bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome and safety of intraoperative defibrillation testing during device replacement: the Simpler trial
Authors: Milman Anat , Nof Eyal , Rav Acha Moshe , Beinart Roy , Kutyifa Valentina , Merkely Béla , Regev Ehud , Biffi Mauro , Cha Yong-Mei , Ovdat Tal , Klempfner Robert , Glikson Michael 
Published: January 2023

AbstractAimsIntraoperative defibrillation testing (DT) during implant or replacement of implantable cardioverter-defibrillators (ICDs) has been a matter of debate for many years. This debate was put to rest by the Simple and Nordic ICD trials, and the practice of testing during new implantations has essentially been almost abandoned. Old registries demonstrated an increased incidence of significant findings in DT during replacements. The aim of the present study was to evaluate frequency of significant findings and safety of DT in subjects undergoing device replacement.Methods and resultsA prospective observational multi-centre study included consecutive patients undergoing ICD generator replacement. The primary outcome was a failure to terminate induced ventricular fibrillation (VF) with a single shock 10 J below the maximal capacity of the device. Secondary outcomes included complications of DT. Patients were followed-up at 1- and 6-months post-procedure. A total of 92 patients were eligible, and consented to the study, of which 84 underwent DT during battery replacement. The median age was 68 years and 79.8% were males. Induction of VF was successful in 84 patients as was a successful conversion on the first attempt in all. There were no procedure-related complications. During follow up one patient had two appropriate ICD shock events. In four patients, ICD programming was changed. None suffered inappropriate shock. There was no evidence of lead malfunction. Two deaths occurred, none of which was related to arrhythmia.ConclusionThe present study found DT was not associated with complications in patients undergoing ICD generator replacement but produced no clinically important information.
A convergent SAV scheme for Cahn–Hilliard equations with dynamic boundary conditions
Authors: Metzger Stefan 
Published: January 2023

Abstract
The Cahn–Hilliard equation is one of the most common models to describe phase separation processes in mixtures of two materials. For a better description of short-range interactions between the material and the boundary, various dynamic boundary conditions for this equation have been proposed. Recently, a family of models using Cahn–Hilliard-type equations on the boundary of the domain to describe adsorption processes was analysed (cf. Knopf, P., Lam, K. F., Liu, C. & Metzger, S. (2021) Phase-field dynamics with transfer of materials: the Cahn–Hilliard equation with reaction rate dependent dynamic boundary conditions. ESAIM: Math. Model. Numer. Anal., 55, 229–282). This family of models includes the case of instantaneous adsorption processes studied by Goldstein, Miranville and Schimperna (2011, A Cahn–Hilliard model in a domain with non-permeable walls. Phys. D, 240, 754–766) as well as the case of vanishing adsorption rates, which was investigated by Liu and Wu (2019, An energetic variational approach for the Cahn–Hilliard equation with dynamic boundary condition: model derivation and mathematical analysis. Arch. Ration. Mech. Anal., 233, 167–247). In this paper, we are interested in the numerical treatment of these models and propose an unconditionally stable, linear, fully discrete finite element scheme based on the scalar auxiliary variable approach. Furthermore, we establish the convergence of discrete solutions towards suitable weak solutions of the original model. Thereby, when passing to the limit, we are able to remove the auxiliary variables introduced in the discrete setting completely. Finally, we present simulations based on the proposed linear scheme and compare them to results obtained using a stable, nonlinear scheme to underline the practicality of our scheme.
Atypical Presentations of Extraparenchymal Neurocysticercosis
Authors: Fan Jason , Tang Rui , Zhang Lily , Hoang Phuong T. , Ayoade Folusakin , Diaz-Perez Julio A. , Moss Heather E. , Jiang Hong 
Published: January 2023

Background:
Neurocysticercosis (NCC) is the most common parasitic infection of the central nervous system and is typically diagnosed through visualization of the cysts in the cerebral parenchyma by neuro-imaging. However, neuro-imaging may not detect extraparenchymal neurocysticercosis (EPNCC), which is a rare manifestation of the disease involving the subarachnoid, meningeal, and intraventricular spaces. We report 2 cases of extraparenchymal neurocysticercosis, and discuss the diagnostic challenges and management of this entity.

