bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic alterations in gene co-expression networks and gene-transcript associations characterize co-morbidities in cocaine use disorder
Authors: Nwaneshiudu Chinwe , Girdhar Kiran , Kleopoulos Steven P. , Fullard John F. , Butelman Eduardo R. , Parvaz Muhammad A. , Goldstein Rita Z. , Alia-Klein Nelly , Roussos Panos 
Published: July 2024

AbstractBackgroundIndividuals with cocaine use disorder (CUD) who attempt abstinence experience craving and relapse, which poses challenges in treatment. Longitudinal studies linking behavioral manifestations in CUD to the blood transcriptome in living individuals are limited. Therefore, we investigated the connection between drug use behaviors during abstinence with blood transcriptomics.MethodsWe conducted a comprehensive longitudinal study involving 12 subjects (9 males, 3 females) with CUD and RNA sequencing on blood collected at a drug-free baseline, and 3, 6 & 9 months thereafter. We categorized subjects into 2 responder groups (high-low) based on scores of drug use variables, and 3 responder groups (low-intermediate-high) on days of abstinence. We investigated differential expression and gene-transcript associations across responder groups at each time point. Lastly, we examined genes that are both co-expressed and showed dynamic expression with time.ResultsGenes with significant transcript associations between high and. intermediate days of abstinence at 9 months were notably enriched for cannabis use disorder, drinks weekly, and coronary artery disease risk genes. Time-specific gene co-expression analysis prioritized transcripts related to immune processes, cell cycle, RNA-protein synthesis, and second messenger signaling for days of abstinence.ConclusionWe demonstrate that abstinence reflects robust changes in drug use behaviors and the blood transcriptome in CUD. We also highlight the importance of longitudinal studies to capture complex biological processes during abstinence in CUD.
A long non-coding RNA LINC00094 regulates the transcriptional expression of lipid metabolism-related genes as a new member of core regulatory circuitry in esophageal squamous cell carcinoma
Authors: Peng Liu , Wang Qiu-Yu , Chen Jia-Xin , Chen Yang , Li Rong-Yao , Liao Lian-Di , Lin Wan , Li Chun-Quan , Li En-Min , Xu Li-Yan 
Published: July 2024

AbstractLINC00094 as a new supper-enhancer (SE)-related long non-coding RNA is associated with poor overall survival of patients with esophageal squamous cell carcinoma (ESCC). However, the transcriptional regulatory mechanism of LINC00094 and the molecular mechanisms by which LINC00094 affects the phenotype of ESCC remains unclear. Here, we found that LINC00094 promoted the proliferation of ESCC cells both in vitro and in vivo. LINC00094 knockdown significantly reduced the expression profiles of transcription activators including transcription factor 3 (TCF3) and Kruppel like factor 5 (KLF5) and lipid metabolism-related genes. Mechanically, TCF3 and KLF5 formed a core regulatory circuitry (CRC) that bound to the SEs of LINC00094 and to their own SEs to regulate the transcriptional expression in a positive feedback loop. LINC00094 recruited TCF3 and KLF5 to form a ternary complex, which forms a new CRC with TCF3 and KLF5 that regulated its own transcription as well as lipid metabolism-related genes. Knockdown of any or all three genes inhibited the expression of genes related to lipid synthesis and consistently reduced total lipid droplet levels. Treatment with SEs inhibitors (THZ1 and JQ1) effectively inhibited the formation of this CRC and the production of lipid droplets in ESCC cells. The high-risk group of CRC-associated signatures were closely associated with poor prognosis in patients with ESCC. Our findings suggest that LINC00094 is involved in the CRC by forming a complex with TCF3 and KLF5, and this regulation model can affect the phenotype of ESCC cells by controlling the expression of lipid metabolism-related genes.HighlightsWe identified a novel functional lncRNA-LINC00094 for esophageal squamous cell carcinoma.LINC00094 forms a complex with the core transcription factors TCF3 and KLF5, thereby forming a core regulatory circuitry to participate in transcriptional regulation in ESCC.A core regulatory circuitry mediated by LINC00094 regulates lipid metabolism in ESCC.
CryoJAM: Automating Protein Homolog Fitting in Medium Resolution Cryo-EM Density Maps
Authors: Carrion Jackson , Manjrekar Mrunali , Mikulevica Anna 
Published: July 2024

