bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accurate Characterization of Conformational Ensembles and Binding Mechanisms of the SARS-CoV-2 Omicron BA.2 and BA.2.86 Spike Protein with the Host Receptor and Distinct Classes of Antibodies Using AlphaFold2-Augmented Integrative Computational Modeling
Authors: Raisinghani Nishank , Alshahrani Mohammed , Gupta Grace , Xiao Sian , Tao Peng , Verkhivker Gennady 
Published: November 2023

AbstractThe latest wave SARS-CoV-2 Omicron variants displayed a growth advantage and the increased viral fitness through convergent evolution of functional hotspots that work synchronously to balance fitness requirements for productive receptor binding and efficient immune evasion. In this study, we combined AlphaFold2-based structural modeling approaches with all-atom MD simulations and mutational profiling of binding energetics and stability for prediction and comprehensive analysis of the structure, dynamics, and binding of the SARS-CoV-2 Omicron BA.2.86 spike variant with ACE2 host receptor and distinct classes of antibodies. We adapted several AlphaFold2 approaches to predict both structure and conformational ensembles of the Omicron BA.2.86 spike protein in the complex with the host receptor. The results showed that AlphaFold2-predicted conformational ensemble of the BA.2.86 spike protein complex can accurately capture the main dynamics signatures obtained from microscond molecular dynamics simulations. The ensemble-based dynamic mutational scanning of the receptor binding domain residues in the BA.2 and BA.2.86 spike complexes with ACE2 dissected the role of the BA.2 and BA.2.86 backgrounds in modulating binding free energy changes revealing a group of conserved hydrophobic hotspots and critical variant-specific contributions of the BA.2.86 mutational sites R403K, F486P and R493Q. To examine immune evasion properties of BA.2.86 in atomistic detail, we performed large scale structure-based mutational profiling of the S protein binding interfaces with distinct classes of antibodies that displayed significantly reduced neutralization against BA.2.86 variant. The results quantified specific function of the BA.2.86 mutations to ensure broad resistance against different classes of RBD antibodies. This study revealed the molecular basis of compensatory functional effects of the binding hotspots, showing that BA.2.86 lineage may have primarily evolved to improve immune escape while modulating binding affinity with ACE2 through cooperative effect of R403K, F486P and R493Q mutations. The study supports a hypothesis that the impact of the increased ACE2 binding affinity on viral fitness is more universal and is mediated through cross-talk between convergent mutational hotspots, while the effect of immune evasion could be more variant-dependent.
New plasma LC-MS/MS assays for the quantitation of beta-amyloid peptides and identification of apolipoprotein E proteoforms for Alzheimer’s disease risk assessment
Authors: Weber Darren M. , Kim Jueun C. , Goldman Scott M. , Clarke Nigel J. , Racke Michael K. 
Published: November 2023

AbstractObjectivesEarly detection of Alzheimer’s disease (AD) represents an unmet clinical need. Beta-amyloid (Aβ) plays an important role in AD pathology, and the Aβ42/40 peptide ratio is a good indicator for amyloid deposition. In addition, variants of theAPOEgene are associated with variable AD risk. Here we describe the development and validation of high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for plasma Aβ40 and Aβ42 quantitation, as well as apolipoprotein E (ApoE) phenotype determination as a surrogate forAPOEgenotype.MethodsAβ40 and Aβ42 were simultaneously immunoprecipitated (IP) from plasma, proteolytically digested, and quantitated by LC-MS/MS. ApoE proteoform status was qualitatively assessed by targeting tryptic peptides from the ApoE2, ApoE3, and ApoE4 proteoforms. Both assays were validated according to CLIA guidelines.ResultsWithin-run precision was 1.8 to 4.2% (Aβ40), 1.9 to 7.2% (Aβ42), and 2.6 to 8.3% (Aβ42/40 ratio). Between-run precision was 3.5 to 5.9% (Aβ40), 3.8 to 8.0% (Aβ42), and 3.3 to 8.7% (Aβ42/40 ratio). Both Aβ40 and Aβ42 were linear from 10 to 2,500 pg/mL. Identified ApoE proteoforms had 100% concordance withAPOEgenotypes.ConclusionWe have developed a precise, accurate, and sensitive high-throughput LC-MS/MS assay for plasma Aβ40, Aβ42, and proteoforms of ApoE.
Hippocampal place code plasticity in CA1 requires postsynaptic membrane fusion
Authors: Plitt Mark H. , Kaganovsky Konstantin , Südhof Thomas C. , Giocomo Lisa M. 
Published: November 2023

