the Japanese version of the Centers for Disease Control and Prevention Health-Related Quality of Life (CDC HRQOL-4) between each group using a linear mixed model. Age-sex adjusted and multivariate models were used to compare each index of the CDC HRQOL-4.

Results

The more time spent exercising, the better the self-rated health. Self-rated health was better and unhealthy days were fewer in the group that exercised more than a certain amount of time than in the group that spent almost no time on exercising. As for physical activity, the group that spent more than 120 minutes/day or that almost never engaged in physical activity had lower self-rated health. The group with more than 120 minutes/day of physical activity also had more unhealthy days.

Conclusions

The results of the present study suggest that exercise habits improve workers’ HRQOL. Interventions to encourage daily exercise even for a short period of time may be an effective strategy to improve workers’ health and productivity.
Long COVID symptoms from Reddit: Characterizing post-COVID syndrome from patient reports
Authors: Sarker Abeed , Ge Yao
Published: June 2021

Objective

To mine Reddit to discover long-COVID symptoms self-reported by users, compare symptom distributions across studies, and create a symptom lexicon.

Materials and Methods

We retrieved posts from the /r/covidlonghaulers subreddit and extracted symptoms via approximate matching using an expanded meta-lexicon. We mapped the extracted symptoms to standard concept IDs, compared their distributions with those reported in recent literature and analyzed their distributions over time.

Results

From 42,995 posts by 4249 users, we identified 1744 users who expressed at least 1 symptom. The most frequently reported long-COVID symptoms were mental health-related symptoms (55.2%), fatigue (51.2%), general ache/pain (48.4%), brain fog/confusion (32.8%) and dyspnea (28.9%) amongst users reporting at least 1 symptom. Comparison with recent literature revealed a large variance in reported symptoms across studies. Temporal analysis showed several persistent symptoms up to 15 months after infection.

Conclusion

The spectrum of symptoms identified from Reddit may provide early insights about long-COVID.
Mass mask-wearing notably reduces COVID-19 transmission
Authors: Leech Gavin , Rogers-Smith Charlie , Sandbrink Jonas B. , Snodin Benedict , Zinkov Robert , Rader Benjamin , Brownstein John S. , Gal Yarin , Bhatt Samir , Sharma Mrinank , Mindermann Sören , Brauner Jan M. , Aitchison Laurence
Published: June 2021

Mask-wearing has been a controversial measure to control the COVID-19 pandemic. While masks are known to substantially reduce disease transmission in healthcare settings [1–3], studies in community settings report inconsistent results [4–6].

Investigating the inconsistency within epidemiological studies, we find that a commonly used proxy, government mask mandates, does not correlate with large increases in mask-wearing in our window of analysis. We thus analyse the effect of mask-wearing on transmission instead, drawing on several datasets covering 92 regions on 6 continents, including the largest survey of individual-level wearing behaviour (n=20 million) [7]. Using a hierarchical Bayesian model, we estimate the effect of both mask-wearing and mask-mandates on transmission by linking wearing levels (or mandates) to reported cases in each region, adjusting for mobility and non-pharmaceutical interventions.

We assess the robustness of our results in 123 experiments spanning 22 sensitivity analyses. Across these analyses, we find that an entire population wearing masks in public leads to a median reduction in the reproduction numberRof 25.8%, with 95% of the medians between 22.2% and 30.9%. In our window of analysis, the median reduction inRassociated with the wearing level observed in each region was 20.4% [2.0%, 23.3%]1. We do not find evidence that mandating mask-wearing reduces transmission. Our results suggest that mask-wearing is strongly affected by factors other than mandates.

