bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interstitial Fibrosis and Arrhythmic Mitral Valve Prolapse: Unravelling Sex-Based Differences
Authors: Tastet Lionel , Dixit Shalini , Nguyen Thuy , Lim Lisa J. , Al-Akchar Mohammad , Bibby Dwight , Arya Farzin , Cristin Luca , Anwar Shafkat , Higuchi Satoshi , Hsia Henry , Lee Yoo Jin , Delling Francesca N. 
Published: January 2024

ABSTRACTBackgroundInterstitial fibrosis as quantified by cardiac magnetic resonance (CMR) has been demonstrated in arrhythmic mitral valve prolapse (MVP), a condition with known female predominance. However, prior studies included only MVP cases with significant mitral regurgitation (MR) or mitral annular disjunction (MAD). We sought to evaluate the association between interstitial fibrosis and complex ventricular ectopy (ComVE) in MVPs unselected for MAD or severe MR, and to investigate the contribution of sex to this association.MethodsWe performed contrast CMR in consecutive individuals with MVP between 2020 and 2022. Extracellular volume fraction (ECV%), a surrogate marker for interstitial fibrosis, was quantified using T1mapping. Replacement fibrosis was assessed using late gadolinium enhancement (LGE). ComVE, defined as frequent premature ventricular contractions and/or non-sustained/sustained ventricular tachycardia (VT), was detected using ambulatory ECG monitoring.ResultsWe identified 59 MVP cases without severe MR (49% women, 80% with mild or less MR) and available ECV% measurement. Among these, 23 (39%) had ComVE, including a case of aborted ventricular fibrillation (VF) and one with sudden arrhythmic death, both females. Global ECV% was significantly greater in ComVE versus non-ComVE (31%[27-33] vs 27%[23-30], p=0.002). In MVP-ComVE, higher segmental ECV% was not limited to the inferolateral/inferior LV wall, but was also demonstrated in atypical segments including the anterior/anterolateral wall (p<0.05). The association between ComVE and ECV% was driven by female sex (32%[30-33] vs 28%[26-30], p=0.003 in females; 31%[25-33] vs 26%[23-30], p=0.22 in males). ECV% remained independently associated with an increased risk of ComVE, including VT/VF, after adjustment for cardiovascular risk factors, MAD, and LGE (p<0.01).ConclusionIn MVP without significant MR, interstitial fibrosis by CMR is associated with an increased risk of ComVE, suggesting a primary myopathic process. The stronger association between interstitial fibrosis and ComVE in females may explain why severe arrhythmic complications are more prevalent among women.Abstract FigureGRAPHICAL ABSTRACT:Expansion of Interstitial Myocardial Fibrosis in Mitral Valve Prolapse with Complex Ventricular Ectopy. Illustrative MVP case with ComVE and greater interstitial fibrosis as demonstrated by T1mapping on CMR (Top). The violin plot shows significantly greater ECV% in MVPs with ComVE compared to non-ComVE (Top). The association between greater interstitial fibrosis (i.e. ECV%) and ComVE was stronger in women than men (Bottom). MR = mitral regurgitation
A high throughput blood-based assay for the early detection of pancreatic cancer
Authors: Montoya Mira Jose L. , Quentel Arnaud , Patel Ranish K. , Keith Dove , Minnier Jessica , David Larry , Esener Sadik C. , Sears Rosalie C. , Lopez Charles D. , Sheppard Brett C. , Demirci Utkan , Wong Melissa H. , Fischer Jared M. 
Published: January 2024

AbstractPancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due in part to the cancer being diagnosed is at a late stage when effective treatment options are limited. Early detection of PDAC via liquid biopsy would revolutionize survival from the disease. To address the lack of effective non-invasive detection assays for PDAC, we developed aproteaseactivity-based assay using amagneticnanosensor (PAC•MANN). The PAC•MANN assay leverages protease activity in blood to amplify the signal of the target-probe based sensor. An initial screening revealed that the PAC•MANN assay could reliably differentiate patients with PDAC from healthy subjects and patients at high risk of PDAC. Finally, in two cohorts: training (n=145) and blinded validation (n=72), we demonstrated that the PAC•MANN assay had high specificity (86%) and sensitivity (78%) for detection of PDAC compared to healthy subjects. This performance was enhanced when combined with the current standard of care assay, CA19-9 (100% specificity, 84% sensitivity). Our results demonstrate a novel assay that is rapid, high-throughput, and requires low specimen volume, which may not only improve cancer detection but could be useful for monitoring of at-risk patients and could be deployed in low resource settings.One sentence summaryA high-throughput, non-invasive, rapid protease-activated nanosensor identifies pancreatic cancer from a small volume of blood
Trajectory of the body mass index of children and adolescents attending a reference mental health center
Authors: Echeveste-Navarrete Juliana , Zavaleta-Ramírez Patricia , Castilla-Peon Maria Fernanda 
Published: January 2024

AbstractObjectivesTo describe the standardized body mass index (z-BMI) trajectory of children and adolescents admitted to a psychiatric reference center in Mexico City according to their diagnosis and medication use. A secondary objective was to compare z-BMI between antipsychotic users and non-users.MethodsDiagnosis, prescribed medications, serial heights, and weights were collected from the medical records.ResultsThe median baseline z-BMI of the 129 analyzed cases was 0.88 (IQR: 0 -1.92), and the overweight/obesity prevalence was 46.8%. At the end of follow-up (median, 50.3 weeks), they had a median change in z-BMI of -0.09 (IQR: - 0.68 -0.42). New long-term users of antipsychotics (n = 29) had an increase in their z-BMI, in contrast to never-users (median difference 0.73, p = 0.01) and to previous users (median difference 0.92, p = 0.047). The 59 subjects with excessive weight at admission had a median change in z -BMI of -0.39 (IQR: - 0.81--0.04). Among patients with excessive weight and depression, a greater decrease in z-BMI was observed in sertraline users (n = 13) compared with fluoxetine users (n = 15) (median -0.65 vs. 0.21, p<0.001).ConclusionsNew long-term users of antipsychotics increased their z-BMI significantly. Patients with depressive disorders and obesity on sertraline therapy tend to decrease their z-BMI.
Association analysis of mitochondrial DNA heteroplasmic variants: methods and application
Authors: Sun Xianbang , Bulekova Katia , Yang Jian , Lai Meng , Pitsillides Achilleas N. , Liu Xue , Zhang Yuankai , Guo Xiuqing , Yong Qian , Raffield Laura M. , Rotter Jerome I. , Rich Stephen S. , Abecasis Goncalo , Carson April P. , Vasan Ramachandran S. , Bis Joshua C. , Psaty Bruce M. , Boerwinkle Eric , Fitzpatrick Annette L. , Satizabal Claudia L. , Arking Dan E. , Ding Jun , Levy Daniel ,   TOPMed mtDNA working group, Liu Chunyu 
Published: January 2024

ABSTRACTWe rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31% of African Ancestry, mean age of 62, with 58% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in theRNR1andRNR2genes (p<0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations (p<0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.
Systematic proteomics in Autosomal dominant Alzheimer’s disease reveals decades-early changes of CSF proteins in neuronal death, and immune pathways
Authors: Shen Yuanyuan , Ali Muhammad , Timsina Jigyasha , Wang Ciyang , Do Anh , Western Daniel , Liu Menghan , Gorijala Priyanka , Budde John , Liu Haiyan , Gordon Brian , McDade Eric , Morris John C. , Llibre-Guerra Jorge J. , Bateman Randall J. , Joseph-Mathurin Nelly , Perrin Richard J. , Maschi Dario , Wyss-Coray Tony , Pastor Pau , Goate Alison , Renton Alan E. , Surace Ezequiel I. , Johnson Erik C. B. , Levey Allan I. , Alvarez Ignacio , Levin Johannes , Ringman John M. , Allegri Ricardo Francisco , Seyfried Nicholas , Day Gregg S. , Wu Qisi , Fernández M. Victoria ,   Dominantly Inherited Alzheimer Network, Ibanez Laura , Sung Yun Ju , Cruchaga Carlos 
Published: January 2024