AbstractObtaining atomic structures of large protein complexes from medium-resolution cryogenic electron-microscopy (cryo-EM) density maps is a critical bottleneck in the cryo-EM workflow. CryoJAM aims to automate this process by using a 3D Convolutional Neural Network model within a U-Net architecture. This model is trained on a novel loss function that leverages Fourier-Shell Correlation (FSC), as a proxy for quality of fit, and Root Mean Squared Error (RMSE) to help optimize fits within real space. Capitalizing on the gold-standard status of FSC in cryo-EM, this method introduces an innovative implementation of FSC into cryo-EM model fitting software, enhancing the precision and efficiency of structural analysis. After 25 epochs, CryoJAM successfully reduced the RMSE in 21 out of 26 of the test cases, effectively fitting homologous protein structures into medium-resolution cryo-EM densities.
Contrasting Kinetics of Highly Similar Chloroalkane Reductive Dehalogenases
Authors: Picott Katherine J. , Edwards Elizabeth A. 
Published: July 2024

ABSTRACTChloroform and trichloroethanes are pervasive groundwater contaminants for which bioremediation has been an effective treatment strategy. Reductive dehalogenase (RDase) enzymes from organohalide-respiring bacteria are essential for their remediation under anaerobic conditions. RDases are responsible for dehalogenating these chlorinated solvents, leading to their removal. This work explores the kinetic characteristics of three closely relatedDehalobacterchloroalkane-reductases—TmrA, CfrA, and AcdA—and identifies differences between their activity on chloroform (CF), 1,1,1-trichloroethane (TCA), and 1,1,2-TCA. The side-by-side comparison of these enzymes has emphasized that TmrA and AcdA are specialized toward CF with both having 4-fold higher maximum specific activity (Vmax) on CF than 1,1,1-TCA, whereas, CfrA has very similar rates on both CF and 1,1,1-TCA. AcdA is the most sensitive to substrate inhibition by CF and 1,1,2-TCA, and inhibition by a common co-contaminant trichloroethene. Finally, the reduction of 1,1,2-TCA, which can produce both 1,2-dichloroethane and vinyl chloride, was assessed for each enzyme. Interestingly, each enzyme has a distinct preference for the major product it produces, indicating a favoured reaction pathway. Despite over 95% sequence identity, TmrA, CfrA, and AcdA exhibit substantial differences in kinetic behaviour, highlighting the importance of understanding such nuances for informed bioremediation strategies.SYNOPSISThree similar dechlorinating enzymes were found to have distinct reaction rates and levels of sensitivity to inhibition. These differences have implications for the enzymes’ use in bioremediation.
Proteostasis Landscapes of Cystic Fibrosis Variants Reveals Drug Response Vulnerability
Authors: McDonald Eli Fritz , Kim Minsoo , Olson John A. , Meiler Jens , Plate Lars 
Published: July 2024

