bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seroprevalence of Brucella antibodies among vaccine manufacturing workers in contact with the Brucella melitensis Rev.1 vaccine strain
Authors: Vives-Soto Manuel , Puerta-García Amparo , Pereira José-Luis , Rodríguez-Sánchez Esteban , Solera Javier 
Published: December 2021

ABSTRACTBackgroundCattle vaccination remains an essential measure for the control of brucellosis. Strict preventive measures are applied to protect vaccine manufacturing workers (VMW) employed in processing these live attenuated vaccines. We analyzed the serological responses of VMW in contact with the Brucella melitensis Rev.1 strain.MethodsWe conducted an observational study of a cohort of VMW in a Spanish biopharmaceutical company, a leader in manufacturing veterinary products. The results of the Brucella serological tests carried out on these workers between 2012 and 2019 were reviewed, as well as demographic data, length of time in the company (seniority), and level of exposure. Multivariate analysis was performed with the logistic regression test.ResultsOf the 115 VMW studied, 47 (41%) showed positive Rose Bengal tests during company check-ups. Exposure levels were correlated with seropositivity, with an adjusted OR of 6.6 (95% CI: 2.1-20.3) for the high exposure and 2.0 (95% CI: 0.6-6.7) for the medium exposure groups. Sixteen (34%) seropositive VMW demonstrated an acute serologic pattern of IgG and IgM antibodies seropositivization, while 31 (66%) manifested a chronic serologic pattern of constant or intermittent positive IgG antibodies with persistently negative IgM antibodies. Seniority was inversely associated with the acute pattern: adjusted OR of 0.88 (95% CI: 0.79-0.97) for each year added. No seropositive VMW showed evidence of active brucellosis during follow up.ConclusionDespite strict safety measures, a percentage of VMW were exposed to the Rev.1 strain. Exposure levels were correlated with seropositivity. None of them developed symptomatic infection during follow-up. Two different serological patterns were observed: an acute IgM-positive pattern or a chronic IgM-negative pattern. Seniority was associated with the chronic pattern.
Cohort Identification Using Semantic Web Technologies: Triplestores as Engines for Complex Computable Phenotyping
Authors: Pfaff Emily R. , Bradford Robert , Clark Marshall , Balhoff James P. , Wang Rujin , Preisser John S. , Walters Kellie , Nielsen Matthew E. 
Published: December 2021

ABSTRACTBackgroundComputable phenotypes are increasingly important tools for patient cohort identification. As part of a study of risk of chronic opioid use after surgery, we used a Resource Description Framework (RDF) triplestore as our computable phenotyping platform, hypothesizing that the unique affordances of triplestores may aid in making complex computable phenotypes more interoperable and reproducible than traditional relational database queries.To identify and model risk for new chronic opioid users post-surgery, we loaded several heterogeneous data sources into a Blazegraph triplestore: (1) electronic health record data; (2) claims data; (3) American Community Survey data; and (4) Centers for Disease Control Social Vulnerability Index, opioid prescription rate, and drug poisoning rate data. We then ran a series of queries to execute each of the rules in our “new chronic opioid user” phenotype definition to ultimately arrive at our qualifying cohort.ResultsOf the 4,163 patients in the denominator, our computable phenotype identified 248 patients as new chronic opioid users after their index surgical procedure. After validation against charts, 228 of the 248 were revealed to be true positive cases, giving our phenotype a PPV of 0.92.ConclusionWe successfully used the triplestore to execute the new chronic opioid user phenotype logic, and in doing so noted some advantages of the triplestore in terms of schemalessness, interoperability, and reproducibility. Future work will use the triplestore to create the planned risk model and leverage the additional links with ontologies, and ontological reasoning.
Post-Translational Modifications Optimize the Ability of SARS-CoV-2 Spike for Effective Interaction with Host Cell Receptors
Authors: Kapoor Karan , Chen Tianle , Tajkhorshid Emad 
Published: December 2021

