bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating Retention Index Score Assumptions to Refine GC-MS Metabolite Identification
Authors: Degnan David J. , Bramer Lisa M. , Flores Javier E. , Paurus Vanessa L. , Corilo Yuri E. , Clendinen Chaevien S. 
Published: January 2023

ABSTRACTAs metabolomics grows into a high-throughput and high demand research field, current metrics for the identification of small molecules in GC-MS still require manual verification. Though steps have been taken to improve scoring metrics by combining spectral similarity (SS) and retention index (RI), the problem persists. A large body of literature has analyzed and refined SS scores, but few studies have explicitly studied improvements to RI scores. Here, we examined whether uninvestigated assumptions of the RI score are valid and propose ways to improve them. Query RI were matched to library RI with a generous window of +/-35 to avoid unintentional removal of valid compound identifications. Each match was manually verified as a true positive, true negative or unknown. Metabolites with at least 30 true positive identifications were included in downstream analyses, resulting in a total of 87 metabolites from samples of varying complexity and type (e.g., amino acid mixtures, human urine, fungal species, etc.). Our results showed that the RI score assumptions of normality, consistent variance across metabolites, and a mean error centered at 0 are often violated. We demonstrated through a cross-validation analysis that modifying these underlying assumptions according to empirical, metabolite-specific distributions improved the true positive and negative rankings. Further, we statistically determined the minimum number of samples required to estimate distributional parameters for scoring metrics. Overall, this work proposes a robust statistical pipeline to reduce the time bottleneck of metabolite identification by improving RI scores and thus minimizes the effort to complete manual verification.
Improved gene regulatory network inference from single cell data with dropout augmentation
Authors: Zhu Hao , Slonim Donna K. 
Published: January 2023

AbstractA major challenge in working with single-cell RNA sequencing data is the prevalence of “dropout,” when some transcripts’ expression values are erroneously not captured. Addressing this issue, which produces zero-inflated count data, is crucial for many downstream data analyses including the inference of gene regulatory networks (GRNs). In this paper, we introduce two novel contributions. First, we propose Dropout Augmentation (DA), a simple but effective model regularization method to address the zero inflation problem in single-cell data by augmenting the data with synthetic dropout events. DA offers a new perspective to solve the “dropout” problem beyond imputation. Second, we present DAZZLE, a stabilized and robust version of the autoencoder-based structure equation model for GRN inference using the DA concept. Benchmark experiments illustrate the improved performance and increased stability of the proposed DAZZLE model over existing approaches. The practical application of the DAZZLE model on a longitudinal mouse microglia dataset containing over 15,000 genes illustrates its ability to handle real-world single cell data with minimal gene filtration. The improved robustness and stability of DAZZLE make it a practical and valuable addition to the toolkit for GRN inference from single-cell data. Finally, we propose that Dropout Augmentation may have wider applications beyond the GRN-inference problem. Project website:https://bcb.cs.tufts.edu/DAZZLE.Author summaryThe prevalence of false zeros in single-cell data, or “dropout,” affects many downstream analyses. A common approach is to eliminate these zeros through data imputation. We propose an alternative solution that focuses on regularizing the model and increasing model robustness against dropout noise. Counter-intuitively, this is done by augmenting the input data with a small number of zeros to simulate additional dropout noise. Validation is performed on the task of gene regulatory network inference. Our proposed model, DAZZLE, which uses the dropout augmentation idea, shows improved performance and robustness.
A computational model of chemically and mechanically induced platelet plug formation
Authors: Cardillo Giulia , Barakat Abdul I. 
Published: January 2023