Methods:
Two cases were identified through clinical records.

Results:
Both patients had an insidious onset with slow progression of disease, and presented with papilledema and cerebrospinal fluid (CSF) eosinophilia. One case was diagnosed with spinal cord biopsy. The other was diagnosed with CSF serology and next-generation sequencing–based pathogen analysis. Both patients were treated with ventriculoperitoneal shunt, systemic antiparasitic agents, and immunosuppression.

Conclusions:
EPNCC is less common than parenchymal NCC. A high level of clinical suspicion is required given its rarity, long incubation period, and slow progression. Diagnosis and treatment can be challenging and requires a multidisciplinary approach.
Novel CAF-identifiers via transcriptomic analysis in oral cancer patients
Authors: Dwivedi Nehanjali , Shukla Nidhi , Das Manjula , Dhar Sujan K 
Published: January 2023

AbstractBackgroundCancer-associated fibroblasts (CAFs), a prominent component of the tumor microenvironment, plays an important role in tumor development, invasion, and drug resistance. The expression of distinct “CAF markers,” which separates CAFs from normal fibroblasts and epithelial cells, have traditionally been used to identify them. These commonly used CAF markers have been reported to differ greatly across microenvironmental subpopulations even within a cancer site.MethodsUsing an unbiased data analysis approach utilizing publicly available and in-house gene expression data from patient derived novel CAF cells, we identified a collection of markers in oral cancer to distinguish CAF populations from tumor epithelia and normal oral fibroblasts.ResultsCOL1A1, SPARC, COL1A2, COL3A1 and TIMP-1 were identified as potential markers which can be utilized to differentiate cancer associated fibroblast from all other cell types including normal fibroblasts in oral cancer.
APOE3Christchurch modulates tau phosphorylation and β-catenin/Wnt/Cadherin signaling in induced pluripotent stem cell-derived cerebral organoids from Alzheimer’s cases
Authors: Mazzarino RC , Perez-Corredor P , Vanderleest TE , Vacano GN , Sanchez JS , Villalba-Moreno ND , Krausemann S , Mendivil-Perez MA , Aguillón D , Jimenez-Del-Río M , Baena A , Sepulveda-Falla D , Lopera FJ , Quiroz YT , Arboleda-Velasquez JF 
Published: January 2023

AbstractAlzheimer’s disease (AD) is the most common cause of dementia among older adults.APOE3Christchurch (R136S,APOE3Ch) variant homozygosity was reported in an individual with extreme resistance to autosomal dominant AD due to thePSEN1E280A mutation. This subject had a delayed clinical age at onset and resistance to tauopathy and neurodegeneration despite extremely high amyloid plaque burden. We established induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and from a non-protected kindred control (withPSEN1E280A andAPOE3/3). We used CRISPR/Cas9 gene editing to successfully remove theAPOE3Chto wild type in iPS cells from the protected case and to introduce theAPOE3Chas homozygote in iPS cells from the non-protected case to examine causality. We found significant reduction of tau phosphorylation (pTau 202/205 and pTau396) in cerebral organoids with theAPOE3Chvariant, consistent with the strikingly reduced tau pathology found in the resistant case. We identified Cadherin and Wnt pathways as signaling mechanisms regulated by theAPOE3Chvariant through single cell RNA sequencing in cerebral organoids. We also identified elevated β-catenin protein, a regulator of tau phosphorylation, as a candidate mediator ofAPOE3Chresistance to tauopathy. Our findings show thatAPOE3Chis necessary and sufficient to confer resistance to tauopathy in an experimentalex-vivomodel establishing a foundation for the development of novel, protected case-inspired therapeutics for tauopathies, including Alzheimer’s.
Deep-learning based bioactive peptides generation and screening against Xanthine oxidase
Authors: Zhang Haiping , Saravanan Konda Mani , Zhang John Z.H. , Wu Xuli 
Published: January 2023