We establish the effectiveness of mass mask-wearing, and highlight that wearing data, not mandate data, are necessary to infer this effect.
Early but not late convalescent plasma is associated with better survival in moderate-to-severe COVID-19
Authors: Briggs Neima , Gormally Michael V. , Li Fangyong , Browning Sabrina L. , Treggiari Miriam M. , Morrison Alyssa , Laurent-Rolle Maudry , Deng Yanhong , Hendrickson Jeanne E. , Tormey Christopher A. , Desruisseaux Mahalia S.
Published: June 2021

Background

Limited therapeutic options exist for coronavirus disease 2019 (COVID-19). COVID-19 convalescent plasma (CCP) is a potential therapeutic, but there is limited data for patients with moderate-to-severe disease.

Research Question

What are outcomes associated with administration of CCP in patients with moderate-to-severe COVID-19 infection?

Study Design and Methods

We conducted a propensity score-matched analysis of patients with moderate-to-severe COVID-19. The primary endpoints were in-hospital mortality. Secondary endpoints were number of days alive and ventilator-free at 30 days; length of hospital stay; and change in WHO scores from CCP administration (or index date) to discharge. Of 151 patients who received CCP, 132 had complete follow-up data. Patients were transfused after a median of 6 hospital days; thus, we investigated the effect of convalescent plasma before and after this timepoint with 77 early (within 6 days) and 55 late (after 6 days) recipients. Among 3,217 inpatients who did not receive CCP, 2,551 were available for matching.

Results

Early CCP recipients, of whom 31 (40%) were on mechanical ventilation, had lower 14-day (15% vs 23%) and 30-day (38% vs 49%) mortality compared to a matched unexposed cohort, with nearly 50% lower likelihood of in-hospital mortality (HR 0.52, [95% CI 0.28-0.96]; P=0.036). Early plasma recipients had more days alive and ventilator-free at 30 days (+3.3 days, [95% CI 0.2 to 6.3 days]; P=0.04) and improved WHO scores at 7 days (−0.8, [95% CI: −1.2 to - 0.4]; P=0.0003) and hospital discharge (−0.9, [95% CI: −1.5 to −0.3]; P=0.004) compared to the matched unexposed cohort. No clinical differences were observed in late plasma recipients.

Interpretation

Early administration of CCP improves outcomes in patients with moderate-to-severe COVID-19, while improvement was not observed with late CCP administration. The importance of timing of administration should be addressed in specifically designed trials.
Remdesivir to treat COVID-19: can dosing be optimized?
Authors: Conway Jessica M. , zur Wiesch Pia Abel
Published: June 2021

The antiviral remdesivir has been approved by regulatory bodies such as EMA and FDA for the treatment of COVID-19. However, its efficacy is debated and toxicity concerns might limit the therapeutic range of this drug. Computational models that aid in balancing efficacy and toxicity would be of great help. Parametrizing models is difficult because the prodrug remdesivir is metabolized to its active form (RDV-TP) upon cell entry, which complicates dose-activity relationships.

Here, we employ a computational model that allows predicting drug efficacy based on the binding affinity of RDV-TP for its target polymerase in SARS-CoV-2. We identify an optimal infusion rate to maximize remdesivir efficacy. We also assess drug efficacy in suppressing both wild-type and resistant strains, and thereby selection of resistance.

Our results differ from predictions using prodrug dose-response curves (pseudo-EC50s). We expect that reaching 90% inhibition (EC90) is insufficient to suppress SARS-CoV-2 in lungs. While standard dosing mildly inhibits viral polymerase and therefore likely reduces morbidity, we also expect selection for resistant mutants for most realistic parameter ranges. To increase efficacy and safeguard against resistance, we recommend continuing remdesivir use with companion antivirals and/or with dosing regimens that substantially increase the levels of RDV-TP.
Massive social protests amid the pandemic in selected Colombian cities: Did they increase COVID-19 cases?
Authors: Moreno-Montoya José , Rodríguez-Villamizar Laura A. , Idrovo Alvaro J.
Published: June 2021

Background

Since April 28, 2021, in Colombia there are social protests with numerous demonstrations in various cities. The aim of this study was to assess the effect of social protests on the number and trend of the confirmed COVID-19 cases in some selected Colombian cities where social protests had more intensity.

