bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of significance of conditionally independent GWAS signals
Authors: Ghasemi Sahar , Teumer Alexander , Wuttke Matthias , Becker Tim 
Published: April 2021

Abstract

Motivation
Multiple independently associated SNPs within a linkage disequilibrium region are a common phenomenon. Conditional analysis has been successful in identifying secondary signals. While conditional association tests are limited to specific genomic regions, they are benchmarked with genome-wide scale criterion, a conservative strategy. Within the weighted hypothesis testing framework, we developed a ‘quasi-adaptive’ method that uses the pairwise correlation (r2) and physical distance (d) from the index association to construct priority functions G =G(r2, d), which assign an SNP-specific α-threshold to each SNP. Family-wise error rate (FWER) and power of the approach were evaluated via simulations based on real GWAS data. We compared a series of different G-functions.

Results
Simulations under the null hypothesis on 1,100 primary SNPs confirmed appropriate empirical FWER for all G-functions. A G-function with optimal r2 = 0.3 between index and secondary SNP which down-weighted SNPs at higher distance step-wise-strong and gave more emphasis on d than on r2 had overall best power. It also gave the best results in application to the real datasets. As a proof of concept, ‘quasi-adaptive’ method was applied to GWAS on free thyroxine (FT4), inflammatory bowel disease (IBD) and human height. Application of the algorithm revealed 5 secondary signals in our example GWAS on FT4, 5 secondary signals in case of the IBD and 19 secondary signals on human height, that would have gone undetected with the established genome-wide threshold (α=5×10−8).

Availability and implementation
https://github.com/sghasemi64/Secondary-Signal.

Supplementary information
Supplementary data are available at Bioinformatics online.
Study of real-valued distance prediction for protein structure prediction with deep learning
Authors: Li Jin , Xu Jinbo 
Published: April 2021

Abstract

Motivation
Inter-residue distance prediction by convolutional residual neural network (deep ResNet) has greatly advanced protein structure prediction. Currently, the most successful structure prediction methods predict distance by discretizing it into dozens of bins. Here, we study how well real-valued distance can be predicted and how useful it is for 3D structure modeling by comparing it with discrete-valued prediction based upon the same deep ResNet.

Results
Different from the recent methods that predict only a single real value for the distance of an atom pair, we predict both the mean and standard deviation of a distance and then fold a protein by the predicted mean and deviation. Our findings include: (i) tested on the CASP13 FM (free-modeling) targets, our real-valued distance prediction obtains 81% precision on top L/5 long-range contact prediction, much better than the best CASP13 results (70%); (ii) our real-valued prediction can predict correct folds for the same number of CASP13 FM targets as the best CASP13 group, despite generating only 20 decoys for each target; (iii) our method greatly outperforms a very new real-valued prediction method DeepDist in both contact prediction and 3D structure modeling and (iv) when the same deep ResNet is used, our real-valued distance prediction has 1–6% higher contact and distance accuracy than our own discrete-valued prediction, but less accurate 3D structure models.

Availability and implementation
https://github.com/j3xugit/RaptorX-3DModeling.

Supplementary information
Supplementary data are available at Bioinformatics online.
Model-Based Geostatistical Methods Enable Efficient Design and Analysis of Prevalence Surveys for Soil-Transmitted Helminth Infection and Other Neglected Tropical Diseases
Authors: Johnson Olatunji , Fronterre Claudio , Amoah Benjamin , Montresor Antonio , Giorgi Emanuele , Midzi Nicholas , Mutsaka-Makuvaza Masceline Jenipher , Kargbo-Labor Ibrahim , Hodges Mary H , Zhang Yaobi , Okoyo Collins , Mwandawiro Charles , Minnery Mark , Diggle Peter J 
Published: April 2021