ABSTRACTCystic Fibrosis (CF) is a lethal genetic disorder caused by variants in CF transmembrane conductance regulator (CFTR). Many variants are treatable with correctors, which enhance the folding and trafficking of CFTR. However, approximately 3% of persons with CF harbor poorly responsive variants. Here, we used affinity purification mass spectrometry proteomics to profile the protein homeostasis (proteostasis) changes of CFTR variants during correction to assess modulated interactions with protein folding and maturation pathways. Responsive variant interactions converged on similar proteostasis pathways during correction. In contrast, poorly responsive variants subtly diverged, revealing a partial restoration of protein quality control surveillance and partial correction. Computational structural modeling showed that corrector VX-445 failed to confer enough NBD1 stability to poor responders. NBD1 secondary stabilizing mutations rescued poorly responsive variants, revealing structural vulnerabilities in NBD1 required for treating poor responders. Our study provides a framework for discerning the underlying protein quality control and structural defects of CFTR variants not reached with existing drugs to expand therapeutics to all susceptible CFTR variants.SIGNIFICANCE STATEMENTCystic Fibrosis (CF) is a lethal genetic disease with variants leading to misfolding of an anion channel protein. Enhancing productive channel folding using a novel class of small molecules calledcorrectorshas emerged as the current CF treatment paradigm. However, correctors fail to reach all patient variants. Using high throughput interactomics, Rosetta simulations, and biochemical trafficking assays, this study demonstrates poorly responsive CF variants experience diverse misfolding pathways caused by structural defects in the core of a nucleotide-binding domain. Stabilizing secondary mutations in this domain rescues poorly responsive variants, paving the way for mechanistic-based therapeutic development for untreatable CF variants and future protein misfolding corrector drugs.COMPETING INTERESTSThe authors declare no competing interests.
GeneticSNUPNvariants cause spinocerebellar atrophy by disrupting global splicing in Purkinje cells
Authors: Okubo Mariko , Ogawa Megumu , Eura Nobuyuki , Inoue Yukiko U. , Dewa Ken-ichi , Owa Tomohiro , Miyashita Satoshi , Murakami Terumi , Nakamura Hisayoshi , Hayashi Shinichiro , Nonaka Ikuya , Ogata Katsuhisa , Hoshino Mikio , Inoue Takayoshi , Nishino Ichizo , Noguchi Satoru 
Published: July 2024

AbstractWe identified genetic variants in theSNUPNgene, which encodes the adapter protein snurportin-1 for the nuclear import of U1 snRNPs, in two families affected by spinocerebellar ataxia. We have elucidated the pathogenicity of these variants and the molecular pathomechanisms underlying this disease by assessing mutant snurportin-1 propertiesin vitro, cerebella at the morphological and molecular levelsex vivo, and motor functions inSnupn-variant knocked-in micein vivo. Mutant snurportin-1 impaired nuclear-cytosol shuttling, leading to defective nuclear transport of U1 snRNPs in cerebellar Purkinje cells. This resulted in aberrant splicing and expression of genes essential for Purkinje cell development and impaired dendrite formation. The malformation of Purkinje cell dendrites resulted in hypoplasia and premature migration of granule cell precursors and interneurons, leading to abnormal lobe development and atrophy in the cerebellum.
Multimodal and Quantitative Analysis of the Epileptogenic Zone in the Pre-Surgical Evaluation of Drug-Resistant Focal Epilepsy
Authors: Karimi-Rouzbahani Hamid , Vogrin Simon , Cao Miao , Plummer Chris , McGonigal Aileen 
Published: July 2024

AbstractSurgical resection for epilepsy often fails due to incomplete Epileptogenic Zone (EZ) localization from standard electroencephalography (EEG), stereo-EEG (SEEG), and Magnetic Resonance Imaging (MRI). Subjective interpretation based on interictal, or ictal recordings limits conventional EZ localization. This study employs multimodal analysis using high-density-EEG (HDEEG), Magnetoencephalography (MEG), functional-MRI (fMRI), and SEEG to overcome these limitations in a patient with drug-resistant MRI-negative focal epilepsy. A teenage boy with drug-resistant epilepsy underwent evaluation. HDEEG, MEG, fMRI, and SEEG were used, with a novel HDEEG-cap facilitating simultaneous EEG-MEG and EEG-fMRI recordings. Electrical and magnetic source imaging were performed, and fMRI data were analysed for homogenous regions. SEEG analysis involved spike detection, spike timing analysis, ictal fast activity quantification, and Granger-based connectivity analysis. Non-invasive sessions revealed consistent interictal source imaging results identifying the EZ in the right anterior cingulate cortex. EEG-fMRI highlighted broader activation in the right cingulate cortex. SEEG analysis localized spikes and fast activity in the right anterior and posterior cingulate gyri. Multi-modal analysis suggested the EZ in the right frontal lobe, primarily involving the anterior and mid-cingulate cortices. Multi-modal non-invasive analyses can optimise SEEG implantation and surgical decision-making. Invasive analyses corroborated non-invasive findings, emphasising the importance of individual-case quantitative analysis across modalities in complex epilepsy cases.
Even A Worm Will Turn: Appendicitis Malpractice Litigation Since 2020
Authors: Menshawey Rahma , Menshawey Esraa 
Published: July 2024

