bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropathic Gastroduodenal Disorders can be Diagnosed by Non-Invasive Body Surface Gastric Mapping: a Comparison with Antroduodenal Manometry
Authors: Sadaka Christian , Xu Binghong , Benitez Alain J , Orians Carolyn M. , Bowerman Corey , Dourlain Jordan , Skaggs Beth , Konka Kimberly G. , Roshkovan Lexi , Humphrey Gayl , Calder Stefan , Schamberg Gabriel , O’Grady Greg , Gharibans Armen A , Mousa Hayat 
Published: November 2024

AbstractBackgroundAntroduodenal manometry (ADM) is the gold standard for diagnosing myopathy and neuropathy in patients with upper gastrointestinal (GI) disorders. However, ADM is invasive and costly. Body surface gastric mapping (BSGM) has emerged as a non-invasive test to assess gastric function. This study evaluates the correlation between BSGM and ADM in children.MethodsClinically indicated ADM was performed using high-resolution water-perfused motility catheters, with simultaneous BSGM. Real-time symptoms were tracked using a validated symptom logging app at 15-min intervals, and Nausea Severity Scale (NSS) scores recorded. Protocols involved a 2 hour fast, provocative testing, a meal, and over 1 hr of postprandial recordings. ADM tracings were categorized into neuropathy, myopathy, postprandial hypomotility, or normal. BSGM metrics included principal gastric frequency, BMI-adjusted amplitude, and Rhythm Index. Gastric emptying data were also evaluated.ResultsFifteen subjects were recruited (13 female; ages 10-19 years, BMI 20.6±3.5 kg/m2). ADM results showed neuropathy (n=4), myopathy (n=1), post-prandial hypomotility (n=4), and normal motility (n=6). Patients with neuropathy had lower rhythm stability (0.16±0.03 vs 0.38±0.17; p=.001), accompanied by higher nausea scores (8.2±1.2 vs 3.15±2.9; p<.001) and bloating (7.3±0.9 vs 2.1±2.0; p<.001). ADM neuropathy correlated completely with dysrhythmia on BSGM. Normal ADM were consistent with normal BSGM in 83.3% of cases. Delayed gastric emptying did not correlate with a neuropathic diagnosis.ConclusionDysrhythmic BSGM phenotype reliably identified gastrointestinal neuropathy with identical results to ADM, with significant correlations to nausea and bloating severity. This study supports considering BSGM as an actionable biomarker when performing ADM is not feasible.Key points–Body Surface Gastric Mapping (BSGM) low stability phenotype correlated perfectly with neuropathy detected on Antroduodenal Manometry (ADM). The BSGM normal phenotype also showed a good correlation with normal ADM studies.–BSGM low stability phenotype was linked to higher severity scores for nausea and bloating.Abbreviations used: Antroduodenal Manometry (ADM), Body Surface Gastric Mapping (BSGM), Gastric Emptying Scintigraphy (GES), Gastroparesis (GP), Functional Dyspepsia (FD), Electrogastrography (EGG)
ALPK3 heterozygous truncating variants cause late-onset hypertrophic cardiomyopathy with frequent apical involvement and apical aneurysm
Authors: Busse Leora , Huth Emily A , Abraham Maria Roselle , Abraham Theodore , Padmanabhan Arun , Wojciak Julianne , Wright Gabrielle , Aatre Rajani , Campagna Rachel , Jackson Erika , Kreykes Sarah , Lane Kimberly , Sawyer Lindsey , Stevens Chelsea , Thomas Matthew , VanDyke Rebecca , Vedantham Vasanth , Higgs Emily J 
Published: November 2024

ABSTRACTHypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder with several established genotype-phenotype relationships. While biallelic truncating variants in theALPK3gene cause severe congenital HCM, recent studies have associated heterozygous truncating variants (ALPK3tv) with milder adult-onset HCM. Here we describe a multicenter cohort of 21 individuals with heterozygous ALPK3tv from 10 institutions in the United States, highlighting distinctive clinical characteristics compared to a control group of 132 patients with HCM caused by deleterious variants in sarcomeric genes. As compared to other HCM genotypes, ALPK3tv patients present at an older age (mean 57.25 years) with significantly lower left ventricular wall thickness (14.09 vs 19.78 mm with echocardiogram and 16.13 vs 21.13 mm with cardiac MRI), a lower prevalence of obstructive HCM (15% of ALPK3tv vs 45% of controls), and a strikingly higher incidence of apical aneurysm (22.22% vs. 2.40% in the control group). These results suggest a milder degree of hypertrophy in heterozygous ALPK3-related HCM as compared to other Mendelian causes of HCM, although the increased occurrence of apical aneurysms could have implications for ventricular arrhythmia risk. Our study underscores the importance of recognizing heterozygous ALPK3tv as a cause of adult-onset HCM and provides a comprehensive characterization of its clinical phenotype.
Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity
Authors: Oswald Brandon M. , DeCamp Lisa M. , Longo Joseph , Dahabieh Michael S. , Bunda Nicholas , Ma Shixin , Watson McLane J , Sheldon Ryan D. , Vincent Michael P. , Johnson Benjamin K. , Ellis Abigail E , Soper-Hopper Molly T. , Isaguirre Christine N , Shen Hui , Williams Kelsey S. , Crawford Peter A. , Kaech Susan , Jang H. Josh , Krawczyk Connie M. , Jones Russell G. 
Published: November 2024

AbstractReducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8+T cell-mediated anti-tumor immunity. DR reshapes CD8+T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth. Mechanistically, DR enhances CD8+T cell metabolic fitness through increased ketone body oxidation (ketolysis), which boosts mitochondrial membrane potential and fuels tricarboxylic acid (TCA) cycle-dependent pathways essential for T cell function. T cells deficient for ketolysis exhibit reduced mitochondrial function, increased exhaustion, and fail to control tumor growth under DR conditions. Our findings reveal a critical role for the immune system in mediating the anti-tumor effects of DR, highlighting nutritional modulation of CD8+T cell fate in the TME as a critical determinant of anti-tumor immunity.
Developmental Stage and Cellular Context Determine Oncogenic and Molecular Outcomes ofEzh2Y641FMutation in Hematopoiesis
Authors: Zimmerman Sarah M. , Procasky Samantha J. , Smith Sofia R. , Liu Jie-Yu , Torrice Chad , Souroullas George P. 
Published: November 2024

AbstractMutations in the histone methyltransferase EZH2, particularly the Y641 hotspot mutation, have been implicated in hematologic malignancies, yet the effect of timing and cellular context on their oncogenic potential has remained unknown. In this study, we utilized a conditional allele with tissue-specific Cre drivers to investigate the effects ofEzh2Y641Fmutations at various stages of development, with a focus on the hematopoietic system. We found that ubiquitous heterozygousEzh2Y641Fexpression at birth, or conditional expression in hematopoietic or mesenchymal stem cells, led to decreased survival due to hematopoietic defects and bone marrow failure, with no evidence of malignancy. In contrast,Ezh2Y641Fexpression in committed B cells drives lymphoma formation, highlighting the lineage-specific oncogenic activity of the mutation. Transcriptomic analysis of B cell progenitors revealed key pathway alterations between Cre models such as altered IL2-Stat5 signaling pathway, differential expression of E2F targets, and altered GTPase pathway expression driven by upregulation of Guanylate Binding Proteins (GBPs) in Mx1-CreEzh2Y641Fpro-B cells. We further found that the GBP locus is regulated by Ezh2-mediated H3K27me3, it is associated with poorer survival in Acute Myeloid Leukemia patients and has variable effects on apoptosis in human lymphoma and leukemia cell lines. These findings suggest that theEzh2Y641Fmutation may alter immune regulatory pathways, cell differentiation and apoptosis, with potential implications for disease progression. Our results highlight the critical role of mutation timing and cellular context in EZH2-driven hematopoietic disease, resulting in distinct downstream changes that shape the oncogenic impact of EZH2.
Telomeric Repeat-Containing RNA Increases in Aged Human Cells
Authors: Hsieh Yu-Hung , Tai Chin-Hua , Yeh Meng-Ting , Chen Yu-Chen , Yang Po-Cheng , Yen Chien-Ping , Han Der-Sheng , Chu Hsueh-Ping Catherine 
Published: November 2024