AbstractObjectivesThrombotic deposition is a major consideration in the development of implantable cardiovascular devices. Recently, it has been experimentally demonstrated that localized changes in the blood shear rate -i.e. shear gradients-play a critical role in thrombogenesis. The goal of the present work is to develop a predictive computational model of platelet plug formation that can be used to assess the thrombotic burden of cardiovascular devices, introducing for the first time the role of shear gradients. We have developed a comprehensive model of platelet-mediated thrombogenesis which includes platelet transport in the blood flow, platelet activation and aggregation induced by both biochemical and mechanical factors, kinetics and mechanics of platelet adhesion, and changes in the local fluid dynamics due to the thrombus growth.MethodsA 2D computational model was developed using the multi-physics finite element solver COMSOL 5.6. The model can be described by a coupled set of convection-diffusion-reaction equations. Platelet adhesion at the surface was modeled via flux boundary conditions. Using a moving mesh for the surface, thrombus growth and consequent alterations in blood flow were modeled. In the case of a stenosis, the notions of shear stress induced platelet activation in the contraction zone and shear gradients induced platelet deposition in the expansion zone downstream of the stenosis were studied.ResultsThe model provides the spatial and temporal evolution of platelet plug in the flow field. The computed platelet plug size evolution was validated against literature data. The results confirm the importance of considering both mechanical and chemical aggregation of platelets.ConclusionsThe developed model represents a potentially useful tool for the optimization of the design of the cardiovascular device flow path.
The Ontology of Biological Attributes (OBA) - Computational Traits for the Life Sciences
Authors: Stefancsik Ray , Balhoff James P. , Balk Meghan A. , Ball Robyn , Bello Susan M. , Caron Anita R. , Chessler Elissa , de Souza Vinicius , Gehrke Sarah , Haendel Melissa , Harris Laura W. , Harris Nomi L. , Ibrahim Arwa , Koehler Sebastian , Matentzoglu Nicolas , McMurry Julie A. , Mungall Christopher J. , Munoz-Torres Monica C. , Putman Tim , Robinson Peter , Smedley Damian , Sollis Elliot , Thessen Anne E , Vasilevsky Nicole , Walton David O. , Osumi-Sutherland David 
Published: January 2023

AbstractExisting phenotype ontologies were originally developed to represent phenotypes that manifest as a character state in relation to a wild-type or other reference. However, these do not include the phenotypic trait or attribute categories required for the annotation of genome-wide association studies (GWAS), Quantitative Trait Loci (QTL) mappings or any population-focused measurable trait data. Moreover, variations in gene expression in response to environmental disturbances even without any genetic alterations can also be associated with particular biological attributes. The integration of trait and biological attribute information with an ever increasing body of chemical, environmental and biological data greatly facilitates computational analyses and it is also highly relevant to biomedical and clinical applications.The Ontology of Biological Attributes (OBA) is a formalised, species-independent collection of interoperable phenotypic trait categories that is intended to fulfil a data integration role. OBA is a standardised representational framework for observable attributes that are characteristics of biological entities, organisms, or parts of organisms. OBA has a modular design which provides several benefits for users and data integrators, including an automated and meaningful classification of trait terms computed on the basis of logical inferences drawn from domain-specific ontologies for cells, anatomical and other relevant entities. The logical axioms in OBA also provide a previously missing bridge that can computationally link Mendelian phenotypes with GWAS and quantitative traits. The term components in OBA provide semantic links and enable knowledge and data integration across specialised research community boundaries, thereby breaking silos.
How PTEN mutations degrade function at the membrane and life expectancy of carriers of mutations in the human brain
Authors: Jang Hyunbum , Chen Jiaye , Iakoucheva Lilia M , Nussinov Ruth 
Published: January 2023

AbstractPTEN dysfunction, caused by loss of lipid phosphatase activity or deletion, promotes pathologies, cancer, benign tumors, and neurodevelopmental disorders (NDDs). Despite efforts, exactly how the mutations trigger distinct phenotypic outcomes, cancer or NDD, has been puzzling. It has also been unclear how to distinguish between mutations harbored by isoforms, are they cancer or NDDs-related. Here we address both. We demonstrate that PTEN mutations differentially allosterically bias P-loop dynamics and its connection to the catalytic site, affecting catalytic activity. NDD-related mutations are likely to sample conformations present in the wild-type, while sampled conformations sheltering cancer-related hotspots favor catalysis-prone conformations, suggesting that NDD mutations are weaker. Analysis of isoform expression data indicates that if the transcript has NDD-related mutations, alone or in combination with cancer hotspots, there is high prenatal expression. If no mutations within the measured days, low expression levels. Cancer mutations promote stronger signaling and cell proliferation; NDDs’ are weaker, influencing brain cell differentiation. Further, exon 5 is impacted by NDD or non-NDD mutations, while exon 7 is exclusively impacted by NDD mutations. Our comprehensive conformational and genomic analysis helps discover how same allele mutations can foster different clinical manifestations and uncovers correlations of splicing isoform expression to life expectancy.
Analysis of NIH K99/R00 Awards and the Career Progression of Awardees
Authors: Woitowich Nicole C , Hengel Sarah R , Solis Christopher , Vilgalys Tauras P , Babdor Joel , Tyrrell Daniel J 
Published: January 2023