Methods

We performed and interrupted time-series analysis (ITSA) and Autoregressive Integrated Moving Average (ARIMA) models, based on the confirmed COVID-19 cases in Colombia, between March 1 and May 15, 2021, for Bogotá, Cali, Barranquilla, Medellín, and Bucaramanga. The ITSA models estimated the effect of social demonstrations on the number and trend of cases for each city by using Newey-West standard errors. ARIMA models assessed the overall pattern of the series and effect of the intervention. We considered May 2, 2021, as the intervention date for the analysis, five days after social demonstrations started in the country.

Findings

During the study period the number of cases by city was 1,014,815 for Bogotá, 192,320 for Cali, 175,269 for Barranquilla, 311,904 for Medellín, and 62,512 for Bucaramanga. Heterogeneous results were found among cities. Only for the cities of Cali and Barranquilla statistically significant changes in trend of the number of cases were obtained after the intervention: positive in the first city, negative in the second one. None ARIMA models show evidence of abrupt changes in the trend of the series for any city and intervention effect was only significant for Bucaramanga.

Interpretation

Social protests had a heterogeneous effect on the number and trend of COVID-19 cases. Different effects might be related to the epidemiologic moment of the pandemic and the characteristics of the social protests. Assessing the effect of social protests within a pandemic is complex and there are several methodological limitations. Further analyses are required with longer time-series data.
Classification and Visualisation of Normal and Abnormal Radiographs; a comparison between Eleven Convolutional Neural Network Architectures
Authors: Ananda Ananda , Ngan Kwun Ho , Karabağ Cefa , Ter-Sarkisov Aram , Alonso Eduardo , Reyes-Aldasoro Constantino Carlos
Published: June 2021

This paper investigates the classification of radiographic images with eleven convolutional neural network (CNN) architectures (GoogleNet, VGG-19, AlexNet, SqueezeNet, ResNet-18, Inception-v3, ResNet-50, VGG-16, ResNet-101, DenseNet-201 and Inception-ResNet-v2). The CNNs were used to classify a series of wrist radiographs from the Stanford Musculoskeletal Radiographs (MURA) dataset into two classes - normal and abnormal. The architectures were compared for different hyper-parameters against accuracy and Cohen’s kappa coefficient. The best two results were then explored with data augmentation. Without the use of augmentation, the best results were provided by Inception-Resnet-v2 (Mean accuracy = 0.723, Mean kappa = 0.506). These were significantly improved with augmentation to Inception-Resnet-v2 (Mean accuracy = 0.857, Mean kappa = 0.703). Finally, Class Activation Mapping was applied to interpret activation of the network against the location of an anomaly in the radiographs.
Defining protein variant functions using high-complexity mutagenesis libraries and enhanced mutant detection software ASMv1.0
Authors: Yang Xiaoping , Hong Andrew L. , Sharpe Ted , Giacomelli Andrew O. , Lintner Robert E. , Alan Douglas , Green Thomas , Hayes Tikvah K. , Piccioni Federica , Fritchman Briana , Kawabe Hinako , Sawyer Edith , Sprenkle Luke , Lee Benjamin P. , Persky Nicole S. , Brown Adam , Greulich Heidi , Aguirre Andrew J. , Meyerson Matthew , Hahn William C. , Johannessen Cory M. , Root David E.
Published: June 2021

Pooled variant expression libraries can test the phenotypes of thousands of variants of a gene in a single multiplexed experiment. In a library encoding all single-amino-acid substitutions of a protein, each variant differs from its reference only at a single codon-position located anywhere along the coding sequence. Consequently, accurately identifying these variants by sequencing is a major technical challenge. A popular but expensive brute-force approach is to divide the pool of variants into multiple smaller sub-libraries that each contains variants of a small region and that must each be constructed and screened individually, but that can then be PCR-amplified and fully sequenced with a single read to allow direct readout of variant abundance. Here we present an approach to screen very large variant libraries with mutations spanning a wide region in a single pool, including library design criteria and mutant-detection algorithms that permit reliable calling and counting of variants from large-scale sequencing data.
Properties of Two-Locus Genealogies and Linkage Disequilibrium in Temporally Structured Samples
Authors: Biddanda Arjun , Steinrücken Matthias , Novembre John
Published: June 2021