AbstractTelomeric repeat-containing RNA (TERRA), transcribed from subtelomeric regions towards telomeric ends, poses challenges in deciphering its complete sequences. Utilizing TERRA-capture RNA-seq and Oxford Nanopore direct RNA sequencing to acquire full-length TERRA, we annotate TERRA transcription regions in the human T2T-CHM13 reference genome. TERRA transcripts encompass hundreds to over a thousand nucleotides of telomeric repeats, predominantly originating from 61-29-37 bp repeat promoters enriched with H3K4me3, RNA pol II, CTCF, and R-loops. We develop a bioinformatics tool, TERRA-QUANT, for quantifying TERRA using RNA-seq datasets and find that TERRA increases with age in blood, brain, and fibroblasts. TERRA upregulation in aged leukocytes is confirmed by RT-qPCR. Single-cell RNA-seq analysis demonstrates TERRA expression across various cell types, with upregulation observed in neurons during human embryonic stem cell differentiation. Additionally, TERRA levels are elevated in brain cells in the early stage of Alzheimer’s disease. Our study provides evidence linking TERRA to human aging and diseases.
Benchmarking GROMACS on Optimized Colab Processors and the Flexibility of Cloud Computing for Molecular Dynamics
Authors: Karagöl Taner , Karagöl Alper 
Published: November 2024

AbstractMoleculardynamics (MD) simulations are widely used computational tools in chemical and biological sciences. For these simulations, GROMACS is a popular open-source alternative among molecular dynamics simulation software designed for biochemical molecules. In addition to software, these simulations traditionally relied on costly infrastructure like supercomputers or clusters forHigh-PerformanceComputing (HPC). In recent years, there has been a significant shift towards using commercial cloud providers’ computing resources, in general. This shift is driven by the flexibility and accessibility these platforms offer, irrespective of an organization’s financial capacity. Many commercial compute platforms such asGoogleComputeEngine (GCE) andAmazonWebServices (AWS) provide scalable computing infrastructure. An alternative to these platforms is Google Colab, a cloud-based platform, provides a convenient computing solution by offering GPU and TPU resources that can be utilized for scientific computing. The accessibility of Colab makes it easier for a wider audience to conduct computational tasks without needing specialized hardware or otherwise costly infrastructure. However, running GROMACS on Colab also comes with limitations. Google Colab imposes usage restrictions, such as time limits for continuous sessions, capped at several hours, and limits on the availability of high-performance GPUs. Users may also face disruptions due to session timeouts or hardware availability constraints, which can be challenging for large or long-running molecular simulations. We have significantly enhanced the performance of GROMACS on Google Colab by re-compiling the software, compared to its default pre-compiled version. We also present a method for integrating Google Drive to save and resume interrupted simulations, ensuring that users can secure files after session-timeouts. Additionally, we detail the setup and utilization of the CUDA and MPI environment in Colab to enhance GROMACS performance. Finally, we compare the efficiency of CUDA-enabled GPUs with Google’s TPUv2 units, highlighting the trade-offs of each platform for molecular dynamics simulations. This work equips researchers, students, and educators with practical MD tools while providing insights to optimize their simulations within the Colab environment.
Finite element model of the non-keratinized buccal tissue under the impact of negative pressure
Authors: Klein Cerrejon David , Gao Daniel , Sachs David 
Published: November 2024