AbstractMany postdoctoral fellows and scholars who hope to secure tenure-track faculty positions in the United States apply to the National Institutes of Health (NIH) for a Pathway to Independence Award. This award has two phases (K99 and R00) and provides funding for up to five years. Using NIH data for the period 2006-2022, we report that ∼230 K99 awards were made every year, representing up to ∼$250 million annual investment. About 40% of K99 awardees were women and ∼89% of K99 awardees went on to receive an R00 award annually. Institutions with the most NIH funding produced the most recipients of K99 awards and recruited the most recipients of R00 awards. The time between a researcher starting an R00 award and receiving a major NIH award (such as an R01) ranged between 4.6 and 7.4 years, and was significantly longer for women, for those who remained at their home institution, and for those hired by an institution that was not one of the 25 institutions with the most NIH funding. Shockingly, there has yet to be a K99 awardee at a historically Black college or university. We go on to show how K99 awardees flow to faculty positions, and to identify various factors that influence the future success of individual researchers and, therefore, also influence the composition of biomedical faculty at universities in the US.
Loss of the endocytic tumor suppressor HD-PTP phenocopies LKB1 and promotes RAS-driven oncogenesis
Authors: Seong Chang-Soo , Huang Chunzi , Boese Austin C. , Hou Yuning , Koo Junghui , Mouw Janna K. , Rupji Manali , Joseph Greg , Johnston H. Richard , Claussen Henry , Switchenko Jeffrey M. , Behera Madhusmita , Churchman Michelle , Kolesar Jill M. , Arnold Susanne M. , Kerrigan Katie , Akerley Wallace , Colman Howard , Johns Margaret A. , Arciero Cletus , Zhou Wei , Marcus Adam I. , Ramalingam Suresh S. , Fu Haian , Gilbert-Ross Melissa 
Published: January 2023

Abstract/SummaryOncogenic RAS mutations drive aggressive cancers that are difficult to treat in the clinic, and while direct inhibition of the most common KRAS variant in lung adenocarcinoma (G12C) is undergoing clinical evaluation, a wide spectrum of oncogenic RAS variants together make up a large percentage of untargetable lung and GI cancers. Here we report that loss-of-function alterations (mutations and deep deletions) in the gene that encodes HD-PTP (PTPN23) occur in up to 14% of lung cancers in the ORIEN Avatar lung cancer cohort, associate with adenosquamous histology, and occur alongside an altered spectrum of KRAS alleles. Furthermore, we show that in publicly available early-stage NSCLC studies loss of HD-PTP is mutually exclusive with loss of LKB1, which suggests they restrict a common oncogenic pathway in early lung tumorigenesis. In support of this, knockdown of HD-PTP in RAS-transformed lung cancer cells is sufficient to promote FAK-dependent invasion. Lastly, knockdown of the Drosophila homolog of HD-PTP (dHD-PTP/Myopic) synergizes to promote RAS-dependent neoplastic progression. Our findings highlight a novel tumor suppressor that can restrict RAS-driven lung cancer oncogenesis and identify a targetable pathway for personalized therapeutic approaches for adenosquamous lung cancer.
Understanding Painful versus Non-Painful Dental Pain in Male and Female Patients: A Transcriptomic Analysis of Human Biopsies
Authors: Patel Biraj , Eskander Michael Andrew , Fang-Mei Chang , Chapa Brett , Shivani Ruparel , Lai Zhao , Chen Yidong , Armen Akopian , Ruparel Nikita B. 
Published: January 2023