SummaryRapid delivery of glutamate receptors to the postsynaptic membrane via vesicle fusion is a central component of synaptic plasticity. However, it is unknown how this process supports specific neural computations during behavior. To bridge this gap, we combined conditional genetic deletion of a component of the postsynaptic membrane fusion machinery, Syntaxin3 (Stx3), in hippocampal CA1 neurons of mice with populationin vivocalcium imaging. This approach revealed that Stx3 is necessary for forming the neural dynamics that support novelty processing, spatial reward memory and offline memory consolidation. In contrast, CA1 Stx3 was dispensable for maintaining aspects of the neural code that exist presynaptic to CA1 such as representations of context and space. Thus, manipulating postsynaptic membrane fusion identified computations that specifically require synaptic restructuring via membrane trafficking in CA1 and distinguished them from neural representation that could be inherited from upstream brain regions or learned through other mechanisms.
Proton pump Inhibitor effect on esophageal protein signature of eosinophilic esophagitis, prediction and evaluation of treatment response
Authors: Molina-Jiménez Francisca , Ugalde-Triviño Lola , Arias-González Laura , Relaño-Rupérez Carlos , Casabona Sergio , Moreno-Monteagudo José Andrés , Pérez-Fernández María Teresa , Martín-Domínguez Verónica , Fernández-Pacheco Jennifer , Laserna-Mendieta Emilio José , Muñoz-Hernández Patricia , García-Martínez Jorge , Muñoz Javier , Lucendo Alfredo J , Santander Cecilio , Majano Pedro 
Published: November 2023

ABSTRACTBackgroundRecently, we have identified a dysregulated protein signature in the esophageal epithelium of eosinophilic esophagitis (EoE) patients; however, the effect of proton pump inhibitor (PPI) treatment on this signature is unknown. Herein, we used a proteomic approach to investigate: (1) whether PPI treatment alters the esophageal epithelium protein profile observed in EoE patients and (2) whether the protein signature at baseline predicts PPI response.MethodsWe evaluated the protein signature of esophageal biopsies using a cohort of adult EoE (n=25) patients and healthy controls (C) (n=10). In EoE patients, esophageal biopsies were taken before (Pre) and after (Post) an 8-week PPI treatment, determining the histologic response. Eosinophil count PostPPI was used to classify the patients: ≥15 eosinophils/hpf as non-responders (NR) and <15 eosinophils/hpf as responders (R). Protein signature was determined and differentially accumulated proteins (DAP) were characterized to identify altered biological processes and signaling pathways.ResultsHigh dimensional analysis of DAP between groups revealed common signatures between three groups of patients with inflammation (R-PrePPI, NR-PrePPI and NR-PostPPI) and without inflammation (C and R- PostPPI). PPI therapy almost reversed the EoE specific esophageal protein signature, which is enriched in pathways associated with inflammation and epithelial barrier function, in R-PostPPI. Furthermore, we identified a set of candidate proteins to differentiate R-PrePPI and NR-PrePPI EoE patients before treatment.ConclusionThese findings provide evidence that PPI therapy reverses the alterations in the protein profile associated with EoE. Interestingly, our results also suggest that PPI response could be predicted at baseline in EoE.
The Association between Multimorbidity and Out-of-Pocket Expenditures for Prescription Medicines among Adults in Denmark: A Population-Based Register Study
Authors: Larkin James , Smith Susan M. , Christensen Line Due , Voss Thomas Schmidt , Vestergaard Claus Høstrup , Paust Amanda , Prior Anders 
Published: November 2023