AbstractBackgroundTo date, there is no high throughput proteomic study in the context of Autosomal Dominant Alzheimer’s disease (ADAD). Here, we aimed to characterize early CSF proteome changes in ADAD and leverage them as potential biomarkers for disease monitoring and therapeutic strategies.MethodsWe utilized Somascan® 7K assay to quantify protein levels in the CSF from 291 mutation carriers (MCs) and 185 non-carriers (NCs). We employed a multi-layer regression model to identify proteins with different pseudo-trajectories between MCs and NCs. We replicated the results using publicly available ADAD datasets as well as proteomic data from sporadic Alzheimer’s disease (sAD). To biologically contextualize the results, we performed network and pathway enrichment analyses. Machine learning was applied to create and validate predictive models.FindingsWe identified 125 proteins with significantly different pseudo-trajectories between MCs and NCs. Twelve proteins showed changes even before the traditional AD biomarkers (Aβ42, tau, ptau). These 125 proteins belong to three different modules that are associated with age at onset: 1) early stage module associated with stress response, glutamate metabolism, and mitochondria damage; 2) the middle stage module, enriched in neuronal death and apoptosis; and 3) the presymptomatic stage module was characterized by changes in microglia, and cell-to-cell communication processes, indicating an attempt of rebuilding and establishing new connections to maintain functionality. Machine learning identified a subset of nine proteins that can differentiate MCs from NCs better than traditional AD biomarkers (AUC>0.89).InterpretationOur findings comprehensively described early proteomic changes associated with ADAD and captured specific biological processes that happen in the early phases of the disease, fifteen to five years before clinical onset. We identified a small subset of proteins with the potentials to become therapy-monitoring biomarkers of ADAD MCs.FundingProteomic data generation was supported by NIH: RF1AG044546
Predictors of Developing Renal Dysfunction Following Diagnosis of Transthyretin Cardiac Amyloidosis
Authors: McDonald Malcolm L , Manla Yosef , Sonnino Alice , Alonso Mileydis , Neicheril Radhika K , Sanchez Alejandro , Lafave Gabrielle , De Armas Yelenis Seijo , Camargo Antonio Lewis , Uppal Dipan , Handa Armaan , Wolinsky David , Thakkar Rivera Nina , Velez Mauricio , Baran David , Estep Jerry D. , Snipelisky David 
Published: January 2024

AbstractBackgroundIn patients with transthyretin cardiac amyloidosis (ATTR-CA), renal dysfunction is a poor prognostic indicator. Limited data are available on variables that portend worsening renal function (wRF) among ATTR-CA patients.ObjectivesThis study assesses which characteristics place patients at higher risk for the development of wRF (defined as a drop of ≥ 10% in GFR) within the first year following diagnosis of ATTR-CA.MethodsWe included patients with ATTR-CA (n=134) evaluated between 2/2016 and 12/2022 and followed for up to one-year at our amyloid clinic. Patients were stratified into two groups: a group with maintained renal function (mRF) and a group with wRF and compared using appropriate testing. Significant variables in the univariate analysis were included in the multivariable logistic regression model to determine characteristics associated with wRF.ResultsWithin a follow-up period of 326±118 days, the median GFR% change measured -6% [-18%, +8]. About 41.8% (n=56) had wRF, while the remainder had mRF. In addition, in patients with no prior history of CKD, 25.5% developed de-novo CKD. On multivariable logistic regression, only NYHA class ≥III (OR: 3.9, 95% CI [1.6-9.3]), history of IHD (OR:0.3, 95% CI [0.1-0.7]), and receiving SGLT-2i (OR: 0.1, 95% CI [0.02-0.5]) were significant predictors of wRF.ConclusionOur study demonstrated that the development of new or worsening renal dysfunction is common following the diagnosis of ATTR-CA. Additionally, we identified worse NYHA class and no prior history of IHD as significant predictors associated with developing wRF, while receiving SGLT2i therapy appeared to be protective in this population.
NSE5 subunit interacts with distant regions of the SMC arms in thePhyscomitrium patensSMC5/6 complex
Authors: Vaculíková Jitka , Holá Marcela , Králová Barbora , Lelkes Edit , Štefanovie Barbora , Vágnerová Radka , Angelis Karel J. , Paleček Jan J. 
Published: January 2024

