bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for multiscale multiplexed representation of visual features in EEG
Authors: Karimi-Rouzbahani Hamid 
Published: July 2023

AbstractDistinct neural processes are often encoded across distinct time scales of neural activations. However, it has remained unclear if this multiscale coding strategy is also implemented for separate features of the same process. One difficulty is that the conventional methods of time scale analysis provide imperfect estimations of time scales when several components are active during a single process. Developing a novel decoding-based time scale estimation method, we detected distinct time scales for simultaneously present features of visual stimuli in electroencephalography. We observed that orientation and colour of grating stimuli were encoded in shorter whereas the spatial frequency and contrast of those stimuli were encoded in longer time scales. The conventional autocorrelation-based estimation of time scale was unable to detect these distinguishable time scales. These results provide new evidence for a multiscale multiplexed neural code in the human visual system and introduces a flexible method for estimating neural time scales.
Structural, Social, and Contextual factors influencing COVID-19 vaccine uptake: A qualitative methods study among Healthcare Workers and Older People in Uganda
Authors: Slivesteri Sande , Ssali Agnes , Bahemuka Ubaldo M , Nsubuga Denis , Muwanga Moses , Nsereko Chris , Ssemwanga Edward , Robert Asaba , Seeley Janet , Elliott Alison , Ruzagira Eugene 
Published: July 2023

AbstractBackgroundThe COVID-19 vaccine rollout program in Uganda was launched in March 2021 with Healthcare Workers (HCWs), older persons (≥50 years), and persons with chronic conditions as priority groups for vaccination. To inform the vaccine rollout efforts, we set out to explore the social and structural factors that influenced the uptake of COVID-19 vaccines among HCWs and older people in Uganda.MethodsBetween September and October 2021, we conducted 33 in-depth interviews with 25 HCWs aged 21–63 years from three hospitals from two districts in the central region of Uganda and eight older people from communities in Wakiso district. Selection was purposive based on sex, occupation, education, cadre of HCWs (doctors, nurses, laboratory technologist, hospital support staff, administrator) and vaccination status. We explored participants’ knowledge, beliefs, personal experiences, barriers, and facilitators to vaccine uptake and suggestions for future COVID-19 vaccine rollout. Interviews were audio-recorded, data was transcribed and translated from the local language, coded, and analysed by themes.ResultsTwenty-two of the 25 (88%) HCWs and 3 of the 8 (38%) older people had received at least one dose of the COVID-19 vaccine at the time of interview.The structural facilitating factors to vaccine uptake included access to correct information, fear of a risky work environment, and mandatory vaccination requirements especially for frontline HCWs. Old age, chronic health conditions, and the fear of death are contextual facilitating factors, while influence from leaders was the main social facilitating factor.Myths and misconceptions about COVID-19 vaccines and the fear of side effects were common social barriers to vaccine uptake among HCWs and older people. Long distances to vaccination centres, vaccine stock-outs, and long queues at the vaccination centres were specific barriers to vaccine uptake for older people. The prerequisite of signing a consent form was a specific structural barrier for the HCWs. Transport challenges linked to long distances to the vaccination centres, for older people, and having underlying chronic health conditions, for both older people and HCWs, were the reported contextual factors.ConclusionFuture roll out of new vaccines should have a comprehensive information dissemination strategy about the vaccines. Improved access to vaccines through community outreaches, reliable vaccine supply and addressing vaccine misinformation, may enhance COVID-19 vaccine uptake in Uganda and other future mass vaccination campaigns.
Evaluating Large Language Models in Extracting Cognitive Exam Dates and Scores
Authors: Zhang Hao , Jethani Neil , Jones Simon , Genes Nicholas , Major Vincent J. , Jaffe Ian S. , Cardillo Anthony B. , Heilenbach Noah , Ali Nadia Fazal , Bonanni Luke J. , Clayburn Andrew J. , Khera Zain , Sadler Erica C. , Prasad Jaideep , Schlacter Jamie , Liu Kevin , Silva Benjamin , Montgomery Sophie , Kim Eric J. , Lester Jacob , Hill Theodore M. , Avoricani Alba , Chervonski Ethan , Davydov James , Small William , Chakravartty Eesha , Grover Himanshu , Dodson John A. , Brody Abraham A. , Aphinyanaphongs Yindalon , Masurkar Arjun , Razavian Narges 
Published: July 2023