AbstractDental pain from apical periodontitis is an infection induced-orofacial pain condition that presents with diversity in pain phenotypes among patients. While 60% of patients with a full-blown disease present with the hallmark symptom of mechanical allodynia, nearly 40% of patients experience no pain. Furthermore, a sexual dichotomy exists, with females exhibiting lower mechanical thresholds under basal and diseased states. Finally, the prevalence of post-treatment pain refractory to commonly used analgesics ranges from 7-19% (~2 million patients), which warrants a thorough investigation of the cellular changes occurring in different patient cohorts. We, therefore, conducted a transcriptomic assessment of periapical biopsies (peripheral diseased tissue) from patients with persistent apical periodontitis. Surgical biopsies from symptomatic male (SM), asymptomatic male (AM), symptomatic female (SF), and asymptomatic female (AF) patients were collected and processed for bulk RNA sequencing. Using strict selection criteria, our study found several unique differentially regulated genes (DEGs) between symptomatic and asymptomatic patients, as well as novel candidate genes between sexes within the same pain group. Specifically, we found the role of cells of the innate and adaptive immune system in mediating nociception in symptomatic patients and the role of genes involved in tissue homeostasis in potentially inhibiting nociception in asymptomatic patients. Furthermore, sex-related differences appear to be tightly regulated by macrophage activity, its secretome, and/or migration. Collectively, we present, for the first time, a comprehensive assessment of peripherally diseased human tissue after a microbial insult and shed important insights into the regulation of the trigeminal system in female and male patients.SummaryClinical diversity paves the way for translational research. We conducted a comprehensive transcriptomic assessment of peripherally diseased human tissue from patients with apical periodontitis to understand better clinical diversity observed in pain phenotypes between patients as well as perform in-depth analyses of sex-related dimorphism in patients with apical periodontitis.
TRPV1 Opening is Stabilized Equally by Its Four Subunits
Authors: Li Shisheng , Nguyen Phuong Tran , Vu Simon , Yarov-Yarovoy Vladimir , Zheng Jie 
Published: January 2023

AbstractCapsaicin receptor TRPV1 is a nociceptor for vanilloid molecules such as capsaicin and resiniferatoxin (RTX). Even though cryo-EM structures of TRPV1 in complex with these molecules are available, how their binding energetically favors the open conformation is not known. Here we report an approach to control the number of bound RTX molecules (0-to-4) in functional mouse TRPV1. The approach allowed direct measurements of each of the intermediate open states under equilibrium conditions at both macroscopic and single-molecule levels. We found that RTX binding to each of the four subunits contributes virtually the same activation energy, which we estimated to be 1.86 kcal/mol and found to arise predominately from destabilizing the closed conformation. We further showed that sequential bindings of RTX increase open probability without altering single-channel conductance, confirming that there is likely a single open-pore conformation for TRPV1 activated by RTX.
Molecular mechanisms of coronary artery disease risk at thePDGFDlocus
Authors: Kim Hyun-Jung , Cheng Paul , Travisano Stanislao , Weldy Chad , Monteiro João P. , Kundu Ramendra , Nguyen Trieu , Sharma Disha , Shi Huitong , Lin Yi , Liu Boxiang , Haldar Saptarsi , Jackson Simon , Quertermous Thomas 
Published: January 2023

AbstractPlatelet derived growth factor (PDGF) signaling has been extensively studied in the context of vascular disease, but the genetics of this pathway remain to be established. Genome wide association studies (GWAS) for coronary artery disease (CAD) have identified a risk locus at 11q22.3, and we have verified with fine mapping approaches that the regulatory variant rs2019090 andPDGFDrepresent the functional variant and putative functional gene. Further, FOXC1/C2 transcription factor (TF) binding at rs2019090 was found to promotePDGFDtranscription through the CAD promoting allele. Employing a constitutivePdgfdknockout allele along with SMC lineage tracing in a male atherosclerosis mouse model we mapped single cell transcriptomic, cell state, and lesion anatomical changes associated with gene loss. These studies revealed that Pdgfd promotes expansion, migration, and transition of SMC lineage cells to the chondromyocyte phenotype and vascular calcification. This is in contrast to protective CAD genesTCF21,ZEB2, andSMAD3which we have shown to promote the fibroblast-like cell transition or perturb the pattern or extent of transition to the chondromyocyte phenotype. Further,Pdgfdexpressing fibroblasts and pericytes exhibited greater expression of chemokines and leukocyte adhesion molecules, consistent with observed increased macrophage recruitment to the plaque. Despite these changes there was no effect ofPdgfddeletion on SMC contribution to the fibrous cap or overall lesion burden. These findings suggest thatPDGFDmediates CAD risk through promoting SMC expansion and migration, in conjunction with deleterious phenotypic changes, and through promoting an inflammatory response that is primarily focused in the adventitia where it contributes to leukocyte trafficking to the diseased vessel wall.
Glutathionylation of Pyruvate Dehydrogenase Complex E2 and Inflammatory Cytokine Production During Acute Inflammation Are Magnified By Mitochondrial Oxidative Stress
Authors: Long David L. , McCall Charles E. , Poole Leslie B. 
Published: January 2023