Archaeogenetics has been revolutionary, revealing insights into demographic history and recent positive selection in many organisms. However, most studies to date have ignored the non-random association of genetic variants at different loci (i.e., linkage disequilibrium, LD). This may be in part because basic properties of LD in samples from different times are still not well understood. Here, we derive several results for summary statistics of haplotypic variation under a model with time-stratified sampling: 1) The correlation between the number of pairwise differences observed between time-staggered samples (πΔt) in models with and without strict population continuity; 2) The product of the LD coefficient, D, between ancient and modern samples, which is a measure of haplotypic similarity between modern and ancient samples; and 3) The expected switch rate in the Li and Stephens haplotype copying model. The latter has implications for genotype imputation and phasing in ancient samples with modern reference panels. Overall, these results provide a characterization of how haplotype patterns are affected by sample age, recombination rates, and population sizes. We expect these results will help guide the interpretation and analysis of haplotype data from ancient and modern samples.
Biogenesis of hepatitis B virus e antigen is driven by translocon-associated protein complex and regulated by conserved cysteines in signal peptide
Authors: Zábranská Helena , Zábranský Aleš , Lubyová Barbora , Hodek Jan , Křenková Alena , Hubálek Martin , Weber Jan , Pichová Iva
Published: June 2021

Hepatitis B virus (HBV) uses e antigen (HBe), which is dispensable for virus infectivity, to modulate host immune responses and achieve viral persistence in human hepatocytes. The HBe precursor (p25) is directed to the endoplasmic reticulum (ER), where cleavage of the signal peptide (sp) gives rise to the first processing product, p22. P22 can be retro-translocated back to the cytosol or enter the secretory pathway and undergo a second cleavage event, resulting in secreted p17 (HBe). Here, we report that translocation of p25 to the ER is promoted by translocon-associated protein complex (TRAP). We found that p25 is not completely translocated into the ER; a fraction of p25 is phosphorylated and remains in the cytoplasm and nucleus. Within the p25 sp sequence, we identified three cysteine residues that control the efficiency of sp cleavage and contribute to proper subcellular distribution of the precore pool.
School yard biodiversity determines short-term recovery of disturbed skin microbiota in children
Authors: Mills Jacob G. , Selway Caitlin A. , Thomas Torsten , Weyrich Laura S. , Lowe Andrew J.
Published: June 2021

The planting and conservation of biodiverse habitat in urban contexts has been proposed as a public health intervention aimed at reducing the prevalence of non-communicable diseases via microbiome rewilding (Mills et al. 2017; Mills et al. 2019). However, our understanding of the effect of urban biodiversity interventions on the human microbiota remains limited, especially on the skin (Hui et al. 2019; Roslund et al. 2020) and in the context of permanent green spaces (Lehtimäki et al. 2018; Selway et al. 2020). Here, we test the short-term response of experimentally disturbed bacterial communities on the skin of healthy children exposed to different school environments – either a ‘classroom’, a ‘sports field’, or a biodiverse ‘forest’ – to understand how exposures to different types of biodiversity may influence skin microbiota. Children exposed to the ‘forest’ had significantly increased skin microbiota diversity when compared to pre-exposure, an effect that increased over three days suggesting long-term effects. The microbiota on children exposed to the ‘forest’ had the largest structural and compositional community change compared to children exposed to ‘sports fields’, which in turn was larger than those who remained in ‘classrooms’. Children exposed to ‘sports fields’ and ‘forests’ also acquired new core bacteria after exposure to green spaces, potentially buffering against disturbances to the skin microbiota’s diversity, while individuals who remained in the ‘classroom’ lost microbes throughout the experiment. Overall, we conclude that urban green spaces can have an enriching influence on the diversity of skin microbiota, including core members shared between all children. These findings have important implications for the design and construction of new school yards and public spaces with respect to biodiversity, health, and human microbiota.
Introgression of type-IV glandular trichomes from Solanum galapagense to cultivated tomato reveals genetic complexity for the development of acylsugar-based insect resistance
Authors: Vendemiatti Eloisa , Therezan Rodrigo , Vicente Mateus H. , de Siqueira Pinto Maísa , Bergau Nick , Yang Lina , Bernardi Walter Fernando , de Alencar Severino M. , Zsögön Agustin , Tissier Alain , Benedito Vagner A. , Peres Lázaro E. P.
Published: June 2021

