bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extending and using anatomical vocabularies in the Stimulating Peripheral Activity to Relieve Conditions (SPARC) program
Authors: Surles-Zeigler Monique C. , Sincomb Troy , Gillespie Thomas H. , de Bono Bernard , Bresnahan Jacqueline , Mawe Gary M. , Grethe Jeffrey S. , Tappan Susan , Heal Maci , Martone Maryann E. 
Published: November 2021

AbstractThe Stimulating Peripheral Activity to Relieve Conditions (SPARC) program is a US National Institutes of Health-funded effort to improve our understanding of the neural circuitry of the autonomic nervous system in support of bioelectronic medicine. As part of this effort, the SPARC program is generating multi-species, multimodal data, models, simulations, and anatomical maps supported by a comprehensive knowledge base of autonomic circuitry. To facilitate the organization of and integration across multi-faceted SPARC data and models, SPARC is implementing the FAIR data principles to ensure that all SPARC products are findable, accessible, interoperable, and reusable. We are therefore annotating and describing all products with a common FAIR vocabulary. The SPARC Vocabulary is built from a set of community ontologies covering major domains relevant to SPARC, including anatomy, physiology, experimental techniques, and molecules. The SPARC Vocabulary is incorporated into tools researchers use to segment and annotate their data, facilitating the application of these ontologies for annotation of research data. However, since investigators perform deep annotations on experimental data, not all terms and relationships are available in community ontologies. We therefore implemented a term management and vocabulary extension pipeline where SPARC researchers may extend the SPARC Vocabulary using InterLex, an online vocabulary management system. To ensure the quality of contributed terms, we have set up a curated term request and review pipeline specifically for anatomical terms involving expert review. Accepted terms are added to the SPARC Vocabulary and, when appropriate, contributed back to community ontologies to enhance autonomic nervous system coverage. Here, we provide an overview of the SPARC Vocabulary, the infrastructure and process for implementing the term management and review pipeline. In an analysis of > 300 anatomical contributed terms, the majority represented composite terms that necessitated combining terms within and across existing ontologies. Although these terms are not good candidates for community ontologies, they can be linked to structures contained within these ontologies. We conclude that the term request pipeline serves as a useful adjunct to community ontologies for annotating experimental data and increases the FAIRness of SPARC data.
The landscape of metabolic brain alterations in Alzheimer’s disease
Authors: Batra Richa , Arnold Matthias , Wörheide Maria A. , Allen Mariet , Wang Xue , Blach Colette , Levey Allan I. , Seyfried Nicholas T. , Ertekin-Taner Nilüfer , Bennett David A. , Kastenmüller Gabi , Kaddurah-Daouk Rima F. , Krumsiek Jan ,   Alzheimer’s Disease Metabolomics Consortium (ADMC)
Published: November 2021

AbstractINTRODUCTIONAlzheimer’s disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in brain has been missing.METHODSWe metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures.RESULTSWe observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than β-amyloid pathology.DISCUSSIONThis work provides a comprehensive reference map of metabolic brain changes in AD which lays the foundation for future mechanistic follow-up studies.
Lateral Line Ablation by Ototoxic Compounds Results in Distinct Rheotaxis Profiles in Larval Zebrafish
Authors: Newton Kyle C , Kacev Dovi , Nilsson Simon R O , Saettele Allison L , Golden Sam A , Sheets Lavinia 
Published: November 2021

ABSTRACTThe zebrafish lateral line is an established model for hair cell organ damage, yet few studies link mechanistic disruptions to changes in biologically relevant behavior. We used larval zebrafish to determine how damage via ototoxic compounds impact rheotaxis. Larvae were treated with CuSO4 or neomycin to disrupt lateral line function then exposed to water flow stimuli. Their swimming behavior was recorded on video then DeepLabCut and SimBA software were used to track movements and classify rheotaxis behavior, respectively. Lateral line-disrupted fish performed rheotaxis, but they swam greater distances, for shorter durations, and with greater angular variance than controls. Furthermore, spectral decomposition analyses confirmed that lesioned fish exhibited ototoxic compound-specific behavioral profiles with distinct changes in the magnitude, frequency, and cross-correlation between fluctuations in linear and angular movements. Our observations demonstrate that lateral line input is needed for fish to hold their station in flow efficiently and reveals that commonly used lesion methods have unique effects on rheotaxis behavior.
Family-Assisted Severity of Illness Monitoring for Hospitalized Children in Low-resource settings – a two-arm interventional pilot study
Authors: von Saint Andre-von Arnim Amelie O. , Kumar Rashmi K. , Clark Jonna D. , Wilfond Benjamin S. , Nguyen Quynh-Uyen P. , Mutonga Daniel M. , Zimmerman Jerry , Oron Assaf P. , Walson Judd L. 
Published: November 2021