AbstractIn our previous work, we have developed LSTM_Pep to generatede novopotential active peptides by finetuning with known active peptides and developed DeepPep to effectively identify protein-peptide interaction. Here, we have combined LSTM_Pep and DeepPep to successfully obtained an activede novopeptide (ARG-ALA-PRO-GLU) of Xanthine oxidase (XOD) with IC50 value of 3.76mg/mL, and XOD inhibitory activity of 64.32%. Consistent with the experiment result, the peptide ARG-ALA-PRO-GLU has the highest DeepPep score, this strongly supports that we can generatede novopotential active peptides by finetune training LSTM_Pep over some known active peptides and identify those active peptides by DeepPep effectively. Our work sheds light on the development of deep learning-based methods and pipelines to effectively generate and obtain bioactive peptides with a specific therapeutic effect and showcases how artificial intelligence can help discoverde novobioactive peptides that can bind to a particular target.
Activation Dynamics of Ubiquitin Specific Protease 7
Authors: Valles Gabrielle J. , Jaiswal Nancy , Korzhnev Dmitry M. , Bezsonova Irina 
Published: January 2023

ABSTRACTUbiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme responsible for the regulation of key human oncoproteins and tumor suppressors including Mdm2 and p53, respectively. Unlike other members of the USP family of proteases, the isolated catalytic domain of USP7 adopts an enzymatically inactive conformation that has been well characterized using X-ray crystallography. The catalytic domain also samples an active conformation, which has only been captured upon USP7 substrate-binding. Here, we utilized CPMG NMR relaxation dispersion studies to observe the dynamic motions of USP7 in solution. Our results reveal that the catalytic domain of USP7 exchanges between two distinct conformations, the inactive conformation populated at 95% and the active conformation at 5%. The largest structural changes are localized within functionally important regions of the enzyme including the active site, the ubiquitin-binding fingers, and the allosteric helix of the enzyme, suggesting that USP7 can adopt its active conformation in the absence of a substrate. Furthermore, we show that the allosteric L299A activating mutation disturbs this equilibrium, slows down the exchange, and increases the residence time of USP7 in its active conformation, thus, explaining the elevated activity of the mutant. Overall, this work shows that the isolated USP7 catalytic domain pre-samples its “invisible” active conformation in solution, which may contribute to its activation mechanism.
Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer
Authors: Yan Wei , Steele Nina G. , Kemp Samantha B. , Menjivar Rosa E. , Du Wenting , Carpenter Eileen S. , Donahue Katelyn L. , Brown Kristee L. , Irizarry-Negron Valerie , Yang Sion , Burns William R. , Zhang Yaqing , di Magliano Marina Pasca , Bednar Filip 
Published: January 2023

AbstractPancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAMs) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, express high levels of Notch receptors with cognate ligands such asJAG1expressed on tumor epithelial cells, endothelial cells and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators including arginase 1 (Arg1) suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Combination of Notch inhibition with PD-1 blockade resulted in increased cytotoxic T cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in PDA patients.
Analysis of the molecular determinants for furin cleavage of the spike protein S1/S2 site in defined strains of the prototype coronavirus murine hepatitis virus (MHV)
Authors: Choi Annette , Kots Ekaterina D. , Singleton Deanndria T. , Weinstein Harel A. , Whittaker Gary R. 
Published: January 2023

