bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unveiling the neuroimaging-genetic intersections in the human brain
Authors: Diez Ibai , Sepulcre Jorge 
Published: May 2021

Purpose of review
The prevalence of new public datasets of brain-wide and single-cell transcriptome data has created new opportunities to link neuroimaging findings with genetic data. The aim of this study is to present the different methodological approaches that have been used to combine this data.

Recent findings
Drawing from various sources of open access data, several studies have been able to correlate neuroimaging maps with spatial distribution of brain expression. These efforts have enabled researchers to identify functional annotations of related genes, identify specific cell types related to brain phenotypes, study the expression of genes across life span and highlight the importance of selected brain genes in disease genetic networks.

Summary
New transcriptome datasets and methodological approaches complement current neuroimaging work and will be crucial to improve our understanding of the biological mechanism that underlies many neurological conditions.
An Atomic Approach to the Design and Implementation of a Research Data Warehouse
Authors: Visweswaran Shyam , McLay Brian , Cappella Nickie , Morris Michele , Milnes John T. , Reis Steven E. , Silverstein Jonathan C. , Becich Michael J. 
Published: May 2021

ABSTRACTObjectiveAs a long-standing Clinical and Translational Science Awards (CTSA) Program hub, the University of Pittsburgh and the University of Pittsburgh Medical Center (UPMC) developed and implemented a modern research data warehouse (RDW) to efficiently provision electronic patient data for clinical and translational research.MethodsBecause UPMC is one of the largest health care systems in the US with multiple vendors’ electronic health record (EHR) systems, we designed and implemented an RDW named Neptune to serve the specific needs of our CTSA. Neptune uses an atomic design where data is stored at a high level of granularity as represented in source systems. Neptune contains robust patient identity management tailored for research; integrates patient data from multiple sources, including EHRs, health plans, and research studies; and includes knowledge for mapping to standard terminologies. Neptune enables efficient provisioning of data to large analytics-oriented data models and to individual investigators.ResultsNeptune contains data for more than 5 million patients longitudinally organized as HIPAA Limited Data with dates and includes structured EHR data, clinical documents, health insurance claims, and research data. Neptune is used as a source for patient data for hundreds of IRB-approved research projects by local investigators and for national projects such as the Accrual to Clinical Trials (ACT) network, the All of Us Research Program, and the National Patient-Centered Clinical Research Network.DiscussionThe design of Neptune was heavily influenced by the large size of UPMC, the varied data sources, and the rich partnership between the University and the healthcare system. It features several desiderata of an RDW, including robust protected health information management, an extensible information storage model, and binding to standard terminologies at the time of data delivery. It also includes several unique aspects, including the physical warehouse straddling the University of Pittsburgh and UPMC networks and management under a HIPAA Business Associates Agreement.ConclusionWe describe the design and implementation of an RDW at a large academic health care system that uses a distinctive atomic design where data is stored at a high level of granularity.
Cerebrovascular Response to an Acute Bout of Short Interval High Intensity Interval Exercise and Recovery in Healthy Adults
Authors: Whitaker Alicen A. , Aaron Stacey E. , Kaufman Carolyn S. , Kurtz Brady K. , Bai Stephen X. , Vidoni Eric D. , Billinger Sandra A. 
Published: May 2021