ABSTRACTStructural Maintenance of Chromosome (SMC) complexes play roles in cohesion, condensation, replication, transcription, and DNA repair. Their cores are composed of SMC proteins with a unique structure consisting of an ATPase head, long arm, and hinge. SMC complexes form long rod-like structures, which can change to ring-like and elbow-bent conformations upon binding ATP, DNA and other regulatory factors. These SMC dynamic conformational changes are involved in their loading, translocation, and DNA loop extrusion. Here, we examined the binding and role of the PpNSE5 regulatory factor ofPhyscomitrium patensPpSMC5/6 complex. We found that the PpNSE5 C-terminal half (aa230-505) is required for binding to its PpNSE6 partner, while the N-terminal half (aa1-230) binds PpSMC subunits. Specifically, the first 71 amino acids of PpNSE5 were required for binding to PpSMC6. Interestingly, the PpNSE5 binding required the PpSMC6 head-proximal joint region and PpSMC5 hinge-proximal arm, suggesting a long distance between binding sites on PpSMC5 and PpSMC6 arms. Given the long distance between these PpSMC sites and the size of PpNSE5, we hypothesize that PpNSE5 either links two antiparallel SMC5/6 complexes or binds one SMC5/6 in elbow-bent conformation.In addition, we generated theP. patensmutant lines (Ppnse5KO1andPpnse5KO2) with CRISPR/Cas9-integrated stop codons in PpNSE5. ThePpnse5KO1mutant line with an N-terminally truncated version of PpNSE5 (starting from an alternative aaMet72) exhibited DNA repair defects while keeping a normal number of rDNA repeats. As the first 71 amino acids of PpNSE5 are required for PpSMC6 binding, our results suggest the specific role of PpNSE5-PpSMC6 interaction in DNA repair. Altogether, our study suggests that PpNSE5 binding to distant regions of the PpSMC5 and PpSMC6 arms serves a specific role in loading at DNA lesions.
Targeted intracellular delivery of molecular cargo to hypoxic human breast cancer stem cells
Authors: Makela Ashley V , Tundo Anthony , Liu Huiping , Schneider Doug , Hermiston Terry , Khodakivskyi Pavlo , Goun Elena , Contag Christopher H 
Published: January 2024

AbstractCancer stem cells (CSCs) drive tumorigenesis, are responsible for metastasis, and resist conventional therapies thus posing significant treatment challenges. CSCs reside in hypoxic tumor regions and therefore, effective therapies must target CSCs within this specific microenvironment. CSCs are characterized by limited distinguishable features, however, surface displayed phosphatidylserine (PS) appears to be characteristic of stem cells and offers a potential target. GlaS, a truncated coagulation protein that is internalized after binding PS, was investigated for intracellular delivery of molecular payloads to CSCs. Intracellular delivery via GlaS was enhanced in patient-derived CD44+ mammary CSCs under hypoxic conditions relative to physoxia or hyperoxia.In vivo, GlaS successfully targeted hypoxic tumor regions, and functional delivery of molecular cargo was confirmed using luciferin conjugated to GlaS via a disulfide linkage (GlaS-SS-luc), which releases luciferin upon intracellular glutathione reduction. Bioluminescence imaging demonstrated effective GlaS-mediated delivery of luciferin, a model drug, to CSCs in culture andin vivo. These findings offer the promise of directed delivery of therapeutic agents to intracellular targets in CSCs.
Training interoceptive awareness with real-time haptic vs. visual heartbeat feedback
Authors: Dobrushina Olga , Tamim Yossi , Wald Iddo Yehoshua , Maimon Amber , Amedi Amir 
Published: January 2024