AbstractSARS-CoV2 spike glycoprotein is prime target for vaccines and for diagnostics and therapeutic antibodies against the virus. While anchored in the viral envelope, for effective virulance, the spike needs to maintain structural flexibility to recognize the host cell surface receptors and bind to them, a property that can heavily hinge upon the dynamics of the unresolved domains, most prominently the stalk. Construction of the complete, membrane-bound spike model and the description of its dynamics remain critical steps in understanding the inner working of this key element in viral infection. Using a hybrid approach, combining homology modeling, protein-protein docking and MD simulations, guided by biochemical and glycomics data, we have developed a full-length, membrane-bound, palmitoylated and fully-glycosylated spike structure in a native membrane. Multi-microsecond MD simulations of this model, the longest known trajectory of the full-spike, reveals conformational dynamics employed by the protein to explore the crowded surface of the host cell. In agreement with cryoEM, three flexiblele hinges in stalk allow for global conformational heterogeneity of spike in the fully-glycosyslated system mediated by glycan-glycan and glycan-lipid interactions. Dynamical range of spike is considerably reduced in its non-glycosylated form, confining the area explored by the spike on the host cell surface. Furthermore, palmitoylation of the membrane domain amplify the local curvature that may prime the fusion. We show that the identified hinge regions are highly conserved in SARS coronaviruses, highlighting their functional importance in enhancing viral infection, and thereby provide novel points for discovery of alternative therapeutics against the virus.SignificanceSARS-CoV2 Spike protein, which forms the basis for high pathogenicity and transmissibility of the virus, is also prime target for the development of both diagnostics and vaccines for the debilitating disease caused by the virus. We present a full model of spike methodically crafted and used to study its atomic-level dynamics by multiple-µs simulations. The results shed new light on the impact of posttranslational modifications in the pathogenicity of the virus. We show how glycan-glycan and glycan-lipid interactions broaden the protein’s dynamical range, and thereby, its effective interaction with the surface receptors on the host cell. Palmitoylation of spike membrane domain, on the other hand, results in a unique deformation pattern that might prime the membrane for fusion.
Steroid hormone signaling activates thermal nociception during Drosophila peripheral nervous system development
Authors: Jaszczak Jacob S. , DeVault Laura , Jan Lily Yeh , Jan Yuh Nung 
Published: December 2021

AbstractSensory neurons enable animals to detect environmental changes and avoid harm. An intriguing open question concerns how the various attributes of sensory neurons arise in development. Drosophila melanogaster larvae undergo a behavioral transition by robustly activating a thermal nociceptive escape behavior during the second half of larval development (3rd instar). The Class 4 dendritic arborization (C4da) neurons are multimodal sensors which tile the body wall of Drosophila larvae and detect nociceptive temperature, light, and mechanical force. In contrast to the increase in nociceptive behavior in the 3rd instar, we find that ultraviolet light-induced Ca2+ activity in C4da neurons decreases during same period of larval development. Loss of ecdysone receptor has previously been shown to reduce nociception in 3rd instar larvae. We find that ligand dependent activation of ecdysone signaling is sufficient to promote nociceptive responses in 2nd instar larvae and suppress expression of subdued (encoding a TMEM16 channel). Reduction of subdued expression in 2nd instar C4da neurons not only increases thermal nociception but also decreases the response to ultraviolet light. Thus, steroid hormone signaling suppresses subdued expression to facilitate the sensory switch of C4da neurons. This regulation of a developmental sensory switch through steroid hormone regulation of channel expression raises the possibility that ion channel homeostasis is a key target for tuning the development of sensory modalities.
Single immunization with recombinant ACAM2000 vaccinia viruses expressing the spike and the nucleocapsid proteins protect hamsters against SARS-CoV-2 caused clinical disease
Authors: Deschambault Yvon , Lynch Jessie , Warner Bryce , Tierney Kevin , Huynh Denise , Vendramelli Robert , Tailor Nikesh , Frost Kathy , Booth Stephanie , Sajesh Babu , LeBlanc Kyle , Layne Christine , Lin Lisa , Beniac Daniel , Carpenter Michael , Safronetz David , Li Xuguang , Kobasa Darwyn , Cao Jingxin 
Published: December 2021