Abstract
Maps of the geographical variation in prevalence play an important role in large-scale programs for the control of neglected tropical diseases. Precontrol mapping is needed to establish the appropriate control intervention in each area of the country in question. Mapping is also needed postintervention to measure the success of control efforts. In the absence of comprehensive disease registries, mapping efforts can be informed by 2 kinds of data: empirical estimates of local prevalence obtained by testing individuals from a sample of communities within the geographical region of interest, and digital images of environmental factors that are predictive of local prevalence. In this article, we focus on the design and analysis of impact surveys, that is, prevalence surveys that are conducted postintervention with the aim of informing decisions on what further intervention, if any, is needed to achieve elimination of the disease as a public health problem. We show that geospatial statistical methods enable prevalence surveys to be designed and analyzed as efficiently as possible so as to make best use of hard-won field data. We use 3 case studies based on data from soil-transmitted helminth impact surveys in Kenya, Sierra Leone, and Zimbabwe to compare the predictive performance of model-based geostatistics with methods described in current World Health Organization (WHO) guidelines. In all 3 cases, we find that model-based geostatistics substantially outperforms the current WHO guidelines, delivering improved precision for reduced field-sampling effort. We argue from experience that similar improvements will hold for prevalence mapping of other neglected tropical diseases.
Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers in South Africa: A Longitudinal Cohort Study
Authors: Nunes Marta C , Baillie Vicky L , Kwatra Gaurav , Bhikha Sutika , Verwey Charl , Menezes Colin , Cutland Clare L , Moore David P , Dangor Ziyaad , Adam Yasmin , Mathivha Rudo , Velaphi Sithembiso C , Tsitsi Merika , Aguas Ricardo , Madhi Shabir A ,   Bara HCW Study Group, Nakwa Firdose , Van Blydenstein Sarah , Venter Michelle , Reddy Denasha , du Plessis Jeanine , Laubscher Matt , van der Merwe Lara , Mbele Nkululeko , Mukendi Beya , McKenzie Shakeel , Mtshali Sihle , Mukendi Christian Kabasele , Nzimande Ayanda , Mandindi Wendy Zimkhitha , Nana Amit Jawaharlal , Rafuma Martin Mosotho , Mathibe Masego Nicole , Moultrie Andrew 
Published: April 2021

Abstract
From April to September 2020, we investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in a cohort of 396 healthcare workers (HCWs) from 5 departments at Chris Hani Baragwanath Hospital, South Africa. Overall, 34.6% of HCWs had polymerase chain reaction–confirmed SARS-CoV-2 infection (132.1 [95% confidence interval, 111.8–156.2] infections per 1000 person-months); an additional 27 infections were identified by serology. HCWs in the internal medicine department had the highest rate of infection (61.7%). Among polymerase chain reaction–confirmed cases, 10.4% remained asymptomatic, 30.4% were presymptomatic, and 59.3% were symptomatic.
Functional megalin is expressed in renal cysts in a mouse model of adult polycystic kidney disease
Authors: Nielsen Marlene L , Mundt Mia C , Lildballe Dorte L , Rasmussen Maria , Sunde Lone , Torres Vicente E , Harris Peter C , Birn Henrik 
Published: April 2021

Abstract

Background
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of cysts and a decline of renal function. The clinical feasibility of the number of potential disease-modifying drugs is limited by systemic adverse effects. We hypothesize that megalin, a multiligand endocytic receptor expressed in the proximal tubule, may be used to facilitate drug uptake into cysts, thereby allowing for greater efficacy and fewer side effects.

Methods
The cyst expression of various tubular markers, including megalin and aquaporin 2 (AQP2), was analysed by immunohistochemistry (IHC) of kidney sections from the ADPKD mouse model (PKD1RC/RC) at different post-natal ages. The endocytic function of megalin in cysts was examined by IHC of kidney tissue from mice injected with the megalin ligand aprotinin.

Results
Cyst lining epithelial cells expressing megalin were observed at all ages; however, the proportion decreased with age. Concomitantly, an increasing proportion of cysts revealed expression of AQP2, partial expression of megalin and/or AQP2 or no expression of the examined markers. Endocytic uptake of aprotinin was evident in megalin-positive cysts, but only in those that remained connected to the renal tubular system.

Conclusions
Megalin-expressing cysts were observed at all ages, but the proportion decreased with age, possibly due to a switch in tubular origin, a merging of cysts of different tubular origin and/or a change in the expression pattern of cyst lining cells. Megalin expressed in cysts was functional, suggesting that megalin-mediated endocytosis is a potential mechanism for drug targeting in ADPKD if initiated early in the disease.
Performance of a Paired-End Sequencing-Based Noninvasive Prenatal Screening Test in the Detection of Genome-Wide Fetal Chromosomal Anomalies
Authors: Pertile Mark D , Flowers Nicola , Vavrek Darcy , Andrews Daniel , Kalista Tasha , Craig Andrew , Deciu Cosmin , Duenwald Sven , Meier Kristen , Bhatt Sucheta 
Published: April 2021

Abstract

Background
Noninvasive prenatal tests (NIPTs) detect fetal chromosomal anomalies with high clinical sensitivity and specificity. We examined the performance of a paired-end sequencing-based NIPT in the detection of genome-wide fetal chromosomal anomalies including common trisomies, sex chromosomal aneuploidies (SCA), rare autosomal aneuploidies (RAAs), and partial deletions/duplications ≥7 Mb.