AbstractBackgroundMultimorbidity, defined as two or more chronic conditions in an individual, is increasing in prevalence and is associated with polypharmacy. Polypharmacy can lead to increased out-of-pocket payments for prescription medicines. This, in turn, can be associated with cost-related non-adherence and impoverishment. Healthcare in Denmark is mostly free at the point-of-use; prescription medicines are one of the only exceptions.ObjectiveTo examine the association between multimorbidity and annual out-of-pocket prescription medicine expenditure for adults in Denmark.MethodsA population-based register study was conducted. The study population included all adults residing in Denmark in 2020. Frequencies and descriptive statistics were used and regression analyses were conducted to assess the association between multimorbidity and annual out-of-pocket prescription medicine expenditure, while controlling for demographic and socioeconomic covariates.ResultsOverall, 1,212,033 (24.2%) individuals had multimorbidity. Individuals with five or more conditions spent, on average, €320 in out-of-pocket prescription medicines expenditure compared to €187 for those with two conditions and €44 for those with no conditions. Amongst those with any out-of-pocket prescription medicine expenditure, having multimorbidity was associated with 2-4 times greater out-of-pocket prescription medicine expenditure than those with zero conditions. Amongst those in the quantile with the highest expenditure, those with five or more conditions spent €408 more than those with no conditions, and those with two conditions spent €185 more than those with no conditions.ConclusionsFor adults in Denmark, multimorbidity was associated with significantly higher out-of-pocket prescription medicine expenditure, even after controlling for demographic and socioeconomic covariates. This is similar to patterns in other countries and likely affects those with lowest income the most, given the known socioeconomic patterning of multimorbidity and raises concerns about cost related non-adherence. Potential protective mechanisms could include subsidies for certain vulnerable patient groups (e.g. those with severe mental illness) and low-income groups.
Exogenous ketosis attenuates acute mountain sickness and mitigates high-altitude hypoxemia
Authors: Stalmans Myrthe , Tominec Domen , Lauriks Wout , Robberechts Ruben , Debevec Tadej , Poffé Chiel 
Published: November 2023

ABSTRACTBackgroundAcute mountain sickness (AMS) represents a considerable issue for individuals sojourning to high altitudes with systemic hypoxemia known to be intimately involved in its development. Based on recent evidence that ketone ester (KE) intake attenuates hypoxemia, we sought to investigate whether exogenous ketosis might mitigate AMS development and improve hypoxic tolerance.MethodsFourteen healthy, male participants were enrolled in two 29h protocols (simulated altitude of 4,000-4,500m) receiving either KE or a placebo (CON) at regular timepoints throughout the protocol in a randomized, crossover manner. Select physiological responses were characterized after 15min and 4h in hypoxia, and the protocol was terminated prematurely upon development of severe AMS.ResultsAll participants tolerated the protocol equally long (n=6, of which n=5 completed the protocol in both conditions) or longer (n=8) in KE. Overall protocol duration increased by 32% on average with KE, and doubled for AMS-developing participants. KE consistently induced diurnal ketosis, a mild metabolic acidosis, hyperventilation, and relative sympathetic dominance. KE also fully negated the progressive hypoxemia that was observed between 15min and 4h in hypoxia in CON, while concomitantly increasing cerebral oxygenation and capillary pO2within this timeframe. This coincided with a KE-induced reduction in cerebral oxygen supply, suggesting that KE reduced cerebral oxygen consumption under hypoxic conditions.ConclusionsThese data indicate that exogenous ketosis improves hypoxic tolerance in humans and attenuates AMS development. The key underlying mechanisms include improved arterial and cerebral oxygenation, in combination with lowered cerebral blood flow and oxygen demand, and increased sympathetic dominance.SummaryKetone ester intake attenuated the development of acute mountain sickness at a simulated altitude of 4,000-4,500m. This likely resulted from a mitigation of arterial and cerebral hypoxemia, reduced cerebral blood flow and increased sympathetic drive.
Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders
Authors: Bakken Nora Refsum , Parker Nadine , Hannigan Laurie J. , Hagen Espen , Parekh Pravesh , Shadrin Alexey , Jaholkowski Piotr , Frei Evgeniia , Birkenæs Viktoria , Hindley Guy , Hegemann Laura , Corfield Elizabeth C. , Tesli Martin , Havdahl Alexandra , Andreassen Ole A. 
Published: November 2023