SUMMARYIncreasing cases of SARS-CoV-2 breakthrough infections from immunization with predominantly spike protein based COVID-19 vaccines highlight the need for alternative vaccines using different platforms and/or antigens. In this study, we expressed SARS-CoV-2 spike and nucleocapsid proteins in a novel vaccinia virus ACAM2000 platform (rACAM2000). Following a single intramuscular immunization, the rACAM2000 co-expressing the spike and nucleocapsid proteins induced significantly improved protection against SARS-CoV-2 challenge in comparison to rACAM2000 expressing the individual proteins in a hamster model, as shown by reduced weight loss and quicker recovery time. The protection was associated with reduced viral loads, increased neutralizing antibody titre and reduced neutrophil-to-lymphocyte ratio. Thus, our study demonstrates that the rACAM2000 expressing a combination of the spike and nucleocapsid antigens is a promising COVID-19 vaccine candidate and further studies will investigate if the rACAM2000 vaccine candidate can induce a long lasting immunity against infection of SARS-CoV-2 variants of concern.
Systems immune profiling of variant-specific vaccination against SARS-CoV-2
Authors: Peng Lei , Park Jonathan J. , Fang Zhenhao , Zhou Xiaoyu , Dong Matthew B. , Xiong Qiancheng , Lin Chenxiang , Chen Sidi 
Published: December 2021

AbstractLipid-nanoparticle(LNP)-mRNA vaccines offer protection against COVID-19. However, multiple variant lineages caused widespread breakthrough infections. There is no report on variant-specific vaccines to date. Here, we generated LNP-mRNAs specifically encoding wildtype, B.1.351 and B.1.617 SARS-CoV-2 spikes, and systematically studied their immune responses in animal models. All three LNP-mRNAs induced potent antibody responses in mice. However, WT-LNP-mRNA vaccination showed reduced neutralization against B.1.351 and B.1.617; and B.1.617-specific vaccination showed differential neutralization. All three vaccine candidates elicited antigen-specific CD8 and CD4 T cell responses. Single cell transcriptomics of B.1.351-LNP-mRNA and B.1.617-LNP-mRNA vaccinated animals revealed a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induced a systemic increase in reactive CD8 T cell population, with a strong signature of transcriptional and translational machineries in lymphocytes. BCR-seq and TCR-seq unveiled repertoire diversity and clonal expansions in vaccinated animals. These data provide direct systems immune profiling of variant-specific LNP-mRNA vaccinationin vivo.
Urinary cell-free DNA as a noninvasive liquid biopsy for hepatocellular carcinoma: a novel tool for diagnostics and monitoring
Authors: Kim Amy K. , Lin Selena Y. , Liu Hsin-Ni , Jain Surbhi , Gade Terence P. , Shieh Fwu-Shan , Chao Max , Hamilton James , Hann Hie-Won , Chang Ting-Tsung , Goryunov Dmitry , Wang Zhili , Su Ying-Hsiu 
Published: December 2021

AbstractBackground & AimsCell-free DNA (cfDNA) has advanced cancer genetic profiling through liquid biopsy. While plasma is traditionally the primary source, emerging evidence highlights urinary cfDNA as a novel and noninvasive alternative. This study aimed to comprehensively assess transrenal DNA (trDNA) as a novel noninvasive biomarker source in HCC patients, compared to blood-based liquid biopsy.Approach & ResultsHBV DNA was used as a biomarker for trDNA. HBV-targeted and HCC-focused next generation sequencing (NGS) and whole genome sequencing (WGS) were used to compare fragment insert-sizes, the genome coverage, and germline genotyping accuracy. Urinary cfDNA overall exhibited a predominantly mononucelosomal pattern similar to plasma cfDNA, but with shorter fragments, broader size distribution and a more pronounced 10-bp periodicity. In contrast, trDNA were shorter and more variable among all patients. In HCC patients, trDNA was even shorter, with distinct 4-mer end motifs, compared to non-HCC trDNA. Higher concentrations of HCC-distinctive 4-mer end motif and TP53 mutations were found in urine compared to plasma. The overall genome coverage breadth by WGS was similar between urine and plasma cfDNA, with a higher fraction of covered cancer-associated mutation hotspots in urine cfDNA. In 101 HCC patients, there was a 78% overall concordance of HCC-associated mutations (TP53, CTNNB1,andhTERT) and in select 15 patients, 97% overall position-level concordance by targeted NGS between plasma and urine cfDNA.ConclusionUrine cfDNA has comparable features with distinct characteristics to plasma cfDNA and is a promising tool for liver cancer studies.
ROR1 is a novel putative druggable target for diffuse glioma
Authors: John Miya , Rao Padmashree , Noor Humaira , Ford Caroline 
Published: December 2021

