bluuebunny/crossref_metadata_2025_split huggingface dataset:
RT-qPCR detection of SARS-CoV-2 mutations S 69-70 del, S N501Y and N D3L associated with variants of concern in Canadian wastewater samples
Authors: Peterson Shelley W. , Lidder Ravinder , Daigle Jade , Wonitowy Quinn , Nagasawa Audra , Mulvey Michael R. , Mangat Chand S. 
Published: May 2021

AbstractSARS-CoV-2 variants of concern (VoC) have been increasingly detected in clinical surveillance in Canada and internationally. These VoC are associated with higher transmissibility rates and in some cases, increased mortality. In this work we present a national wastewater survey of the distribution of three SARS-CoV-2 mutations found in the B.1.1.7, B.1.351, and P.1 VoC, namely the S-gene 69-70 deletion, N501Y mutation, and N-gene D3L. RT-qPCR allelic discrimination assays were sufficiently sensitive and specific for detection and relative quantitation of SARS-CoV-2 variants in wastewater to allow for rapid population-level screening and surveillance. We tested 261 samples collected from 5 Canadian cities (Vancouver, Edmonton, Toronto, Montreal, and Halifax) and 6 communities in the Northwest Territories from February 16th to March 28th, 2021. VoC were not detected in the Territorial communities, suggesting the absence of VoC SARS-CoV-2 cases in those communities. Percentage of variant remained low throughout the study period in the majority of the sites tested, however the Toronto sites showed a marked increase from ~25% to ~75% over the study period.The results of this study highlight the utility of population level molecular surveillance of SARS-CoV-2 VoC using wastewater. Wastewater monitoring for VoC can be a powerful tool in informing public health responses, including monitoring trends independent of clinical surveillance and providing early warning to communities.
Trajectory of Growth of SARS-CoV-2 Variants in Houston, Texas, January through May 2021 Based on 12,476 Genome Sequences
Authors: Olsen Randall J. , Christensen Paul A. , Long S. Wesley , Subedi Sishir , Hodjat Parsa , Olson Robert , Nguyen Marcus , Davis James J. , Yerramilli Prasanti , Saavedra Matthew Ojeda , Pruitt Layne , Reppond Kristina , Shyer Madison N. , Cambric Jessica , Gadd Ryan , Thakur Rashi M. , Batajoo Akanksha , Finkelstein Ilya J. , Gollihar Jimmy , Musser James M. 
Published: May 2021

AbstractGenetic variants of the SARS-CoV-2 virus are of substantial concern because they can detrimentally alter the pandemic course and disease features in individual patients. Here we report SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist healthcare system diagnosed from January 1, 2021 through May 31, 2021. The SARS-CoV-2 variant designated U.K. B.1.1.7 increased rapidly and caused 63%-90% of all new cases in the Houston area in the latter half of May. Eleven of the 3,276 B.1.1.7 genomes had an E484K change in spike protein. Compared with non-B.1.1.7 patients, individuals with B.1.1.7 had a significantly lower cycle threshold value (a proxy for higher virus load) and significantly higher rate of hospitalization. Other variants (e.g., B.1.429, B.1.427, P.1, P.2, and R.1) also increased rapidly, although the magnitude was less than for B.1.1.7. We identified 22 patients infected with B.1.617 “India” variants; these patients had a high rate of hospitalization. Vaccine breakthrough cases (n=207) were caused by a heterogeneous array of virus genotypes, including many that are not variants of interest or concern. In the aggregate, our study delineates the trajectory of concerning SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, and heralds the arrival and spread of B.1.617 variants in the metroplex.
Feasibility of Rapid Case Ascertainment for Cancer in East Africa: An Investigation of Community-Representative Kaposi Sarcoma in the Era of Antiretroviral Therapy
Authors: Semeere Aggrey , Byakwaga Helen , Laker-Oketta Miriam , Freeman Esther , Busakhala Naftali , Wenger Megan , Kasozi Charles , Ssemakadde Matthew , Bwana Mwebesa , Kanyesigye Michael , Kadama-Makanga Philippa , Rotich Elyne , Kisuya Job , Sang Edwin , Wools-Kaloustian Kara , Maurer Toby , Kambugu Andrew , Martin Jeffrey 
Published: May 2021