Glandular trichomes are involved in the production of food- and medicine-relevant chemicals in plants, besides being associated with pest resistance. In some wild Solanum species closely related to the cultivated tomato (S. lycopersicum), the presence of type-IV glandular trichomes leads to the production of high levels of insecticide acylsugars (AS). Conversely, low AS production observed in the cultivated tomato is attributed to its incapacity to develop type-IV trichomes in adult organs. Therefore, we hypothesized that cultivated tomatoes engineered to harbor type-IV trichomes on the leaves of mature plants can be pest resistant. We introgressed into the tomato cultivar Micro-Tom (MT) the capability of S. galapagense to maintain the development of type-IV trichomes throughout all plant stages, thus creating a line named “Galapagos enhanced trichomes” (MT-Get). Mapping-by-sequencing of MT-Get revealed that five chromosomal regions of S. galapagense were present in MT-Get. Further mapping reveled that S. galapagense alleles on chromosomes 1, 2 and 3 are sufficient for the presence of type-IV trichomes, but in lower densities. GC-MS, LC-MS, and gene expression analyses demonstrated that the increased density of type-IV trichomes was not accompanied by high AS production and exudation in MT-Get. Moreover, MT-Get did not differ from MT in its susceptibility to whitefly (Bemisia tabaci). Our findings demonstrates that type-IV glandular trichome development along with AS production and exudation are partially uncoupled at the genetic level. The MT-Get genotype represents a valuable resource for further studies involving the biochemical manipulation of type-IV trichome content through either genetic introgression or transgenic approaches.

Significance Statement

This work identified loci in the tomato genome that control the heterochronic development of type-IV glandular trichomes and uncoupled the genetic control of this type of trichome ontogeny from acylsugar biosynthesis and accumulation, revealing a higher than anticipated genetic complexity of acylsugar-based insect resistance. The findings reported herein will contribute to further dissect the genetics of trichome development in tomato as well as to introgress broad and durable insect resistance in tomato and other Solanaceae.
RPAP2 regulates a transcription initiation checkpoint by prohibiting assembly of preinitiation complex
Authors: Chen Xizi , Qi Yilun , Wang Xinxin , Wang Zhenning , Wang Li , Song Aixia , Li Jiabei , Zhao Dan , Zhang Hongwei , Jin Qianwei , Chen Fei Xavier , Xu Yanhui
Published: June 2021

RNA polymerase II (Pol II)-mediated transcription in metazoan requires precise regulation. RNA polymerase II-associated protein 2 (RPAP2) was previously identified to transport Pol II from cytoplasm to nucleus and dephosphorylates Pol II C-terminal domain (CTD). We found that RPAP2 binds hypo/hyper-phosphorylated Pol II with undetectable phosphatase activity. Structure of RPAP2-Pol II shows mutually exclusive assembly of RPAP2-Pol II and pre-initiation complex (PIC) due to three steric clashes. RPAP2 prevents/disrupts Pol II-TFIIF interaction and impairs in vitro transcription initiation, suggesting a function in prohibiting PIC assembly. Loss of RPAP2 in cells leads to global accumulation of TFIIF and Pol II at promoters, indicating critical role of RPAP2 in inhibiting PIC assembly independent of its putative phosphatase activity. Our study indicates that RPAP2 functions as a gatekeeper to prohibit PIC assembly and transcription initiation and suggests a novel transcription checkpoint.
After traumatic brain injury oligodendrocytes regain a plastic phenotype and can become astrocytes
Authors: Bai Xianshu , Zhao Na , Huang Wenhui , Caudal Laura C. , Zhao Renping , Hirrlinger Johannes , Walz Wolfgang , Kirchhoff Frank , Scheller Anja
Published: June 2021