AbstractIntroductionPediatric mortality remains unacceptably high in many low-resource settings, with inpatient deaths often associated with delayed recognition of clinical deterioration. The Family-Assisted Severe Febrile Illness ThERapy (FASTER) tool has been developed for caregivers to assist in monitoring their hospitalized children and alert clinicians. While utilization of the tool is feasible, the impact on outcomes in low-resource settings has not been studied.MethodsRandomized controlled pilot study at Kenyatta National Hospital, Kenya. Children hospitalized with acute febrile illness with a caregiver at the bedside for 24 hours were enrolled. Caregivers were trained using the FASTER tool (monitors work of breathing, mental status, perfusion, producing color-coded flags to signal illness severity). The primary outcome was the frequency of clinician reassessments between intervention (FASTER) and control (standard care) arms. Secondary outcomes included survey assessments of clinician and caregiver experiences with the tool. The study was registered with ClinicalTrials.govNCT03513861.Results150 patient/caregiver pairs were enrolled, 139 included in the analysis, 74 in the intervention, 65 in the control arm. Patients’ median age was 0.9 (range 0.2-10) and 1.1 years (range 0.2-12) in intervention versus control arms. The most common diagnoses were pneumonia (80[58%]), meningitis (58[38%]) and malaria (34[24%]). 134(96%) caregivers were patients’ mothers. Clinician visits/hour increased with patients’ illness severity in both arms, but without difference in frequency between arms (point estimate for the difference -0.2%, p=0.99). Of the 16 deaths, 8 (four/arm) occurred within 2 days of enrollment. Forty clinicians were surveyed, 33(82%) reporting that FASTER could improve outcomes of very sick children in low-resource settings; 26(65%) rating caregivers as able to adequately capture patients’ severity of illness. Of 70 caregivers surveyed, 63(90%) reported that FASTER training was easy to understand; all(100%) agreed that the intervention would improve care of hospitalized children and help identify sick children in their community.DiscussionAlthough we observed no difference in recorded frequency of clinician visits with FASTER monitoring, the tool was rated positively by caregivers and clinicians. Further research to refine implementation with additional input from all stakeholders might increase the effectiveness of FASTER in detecting and responding to clinical deterioration in low-resource settings.
Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells
Authors: Okahashi Nobuyuki , Shima Tomoki , Kondo Yuya , Araki Chie , Tsuji Shuma , Sawai Akane , Uehara Hikaru , Kohno Susumu , Shimizu Hiroshi , Takahashi Chiaki , Matsuda Fumio 
Published: November 2021

AbstractAdenosine triphosphate (ATP) regeneration by substrate-level phosphorylation is a general feature of cancer metabolism, even under normoxic conditions (aerobic glycolysis). However, it is unclear why cancer cells prefer inefficient aerobic glycolysis over the highly efficient process of oxidative phosphorylation for ATP regeneration. To investigate the metabolic principles underlying aerobic glycolysis, we performed13C-metabolic flux analysis of 12 cultured cancer cell lines and explored the metabolic constraints required to reproduce the results usingin silicometabolic simulations. We found that the measured flux distribution can be reproduced by maximizing the ATP consumption in the flux balance analysis considering a limitation of metabolic heat dissipation (enthalpy change). It suggests that aerobic glycolysis may be preferable because metabolic heat production during one mol of ATP regeneration by aerobic glycolysis was less than that produced by oxidative phosphorylation (OXPHOS). Consistent with the simulation, OXPHOS inhibition induced metabolic redirection to aerobic glycolysis while maintaining the intracellular temperature. Furthermore, the dependency on aerobic glycolysis was partly alleviated upon culturing at low temperatures. Our data suggest that metabolic thermogenesis is an important factor in understanding aerobic glycolysis in cancer cells and that an advantage of aerobic glycolysis is the reduction in metabolic heat generation during ATP regeneration.
Validation of cervical lesion proportion measure using a gridded imaging technique to assess cervical pathology in women with genital schistosomiasis
Authors: Aaroe Katrina Kaestel , Schmidt Arenholt Louise Thomsen , Norderud Kanutte , Lumholdt Mads , Randrianasolo Bodo Sahondra , Ramarokoto Charles Emile , Rabozakandraina Oliva , Broennum Dorthe , Feldmeier Hermann , Christian Leutscher Peter Derek 
Published: November 2021