AbstractIntroductionHigh intensity interval exercise (HIIE) is performed widely. However, the field possesses limited knowledge regarding the acute HIIE cerebrovascular response. Our objective was to characterize the middle cerebral artery blood velocity (MCAv) response during an acute bout of short interval HIIE in healthy adults. We hypothesized MCAv would decrease below BL 1) during HIIE, 2) following HIIE, 3) and 30-minutes after HIIE. As a secondary objective, we investigated sex differences in the MCAv response during HIIE.MethodsFourteen healthy adults (7 male) completed the HIIE session. The 10-minute HIIE session included alternating 1-minute bouts of high-intensity and low-intensity intervals. MCAv, mean arterial pressure (MAP), heart rate (HR), and expired end tidal carbon dioxide (PETCO2), were recorded at BL, during HIIE, following HIIE, and 30-minutes after HIIE.ResultsContrary to our hypothesis, MCAv remained above BL for the HIIE duration. MCAv peaked at the third minute then decreased concomitantly with PETCO2. MCAv was lower than BL after HIIE (p=0.03). Thirty minutes after HIIE, MCAv returned to near BL values (p = 0.47). Women showed higher BL MCAv ( = 70.9 ± 8.1 cm·s-1) compared to men ( = 59.3 ± 5.8 cm·s-1, p = 0.01). A greater magnitude of MCAv response was observed in men resulting in non-significant differences during HIIE secondary to higher workload (p = 0.03).ConclusionsCollectively, these findings show that in healthy adults, MCAv remained above BL during a 10-minute short-interval HIIE and returned to resting values 30 minutes after exercise.
The performance of the SARS-CoV-2 RT-PCR test as a tool for detecting SARS-CoV-2 infection in the population: A survey of routine laboratory RT-PCR test results from the region of Münster, Germany
Authors: Stang Andreas , Robers Johannes , Schonert Birte , Jöckel Karl-Heinz , Spelsberg Angela , Keil Ulrich , Cullen Paul 
Published: May 2021

SummaryObjectivesTo evaluate the population-based performance of the SARS-CoV-2 RT-PCR test as a tool for detecting SARS-CoV-2 infection during the pandemic in 2020.MethodsWe analysed SARS-CoV-2 RT-PCR results of 162,457 people living in Münster, Germany screened at nursing homes, testing sites, at schools, regional hospitals, and by general practitioners. All PCRs were done with the same cobas SARS-CoV-2 RT-PCR system (Roche Diagnostics). We stratified positive RT-PCR results by cycle threshold (Ct) values, periods of the national test strategy, age, sex, and symptoms.ResultsAmong 162,457 individuals, 4164 (2.6%) had a positive RT-PCR test result, defined as Ct<40. Depending on the national test strategy, higher positive rates were associated with testing predominantly symptomatic people. Children (0-9 years) and older adults (70+ years). Only 40.6% of test positives showed low Ct values < 25 (potentially infectious). The percentage of Ct values below 25 was lower among children (0-9), adolescents (10-19), and among the elderly (70+ years).ConclusionsRT-PCR testing as a tool for mass screening should not be used alone as a base for pandemic decision making including measures such as quarantine, isolation, and lockdown.
multiSero: open multiplex-ELISA platform for analyzing antibody responses to SARS-CoV-2 infection
Authors: Byrum Janie R. , Waltari Eric , Janson Owen , Guo Syuan-Ming , Folkesson Jenny , Chhun Bryant B. , Vinden Joanna , Ivanov Ivan E. , Forst Marcus L. , Li Hongquan , Larson Adam G. , Wu Wesley , Tato Cristina M. , McCutcheon Krista M. , Peluso Michael J. , Henrich Timothy J. , Deeks Steven G. , Prakash Manu , Greenhouse Bryan , Pak John E. , Mehta Shalin B. 
Published: May 2021

AbstractSerology has provided valuable diagnostic and epidemiological data on antibody responses to SARS-CoV-2 in diverse patient cohorts. Deployment of high content, multiplex serology platforms across the world, including in low and medium income countries, can accelerate longitudinal epidemiological surveys. Here we report multiSero, an open platform to enable multiplex serology with up to 48 antigens in a 96-well format. The platform consists of three components: ELISA-array of printed proteins, a commercial or home-built plate reader, and modular python software for automated analysis (pysero). We validate the platform by comparing antibody titers against the SARS-CoV-2 Spike, receptor binding domain (RBD), and nucleocapsid (N) in 114 sera from COVID-19 positive individuals and 87 pre-pandemic COVID-19 negative sera. We report data with both a commercial plate reader and an inexpensive, open plate reader (nautilus). Receiver operating characteristic (ROC) analysis of classification with single antigens shows that Spike and RBD classify positive and negative sera with the highest sensitivity at a given specificity. The platform distinguished positive sera from negative sera when the reactivity of the sera was equivalent to the binding of 1 ng mL−1 RBD-specific monoclonal antibody. We developed normalization and classification methods to pool antibody responses from multiple antigens and multiple experiments. Our results demonstrate a performant and accessible pipeline for multiplexed ELISA ready for multiple applications, including serosurveillance, identification of viral proteins that elicit antibody responses, differential diagnosis of circulating pathogens, and immune responses to vaccines.
Sunshine on KOL : a retrospective study about financial ties between medical key opinion leaders and pharmaceutical industry in France
Authors: Clinckemaillie Marie , Scanff Alexandre , Naudet Florian , Barbaroux Adriaan 
Published: May 2021