AbstractBACKGROUNDRapid case ascertainment (RCA) refers to the expeditious and detailed examination of patients with a potentially rapidly fatal disease shortly after diagnosis. RCA is frequently performed in resource-rich settings to facilitate cancer research. Despite its utility, RCA is rarely implemented in resource-limited settings and has not been performed for malignancies. One cancer and context that would benefit from RCA in a resource-limited setting is HIV-related Kaposi sarcoma (KS) in sub-Saharan Africa.METHODSTo determine the feasibility of RCA of KS, we searched for all potential newly diagnosed KS among HIV-infected adults attending three community-based facilities in Uganda and Kenya. Searching involved querying of electronic medical records, pathology record review, and notification by clinicians. Upon identification, a team verified eligibility and attempted to locate patients to perform RCA, which included epidemiologic, clinical and laboratory measurements.RESULTSWe identified 593 patients with suspected new KS. Of the 593, 171 were ineligible, mainly because biopsy failed to confirm KS (65%) or KS was not new (30%). Among the 422 remaining, RCA was performed within 1 month for 56% of patients and within 3 months for 65% (95% confidence interval: 59 to 70%). Reasons for not performing RCA included intervening death (47%), inability to contact (44%), refusal/unsuitable to consent (8.3%), and patient re-location (0.7%).CONCLUSIONSWe found that RCA — an important tool for cancer research in resource-rich settings — is feasible for the investigation of community-representative KS in East Africa. Feasibility of RCA for KS suggests feasibility for other cancers in Africa.
Multi-trait GWAS of atherosclerosis detects novel pleiotropic loci
Authors: Bellomo Tiffany R. , Bone William P. , Chen Brian Y. , Gawronski Katerina A. B. , Zhang David , Park Joseph , Levin Michael , Tsao Noah , Klarin Derek , Lynch Julie , Assimes Themistocles L. , Gaziano J. Michael , Wilson Peter W. , Cho Kelly , Vujkovic Marijana ,   the VA Million Veteran Program, O’Donnell Christopher J. , Chang Kyong-Mi , Tsao Phil S. , Rader Daniel J. , Ritchie Marylyn D. , Voight Benjamin F. , Damrauer Scott M. 
Published: May 2021

ABSTRACTRationaleAlthough affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. Analysis of their shared genetic architecture, along with that of common risk factors, may identify novel common biology.ObjectiveTo identify novel pleiotropic genetic loci associated with atherosclerosis and provide a better understanding of biological pathways underlying atherosclerosis.Methods and ResultsSummary statistics from genome wide association studies (GWAS) of nine known atherosclerotic (CAD, PAD) or atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein (LDL), high density lipoprotein, total cholesterol, and triglycerides) were combined to perform 15 separate multi-trait genetic association scans which resulted in 31 unique novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified 34 candidate causal genes across 14 of the detected signals. Notably, the signal between PAD and CAD at theVDAC2locus (rs7088974) colocalized withVDAC2expression in aorta and tibial artery tissues. Additionally, the signal between PAD and LDL at thePCSK6locus (rs1531817) affectsPCSK6splicing in human liver tissue and induced pluripotent derived hepatocyte like cells.ConclusionsJoint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation.VDAC2andPCSK6represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.
Prioritizing disease-causing metabolic genes by integrating metabolomics with whole exome sequencing data
Authors: Bongaerts Michiel , Bonte Ramon , Demirdas Serwet , Huidekoper Hidde , Langendonk Janneke , Wilke Martina , de Valk Walter , Blom Henk J. , Reinders Marcel J.T. , Ruijter George J. G. 
Published: May 2021