Methods
Frozen plasma samples from pregnant women were tested using the VeriSeq NIPT Solution v2 assay. All samples were previously tested with a laboratory-developed NIPT and had known clinical outcomes. Individuals performing the sequencing were blinded to clinical outcome data. Clinical sensitivity and specificity were determined for basic (chromosomes 21, 18, 13, X, and Y) and genome-wide screening modes.

Results
Of 2335 samples that underwent genome-wide analysis, 28 did not meet QC requirements, resulting in a first-pass assay failure rate of 1.2%. Basic screening analysis, excluding known mosaics, correctly classified 130/130 trisomy 21 samples (sensitivity &gt;99.9%, 95% confidence interval [CI] 97.1%–100%), 41/41 trisomy 18 samples (sensitivity &gt;99.9%, 95% CI 91.4%–100%), and 26/26 trisomy 13 samples (sensitivity &gt;99.9%, 95% CI 87.1%–100%) with 6 false-positive results; specificities ≥99.90% were reported for all 3 trisomies. Concordance for SCAs ranged from 90.5%–100%. Genome-wide screening analysis including known mosaics correctly classified 27/28 RAAs and 20/27 partial deletions/duplications with a specificity of 99.80% for both anomalies, and an overall genome-wide specificity for all anomalies of 99.34%.

Conclusions
The VeriSeq NIPT Solution v2 assay enables accurate identification of fetal aneuploidy, allowing detection of genome-wide fetal chromosomal anomalies with high clinical sensitivities and specificities and a low assay failure rate.
Clinical Trial Notification [CTN] identification number [ID]: CT-2018-CTN-01585-1 v1, Protocol: NIPT T05 002.
Robotic thymectomy for thymoma in patients with myasthenia gravis: neurological and oncological outcomes
Authors: Romano Gaetano , Zirafa Carmelina Cristina , Ceccarelli Ilaria , Guida Melania , Davini Federico , Maestri Michelangelo , Morganti Riccardo , Ricciardi Roberta , Hung Key Teresa , Melfi Franca 
Published: April 2021

Abstract OBJECTIVESThe goal of this study was to analyse the outcomes in 53 patients with thymoma, 34 of whom had myasthenia gravis (MG), who were treated with robotic surgery. The oncological outcomes of the whole series of patients were analysed. Furthermore, because consistent data are not yet available in the literature, the main focus was the analysis of the neurological results of the patients affected by MG and thymoma.METHODSThe clinical outcomes of 53 patients with a diagnosis of thymoma who underwent robotic thymectomy between January 2014 and December 2019 in our institution were collected and evaluated; 34 of these patients had a concomitant diagnosis of MG. The neurological status of the patients was determined from a clinical evaluation according to the Osserman classification and on pre- and post-surgery Myasthenia Gravis Composite scores, whereas neurological clinical outcomes were assessed using the Myasthenia Gravis Foundation of America Post-Intervention Score. Reduction of steroid therapy was also considered. The recurrence rate, adjuvant radiotherapy and overall survival of the patients with a thymoma were evaluated.RESULTSNeurological outcomes: improvement of the clinical conditions was obtained in 26 patients (76.5%) following the operation: complete stable remission was observed in 5 patients (14.7%), pharmacological remission in 10 (29.4%) and minimal manifestation in 11 (32.3%). Four patients (11.8%) exhibited no substantial change from the pretreatment clinical manifestations or reduction in MG medication and 4 (11.8%) patients experienced worsening of clinical conditions. In 21 patients (61.7%) a reduction of the dosage of steroid therapy was obtained. Oncological outcomes: at an average follow-up of 36 months, the overall survival was 96%, 4 patients (7.5%) had pleural relapses and 12 patients (22.6%) underwent postoperative radiotherapy, according to their stage. In accordance with Masaoka staging, 34% were in stage I, 56.6% in stage II and 9.4% in stage IIICONCLUSIONSOur results suggest that robotic surgical treatment of patients with thymoma and concomitant MG is effective in improving the neurological outcomes. Moreover, the oncological results obtained in this series confirm the efficacy of robotic surgery for the treatment of thymic malignancies, with results in line with those of open surgery. However, due to the indolent growth of thymomas, further observations with longer follow-up are necessary.
Isolation and identification of a human intestinal bacterium capable of daidzein conversion
Authors: Guo Yingyu , Zhao Lichao , Fang Xiang , Zhong Qingping , Liang Huijun , Liang Wenou , Wang Li 
Published: April 2021