AbstractFemale genital schistosomiasis (FGS) is characterized by a pattern of lesions which manifest at the cervix and the vagina, such as homogeneous and grainy sandy patches, rubbery papules in addition to neovascularization. A tool for quantification of the lesions is needed to improve FGS research and control programs. Hitherto, no tools are available to quantify clinical pathology at the cervix in a standardized and reproducible manner. This study aimed to develop and validate a cervical lesion proportion (CLP) measure for quantification of cervical pathology in FGS. A digital imaging technique was applied in which a grid containing 424 identical squares was positioned on high resolution digital images from the cervix of 70 women with FGS. A CLP was made for each image by counting the total number of squares containing at least one type of pathognomonic lesions. For validation of inter- and intra-observer reliability, three different observers estimated CLP independently. In addition, a rubbery papule count (RPC) was determined in a similar manner. The intraclass correlation coefficient was 0.94 (excellent) for the CLP inter-rater reliability and 0.90 (good) for intra-rater reliability and the coefficients for the RPC were 0.88 and 0.80 (good), respectively. The CLP facilitated a reliable and reproducible quantification of the surface of the cervix affected by FGS pathognomonic lesions. Grading of cervical pathology by CLP can provide insight into the natural course of schistosome egg-induced pathology of the cervix. Moreover, CLP provides a measure for the efficacy of treatment.Author summaryFemale genital schistosomiasis (FGS) is characterized by development of egg-induced chronic inflammatory lesions of the cervix and the vagina. FGS causes various symptoms such vaginal discharge, dyspareunia and post-coital bleeding, and the disease is further associated with reproductive complications such as ectopic pregnancy and infertility. Moreover, FGS is today considered as a major risk factor for transmission of HIV in Sub-Saharan Africa. General prevention directed against Schistosoma infection and use of praziquantel as anthelmintic drug therapy are cornerstones in the FGS control strategy. In that overall context, we have developed an important new digital image tool for quantitative assessment of FGS evoked cervical lesions, which enables evaluation of treatment outcome at individual as well as community level. The tool will also provide new information in understanding the natural history of FGS including development of clinical pathology.
Association of EBV (Type 1 and 2) with Histopathological Outcomes in Breast Cancer in Pakistani Women
Authors: Ilyas Yusra , Khan Sanaullah , Khan Naveed 
Published: November 2021

AbstractIntroductionBreast cancer is one of the major and frequent tumors in the public health sector globally. The rising global prevalence of breast cancer has aroused attention in a viral etiology. Other than genetic and hormonal roles, viruses like Epstein - Barr virus (EBV) also participate in the development and advancement of breast cancer.AimThis study was conducted to detect the frequency of EBV genotypes in breast cancer patients and compare it with histopathological breast cancer changes.MethodsFormalin-fixed paraffin-embedded samples of breast cancer (N=60) ages ranged from 22-70 years were collected. EBV DNA was isolated, amplified, typed through PCR, and correlated with histopathological outcomes of breast cancer using SPSS software version 26.ResultsOur findings suggest that among breast cancer factors, Invasive ductal carcinoma (IDC) was the most common pathological pattern found among patients (90%), observed statistically significant (p= 0.01275). In regards to clinical staging, 8 (13.3 %) patients diagnosed with stage I, 39 (65 %) with stage II, and 13 (21.6 %) with stage III reported statistically significant association (p=0.0003). EBV DNA was detected in 68.3% (41/60) breast cancer patients, reported a statistically significant difference between the prevalence of EBV in breast cancer patients and normal samples (p= 0.001). Of 41 EBV-positive samples, 40 were EBV-1, while only 1 had EBV-2 infection (p < 0.001). No influence on cancer histology was observed. Regarding the association of breast cancer with EBV, histological type (P =0.209), tumor stage (P = 0.48), tumor grade (0.356), tumor sizes (p= 0.976), age (p= 0.1055), tumor laterality (p= 0.533) and ER/PR status (p=0.773) showed no significant association.ConclusionEBV-1 is prevalent in breast cancer patients and associated with IDC in the study area. For conclusive evidence, more studies are required based on a large sample size and by using more sensitive techniques.
Recapitulation of patient-specific 3D chromatin conformation using machine learning and validation of identified enhancer-gene targets
Authors: Xu Duo , Forbes Andre Neil , Cohen Sandra , Palladino Ann , Karadimitriou Tatiana , Khurana Ekta 
Published: November 2021