ABSTRACTWe have analyzed the spike protein S1/S2 cleavage site of selected strains of MHV by the cellular protease furin, in order to understand the structural requirements underlying the sequence selectivity of the scissile segment. The probability of cleavage of the various MHV strains was first evaluated from furin cleavage scores predicted by the ProP computer software, and then cleavage was measured experimentally with a fluorogenic peptide cleavage assay consisting of S1/S2 peptide mimics and purified furin. We found thatin vitrocleavability varied across MHV strains in line with predicted results—but with the notable exception of MHV-A59, which was not cleaved despite a high score predicted for its sequence. Using the known X-Ray structure of furin in complex with a substrate-like inhibitor as an initial structural reference, we carried out molecular dynamics (MD) simulations to learn the modes of binding of the peptides in the furin active site, and the suitability of the complex for initiation of the enzymatic cleavage. We thus identified the 3D structural requirements of the furin active site configuration that enable bound peptides to undergo cleavage, and the way in which the various strains tested experimentally are fulfilling these requirements. We find that despite some flexibility in the organization of the peptide bound to the active site of the enzyme, the presence of a histidine at P2 of MHV-A59 fails to properly orient the sidechain of His194 of the furin catalytic triad and therefore produces a distortion that renders the peptide/complex structural configuration in the active site incompatible with requirements for cleavage initiation. The Ser/Thr in P1 of MHV-2 and MHV-S has a similar effect of distorting the conformation of the furin active site residues produced by the elimination of the canonical salt-bridge formed by arginine in P1 position. This work informs a study of coronavirus infection and pathogenesis with respect to the function of the viral spike protein, and suggests an important process of viral adaptation and evolution within the spike S1/S2 structural loop.
Longitudinal changes in Alzheimer’s-related plasma biomarkers and brain amyloid
Authors: Bilgel Murat , An Yang , Walker Keenan A. , Moghekar Abhay R. , Ashton Nicholas J. , Kac Przemysław R. , Karikari Thomas K. , Blennow Kaj , Zetterberg Henrik , Jedynak Bruno M. , Thambisetty Madhav , Ferrucci Luigi , Resnick Susan M. 
Published: January 2023

AbstractIntroductionUnderstanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer’s progression assessment strategies.MethodsWe examined the temporal order of changes in plasma amyloid-β ratio (Aβ42/Aβ40), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios (p-tau181/Aβ42, p-tau231/Aβ42) relative to11C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB−/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up.ResultsPiB groups exhibited different rates of longitudinal change in Aβ42/Aβ40(β= 5.41 × 10-4, SE = 1.95 × 10-4,p= 0.0073). Change in brain amyloid correlated with change in GFAP (r= 0.5, 95% CI = [0.26, 0.68]). Greatest relative decline in Aβ42/Aβ40(-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]).DiscussionPlasma Aβ42/Aβ40may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time.
Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing
Authors: Felker Stephanie A , Lawlor James MJ , Hiatt Susan M , Thompson Michelle L , Latner Donald R , Finnila Candice R , Bowling Kevin M , Bonnstetter Zachary T , Bonini Katherine E , Kelly Nicole R , Kelley Whitley V , Hurst Anna CE , Kelly Melissa A , Nakouzi Ghunwa , Hendon Laura G , Bebin E Martina , Kenny Eimear E , Cooper Gregory M 
Published: January 2023

ABSTRACTPurposeNeurodevelopmental disorders (NDDs) often result from rare genetic variation, but genomic testing yield for NDDs remains around 50%, suggesting some clinically relevant rare variants may be missed by standard analyses. Here we analyze “poison exons” (PEs) which, while often absent from standard gene annotations, are alternative exons whose inclusion results in a premature termination codon. Variants that alter PE inclusion can lead to loss-of-function and may be highly penetrant contributors to disease.MethodsWe curated published RNA-seq data from developing mouse cortex to define 1,937 PE regions conserved between humans and mice and potentially relevant to NDDs. We then analyzed variants found by genome sequencing in multiple NDD cohorts.ResultsAcross 2,999 probands, we found six clinically relevant variants in PE regions that were previously overlooked. Five of these variants are in genes that are part of the sodium voltage-gated channel alpha subunit family (SCN1A, SCN2A, andSCN8A), associated with epilepsies. One variant is inSNRPB, associated with Cerebrocostomandibular Syndrome. These variants have moderate to high computational impact assessments, are absent from population variant databases, and were observed in probands with features consistent with those reported for the associated gene.ConclusionWith only a minimal increase in variant analysis burden (most probands had zero or one candidate PE variants in a known NDD gene, with an average of 0.77 per proband), annotation of PEs can improve diagnostic yield for NDDs and likely other congenital conditions.
Identifying the suite of genes central to swimming in the biocontrol bacteriaPseudomonas protegensPf-5
Authors: Fabian BK , Foster C , Asher A , Hassan KA , Paulsen IT , Tetu SG 
Published: January 2023