AbstractThe cell surface receptor ROR1 is a therapeutic target of growing interest in oncology; however, its role in glioma has not been established thus far. This study analyzed associations between ROR1 mRNA expression and clinical outcomes, and histological and molecular subtypes in four independent glioma (grades II-IV) transcriptomic datasets (The Cancer Genome Atlas-GBMLGG, Chinese Glioma Genome Atlas, Repository for Molecular Brain Neoplasia, and GSE16011), encompassing a total of 2,388 cases. The data strongly suggests that ROR1 may be associated with poorer outcomes and more aggressive disease. Taken together, ROR1 should be further examined as a novel putative druggable target for glioma, a cancer that currently has very limited therapeutic options.
Persistent Symptoms Among Frontline Health Workers Post-acute COVID-19 Infection
Authors: Wose Kinge CN , Hanekom S , Smith A-L , Akpan F , Mothibi E , Maotoe T , Lebatie F , Majuba P , Sanne I , Chasela C 
Published: December 2021

AbstractBackgroundGrowing evidence shows that a significant number of patients with COVID-19 experience prolonged/persistent symptoms, also known as Long COVID. Reports of Long COVID are rising but little is known about prevalence in non-hospitalized patients.ObjectiveWe sought to identify the persistent symptoms of COVID-19 in frontline workers at Right to Care (RTC) South Africa who have past the acute phase of illness with a view to establishing rehabilitation programs for its employees and the community at large.MethodsThis was a cross-sectional survey. We analysed data from 207 eligible COVID-19 positive RTC frontline workers who participated in a post-COVID online self-administered survey. The survey was active for two months. Frequencies and median were calculated for categorical and continuous variables, respectively.ResultsThe survey response rate was 30% (62 out of 207); of the 62 respondents with a median age of 33.5 years (IQR= 30–44 years), 47 (76%) were females. The majority (n=55; 88.7%) self-isolated and 7 (11.3%) were admitted to hospital at time of diagnosis. The most common comorbid condition reported was hypertension particularly among workers aged 45–55 years. Headache, body ache, fatigue, loss of smell, dry cough, fever, and loss of appetite were the most common reported symptoms at time of diagnosis. Persistent symptoms were characterized by fatigue, anxiety, difficulty sleeping, chest pain, muscle pain and brain fog, being the six most reported.ConclusionThe impact of persistent/Long COVID-19 on the health of frontline workers could have direct impact in health service delivery. Given the rise in cases of COVID-19 in South Africa and the world at large, the prevalence of Long COVID is likely to be substantial and therefore need for rehabilitation programs targeted at each of the persistent (Long) COVID symptoms is critical.
Smartphone Movement Sensors for Remote Monitoring of Respiratory Rate: Observational Study
Authors: Valentine Sophie , Klasmer Benjamin , Dabbah Mohammad , Balabanovic Marko , Plans David 
Published: December 2021

AbstractBackgroundMobile health offers potential benefits to patients and healthcare systems alike. Existing remote technologies to measure respiratory rate (RR) have limitations, such as cost, accessibility and reliability. Using smartphone sensors to measure RR may offer a potential solution.ObjectiveThe aim of this study was to conduct a comprehensive assessment of a novel mHealth smartphone application designed to measure RR using movement sensors.MethodsIn Study 1, 15 participants simultaneously measured their RR with the app, and an FDA cleared reference device. A novel reference method to allow the app to be evaluated ‘in the wild’ was also developed. In Study 2, 165 participants measured their RR using the app, and these measures were compared to the novel reference. Usability of the app was also assessed in both studies.ResultsThe app, when compared to the FDA-cleared and novel references, respectively, showed a mean absolute error (MAE) of 1.65 (SD=1.49) and 1.14 (1.44), relative MAE of 12.2 (9.23) and 9.5 (18.70) and bias of 0.81 (limits of agreement (LoA) =-3.27-4.89) and 0.08 (−3.68-3.51). Pearson correlation coefficients were 0.700 and 0.885. 93% of participants successfully operated the app on their first use.ConclusionsThe accuracy and usability of the app demonstrated here show promise for the use of mHealth solutions employing smartphone sensors to remotely monitor RR. Further research should validate the benefits that this technology may offer patients and healthcare systems.
Bite force performance from wild derived mice has undetectable heritability despite having heritable morphological components
Authors: Ginot Samuel , Hallgrímsson Benedikt , Agret Sylvie , Claude Julien 
Published: December 2021