AbstractImportanceLarge language models (LLMs) are crucial for medical tasks. Ensuring their reliability is vital to avoid false results. Our study assesses two state-of-the-art LLMs (ChatGPT and LlaMA-2) for extracting clinical information, focusing on cognitive tests like MMSE and CDR.ObjectiveEvaluate ChatGPT and LlaMA-2 performance in extracting MMSE and CDR scores, including their associated dates.MethodsOur data consisted of 135,307 clinical notes (Jan 12th, 2010 to May 24th, 2023) mentioning MMSE, CDR, or MoCA. After applying inclusion criteria 34,465 notes remained, of which 765 underwent ChatGPT (GPT-4) and LlaMA-2, and 22 experts reviewed the responses. ChatGPT successfully extracted MMSE and CDR instances with dates from 742 notes. We used 20 notes for fine-tuning and training the reviewers. The remaining 722 were assigned to reviewers, with 309 each assigned to two reviewers simultaneously. Inter-rater-agreement (Fleiss’ Kappa), precision, recall, true/false negative rates, and accuracy were calculated. Our study follows TRIPOD reporting guidelines for model validation.ResultsFor MMSE information extraction, ChatGPT (vs. LlaMA-2) achieved accuracy of 83% (vs. 66.4%), sensitivity of 89.7% (vs. 69.9%), true-negative rates of 96% (vs 60.0%), and precision of 82.7% (vs 62.2%). For CDR the results were lower overall, with accuracy of 87.1% (vs. 74.5%), sensitivity of 84.3% (vs. 39.7%), true-negative rates of 99.8% (98.4%), and precision of 48.3% (vs. 16.1%). We qualitatively evaluated the MMSE errors of ChatGPT and LlaMA-2 on double-reviewed notes. LlaMA-2 errors included 27 cases of total hallucination, 19 cases of reporting other scores instead of MMSE, 25 missed scores, and 23 cases of reporting only the wrong date. In comparison, ChatGPT’s errors included only 3 cases of total hallucination, 17 cases of wrong test reported instead of MMSE, and 19 cases of reporting a wrong date.ConclusionsIn this diagnostic/prognostic study of ChatGPT and LlaMA-2 for extracting cognitive exam dates and scores from clinical notes, ChatGPT exhibited high accuracy, with better performance compared to LlaMA-2. The use of LLMs could benefit dementia research and clinical care, by identifying eligible patients for treatments initialization or clinical trial enrollments. Rigorous evaluation of LLMs is crucial to understanding their capabilities and limitations.
Hepatitis C risk score as a tool to identify infected individuals: A demonstration study in Egypt
Authors: El-Khoury Rayane , Chemaitelly Hiam , Alaama Ahmed S. , Hermez Joumana G. , Nagelkerke Nico , Abu-Raddad Laith J. 
Published: July 2023

AbstractHepatitis C virus (HCV) infection is a global health challenge. By the end of 2021, WHO estimated that less than quarter of global HCV infections were diagnosed. There is a need for a public health tool that can facilitate identification of infected persons and linking them to testing and treatment. We derived and validated a risk score to identify infected persons in Egypt and provided a demonstration of its utility. The 2008 and 2014 Egypt Demographic and Health Surveys were used to derive two risk scores using multivariable logistic regression. Both scores showed similar dependence on sex, age, and type of place of residence. Both risk scores demonstrated high and similar areas under the curve of 0.77 (95% CI: 0.76-0.78) and 0.78 (95% CI: 0.77-0.80), respectively. For the 2008 Risk Score, sensitivity was 73.7%, specificity was 68.5%, positive predictive value (PPV) was 27.8%, and negative predictive value (NPV) was 94.1%. For the 2014 Risk Score, sensitivity was 64.0%, specificity was 78.2%, PPV was 22.2%, and NPV was 95.7%. Each score was validated by applying it to a different survey database than the one used to derive it. Implementation of HCV risk scores is an effective strategy to identify carriers of HCV infection and to link them to testing and treatment at low cost to national programs.
A curated census of pathogenic and likely pathogenic UTR variants and evaluation of deep learning models for variant effect prediction
Authors: Bohn Emma , Lau Tammy , Wagih Omar , Masud Tehmina , Merico Daniele 
Published: July 2023