ABSTRACTObjectiveTo investigate the nature, extent and evolution of financial relationships between key opinion leaders (KOL) or non-KOL physicians and pharmaceutical and device companies in France.DesignRetrospective and descriptive studySettingAll doctors practicing in France, with a focus on 548 KOL defined as board members of all the professional medical associations having published clinical practice guidelines in 2018 or 2019. These 99 associations were identified by the cross-checking of 3 databases.Main outcome measuresThe number and the amount of gifts (year by year since 2014), remunerations and agreements (year by year since 2017).ResultsPhysicians had 818m€ ($936m, £741m) of gifts declared from 2014 to 2019. 83% of KOL had such links of interest. The 548 identified KOL represented 0.24% of physicians in France but received 1.5% of the total amount of gifts, i.e. €12.3m ($14m, £11m or €3 700 per capita per year).Physicians had 125m€ ($143m and 114m£) of agreements declared from 2017 to 2019. The 548 KOL received 0.72% of the agreements and 2.5% of the value of the agreements, i.e. 3.1m€ ($3.6m, £2.8m) or €1 900 per capita per year ($2200, £1700).Physicians had 156m€ ($178m and 141m£) of remunerations declared from 2017 to 2019. The 548 identified KOL received 4.4% of the total value of remunerations to physicians, i.e. 6.8m€ ($7.8m, £6.2m) or 4 100€ per capita per year ($4 800, £3 700).Almost every professional medical associations (99%) had in their board at least one KOL with a financial tie.ConclusionFinancial relationships between KOL and the industry in France are extensive, KOL have much more financial ties than non-KOL practitioners. The main limit of this study arises from the quality of information provided on the French Transparency in Healthcare database.Pre-registration: osf.io/m8syhStrengths and limitations of this studyThis is the first attempt to provide data on the extent of the links of interest between opinion leaders and pharmaceutical industry in France.Author crossed the nationwide databases of financial ties with three databases of professional medical associations.All medical doctors practicing in France were inclused, with a focus on 548 KOL defined as board members of all the professional medical associations having published clinical practice guidelines in 2018 or 2019.These 99 associations were identified by the cross-checking of 3 different catalogs of French professional associations.The major links between key opinion leaders and industry ask the question of the independence of the experts, and raises concern that guidelines can be influenced by industry.
Intra-host evolution provides for continuous emergence of SARS-CoV-2 variants
Authors: Landis Justin T. , Moorad Razia , Pluta Linda J. , Caro-Vegas Carolina , McNamara Ryan P , Eason Anthony B. , Bailey Aubrey , Villamor Femi Cleola S. , Juarez Angelica , Wong Jason P. , Yang Brian , Broussard Grant S. , Damania Blossom , Dittmer Dirk P. 
Published: May 2021