AbstractFitness-related traits tend to have low heritabilities. Conversely, morphology tends to be highly heritable. Yet, many fitness-related performance traits such as running speed or bite force depend critically on morphology. Craniofacial morphology correlates with bite performance in several groups including rodents. However, within species, this relationship is less clear, and the genetics of performance, morphology and function are rarely analyzed in combination. Here, we use a half-sib design in outbred wild-derived Mus musculus to study the morphology-bite force relationship and determine whether there is additive genetic (co-)variance for these traits. Results suggest that bite force has undetectable additive genetic variance and heritability in this sample, while morphological traits related mechanically to bite force exhibit varying levels of heritability. The most heritable traits include the length of the mandible which relates to bite force. Despite its correlation with morphology, realized bite force was not heritable, which suggests it is less responsive to selection in comparison to its morphological determinants. We explain this paradox with a non-additive, many-to-one mapping hypothesis of heritable change in complex traits. We furthermore propose that performance traits could evolve if pleiotropic relationships among the determining traits are modified.
Contour, a semi-automated segmentation and quantitation tool for cryo-soft-X-ray tomography
Authors: Nahas Kamal L , Fernandes João Ferreira , Crump Colin , Graham Stephen , Harkiolaki Maria 
Published: December 2021

AbstractCryo-soft-X-ray tomography is being increasingly used in biological research to study the morphology of cellular compartments and how they change in response to different stimuli, such as viral infections. Segmentation of these compartments is limited by time-consuming manual tools or machine learning algorithms that require extensive time and effort to train. Here we describeContour, a new, easy-to-use, highly automated segmentation tool that enables accelerated segmentation of tomograms to delineate distinct cellular compartments. UsingContour, cellular structures can be segmented based on their projection intensity and geometrical width by applying a threshold range to the image and excluding noise smaller in width than the cellular compartments of interest. This method is less laborious and less prone to errors from human judgement than current tools that require features to be manually traced, and does not require training datasets as would machine-learning driven segmentation. We show that high-contrast compartments such as mitochondria, lipid droplets, and features at the cell surface can be easily segmented with this technique in the context of investigating herpes simplex virus 1 infection.Contourcan extract geometric measurements from 3D segmented volumes, providing a new method to quantitate cryo-soft-X-ray tomography data.Contourcan be freely downloaded atgithub.com/kamallouisnahas/Contour.Impact StatementMore research groups are using cryo-soft-X-ray tomography as a correlative imaging tool to study the ultrastructure of cells and tissues but very few tomograms are segmented with existing segmentation programs. Segmentation is usually a prerequisite for measuring the geometry of features in tomograms but the time- and labour-intensive nature of current segmentation techniques means that such measurements are rarely across a large number of tomograms, as is required for robust statistical analysis.Contourhas been designed to facilitate the automation of segmentation and, as a result, reduce manual effort and increase the number of tomograms that can be segmented. Because it requires minimal manual intervention,Contouris not as prone to human error as programs that require the users to trace the edges of cellular features. Geometry measurements of the segmented volumes can be calculated using this program, providing a new platform to quantitate cryoSXT data.Contouralso supports quantitation of volumes imported from other segmentation programs. The generation of a large sample of segmented volumes withContourthat can be used as a representative training dataset for machine learning applications is a long-term aspiration of this technique.
Physical association of functionally antagonistic enzymes: KDM5A interacts with MLLs to regulate gene expression in a promoter specific manner facilitating EMT and pluripotency
Authors: Kirtana R , Manna Soumen , Patra Samir Kumar 
Published: December 2021

AbstractDifferential expression of genes involved in physiological processes are a collaborative outcome of interactions among signalling molecules, downstream effectors and epigenetic modifiers, which together dictate the regulation of genes in response to specific stimuli. MLLs and KDM5A are functionally antagonistic proteins as one acts as writer and the other as eraser of the active chromatin mark, i.e., H3K4me3. KDM5A promotes EMT by occupying promoters of both epithelial and mesenchymal markers. Through this work, it is illustrated that when bound to E-cadherin promoter, KDM5A acts as a classical repressor by demethylating H3K4me3, but on mesenchymal marker promoters, it acts as a transcriptional activator by inhibiting the activity of HDACs and increasing H3K18ac. Further it is demonstrated that KDM5A occupancy enhances either MLL1 or MLL2 by physically interacting with them and that signalling pathways regulate the enzymatic activity of KDM5A probably by phosphorylation. When not active, KDM5A signals for MLL occupancy, a mechanism that can be called epigenetic signalling.