AbstractBackgroundAppendicitis is the inflammation of the vermiform appendix, and it is the most common abdominal surgical emergency in the world. Its diagnosis, however, has many pitfalls including lack of a pathognomonic sign or symptoms, and the low predictive value of laboratory testing. Appendicitis is a leading cause of malpractice concerns.MethodsUsing Google Case Law, we used the search terms “appendicitis”, and “malpractice” to identify appendicitis litigation cases. We included cases published since 2020. We included any case where a confirmed diagnosis of appendicitis was made. We included cases filed for malpractice due to complications of appendicitis and its treatment. Outcomes of interest included: the state the case was published, the defendants, the date of when the patient first complained of abdominal pain to when they had had an appendectomy/treatment, diagnostics and consultations, medical and legal issues, and final verdict/opinion/decisions on the cases.ResultsA total of 44 cases were identified, which were screened for inclusion. A total of 14 cases met the inclusion criteria and were analyzed. Most cases did not present in an atypical way, the majority of patients presented with clear statements of abdominal pain of varying severity. The majority of the defendants were MD’s and hospitals. The average time from symptom to diagnosis was 2.4 ±2.1 days, while the longest time for diagnosis was 7 days. The leading medico-legal issues were failure to diagnose and delayed diagnosis, while among the cases, 35.7% had outcomes in favor of the plaintiff.ConclusionsAppendicitis remains an area of high risk of litigation. Malpractice suits are often due to failure to diagnose and failure to treat, but there maybe proactive measures to address the modern pitfalls to promote a decreased litigation risk and patient safety
PodGPT: An audio-augmented large language model for research and education
Authors: Jia Shuyue , Bit Subhrangshu , Searls Edward , Lauber Meagan V. , Claus Lindsey A. , Fan Pengrui , Jasodanand Varuna H. , Veerapaneni Divya , Wang William M. , Au Rhoda , Kolachalama Vijaya B. 
Published: July 2024

AbstractThe proliferation of scientific podcasts has generated an extensive repository of audio content, rich in specialized terminology, diverse topics, and expert dialogues. Here, we introduce a computational framework designed to enhance large language models (LLMs) by leveraging this informational content from publicly accessible podcast data across science, technology, engineering, mathematics and medical (STEMM) disciplines. This dataset, comprising over 3, 700 hours of audio content, was transcribed to generate over 42 million text tokens. Our model, PodGPT, integrates this wealth of complex dialogue found in audio podcasts to improve understanding of natural language nuances, cultural contexts, as well as scientific and medical knowledge. PodGPT also employs retrieval augmented generation (RAG) on a vector database built from articles in Creative Commons PubMed Central andThe New England Journal of Medicine, enhancing STEMM research and education by providing real-time access to emerging scientific literature. Evaluated across multiple benchmarks, PodGPT demonstrated an average improvement of 3.51 percentage points over standard open-source benchmarks and 3.81 percentage points when augmented with evidence from the RAG pipeline. Moreover, it showcased an average improvement of 4.06 percentage points in its zero-shot multi-lingual transfer ability, effectively generalizing to different linguistic contexts. By harnessing the untapped potential of podcast content, PodGPT advances natural language processing and conversational AI, offering enhanced capabilities for STEMM research and education.
Screening and treatment time in school-based caries prevention: A randomized clinical trial
Authors: Godín Tamarinda J. Barry , Hawthorne Gabriel , Shah Radhika , Ruff Ryan Richard 
Published: July 2024