ABSTRACTEquol, which produced from daidzein (one of the principal isoflavones), is recognized to be the most resultful in stimulating an estrogenic and antioxidant response. The daidzein transformation was studied during fermentation of five growth media inoculated with feces from a healthy human, and a daidzein conversion strain was isolated. To enrich the bacterial population involved in daidzein metabolism in a complex mixture, fecal samples were treated with antibiotics. The improved propidium monoazide combined with the quantitative polymerase chain reaction (PMAxx-qPCR) assay showed that the ampicillin treatment of samples did result in a reduction of the total visible bacteria counts by 52.2% compared to the treatment without antibiotics. On this basis, the newly isolated rod-shaped, Gram-positive anaerobic bacterium, named strain Y11 (MN560033), was able to metabolize daidzein to equol under anaerobic conditions, with a conversion ratio (equol ratio: the amount of equol produced/amount of supplemented daizein) of 0.56 over 120 h. The 16S rRNA partial sequence of the strain Y11 exhibited 99.8% identity to that of Slackia equolifaciens strain DZE (NR116295). This study will provide new insights into the biotransformation of equol from daidzein by intestinal microbiota from the strain-level and explore the possibility of probiotic interventions.
Preliminary Evidence that Intraspecific Competition Increases Size of Restoration-Planted Pitch and Shortleaf Pines in a Mixed-Hardwood Clearcut in the Southern Appalachians
Authors: McNab W Henry 
Published: April 2021

Abstract
Oak-pine (Quercus L. - Pinus L.) forest communities on low ridges in the southern Appalachian Mountains are losing diversity as mature pitch (P. rigida Mill.) and shortleaf (P. echinata Mill.) pines die and do not regenerate under a hardwood canopy. Restoration of biodiversity by planting pine seedlings is well known, but little is known regarding whether the configuration of planted seedlings affects growth and subsequent size (diameter at breast height, dbh) as trees age. The purpose of this study was to test the hypothesis that pines growing in groups of two or more trees respond with increased growth (expressed by dbh) to intraspecific competition with other pines compared to single trees subjected only to interspecific competition with surrounding hardwoods. For 13-year-old pitch and shortleaf pines, trees were larger in dbh when occurring in groups than trees occurring singly. Regression indicated that intraspecific competition accounted for 16% of the dbh variation of pitch pine and 29% for shortleaf pine. This study originated from chance observations in a small study of pine restoration. If a designed study confirms these results, resource managers could restore biodiversity with reduced site disturbance and establishment costs by planting pine seedlings in small groups rather than rows.
Gene Coexpression Network Reveals Highly Conserved, Well-Regulated Anti-Ageing Mechanisms in Old Ant Queens
Authors: Harrison Mark C , Niño Luisa M Jaimes , Rodrigues Marisa Almeida , Ryll Judith , Flatt Thomas , Oettler Jan , Bornberg-Bauer Erich 
Published: April 2021

AbstractEvolutionary theories of ageing predict a reduction in selection efficiency with age, a so-called “selection shadow,” due to extrinsic mortality decreasing effective population size with age. Classic symptoms of ageing include a deterioration in transcriptional regulation and protein homeostasis. Understanding how ant queens defy the trade-off between fecundity and lifespan remains a major challenge for the evolutionary theory of ageing. It has often been discussed that the low extrinsic mortality of ant queens, that are generally well protected within the nest by workers and soldiers, should reduce the selection shadow acting on old queens. We tested this by comparing strength of selection acting on genes upregulated in young and old queens of the ant, Cardiocondyla obscurior. In support of a reduced selection shadow, we find old-biased genes to be under strong purifying selection. We also analyzed a gene coexpression network (GCN) with the aim to detect signs of ageing in the form of deteriorating regulation and proteostasis. We find no evidence for ageing. In fact, we detect higher connectivity in old queens indicating increased transcriptional regulation with age. Within the GCN, we discover five highly correlated modules that are upregulated with age. These old-biased modules regulate several antiageing mechanisms such as maintenance of proteostasis, transcriptional regulation, and stress response. We observe stronger purifying selection on central hub genes of these old-biased modules compared with young-biased modules. These results indicate a lack of transcriptional ageing in old C. obscurior queens, possibly facilitated by strong selection at old age and well-regulated antiageing mechanisms.
Fine-Scale Spatial Genetic Structure with Nonuniform Distribution of Individuals
Authors: Doligez Agnès , Baril Claire , Joly Hélène I 
Published: April 2021