After acute brain injuries various response cascades are evoked that direct the formation of the glial scar. Here, we report that acute lesions associated with a disruption of the blood-brain barrier trigger a re-programming within the oligodendrocyte lineage. In PLP-DsRed1/GFAP-EGFP and PLP-EGFPmem/GFAP-mRFP1 transgenic mice with cortical injuries, we transiently found PLP transgene-labelled cells with activated GFAP promoter activity adjacent to the lesion site. We termed them AO cells, based on their concomitant activity of astro- and oligodendroglial genes. By fate mapping using PLP- and GFAP-split Cre complementation and NG2-CreERT2 mice we observed that major portions of AO cells surprisingly differentiated into astrocytes. Using repeated long-term in vivo two-photon laser-scanning microscopy (2P-LSM) we followed oligodendrocytes after injury. We observed their conversion into astrocytes via the AO cell stage with silencing of the PLP promoter and simultaneous activation of the GFAP promoter. In addition, we provide evidence that this oligodendrocyte-to-astrocyte conversion depends on local cues. At the lesion site higher expression levels of various glial differentiation factors were detected. And indeed, local injection of IL-6 promoted the formation of AO cells. In summary, our findings highlight the plastic potential of oligodendrocytes in acute brain trauma. An altered environmental milieu affects gene expression programs of mature oligodendrocytes and induces a plastic differentiation stage with astrogliogenic potential via transitional AO cells.
Probing Affinity, Avidity, Anti-Cooperativity, and Competition in Antibody and Receptor Binding to the SARS-CoV-2 Spike by Single Particle Mass Analyses
Authors: Yin Victor , Lai Szu-Hsueh , Caniels Tom G. , Brouwer Philip J.M. , Brinkkemper Mitch , Aldon Yoann , Liu Hejun , Yuan Meng , Wilson Ian A. , Sanders Rogier W. , van Gils Marit J. , Heck Albert J.R.
Published: June 2021

Determining how antibodies interact with the spike (S) protein of the SARS-CoV-2 virus is critical for combating COVID-19. Structural studies typically employ simplified, truncated constructs that may not fully recapitulate the behaviour of the original complexes. Here, we combine two single particle mass analysis techniques (mass photometry and charge-detection mass spectrometry) to enable measurement of full IgG binding to the trimeric SARS-CoV-2 S ectodomain. Our experiments reveal that antibodies targeting the S-trimer typically prefer stoichiometries lower than the symmetry-predicted 3:1 binding. We determine that this behaviour arises from the interplay of steric clashes and avidity effects that are not reflected in common antibody constructs (i.e. Fabs). Surprisingly, these sub-stoichiometric complexes are fully effective at blocking ACE2 binding despite containing free receptor binding sites. Our results highlight the importance of studying antibody/antigen interactions using complete, multimeric constructs and showcase the utility of single particle mass analyses in unraveling these complex interactions.
Ovipositor and mouthparts in a fossil insect support a novel ecological role for early orthopterans in Pennsylvanian forests
Authors: Chen Lu , Gu Jun-Jie , Yang Qiang , Ren Dong , Blanke Alexander , Béthoux Olivier
Published: June 2021