AbstractThe perception of signals from within the body, known as interoception, is increasingly recognized as a prerequisite for physical and mental health. The study is dedicated to the development of effective technological approaches for enhancing interoceptive awareness. We provide evidence of the effectiveness and practical feasibility of a novel real-time haptic heartbeat supplementation technology combining principles of biofeedback and sensory enhancement. In a randomized controlled study, we applied the developed naturalistic haptic feedback on a group of 30 adults, while another group of 30 adults received more traditional real-time visual heartbeat feedback. A single session of haptic, but not visual heartbeat feedback resulted in increased interoceptive accuracy and confidence, as measured by the heart rate discrimination task, and in a shift of attention towards the body. Participants rated the developed technology as more helpful and pleasant than the visual feedback, thus indicating high user satisfaction. The study highlights the importance of matching sensory characteristics of the feedback to the natural bodily prototype. Our work suggests that real-time haptic feedback might be a superior approach to strengthen mind-body interaction in interventions for physical and mental health.HighlightsWe developed a naturalistic real-time haptic feedback system for enhancing cardiac interoception.The intervention resulted in higher interoceptive accuracy and confidence, and in a shift of attention towards the body.Haptic feedback outperformed traditional visual feedback in efficacy and user satisfaction.Results of the study indicate the importance of feedback sensory characteristics in mind-body technologies.
Tissue-specific RNA-seq defines genes governing male tail tip morphogenesis inC. elegans
Authors: Kiontke Karin , Herrera R. Antonio , Mason D. Adam , Woronik Alyssa , Vernooy Stephanie , Patel Yash , Fitch David H. A. 
Published: January 2024

AbstractCaenorhabditis elegansmales undergo sex-specific tail tip morphogenesis (TTM) under the control of the transcription factor DMD-3. To find genes regulated by DMD-3, We performed RNA-seq of laser-dissected tail tips. We identified 564 genes differentially expressed (DE) in wild-type males vs.dmd-3(-)males and hermaphrodites. The transcription profile ofdmd-3(-)tail tips is similar to that in hermaphrodites. For validation, we analyzed transcriptional reporters for 49 genes and found male-specific or male-biased expression for 26 genes. Only 11 DE genes overlapped with genes found in a previous RNAi screen for defective TTM. GO enrichment analysis of DE genes finds upregulation of genes within the UPR (unfolded protein response) pathway and downregulation of genes involved in cuticle maintenance. Of the DE genes, 40 are transcription factors, indicating that the gene network downstream of DMD-3 is complex and potentially modular. We propose modules of genes that act together in TTM and are coregulated by DMD-3, among them the chondroitin synthesis pathway and the hypertonic stress response.
Sexually dimorphic effects of Amylin 1 receptor activation in trigeminovascular neurons
Authors: Labastida-Ramírez Alejandro , Rubio-Beltran Eloisa , Holland Philip R. , Hoffmann Jan 
Published: January 2024

AbstractBackgroundMigraine is more prevalent in women, and although the mechanisms involved in this disparity remain poorly understood, an interaction between the trigeminovascular system and cycling estrogen levels in biologically-predisposed women has been suggested. We investigated the role of amylin 1 (AMY1) receptor activation in the modulation of the trigeminal nociceptive system in female rats across the estrous cycle in cycle stages with falling and rising estrogen levels and compared these to the responses in males.MethodsWe recorded neuronal activityin vivowithin the trigeminocervical complex (TCC) and examined the effects of targeting AMY1receptors on ongoing spontaneous and dural stimulus-evoked firing rates of trigeminovascular neurons. The selective AMY1receptor agonist pramlintide and AMY1receptor antagonist AC 187 were used. Estrous cycle stages were identified via cytology from vaginal smears.ResultsAdministration of pramlintide increased the spontaneous activity and dural stimulus-evoked neuronal responses in the TCC, only during falling estrogen phases of the female estrous cycle. Moreover, the administrationper seof AC 187 decreased spontaneous evoked firing rates of central trigeminovascular neurons in females and males, whereas pretreatment with AC 187 prevented pramlintide-induced increases in spontaneous activity and dural stimulus-evoked responses in females with falling estrogen levels.ConclusionAMY1receptors modulate the trigeminal nociceptive system. The facilitating effect is most pronounced in female rats during falling estrogen phases of the estrous cycle. Our data also supports selective AMY1receptor antagonists as potentially effective targets for the treatment of migraine.