AbstractBackgroundSchool-based caries prevention can increase access to dental services for underrepresented children and reduce the risk of tooth decay.MethodsThe CariedAway study was a longitudinal pragmatic randomized trial of silver diamine fluoride (SDF), fluoride varnish, dental sealants, and atraumatic restorations (ART) provided as part of a school caries prevention program. Using electronic health record software and reproducible procedures, we estimated the total time required to screen and treat program participants. Differences at initial treatment between interventions, provider (registered nurse and dental hygienist), dentition mix, and caries burden were determined using linear regression with cluster standard error estimation, and longitudinal effects were estimated using linear mixed effects models.ResultsA total of 7418 children were enrolled in the CariedAway trial, of which 7176 (97%) had viable data recorded for screening and treatment time. Overall treatment time for children receiving SDF and fluoride varnish was 283 seconds (SD=739), compared to 753 seconds (SD=2166) for children receiving dental sealants and ART. At the initial program visit, treatment time using SDF was significantly shorter than sealants and ART (B = −458.8, 95% CI = −650.1, −266.8) and treatment time decreased with each subsequent observation (B = −51.9, 95% CI = −68.4, −35.4). Treatment time significantly increased as the number of carious teeth per child increased, and there were no differences in treatment time using SDF between registered nurses and dental hygienists.ConclusionsThe sustainability of school-based caries prevention can be supported by robust data on program logistics and treatment time. These results can be leveraged by future school-based sealant and SDF programs to estimate the total reach and effectiveness of intended treatments.
Bacterial Protein Signatures Identified inPorphyromonas gingivalisContaining-Autophagic Vacuoles Reveal Co-Evolution Between Oral Red/Orange Complex Bacteria and Gut Bacteria
Authors: Paul Ayana , Wellslager Bridgette , Williamson Maddie , Yilmaz Özlem 
Published: July 2024

AbstractModern oral bacterial species present as a concoction of commensal and opportunistic pathogens originating from their evolution in humans. Due to the intricate colonization mechanisms shared amongst oral and gut bacteria, these bacteria have likely evolved together to establish and adapt in the human oro-digestive tract, resulting in the transfer of genetic information. Our liquid chromatography-with-tandem-mass-spectrometry (LC-MS-MS) analyses have revealed protein signatures, Elongation Factor Tu, RagB/SusD nutrient uptake outer membrane protein and DnaK, specifically fromPorphyromonas gingivalis-containing autophagic vacuoles isolated from the infected human primary gingival epithelial cells. Interestingly, our Mass-Spectrometry analysis reported similar proteins from closely related oral bacteria,Tannerella forsythiaandPrevotella intermedia. In our phylogenetic study of these key protein signatures, we have established that pathogenic oral bacteria share extensive relatedness to each other and gut resident bacteria. We show that in the virulence factors identified from gut bacteria, Elongation Factor Tu and DnaK, there are several structural similarities and conservations with proteins from oral pathogenic bacteria. There are also major similarities in the RagB/SusD proteins of oral bacteria to prominent gut bacteria. These findings not only highlight the shared virulence mechanisms amongst oral bacterial pathogens/pathobionts but also gut bacteria and elucidate their co-evolutions in the human host.
Systematic characterization of indel variants using a yeast-based protein folding sensor
Authors: Larsen-Ledet Sven , Lindemose Søren , Panfilova Aleksandra , Gersing Sarah , Suhr Caroline H. , Genzor Aitana Victoria , Lanters Heleen , Nielsen Sofie V. , Lindorff-Larsen Kresten , Winther Jakob R. , Stein Amelie , Hartmann-Petersen Rasmus 
Published: July 2024

AbstractGene variants resulting in insertions or deletions of amino acid residues (indels) have important consequences for evolution and are often linked to disease, yet compared to missense variants the effects of indels are poorly understood and predicted. To approach this issue, we developed a sensitive protein folding sensor based on complementation of uracil auxotrophy in yeast by circular permutated orotate phosphoribosyltransferase (CPOP). The sensor accurately reports on the folding of disease-linked missense variants andde novodesigned proteins. Applying the folding sensor to a saturated library of single amino acid indel variants in human DHFR revealed that most regions which tolerate indels are confined to internal loops and the N- and C-termini. Surprisingly, indels are also allowed at a central α-helix. Several indels are temperature-sensitive and the folding of most of these indels is rescued upon binding to the competitive DHFR inhibitor methotrexate. Rosetta and AlphaFold2 predictions correlate with the observed effects, suggesting that most indels operate by destabilizing the native fold and that these computational tools may be useful for classification of indels observed in population sequencing.