AbstractRegulatory networks containing enhancer to gene edges define cellular state and their rewiring is a hallmark of cancer. While efforts, such as ENCODE, have revealed these networks for reference tissues and cell-lines by integrating multi-omics data, the same methods cannot be applied for large patient cohorts due to the constraints on generating ChIP-seq and three-dimensional data from limited material in patient biopsies. We trained a supervised machine learning model using genomic 3D signatures of physical enhancer-gene connections that can predict accurate connections using data from ATAC-seq and RNA-seq assays only, which can be easily generated from patient biopsies. Our method overcomes the major limitations of correlation-based approaches that cannot distinguish between distinct target genes of given enhancers in different samples, which is a hallmark of network rewiring in cancer. Our model achieved an AUROC (area under receiver operating characteristic curve) of 0.91 and, importantly, can distinguish between active regulatory elements with connections to target genes and poised elements with no connections to target genes. Our predicted regulatory elements are validated by multi-omics data, including histone modification marks from ENCODE, with an average specificity of 0.92. Application of our model on chromatin accessibility and transcriptomic data from 400 cancer patients across 22 cancer types revealed novel cancer-type and subtype-specific enhancer-gene connections for known cancer genes. In one example, we identified two enhancers that regulate the expression of ESR1 in only ER+ breast cancer (BRCA) samples but not in ER-samples. These enhancers are predicted to contribute to the high expression of ESR1 in 93% of ER+ BRCA samples. Functional validation using CRISPRi confirms that inhibition of these enhancers decreases the expression of ESR1 in ER+ samples.
Reconstructing mutational lineages in breast cancer by multi-patient-targeted single cell DNA sequencing
Authors: Leighton Jake , Hu Min , Sei Emi , Meric-Bernstam Funda , Navin Nicholas E. 
Published: November 2021

AbstractSingle cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells, however most genomic regions characterized in single cells are non-informative. To overcome this issue, we developed a Multi-Patient-Targeted (MPT) scDNA-seq sequencing method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 TNBC patients, which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From this data, we reconstructed mutational lineages and identified early mutational and copy number events, including early TP53 mutations that occurred in all five patients. Collectively, our data suggests that MPT can overcome technical obstacles for studying tumor evolution using scDNA-seq by profiling information-rich mutation sites.
DNA methylation of Nuclear Factor of Activated T Cells 1 mediates the prospective relation between exposure to different traumatic event types and post-traumatic stress disorder
Authors: Occean James R. , Wani Agaz H. , Donglasan Janelle , Aiello Allison E. , Galea Sandro , Koenen Karestan C. , Qu Annie , Wildman Derek E. , Uddin Monica 
Published: November 2021

AbstractBackgroundThe mechanisms through which exposure to differing trauma types become biologically embedded to shape the risk for subsequent post-traumatic stress disorder (PTSD) is unclear. DNA methylation (5-mC), particularly in stress-relevant genes, may play a role in this relationship.MethodsWe conducted path analysis using generalized structural equation modeling to investigate whether blood-derived 5-mC in Nuclear Factor of Activated T Cells 1 (NFATC1) mediated the prospective association between each of five different trauma types (“assaultive violence”, “other injury or shocking experience”, “learning of trauma to loved one”, “sudden, unexpected death of a close friend or relative”, and “other”) and lifetime PTSD assessed prospectively in the Detroit Neighborhood Health Study (n=183).ResultsAll five trauma types were significantly associated with reduced methylation atNFATC1CpG site, cg17057218. Three of the five trauma types were significantly associated with increased methylation atNFATC1CpG site, cg22324981. Moreover, methylation at cg17057218 significantly mediated 23-34% of the total effect for three of the five trauma types (assaultive violence, other injury or shocking experience, and learning of trauma to a loved one), while methylation at cg22324981 mediated 36-53% of the total effect for two of the five trauma types (other injury or shocking experience and other). These CpG sites were differentially associated with transcription factor binding sites and chromatin state signatures.LimitationsProspective assessment of lifetime PTSD, rather than PTSD onset.ConclusionsNFATC15-mC may be a potential mechanism in the relationship between some trauma types and prospective risk for PTSD. This finding may help inform treatment for trauma-specific PTSD.
How do avian embryos resume development following diapause? A new role for TGF-β in regulating pluripotency-related genes
Authors: Pokhrel Narayan , Genin Olga , Sela-Donenfeld Dalit , Cinnamon Yuval 
Published: November 2021

AbstractAvian embryos can halt their development for long periods at low temperature in a process called diapause and successfully resume development when reincubated at maternal body temperature. Successful resumption of development depends on different factors, including temperature. We have recently shown that embryos that enter diapause at 18 °C present a significant reduction in their ability to develop normally when put back into incubation, compared to embryos entering diapause at 12 °C. However, the mechanisms underlying these differences are unknown. To address this question, transcriptome analysis was performed to compare the effect of diapause temperature on gene expression, and to identify pathways involved in the process. Genetic comparison and pathway-enrichment analysis revealed that TGF-β and pluripotency-related pathways are differentially regulated at the two temperatures, with higher expression at 12 °C compared to 18 °C. Investigating the involvement of the TGF-β pathway revealed an essential role for BMP4 in regulating the expression of the transcription factors Nanog and Id2, which are known to regulate pluripotency and self-renewal in embryonic stem cells. BMP4 gain- and loss-of-function experiments in embryos in diapause at the different temperatures revealed the main role of BMP4 in enabling resumption of normal development following diapause. Collectively, these findings identify molecular regulators that facilitate embryos’ ability to undergo diapause at different temperatures and resume a normal developmental program.