ABSTRACTLipopolysaccharide (LPS) is a known inducer of inflammatory signaling which triggers generation of reactive oxygen species (ROS) and cell death in responsive cells like THP-1 promonocytes and freshly isolated human monocytes. A key LPS-responsive metabolic pivot point is the 9 megadalton mitochondrial pyruvate dehydrogenase complex (PDC), which provides pyruvate dehydrogenase (E1), lipoamide-linked transacetylase (E2) and lipoamide dehydrogenase (E3) activities to produce acetyl-CoA from pyruvate. While phosphorylation-dependent decreases in PDC activity following LPS treatment or sepsis have been deeply investigated, redox-linked processes have received less attention. Data presented here demonstrate that LPS-induced reversible oxidation within PDC occurs in PDCE2 in both THP-1 cells and primary human monocytes. Knockout of PDCE2 by CRISPR and expression of FLAG-tagged PDCE2 in THP-1 cells demonstrated that LPS-induced glutathionylation is associated with wild type PDCE2 but not mutant protein lacking the lipoamide-linking lysine residues. Moreover, the mitochondrially-targeted electrophile MitoCDNB, which impairs both glutathione-and thioredoxin-based reductase systems, elevates ROS similar to LPS but does not cause PDCE2 glutathionylation. However, LPS and MitoCDNB together are highly synergistic for PDCE2 glutathionylation, ROS production, and cell death. Surprisingly, the two treatments together had differential effects on cytokine production; pro-inflammatory IL-1β production was enhanced by the co-treatment, while IL-10, an important anti-inflammatory cytokine, dropped precipitously compared to LPS treatment alone. This new information may expand opportunities to understand and modulate PDC redox status and activity and improve the outcomes of pathological inflammation.HighlightsPDCE2 is glutathionylated (-SSG) during acute inflammation in monocytesLipopolysaccharide-induced PDCE2-SSG occurs in THP1 cells and human monocytes.Lipoamide-deficient PDCE2 lowers LPS-induced PDCE2-SSG and ROS production.MitoCDNB leads to ROS production without PDCE2-SSG, but is synergistic with LPSMitoCDNB causes the LPS-stimulated cytokine profile to become more proinflammatoryGraphical Abstract
Phenotypically Complex Living Materials Containing Engineered Cyanobacteria
Authors: Datta Debika , Weiss Elliot L. , Wangpraseurt Daniel , Hild Erica , Chen Shaochen , Golden James W. , Golden Susan S. , Pokorski Jonathan K. 
Published: January 2023

SummaryA cyanobacterial photosynthetic biocomposite material was fabricated using 3D-printing and bioengineered to produce multiple functional outputs in response to an external chemical stimulus. Our investigations show the advantages of utilizing additive manufacturing techniques in controlling the design and shape of the fabricated materials, which proved to be important for the support and growth of obligate phototrophic microorganisms within the material. As an initial proof-of-concept, a synthetic theophylline-responsive riboswitch inSynechococcus elongatusPCC 7942 was used for regulating the expression of a yellow fluorescent protein (YFP) reporter. Upon induction with theophylline, the encapsulated cells produced YFP within the hydrogel matrix. Subsequently, a strain ofS. elongatuswas engineered to produce an oxidative enzyme that is useful for bioremediation, laccase, expressed either constitutively or under the control of the riboswitch. The responsive biomaterial can decolorize a common textile dye pollutant, indigo carmine, potentially serving as a useful tool in environmental bioremediation. Finally, cells were engineered to have the capacity for inducible cell death to eliminate their presence once their activity is no longer required, which is an important function for biocontainment and minimizing unintended environmental impact. By integrating genetically engineered stimuli-responsive cyanobacteria in patterned volumetric 3D-printed designs, we demonstrate the potential of programmable photosynthetic biocomposite materials capable of producing functional outputs including, but not limited to, bioremediation.