SummaryVariants of concern (VOC) in SARS-CoV-2 refer to viral genomes that differ significantly from the ancestor virus and that show the potential for higher transmissibility and/or worse clinical progression. VOC have the potential to disrupt ongoing public health measures and vaccine efforts. Yet, little is known regarding how frequently different viral variants emerge and under what circumstances. We report a longitudinal study to determine the degree of SARS-CoV-2 sequence evolution in 94 COVID-19 cases and to estimate the frequency at which highly diverse variants emerge. 2 cases accumulated ≥9 single-nucleotide variants (SNVs) over a two-week period and 1 case accumulated 23 SNVs over a three-week period, including three non-synonymous mutations in the Spike protein (D138H, E554D, D614G). We estimate that in 2% of COVID cases, viral variants with multiple mutations, including in the Spike glycoprotein, can become the dominant strains in as little as one month of persistent in patient virus replication. This suggests the continued local emergence of VOC independent of travel patterns. Surveillance by sequencing for (i) viremic COVID-19 patients, (ii) patients suspected of re-infection, and (iii) patients with diminished immune function may offer broad public health benefits.
Pigment pattern morphospace ofDaniofishes: evolutionary diversification and mutational effects
Authors: McCluskey Braedan M. , Liang Yipeng , Lewis Victor M. , Patterson Larissa B. , Parichy David M. 
Published: May 2021

AbstractMolecular and cellular mechanisms underlying differences in adult form remain largely unknown. Adult pigment patterns of fishes in the genusDanio, which includes zebrafish,D. rerio, include horizontal stripes, vertical bars, spots and uniform patterns, and provide an outstanding opportunity to identify causes of species level variation in a neural crest derived trait. Yet understanding such variation requires quantitative approaches to assess phenotypes, and such methods have been mostly lacking for pigment patterns. We introduce metrics derived from information theory that describe patterns and pattern variation inDaniofishes. We find that such metrics used singly and in multivariate combinations are suitable for distinguishing general pattern types, and can reveal even subtle phenotypic differences attributable to mutations. Our study provides new tools for analyzing pigment pattern inDanioand potentially other groups, and sets the stage for future analyses of pattern morphospace and its mechanistic underpinnings.Summary statementWe provide quantitative metrics for studying pigment patterns of zebrafish and other species. These metrics are applicable to changes between species as well as impacts of laboratory induced mutations
Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation
Authors: Baca Sylvan C. , Singler Cassandra , Zacharia Soumya , Seo Ji-Heui , Morova Tunc , Hach Faraz , Ding Yi , Schwarz Tommer , Huang Chia-Chi Flora , Kalita Cynthia , Groha Stefan , Pomerantz Mark M. , Wang Victoria , Linder Simon , Sweeney Christopher J. , Zwart Wilbert , Lack Nathan A. , Pasaniuc Bogdan , Takeda David Y. , Gusev Alexander , Freedman Matthew L. 
Published: May 2021

AbstractMethods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.
Ribosome protein mutant cells rely on the GR64 cluster of gustatory receptors for survival and proteostasis in Drosophila
Authors: Baumgartner Michael E. , Kucinski Iwo , Piddini Eugenia 
Published: May 2021

AbstractMutations in ribosome protein (Rp) genes and ribosome biogenesis factors result in debilitating diseases known as ribosomopathies. Recent studies in Drosophila have shown that cells heterozygous mutant for Rp genes (Rp/+) exhibit proteotoxic stress and aggregates, which drive stress pathway activation and apoptosis. Understanding how Rp/+ cells fend off proteotoxic stress could suggest mechanisms to ameliorate these and other conditions caused by proteotoxic stress. Here we find that Rp/+ epithelial cells express all six Gustatory Receptor 64 (Gr64) genes, a cluster of sugar receptors involved in taste sensation. We show that Rp/+ cells depend on Gr64 for survival and that loss of Gr64 autonomously exacerbates stress pathway activation and proteotoxic stress by negatively effecting autophagy and proteasome function in Rp/+ cells. This work identifies a non-canonical role in proteostasis maintenance for a family of gustatory receptors known for their function in neuronal sensation.
Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes
Authors: Sjödahl Gottfrid , Abrahamsson Johan , Holmsten Karin , Bernardo Carina , Chebil Gunilla , Eriksson Pontus , Johansson Iva , Kollberg Petter , Lindh Claes , Lövgren Kristina , Marzouka Nour-al-Dain , Olsson Hans , Höglund Mattias , Ullén Anders , Liedberg Fredrik 
Published: May 2021