AbstractVariants in 5’ and 3’ untranslated regions (UTR) contribute to rare disease. While predictive algorithms to assist in classifying pathogenicity can potentially be highly valuable, the utility of these tools is often unclear, as it depends on carefully selected training and validation conditions. To address this, we developed a high-confidence set of pathogenic (P) and likely pathogenic (LP) variants and assessed deep learning (DL) models for predicting their molecular effect. 3’ and 5’ UTR variants documented as P or LP (P/LP) were obtained from ClinVar and refined by reviewing the annotated variant effect and reassessing evidence of pathogenicity following published guidelines. Prediction scores from sequence-based DL models were compared between three groups: P/LP variants acting though the mechanism for which the model was designed (model-matched), those operating through other mechanisms (model-mismatched), and putative benign variants. PhyloP was used to compare conservation scores between P/LP and putative benign variants. 295 3’ and 188 5’ UTR variants were obtained from ClinVar, of which 26 3’ and 68 5’ UTR variants were classified as P/LP. Predictions by DL models achieved statistically-significant differences when comparing model-matched P/LP variants to both putative benign variants and model-mismatched P/LP variants, as well as when comparing all P/LP variants to putative benign variants. PhyloP conservation scores were significantly higher among P/LP compared to putative benign variants for both the 3’ and 5’ UTR. In conclusion, we present a high-confidence set of P/LP 3’ and 5’ UTR variants spanning a range of mechanisms and supported by detailed pathogenicity and molecular mechanism evidence curation. Predictions from DL models further substantiate these classifications. These datasets will support further development and validation of DL algorithms designed to predict the functional impact of variants that may be implicated in rare disease.
Drug-coated versus conventional balloons to improve recanalization of a coronary chronic total occlusion after failed attempt
Authors: Amat-Santos Ignacio J. , Marengo Giorgio , Ybarra Luiz F. , Fernández-Diaz Jose Antonio , Regueiro Ander , Gutiérrez Alejandro , Martín-Moreiras Javier , Sánchez-Luna Juan Pablo , González-Gutiérrez Jose Carlos , Fernandez-Cordon Clara , Carrasco-Moraleja Manuel , Rinfret Stéphane 
Published: July 2023

ABSTRACTBackgroundChronic total occlusion (CTO) plaque modification (CTO-PM) is often used for unsuccessful CTO interventions.MethodsMulticenter, prospective study including consecutive patients with failed CTO recanalization. At the end of the failed procedure, patients received either conventional (CB) or drug-coated balloon (DCB) or at the operator’s discretion for CTO-PM and underwent new attempt of CTO recanalization ∼3 months later.ResultsA total of 55 patients were enrolled (DCB: 22; CB 33), with a median age of 66 years. Median J-score was 3 and CCS angina class III-IV was present in 40% of the patients. After the first CTO-PCI attempt no in hospital cardiac deaths were registered, with 3.6% rates of in-hospital myocardial infarction. The success rate of the second CTP PCI attempt was 86.8%, with periprocedural complication rate of 5.7% and without difference between DCB and CB groups. Compared with CB, in the DCB group, the second CTO-PCI required a shorter median fluoroscopy time (33 vs 60min, p<0.001), lower contrast volume (170 vs 321cc, p<0.001) and lower radiation dose (1.7 vs 3.3Gy, p<0.001). At 1-year follow up outcomes were comparable between the 2 strategies, target lesion failure occurred in 5.7% and major adverse cardiovascular events in 11.2%.ConclusionsPM after CTO recanalization failure is safe and warrants high success rates when 2ndattempt is performed. A DCB strategy for CTO-PM does not seem to ensure higher success or better clinical outcomes, but its use was associated with simpler staged procedures.
The Hidden Biocatalytic Potential of the Old Yellow Enzyme Family
Authors: White David W. , Iamurri Samantha , Keshavarz-Joud Parisa , Blue Tamra , Copp Janine , Lutz Stefan 
Published: July 2023