Lobeattid insects represented a high portion of the earliest known, Pennsylvanian insect faunas. However, their systematic affinities and their role as foliage feeders which severely influenced their ecosystems remain debated. We investigated hundreds of samples of a new lobeattid species from the Xiaheyan locality using Reflectance Transforming Imaging combined with geometric morphometrics in order to assess its morphology, infer its ecological role, and phylogenetic position.Ctenoptilus frequenssp. nov. possessed a sword-shaped ovipositor whose valves interlocked by two ball-and-socket mechanisms. This unambiguously supports lobeattids as stem-relatives of all Orthoptera (crickets, grasshoppers, katydids). Given the herein presented and other remains, it follows that this group experienced an early diversification coupled with high levels of abundance. The ovipositor shape additionally indicates that ground was the preferred substrate for eggs. Visible mouthparts made it possible to assess the efficiency of the mandibular food uptake system in comparison to a wide array of recent species. The new species was omnivorous which explains the paucity of external damage on contemporaneous plant foliage.
The SAGA core module is critical duringDrosophilaoogenesis and is broadly recruited to promoters
Authors: Soffers Jelly H.M. , Alcantara Sergio Garcia-Moreno , Li Xuanying , Shao Wanqing , Seidel Christopher W. , Li Hua , Zeitlinger Julia , Abmayr Susan M. , Workman Jerry L.
Published: June 2021

The Spt/Ada-Gcn5 Acetyltransferase (SAGA) coactivator complex has multiple modules with different enzymatic and non-enzymatic functions. How each module contributes to gene activation in specific biological contexts is not well understood. Here we analyzed the role of the non-enzymatic core module duringDrosophilaoogenesis. We show that depletion of several SAGA-specific subunits belonging to the core module blocked egg chamber development during mid-oogenesis stages, resulting in stronger phenotypes than those obtained after depletion of SAGA’s histone acetyltransferase module or deubiquitination module. These results, as well as additional genetic analyses pointing to an interaction with TBP, suggested a differential role of SAGA modules at different promoter types. However, SAGA subunits co-occupied all promoter types of active genes in ChIP-seq and ChIP-nexus experiments. Thus, the SAGA complex appears to occupy promoters in its entirety, consistent with the strong biochemical integrity of the complex. The high-resolution genomic binding profiles are congruent with SAGA recruitment by activators upstream of the start site, and retention on chromatin by interactions with modified histones downstream of the start site. The stronger genetic requirement of the core module during oogenesis may therefore be explained through its interaction with TBP or its role in recruiting the enzymatic modules to the promoter. We propose the handyman principle, which posits that a distinct genetic requirement for specific components may conceal the fact that the entire complex is physically present.

Author Summary

Embryonic development critically relies on the differential expression of genes in different tissues. This involves the dynamic interplay between DNA, sequence-specific transcription factors, coactivators and chromatin remodelers which guide the transcription machinery to the appropriate promoters for productive transcription. To understand how this happens at the molecular level, we need to understand when and how coactivator complexes such as SAGA function. SAGA consists of multiple modules with well characterized enzymatic functions. This study shows that the non-enzymatic core module of SAGA is required forDrosophilaoogenesis, while the enzymatic functions are largely dispensable. Despite this differential requirement, SAGA subunits appear to be broadly recruited to all promoter types, consistent with the biochemical integrity of the complex. These results suggest that genetic requirements and physical organization do not always go hand in hand.
Cortical neuroprosthesis-mediated functional ipsilateral control of locomotion in rats with spinal cord hemisection
Authors: Massai Elena , Bonizzato Marco , De Jesus Isley , Drainville Roxanne , Martinez Marina
Published: June 2021