AbstractThe integration of metabolomics data with sequencing data is a key step towards improving the diagnostic process for finding the disease-causing gene(s) in patients suspected of having an inborn error of metabolism (IEM). The measured metabolite levels could provide additional phenotypical evidence to elucidate the degree of pathogenicity for variants found in metabolic genes. We present a computational approach, called Reafect, that calculates for each reaction in a metabolic pathway a score indicating whether that reaction is being deficient or not. When calculating this score, Reafect takes multiple factors into account: the magnitude and sign of alterations in the metabolite levels, the reaction distances between metabolites and reactions in the pathway, and the biochemical directionality of the reactions. We applied Reafect to untargeted metabolomics data of 72 patient samples with a known IEM and found that in 80% of the cases the correct deficient enzyme was ranked within the top 5% of all considered enzyme deficiencies. Next, we integrated Reafect with CADD scores (a measure for variant deleteriousness) and ranked the potential disease-causing genes of 27 IEM patients. We observed that this integrated approach significantly improved the prioritization of the disease-causing genes when compared with the two approaches individually. For 15/27 IEM patients the correct disease-causing gene was ranked within the top 0.2% of the set of potential disease-causing genes. Together, our findings suggest that metabolomics data improves the identification of disease-causing genetic variants in patients suffering from IEM.
The impact of resource provisioning on the epidemiological responses of different parasites
Authors: Erazo Diana , Pedersen Amy B. , Fenton Andy 
Published: May 2021

AbstractEvents such as anthropogenic activities and periodic tree masting can alter resource provisioning in the environment, directly affecting animals, and potentially impacting the spread of infectious diseases in wildlife. The effect of these supplemental resources on infectious diseases can manifest through different pathways, affecting host susceptibility, transmission and host demography.To date however, empirical research has tended to examine these different pathways in isolation, for example by quantifying the effects of provisioning on host behaviour in the wild or changes in immune responses in controlled laboratory studies. Further, while theory has investigated the interactions between these pathways, thus far this work has focussed on a narrow subset of pathogen types, typically directly-transmitted microparasites. Given the diverse ways that provisioning can affect host susceptibility, contact patterns or host demography, we may expect the epidemiological consequences of provisioning to depend on key aspects of parasite life-history, such as the duration of infection and transmission mode.We developed a suite of generic epidemiological models to compare how resource provisioning alters responses for different parasites that vary in their biology (micro- and macro-parasite), transmission mode (direct, environmental, and vector transmitted) and duration of infection (acute, latent, and chronic). Next, we parameterised these different parasite types using data from the diverse parasite community of wild wood mice as a case study.We show there are common epidemiological responses to host resource provisioning across all parasite types examined. In particular, the response to provisioning could be driven in opposite directions, depending on which host pathways (contact rate, susceptibility or host demography) are most altered by the addition of resources to the environment. Broadly, these responses were qualitatively consistent across all parasite types, emphasising the importance of identifying general trade-offs between provisioning-altered parameters.Despite the qualitative consistency in responses to provisioning across parasite types, we found notable quantitative differences between parasites, suggesting specific epidemiological outcomes could strongly depend on parasite type, infection duration and permanency of recovery, and whether the parasite is directly, environmentally, or vector transmitted. These analyses therefore highlight the importance of knowing key specific aspects of host-parasite biology, such as host contact behaviours, parasite interactions with the host immune system, and how resource availability shapes host demographics, in order to understand and predict epidemiological responses to provisioning for any specific host-parasite system.
Serine catabolism generates NADPH to support hepatic lipogenesis
Authors: Zhang Zhaoyue , TeSlaa Tara , Xu Xincheng , Zeng Xianfeng , Yang Lifeng , Xing Gang , Tesz Gregory J , Clasquin Michelle F , Rabinowitz Joshua D 
Published: May 2021

SummaryCarbohydrate can be converted into fat by de novo lipogenesis1,2. This process is known to occur in adipose and liver, and its activity is upregulated in fatty liver disease3. Chemically, de novo lipogenesis involves polymerization and reduction of acetyl-CoA, using NADPH as the electron donor1. While regulation of the responsible enzymes has been extensively studied, the feedstocks used to generate acetyl-CoA and NADPH remain unclear. Here we show that, while de novo lipogenesis in adipose is supported by glucose and its catabolism via the pentose phosphate pathway to make NADPH, liver makes fat without relying on glucose. Instead, liver derives acetyl-CoA from acetate and lactate, and NADPH from folate-mediated serine catabolism. Such NADPH generation involves the cytosolic serine pathway running in liver in the opposite direction observed in most tissues and tumors4,5, with NADPH made by the SHMT1-MTHFD1-ALDH1L1 reaction sequence. Thus, specifically in liver, folate metabolism is wired to support cytosolic NADPH production for lipogenesis. More generally, while the same enzymes are involved in fat synthesis in liver and adipose, different substrates are utilized, opening the door to tissue-specific pharmacological interventions.
3D-MASNet: 3D Mixed-scale Asymmetric Convolutional Segmentation Network for 6-month-old Infant Brain MR Images
Authors: Zeng Zilong , Zhao Tengda , Sun Lianglong , Zhang Yihe , Xia Mingrui , Liao Xuhong , Zhang Jiaying , Shen Dinggang , Wang Li , He Yong 
Published: May 2021