AbstractSwimming motility is a key bacterial trait, important to success in many niches, including assisting in colonization of host surfaces. Biocontrol bacteria, such asPseudomonas protegensPf-5 are increasingly being used as an agricultural tool to control crop diseases, where motility is a factor in successful colonization of the plant rhizosphere. Swimming motility has been studied in a range of bacteria and typically involves a suite of flagella and chemotaxis genes, however the specific gene set employed for both regulation and biogenesis can differ substantially between organisms. Here we used transposon directed insertion site sequencing (TraDIS), a genome-wide approach, to identify 249 genes involved inP. protegensPf-5 swimming motility. As expected, flagella and chemotaxis genes comprised a large proportion of these genes. However we also identified a suite of additional genes important for swimming, including genes related to peptidoglycan turnover, O-antigen biosynthesis, cell division, signal transduction, c-di-GMP turnover and phosphate transport, along with 27 conserved hypothetical proteins. Experimental gene knockout mutants and TraDIS data together suggest that defects in the Pst phosphate transporter lead to enhanced swimming motility. Overall, this study expands our knowledge of pseudomonad motility and highlights the utility of a TraDIS-based approach for systematically analyzing the functions of thousands of genes. This work sets a foundation for understanding how swimming motility may be related to the inconsistency in biocontrol bacteria effectiveness and reliability in the field.ImportanceBiocontrol bacteria, such asPseudomonas protegensPf-5 are increasingly being used as an agricultural tool to control crop diseases, and motility is a key factor in their successful colonization of plant surfaces. Here we use a high-throughput approach to identify the suite of genes important for swimming motility inP. protegensPf-5. These included flagella and chemotaxis genes, as well as a variety of cell surface, cell division and signalling genes. We also show that defects in the Pst phosphate transporter lead to enhanced swimming motility, a hitherto unreported link between phosphate transport and swimming motility. Understanding the genetic basis of swimming motility enhances our knowledge of key processes in biocontrol bacteria that are needed to ensure their competitive success. This will contribute to developing strategies to increase the utility of biocontrol bacteria in agricultural settings to prevent crop losses.
Lytic bacteriophage vB_KmiS-Kmi2C disrupts biofilms formed by members of theKlebsiella oxytocacomplex, and represents a novel virus family and genus
Authors: Newberry Fiona , Shibu Preetha , Smith-Zaitlik Thomas , Eladawy Mohamed , McCartney Anne L. , Hoyles Lesley , Negus David 
Published: January 2023

ABSTRACTAIMSThis study aimed to characterise the lytic phage vB_KmiS-Kmi2C, isolated from sewage water on a GES-positive strain ofKlebsiella michiganensis.METHODS AND RESULTSComparative phylogenetic and network-based analyses were used to characterise the genome of phage vB_KmiS-Kmi2C (circular genome of 42,234 bp predicted to encode 55 genes), demonstrating it shared little similarity with other known phages. The phage was lytic on clinical strains ofK. oxytoca(n=2) andK. michiganensis(n=4), and was found to both prevent biofilm formation and disrupt established biofilms produced by these strains.CONCLUSIONSWe have identified a phage capable of killing clinically relevant members of theKlebsiella oxytocacomplex (KoC). The phage represents a novel virus family (proposed nameDilsviridae) and genus (proposed nameDilsvirus).SIGNIFICANCE AND IMPACT OF THE STUDYIdentification a novel lytic phage active against clinically relevant strains of the KoC provides an alternative to antibiotics to treat these increasingly antimicrobial-resistant opportunistic pathogens. The unusual way in which the phage can disrupt established biofilms may allow us to identify novel phage-based approaches for biofilm remediation in the future.