AbstractThe rapid advancement of sequencing technology has created an immense reservoir of protein sequence-function information that has yet to be fully utilized for fundamental or biocatalytic applications. For example, ene reductases from the ‘old yellow enzyme’ (OYE) family catalyze the asymmetric hydrogenation of activated alkenes with enhanced stereoselectivity - key transformations for sustainable production of pharmaceutical and industrial synthons. Despite the proven biocatalytic application, the OYE family remains relatively underexplored with only 0.1% of identified members having any experimental characterization. Here, a platform of integrated bioinformatics and synthetic biology techniques was employed to systematically organize and screen the natural diversity of the OYE family. Using protein similarity networks, the known and unknown regions of the >115,000 members of the OYE family were broadly explored to identify phylogenetic and sequence-based trends. From this analysis, 118 novel enzymes were characterized across the family to broadly explore and expand the biocatalytic performance and substrate scope of known OYEs. Over a dozen novel enzymes were identified exhibiting enhanced catalytic activity or altered stereospecificity. Beyond well-established ene reduction, we detected widespread occurrence of oxidative chemistry amongst OYE family members at ambient conditions. Crystallography studies of selected OYEs yielded structures for two enzymes, contributing to a better understanding of their unique performance. Their structures revealed an unusual loop conformation within a novel OYE subclass. Overall, our study significantly expands the known functional and chemical diversity of OYEs while identifying superior biocatalysts for asymmetric reduction and oxidation.
The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain
Authors: van Vlimmeren Anne E. , Voleti Rashmi , Chartier Cassandra A. , Jiang Ziyuan , Karandur Deepti , Humphries Preston A. , Lo Wan-Lin , Shah Neel H. 
Published: July 2023

AbstractMutations in the tyrosine phosphatase SHP2 are associated with a variety of human diseases. Most mutations in SHP2 increase its basal catalytic activity by disrupting auto-inhibitory interactions between its phosphatase domain and N-terminal SH2 (phosphotyrosine recognition) domain. By contrast, some disease-associated mutations located in the ligand-binding pockets of the N- or C- terminal SH2 domains do not increase basal activity and likely exert their pathogenicity through alternative mechanisms. We lack a molecular understanding of how these SH2 mutations impact SHP2 structure, activity, and signaling. Here, we characterize five SHP2 SH2 domain ligand-binding pocket mutants through a combination of high-throughput biochemical screens, biophysical and biochemical measurements, and molecular dynamics simulations. We show that, while some of these mutations alter binding affinity to phosphorylation sites, the T42A mutation in the N-SH2 domain is unique in that it also substantially alters ligand-binding specificity, despite being 8-10 Å from the specificity-determining region of the SH2 domain. This mutation exerts its effect on sequence specificity by remodeling the phosphotyrosine binding pocket, altering the mode of engagement of both the phosphotyrosine and surrounding residues on the ligand. The functional consequence of this altered specificity is that the T42A mutant has biased sensitivity toward a subset of activating ligands and enhances downstream signaling. Our study highlights an example of a nuanced mechanism of action for a disease-associated mutation, characterized by a change in protein-protein interaction specificity that alters enzyme activation.Significance StatementThe protein tyrosine phosphatase SHP2 is mutated in a variety of human diseases, including several cancers and developmental disorders. Most mutations in SHP2 hyperactivate the enzyme by destabilizing its auto-inhibited state, but several disease-associated mutations do not conform to this mechanism. We show that one such mutation, T42A, alters the ligand binding specificity of the N-terminal regulatory domain of SHP2, causing the mutant phosphatase to be more readily activated by certain upstream signals than the wild-type phosphatase. Our findings reveal a novel mode of SHP2 dysregulation that will improve our understanding of pathogenic signaling. Our study also illustrates how mutations distal to the specificity-determining region of a protein can alter ligand binding specificity.
MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention
Authors: Qiu Bin , Lawan Ahmed , Xirouchaki Chrysovalantou E. , Yi Jae-Sung , Robert Marie , Zhang Lei , Brown Wendy , Fernández-Hernando Carlos , Yang Xiaoyong , Tiganis Tony , Bennett Anton M. 
Published: July 2023

ABSTRACTNonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKα) activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed mice. The focus of this work was to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreased liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed mice released nuclear LKB1 into the cytoplasm to activate AMPKα and prevent hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKα which triggers hepatocyte death and the development of NASH.
TheDrosophilaTumour Suppressor Lgl and Vap33 activate the Hippo pathway by a dual mechanism, involving RtGEF/Git/Arf79F and inhibition of the V-ATPase
Authors: Portela Marta , Mukherjee Swastik , Paul Sayantanee , La Marca John E. , Parsons Linda M. , Veraksa Alexey , Richardson Helena E. 
Published: July 2023

AbstractThe tumour suppressor, Lethal (2) giant larvae (Lgl), is an evolutionarily conserved protein that was discovered in the vinegar fly,Drosophila, where its depletion results in tissue overgrowth and loss of cell polarity and tissue architecture. Our previous studies have revealed a new role for Lgl in linking cell polarity and tissue growth through regulation of the Notch (proliferation and differentiation) and the Hippo (negative tissue growth control) signalling pathways. Moreover, Lgl regulates vesicle acidification, via the Vacuolar ATPase (V-ATPase), and we showed that Lgl inhibits V-ATPase activity through Vap33 (a Vamp (v-SNARE)-associated protein, involved in endo-lysosomal trafficking) to regulate the Notch pathway. However, how Lgl acts to regulate the Hippo pathway was unclear. In this current study, we show that V-ATPase activity inhibits the Hippo pathway, whereas Vap33 acts to activate Hippo signalling. Using anin vivoaffinity-purification approach we found that Vap33 binds to the actin cytoskeletal regulators RtGEF (Pix, a Rho-type guanine nucleotide exchange factor) and Git (G protein-coupled receptor kinase interacting ArfGAP), which also bind to the Hpo protein kinase, and are involved in the activation of the Hippo pathway. Vap33 genetically interacts with RtGEF and Git in Hippo pathway regulation. Additionally, we show that the ADP ribosylation factor Arf79F (Arf1), which is a Hpo interactor, is involved in the inhibition of the Hippo pathway. Altogether our data suggests that Lgl acts via Vap33 to activate the Hippo pathway by a dual mechanism, 1) through interaction with RtGEF/Git/Arf79F, and 2) through interaction and inhibition of the V-ATPase, thereby controlling epithelial tissue growth.
SMU_1361c regulates the oxidative stress response ofStreptococcus mutans
Authors: Yu Shuxing , Huang Jun , Liu Yaqi , Li Jing , Zhang Qiong , Wang Yan , Gong Tao , Ma Qizhao , Zou Jing , Li Yuqing 
Published: July 2023

AbstractDental caries is the most common chronic infectious diseases around the world and disproportionately affects the marginalized socioeconomic group.Streptococcus mutans, considered a primary etiological agent of caries, must depend on the coordinated physiological response to tolerate the oxidative stress generated by commensal species within dental plaque, which is a critical aspect of its pathogenicity. Here, we identified and characterized a novel TetR family regulator SMU_1361c, encoded by the TnSmu2 operon, which appears to be acquired by the bacteria via horizontal genes transfer. Surprisingly,smu_1361cfunctions as a transcriptional repressor to regulate gene expression outside its operon, involved in the oxidative stress response ofS. mutans. Thesmu_1361coverexpression strain UA159/pDL278-1361cwas more susceptible to oxidative stress and less competitive against hydrogen peroxide generated by commensal speciesStreptococcus gordoniiandStreptococcus sanguinis. Transcriptomics analysis revealed thatsmu_1361coverexpression resulted in the significant downregulation of 22 genes mainly belonging to three gene clusters responsible for the oxidative stress response. The conversed DNA binding motif of SMU_1361c was determined by electrophoretic mobility shift and DNase I footprinting assay with purified SMU_1361c protein, therefore,smu_1361cis directly involved in gene transcription related to the oxidative stress response. Crucially, our finding provides a new understanding of howS. mutansdeals with the oxidative stress that is required for pathogenesis and will facilitate the development of new and improved therapeutic approaches for dental caries.