AbstractPrecise segmentation of infant brain MR images into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) are essential for studying neuroanatomical hallmarks of early brain development. However, for 6-month-old infants, the extremely low-intensity contrast caused by inherent myelination hinders accurate tissue segmentation. Existing convolutional neural networks (CNNs) based segmentation models for this task generally employ single-scale symmetric convolutions, which are inefficient for encoding the isointense tissue boundaries in baby brain images. Here, we propose a 3D mixed-scale asymmetric convolutional segmentation network (3D-MASNet) framework for brain MR images of 6-month-old infants. We replaced the traditional convolutional layer of an existing to-be-trained network with a 3D mixed-scale convolution block consisting of asymmetric kernels (MixACB) during the training phase and then equivalently converted it into the original network. Five canonical CNN segmentation models were evaluated using both T1- and T2-weighted images of 23 6-month-old infants from iSeg-2019 datasets, which contained manual labels as ground truth. MixACB significantly enhanced the average accuracy of all five models and obtained the most considerable improvement in the fully convolutional network model (CC-3D-FCN) and the highest performance in the Dense U-Net model. This approach further obtained Dice coefficient accuracies of 0.931, 0.912, and 0.961 in GM, WM, and CSF, respectively, ranking first among 30 teams on the validation dataset of the iSeg-2019 Grand Challenge. Thus, the proposed 3D-MASNet can improve the accuracy of existing CNNs-based segmentation models as a plug-and-play solution that offers a promising technique for future infant brain MRI studies.
Inhibition of immunoglobulin class-switching prevents pemphigus onset in desmoglein 3-specific B cell receptor knock-in mouse
Authors: Nomura Hisashi , Wada Naoko , Takahashi Hayato , Kase Yuko , Yamagami Jun , Egami Shohei , Iriki Hisato , Mukai Miho , Kamata Aki , Ito Hiromi , Fujii Hideki , Ishikura Tomoyuki , Koseki Haruhiko , Watanabe Takashi , Yamada Taketo , Ohara Osamu , Koyasu Shigeo , Amagai Masayuki 
Published: May 2021

ABSTRACTAlthough immunoglobulin class-switching is essential for humoral immunity, its role in B-cell immune tolerance remains unclear. Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3, an adhesion molecule of keratinocytes. In this study, we generated knock-in mice that express anti-Dsg3 AK23 autoantibodies. Knock-in B cells developed normallyin vivoand showed Ca2+influx upon IgM cross-linkingin vitro. The mice predominantly produced circulating AK23 IgM but little IgG antibodies. Although no IgG deposition or blister formation was observed in Dsg3-bearing tissues, Dsg3 immunization forced to induce pemphigus phenotype after class-switching to IgGin vivo. Transcriptomic analysis revealed thatFCGR2Band FcγRIIB-related genes were downregulated in B cells from peripheral blood of pemphigus patients. Indeed, in AK23 knock-in mice,Fcgr2bdeficiency or haploinsufficiency spontaneously led to class-switching, AK23 IgG production, and pemphigus phenotype development. Thus, inhibition of pathogenic class-switching is a crucial tolerogenic process to prevent pemphigus onset, where attenuated FcγRIIB signaling is one of the key predispositions to break this tolerogenic state.
A Spatiotemporal Map of Reading Aloud
Authors: Woolnough Oscar , Donos Cristian , Curtis Aidan , Rollo Patrick S. , Roccaforte Zachary J. , Dehaene Stanislas , Fischer-Baum Simon , Tandon Nitin 
Published: May 2021