Abstract
This paper presents the first theoretical study of spatial genetic structure within nonuniformly distributed continuous plant populations. A novel individual-based model of isolation by distance was constructed to simulate genetic evolution within such populations. We found larger values of spatial genetic autocorrelations in highly clumped populations than in uniformly distributed populations. Most of this difference was caused by differences in mean dispersal distances, but aggregation probably also produced a slight increase in spatial genetic structure. Using an appropriate level of approximation of the continuous distribution of individuals in space, we assessed the potential effects of density, seed and pollen dispersal, generation overlapping, and overdominance selection at an independent locus, on fine-scale genetic structure, by varying them separately in a few particular cases with extreme clumping. When selfing was allowed, all these input variables influenced both aggregation and spatial genetic structure. Most variations in spatial genetic structure were closely linked to variations in clumping and/or local density. When selfing was not allowed, spatial genetic structure was lower in most cases.
Isolation of the GA-Response Mutant sly1 as a Suppressor of ABI1-1 in Arabidopsis thaliana
Authors: Steber Camille M , Cooney Sarah E , McCourt Peter 
Published: April 2021

Abstract
Seed dormancy and germination in higher plants are partially controlled by the plant hormones abscisic acid (ABA) and gibberellic acid (GA). ABA establishes dormancy during embryo maturation, whereas GA breaks dormancy and induces germination. Previous attempts to identify GA response genes were confounded because GA mutants are not expected to germinate and, unlike GA auxotrophs, should fail to be rescued by exogenous GA. Here, we describe a screen for suppressors of the ABA-insensitive mutant ABI1-1 that enriches for GA auxotrophs and GA-insensitive mutants. The vast majority (76%) of the suppressors of ABI1-1 strongly resemble GA auxotrophs in that they are severely dwarfed and have dark green foliage and flowers with underdeveloped petals and stamen. Three isolates were alleles of the GA auxotroph ga1. The remaining severe dwarves were not rescued by GA and belong to a single complementation group that we designate sly1 (Sleepy 1). The alleles of sly1 identified are the first recessive GA-insensitive mutations to reflect the full spectrum of GA-associated phenotypes, including the failure to germinate in the absence of the ABI1-1 lesion. Thus, we postulate that SLY1 is a key factor in GA reception.
Selection of T-DNA-Tagged Male and Female Gametophytic Mutants by Segregation Distortion in Arabidopsis
Authors: Howden Ross , Park Soon Ki , Moore James M , Orme James , Grossniklaus Ueli , Twell David 
Published: April 2021

Abstract
As a strategy for the identification of T-DNA-tagged gametophytic mutants, we have used T-DNA insertional mutagenesis based on screening for distorted segregation ratios by antibiotic selection. Screening of ~1000 transgenic Arabidopsis families led to the isolation of eight lines showing reproducible segregation ratios of ~1:1, suggesting that these lines are putative gametophytic mutants caused by T-DNA insertion at a single locus. Genetic analysis of T-DNA transmission through reciprocal backcrosses with wild type showed severe reductions in genetic transmission of the T-DNA through the male and/or female gametes. Direct evidence for mutant phenotypes in these lines was investigated by DAPI staining of mature pollen grains and by the analysis of seed set and embryo sac morphology in cleared ovules. One line, termed limpet pollen, showed a novel pollen phenotype in that the generative cell failed to migrate inward after pollen mitosis I, such that the generative or sperm cells remained against the pollen wall. Two other lines, andarta and tistrya, were defective in female transmission and showed an early arrest of embryo sac development with the viable megaspore not initiating the nuclear division cycles. These data demonstrate the efficacy of a segregation ratio distortion strategy for the identification of T-DNA-tagged gametophytic mutants in Arabidopsis.