ABSTRACTBackgroundSymptoms related to mood and anxiety disorders often present in childhood and adolescence. Some of the genetic liability for mental disorders, and emotional and behavioral difficulties seems to be shared. Yet, it is unclear how genetic liability for mood and anxiety disorders influence trajectories of childhood emotional and behavioral difficulties, and if specific developmental patterns associate with higher genetic liability for these disorders.MethodsThis study uses data from a genotyped sample of children (n= 54,839) from the Norwegian Mother, Father and Child Cohort Study (MoBa). We use latent growth models (1.5-5 years) and latent profile analyses (1.5-8 years) to quantify childhood trajectories and profiles of emotional and behavioral difficulties and diagnoses. We examine associations between these trajectories and profiles with polygenic scores for bipolar disorder (PGSBD), anxiety (PGSANX), depression (PGSDEP), and neuroticism (PGSNEUR).ResultsAssociations between PGSDEP, PGSANXand PGSNEUR, and emotional and behavioral difficulties in childhood were developmentally stable rather than age specific. Higher PGSANXand PGSDEPwere associated with steeper increases in behavioral difficulties across early childhood. Latent profile analyses identified five profiles. All PGS were associated with probability of classification into profiles characterized by some form of difficulties (vs. a normative reference profile), but only PGSBDwas uniquely associated with a single developmental profile.ConclusionsOur findings indicate that genetic risk for mood disorders and related traits contribute to a more rapidly increasing and higher overall burden of emotional and behavioral difficulties across early and middle childhood, with some indications for disorder-specific profiles. These findings of associations between childhood trajectories and symptom profiles and genetic and clinical susceptibility for mental disorders, may form the basis for more targeted early interventions.
Transcriptome profiling of cerebrospinal fluid in Alzheimer’s Disease reveals molecular dysregulations associated with disease
Authors: De Sota Rhys E. , Khoury Samantha J. , Zhuang Jiali , Rissman Robert A. , Brewer James B. , Quake Stephen R. , Sninsky John J. , Toden Shusuke 
Published: November 2023

ABSTRACTDespite the increasing prevalence of neurodegenerative diseases, the molecular characterization of the brain remains challenging due to limited access to the tissue. Cerebrospinal fluid (CSF) contains a significant proportion of molecular contents originating from the brain, and characterizing these molecules has served as a surrogate to evaluate molecular dysregulation in the brain. Here we performed cell-free messenger RNA (cf-mRNA) RNA-sequencing on 52 human CSF samples, and further compared their transcriptomic profiles to matched plasma samples. In addition, we evaluated the molecular dysregulation of cf-mRNA in CSF between individuals with Alzheimer’s disease (AD) and non-cognitively impaired (NCI) controls. The molecular content of CSF cf-mRNA was distinct from plasma cf-mRNA, with a substantially higher number of brain-associated genes identified in CSF. We identified a large set of dysregulated gene transcripts in the CSF cf-mRNA population of individuals with AD, and these gene transcripts were used to establish a diagnostic classifier to discriminate AD from NCI subjects. Notably, the gene transcripts were enriched in biological processes closely associated with AD, such as brain development and synaptic signaling. We also discovered a subset of gene transcripts within AD subjects that exhibit a strong correlation between CSF and plasma cf-mRNA. This study not only reveals the novel cf-mRNA content of CSF but also highlights the potential of CSF cf-mRNA profiling as a tool to garner pathophysiological insights into AD.
EMS injury cause codes more accurate than emergency department visit ICD-10-CM codes for firearm injury intent in North Carolina
Authors: Snyder Nicole L. , Ising Amy , Waller Anna E. 
Published: November 2023

AbstractBackgroundThe timeliness, accuracy, and completeness of data for firearm injury surveillance is crucial for public health surveillance efforts and informing injury prevention measures. While emergency department (ED) visit data can provide near real-time information on firearms injuries, there are concerns surrounding the accuracy of intent coding in these data. We examined whether emergency medical service (EMS) data provide more accurate firearm injury intent coding in comparison to ED data.MethodsWe applied a firearm injury definition to EMS encounter data in NC’s statewide syndromic surveillance system (NC DETECT), from January 1, 2021, through December 31, 2022. Each record was manually reviewed to determine shooter and intent, and the corresponding manual classifications were compared to the injury cause codes entered in the EMS data and to ED visit records, where linkage was possible.ResultsWe identified 9557 EMS encounters from January 1, 2021, through December 31, 2022 meeting our firearm injury definition. After removing false positives and duplicates, 8584 records were available for manual injury classification. Overall, our analysis demonstrated that manual and EMS injury cause code classification were comparable. However, for the 3401 EMS encounters that could be linked to an ED visit record, only 18.3% (n = 355) of the 1945 assaults and 22.2% (n = 38) of the 171 intentional self-harm suicide encounters we identified in the EMS records were identified as assault firearm injures in the ED visit data. This demonstrates a marked difference in the intent coding between the two data sources.ConclusionsThis study illustrates both the value of examining EMS encounters for firearm injury intent, and the challenges of accurate intent coding in the ED setting. The results also suggest the importance of developing better guidance around intent coding for firearm injuries in the ED.
Randomised, controlled, feasibility trial comparing vasopressor infusion administered via peripheral cannula versus central venous catheter for critically ill adults: a study protocol
Authors: Watts Stacey , Apte Yogesh , Holland Thomas , Hatt April , Craswell Alison , Lin Frances , Tabah Alexis , Ware Robert S , Byrnes Joshua , Anstey Christopher , Keijzers Gerben , Ramanan Mahesh 
Published: November 2023