SummaryFor muscle-invasive bladder cancer (MIBC), there are no tissue biomarkers in clinical use that identify patients sensitive or resistant to neoadjuvant chemotherapy. The present study investigates how molecular subtypes impact pathological response and survival in 149 patients receiving preoperative cisplatin-based chemotherapy. Tumor classification was performed by transcriptomic profiling and by a 13-marker immunostaining panel. Furthermore, we explored differential gene expression and chemotherapy response beyond molecular subtypes. Tumors with Genomically Unstable (GU) and Urothelial-like (Uro) subtypes had higher proportions of pathological response and superior survival outcomes as compared to the Basal-Squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Based on our findings, we suggest that urothelial cancer of the luminal-like GU- and Uro-subtypes are more responsive to cisplatin-based chemotherapy. We also found the gene coding for osteopontin (SPP1) to display a subtype-dependent effect on chemotherapy response, confirmed at the protein level by immunohistochemistry. Combined analyses of second-generation, subtype-specific biomarkers may be an additional way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.
Astrocytic Regulation of Basal Ganglia Dopamine/D2-Dependent Behaviors
Authors: Mastrogiacomo Rosa , Trigilio Gabriella , Dautan Daniel , Devroye Céline , Ferretti Valentina , Vitali Enrica , Orso Genny , Marotta Roberto , Maltese Federica , Piras Gessica , Forgiarini Alessia , Pacinelli Giada , Rothmond Debora A. , Waddington John L. , Drago Filippo , De Luca Maria Antonietta , Leggio Gian Marco , Weickert Cynthia S. , Managò Francesca , Papaleo Francesco 
Published: May 2021

AbstractAstrocytic involvement in dopamine dynamics related to motivational and sensorimotor gating abilities is unknown. We found that dysbindin-1 (Dys1) hypofunction increases the activity of astrocytes, which express only the isoform Dys1A that is reduced in the caudate of patients with schizophrenia. Astrocytic Dys1A disruption resulted in avolition and sensorimotor gating deficits, increased astrocytic dopamine D2 receptors and decreased dopaminergic tone within basal ganglia. Notably, astrocytic Dys1A hypofunction disrupted dopamine dynamics linked to reward expectancy and interconnected with astrocytes Ca2+responses mainly in the globus pallidus externus (GPe). Finally, we proved these phenotypes were mediated by D2 receptors in astrocytes as their selective deletion in astrocytes either in GPe or SNc/VTA enhanced motivation and sensorimotor gating abilities as well as dopaminergic release in the GPe. Therefore, astrocytes control motivational and sensorimotor gating processes through Dys1A/D2-dependent mechanisms within the basal ganglia.
Mitogen-activated protein kinases contribute to temperature induced cardiac remodelling in rainbow trout (Oncorhynchus mykiss) heart
Authors: Ding Y. , Johnston E.F. , Gillis T.E 
Published: May 2021

AbstractRainbow trout (Oncorhynchus mykiss) live in temperate environments and experience seasonal changes in temperature that range between 4°C and 20°C. Laboratory studies demonstrate that cold and warm acclimation of male trout can have oppositional effects on cardiac hypertrophy and the collagen content of the heart. The cellular mechanisms behind temperature induced cardiac remodelling are unclear, as is why this response differs between male and female fish. Recent work utilizing cultured trout cardiac fibroblasts suggests that collagen deposition is regulated, at least in part, by mitogen-activated protein kinase (MAPK) cell signalling pathways. We therefore hypothesized that temperature-dependent cardiac remodelling is regulated by these same cell signalling pathways. To test this, male and female trout were acclimated to 18°C (warm) in the summer and to 4°C (cold) in the winter and the activation of MAPK pathways in the hearts were characterized and compared to that of control fish maintained at 12°C. Animals, maintained under a natural photoperiod matched to time of year, were sampled throughout each acclimation. p38 MAPK phosphorylation increased in the hearts of female fish during the cold acclimation protocol and the phosphorylation of extracellular signal-regulated kinase (ERK) increased in the hearts of male fish with warm acclimation. These results indicate that thermal acclimation has transient and sex-specific effects on the phosphorylation of MAPKs.