AbstractReading words aloud is a fundamental aspect of literacy. The rapid rate at which multiple distributed neural substrates are engaged in this process can only be probed via techniques with high spatiotemporal resolution. We probed this with direct intracranial recordings covering most of the left hemisphere in 46 humans as they read aloud regular, exception and pseudo-words. We used this to create a spatiotemporal map of word processing and to derive how broadband gamma activity varies with multiple word attributes critical to reading speed: lexicality, word frequency and orthographic neighborhood. We found that lexicality is encoded earliest in mid-fusiform (mFus) cortex and precentral sulcus, and is represented reliably enough to allow single-trial lexicality decoding. Word frequency is first represented in mFus and later in the inferior frontal gyrus (IFG) and inferior parietal sulcus (IPS), while orthographic neighborhood sensitivity resides solely in IPS. We thus isolate the neural correlates of the distributed reading network involving mFus, IFG, IPS, precentral sulcus and motor cortex and provide direct evidence for dual-route models of reading, with parallel processes via the lexical route from mFus to IFG, and the sub-lexical route from IPS and precentral sulcus to anterior IFG.
Alpha Oscillatory Activity Causally Linked to Working Memory Retention: Insights from Online Phase-corrected Closed-loop Transcranial Alternating Current Stimulation (tACS)
Authors: Chen Xueli , Ma Ru , Zhang Wei , Wu Qianying , Yimiti Ajiguli , Xia Xinzhao , Cui Jiangtian , Zeng Ginger Qinghong , Bu Junjie , Chen Qi , Yu Nancy Xiaonan , Wang Shouyan , Deng Zhi-De , Sack Alexander T. , Laughlin Myles Mc , Zhang Xiaochu 
Published: May 2021

ABSTRACTAlthough previous studies have reported correlations between alpha oscillations and the “retention” sub-process of working memory (WM), causal evidence has been limited in human neuroscience due to the lack of delicate modulation of human brain. Conventional tACS is not suitable for demonstrating the causal evidence for parietal alpha oscillations in WM retention because of its inability to modulate brain oscillations within a short period (i.e., the retention sub-process). Here, we developed an online phase-corrected closed-loop transcranial alternating current stimulation (tACS) system capable of precisely correcting for the phase differences between tACS and concurrent endogenous oscillations. This system permits both up- and down-regulation of brain oscillations at the target stimulation frequency within a short stimulation period, and is here applied to empirically demonstrate that parietal alpha oscillations causally relate to WM retention. Our experimental design included both in-phase and anti-phase alpha-tACS applied to 39 participants during the retention sub-processes of a modified Sternberg paradigm. Compared to in-phase alpha-tACS, anti-phase alpha-tACS decreased both WM performance and alpha activity. Moreover, the in-phase tACS-induced changes in WM performance were positively correlated with alpha oscillatory activity. These findings strongly support a causal link between alpha oscillations and WM retention, and illustrate the broad application prospects of phase-corrected tACS.
Karyon: a computational framework for the diagnosis of hybrids, aneuploids, and other non-standard architectures in genome assemblies
Authors: Naranjo-Ortiz Miguel A. , Molina Manu , Mixão Verónica , Gabaldón Toni 
Published: May 2021

AbstractRecent technological developments have made genome sequencing and assembly accessible to many groups. However, the presence in sequenced organisms of certain genomic features such as high heterozygosity, polyploidy, aneuploidy, or heterokaryosis can challenge current standard assembly procedures and result in highly fragmented assemblies. Hence, we hypothesized that genome databases must contain a non-negligible fraction of low-quality assemblies that result from such type of intrinsic genomic factors. Here we present Karyon, a Python-based toolkit that uses raw sequencing data and de novo genome assembly to assess several parameters and generate informative plots to assist in the identification of non-chanonical genomic traits. Karyon includes automated de novo genome assembly and variant calling pipelines. We tested Karyon by diagnosing 35 highly fragmented publicly available assemblies from 19 different Mucorales (Fungi) species. Our results show that 6 (17%) of the assemblies presented signs of unusual genomic configurations, suggesting that these are common, at least within the Fungi.