Control of voluntary limb movement is predominantly attributed to the contralateral motor cortex. However, increasing evidence suggests the involvement of ipsilateral cortical networks in this process, especially in motor tasks requiring bilateral coordination, such as locomotion. In this study, we combined a unilateral thoracic spinal cord injury (SCI) with a cortical neuroprosthetic approach to investigate the functional role of the ipsilateral motor cortex in rat movement through spared contralesional pathways. Our findings reveal that in all SCI rats, stimulation of the ipsilesional motor cortex promoted a bilateral synergy. This synergy involved the elevation of the contralateral foot along with ipsilateral hindlimb extension. Additionally, in two out of seven animals, stimulation of a sub-region of the hindlimb motor cortex modulated ipsilateral hindlimb flexion. Importantly, ipsilateral cortical stimulation delivered after SCI immediately alleviated multiple locomotor and postural deficits, and this effect persisted after ablation of the homologous motor cortex. These results provide strong evidence of a causal link between cortical activation and precise ipsilateral control of hindlimb movement. This study has significant implications for the development of future neuroprosthetic technology and our understanding of motor control in the context of spinal cord injury.
Myosin VI regulates ciliogenesis by promoting the turnover of the centrosomal/satellite protein OFD1
Authors: Magistrati Elisa , Maestrini Giorgia , Lince-Faria Mariana , Beznoussenko Galina , Mironov Alexandre , Maspero Elena , Bettencourt-Dias Mónica , Polo Simona
Published: June 2021

The actin motor protein myosin VI is a multivalent protein with diverse functions. Here, we identified and characterised a myosin VI ubiquitous interactor, the oral-facial-digital syndrome 1 (OFD1) protein, whose mutations cause malformations of the face, oral cavity, digits, and polycystic kidney disease. We found that myosin VI regulates the localisation of OFD1 at the centrioles and, as a consequence, the recruitment of the distal appendage protein cep164. Myosin VI depletion in non-tumoural cell lines causes an aberrant localisation of OFD1 along the centriolar walls, which is due to a reduction in the OFD1 mobile fraction. Finally, loss of myosin VI triggers a severe defect in ciliogenesis that could be causally linked to an impairment in the autophagic removal of OFD1 from satellites. Altogether, our results highlight an unprecedent layer of regulation of OFD1 and a pivotal role of myosin VI in coordinating the formation of the distal appendages and primary cilium with important implications for the genetic disorders known as ciliopathies.
The Caenorhabditis elegans TDRD5/7-like protein, LOTR-1, interacts with the helicase ZNFX-1 to balance epigenetic signals in the germline
Authors: Marnik Elisabeth A. , Almeida Miguel V. , Cipriani P. Giselle , Chung George , Caspani Edoardo , Karaulanov Emil , Butter Falk , Sharp Catherine S. , Zinno John , Gan Hin Hark , Piano Fabio , Ketting René F , Gunsalus Kristin C. , Updike Dustin L.
Published: June 2021

LOTUS and Tudor domain containing proteins have critical roles in the germline. Proteins that contain these domains, such as Tejas/Tapas in Drosophila, help localize Vasa to the germ granules and facilitate piRNA-mediated transposon silencing. The homologous proteins in mammals, TDRD5 and TDRD7, are required during spermiogenesis. Until now, proteins containing both LOTUS and Tudor domains in Caenorhabditis elegans have remained elusive. Here we describe LOTR-1 (D1081.7), which derives its name from its LOTUS and Tudor domains. Interestingly, LOTR-1 docks next to P granules to colocalize with the broadly conserved Z-granule helicase, ZNFX-1. LOTR-1’s Z-granule association requires its Tudor domain, but both LOTUS and Tudor deletions affect brood size when coupled with a knockdown of the Vasa homolog glh-1. In addition to interacting with the germ-granule components WAGO-1, PRG-1 and DEPS-1, we identified a Tudor-dependent association with ZNFX-1. Like znfx-1 mutants, lotr-1 mutants lose small RNAs from the 3’ ends of WAGO and Mutator targets, reminiscent of the loss of piRNAs from the 3’ ends of piRNA precursor transcripts in mouse Tdrd5 mutants. Our work suggests that LOTR-1 acts in a conserved mechanism that brings small RNA generating mechanisms towards the 3’ ends of small RNA templates or precursors.