AbstractBackgroundWhen clinicians need to administer a vasopressor infusion, they are faced with the choice of administration via either peripheral intravenous catheter (PIVC) or central venous catheter (CVC). Vasopressor infusions have traditionally been administered via central venous catheters (CVC) rather than Peripheral Intra Venous Catheters (PIVC), primarily due to concerns of extravasation and resultant tissue injury. This practice is not guided by contemporary RCT evidence. Observational data suggests safety of vasopressor infusion via PIVC. To address this evidence gap, we have designed the “Vasopressors Infused via Peripheral or Central Access” (VIPCA) randomised controlled trial (RCT).MethodsThe VIPCA trial is a single-centre, feasibility, parallel-group RC. Eligible critically ill patients requiring a vasopressor infusion will be identified by emergency department (ED) or intensive care unit (ICU) staff and randomised to receive vasopressor infusion via either PIVC or CVC. Primary outcome is feasibility, a composite of recruitment rate, proportion of eligible patients randomised, protocol fidelity, retention and missing data. Primary clinical outcome is days alive and out of hospital up to day-30. Secondary outcomes will include safety and other clinical outcomes, and process and cost measures. Specific aspects of safety related to vasopressor infusions such as extravasation, leakage, device failure, tissue injury and infection will be assessed.DiscussionVIPCA is a feasibility RCT whose outcomes will inform the feasibility and design of a multicentre Phase-3 trial comparing routes of vasopressor delivery. The exploratory economic analysis will provide input data for the full health economic analysis which will accompany any future Phase-3 RCT.Trial RegistrationThis trial was registered prospectively on the Australian and New Zealand Clinical Trials Registry. (ACTRN12621000721808)
Comparison of troponin and natriuretic peptides in takotsubo syndrome and acute coronary syndrome: a meta-analysis
Authors: Couch Liam S , Garrard James W , Henry John A , Kotronias Rafail A , Alaour Bashir , De Maria Giovanni Luigi , Channon Keith M , Banning Adrian P , Lyon Alexander R , Marber Michael S , Kaier Thomas E 
Published: November 2023

AbstractBackgroundTakotsubo syndrome (TTS) is an acute heart failure syndrome which resembles acute coronary syndrome (ACS) at presentation. Differentiation requires coronary angiography, but where this does not occur immediately, cardiac biomarkers may provide additional utility. We performed a meta-analysis to compare troponin and natriuretic peptides (NPs) in TTS and ACS to determine if differences in biomarker profile can aid diagnosis.MethodsWe searched five literature databases for studies reporting NPs (BNP/NT-pro-BNP) or troponin I/T in TTS and ACS, identifying 28 studies for troponin/NPs (5618 and 1145 patients respectively).ResultsTroponin was significantly lower in TTS than ACS (standardized mean difference (SMD) −0.86; 95% CI −1.08-−0.64; p<0.00001), with an absolute difference of 75 times the upper limit of normal (xULN) higher in ACS than TTS. Conversely, NPs were significantly higher in TTS (SMD 0.62; 0.44-0.80; p<0.00001) and 5.8xULN greater absolutely. Area under the curve (AUC) for troponin in ACSversusTTS was 0.82 (0.70-0.93), and 0.92 (0.80-1.00) for STEMI vs. TTS. For NPs, AUC was 0.69 (0.48-0.89). Combination of troponin and NPs with logistic regression did not improve AUC. Recursive partitioning and regression tree analysis calculated a troponin threshold ≥26xULN that identified 95% cases as ACS where and specificity for ACS were 85.71% and 53.57% respectively, with 94.32% positive predictive value and 29.40% negative predictive value.ConclusionsTroponin is lower and NPs higher in TTSversusACS. Troponin had greater power than NPs at discriminating TTS and ACS, and with troponin ≥26xULN patients are far more likely to have ACS.