AbstractThe buccal mucosa is a highly interesting site for non-invasive drug delivery due to its relatively permeable epithelium and good accessibility. Recently, device-based systems have enabled the delivery of macromolecular drugs by leveraging mechanical stretching forces on the tissue to assist drug diffusion. Despite the successful exploitation of the buccal route with such systems, the biomechanics of buccal tissue are still poorly characterized and understood due to a lack of adequate characterization methods. Therefore, we propose a combination of physiological tissue modeling with simple suction experiments as a tool for characterizing and understanding the buccal tissue under the impact of negative pressure. Here, we present an initial step towards a multiphasic and poroelastic model specifically designed for the non-keratinized buccal tissue under the impact of negative pressure. A validated finite element model (FEM) for human skin was adapted to represent the histological structure of porcine buccal tissue. We performed suction experiments using the NIMBLE device, specifically developed for measuring skin stiffness, to characterize its mechanical behavior and train the FEM model. The resulting simulation tracks essential physiological parameters and allows the prediction of measurable changes in the tissue, such as the thinning of the epithelium and single-cell stretching. The FEM simulation was validated through histochemically stained tissue sections at the NIMBLE application site. A good correlation was demonstrated between predicted and experimentally observed changes. This work serves as a first step towards a computational representation of buccal tissue under the impact of negative pressure.
Optimization of the VSV G backbone for amino terminal fusion with nanobodies allowing its retargeting to receptors of therapeutic interest
Authors: Duquénois Isoline , Thébault Stéphanie , Johari Sarah , Raux Hélène , Ouldali Malika , Lagaudrière-Gesbert Cécile , Perez Franck , Albertini Aurélie A. , Gaudin Yves 
Published: November 2024

SummaryVesicular stomatitis virus (VSV) is a promising oncolytic virus. Additionally, its glycoprotein G is the most commonly used envelope glycoprotein to pseudotype lentiviral vectors for gene therapy. However, G receptors (LDLR family members) are ubiquitous and expressed at the surface of non-target cells, precludingin vivogene therapy. Recently, we identified G mutants that no longer bind to LDLR but retain their fusion activity. This opened the possibility of specifically retargeting the glycoprotein to receptors of interest. Here, we constructed chimeric glycoproteins fused with a nanobody at the amino-terminus of G. By experimental evolution, we identified two mutations in G improving the folding and functionality of chimeric Gs, regardless of the nanobody inserted at the amino-terminus. We then constructed chimeric glycoproteins using several nanobodies targeting HER2 receptor and, into these chimeras, we introduced mutations that abolish the recognition of LDL receptors. VSV and lentiviruses pseudotyped with these glycoproteins specifically infect cells expressing HER2. We have therefore identified G mutations that optimize the G scaffold to tolerate amino-terminal insertion of a nanobody and establish proof of concept that this approach can be used to confer a new tropism on G. This paves the way for targetedin vivotherapies.
Differential Expression Analysis with InMoose, the Integrated Multi-Omic Open-Source Environment in Python
Authors: Colange Maximilien , Appé Guillaume , Meunier Léa , Weill Solène , Nordor Akpéli , Behdenna Abdelkader 
Published: November 2024

AbstractWe present the differential expression features of InMoose, a Python implementation of R toolslimma, edgeR, andDESeq2. We experimentally show that InMoose stands as a drop-in replacement for those tools, with nearly identical results. This ensures reproducibility when interfacing both languages in bioinformatic pipelines. InMoose is an open source software released under the GPL3 license, available atwww.github.com/epigenelabs/inmooseandhttps://inmoose.readthedocs.io.
DistinguishingPEXgene variant severity for mild, severe, and atypical peroxisome biogenesis disorders inDrosophila
Authors: Gomez Vanessa A. , Kanca Oguz , Jangam Sharayu V. , Srivastav Saurabh , Andrews Jonathan C. , Wangler Michael F. 
Published: November 2024

AbstractPeroxisomal biogenesis disorders (PBD) are autosomal recessive disorders caused by loss-of-function mutations of one of thePEXgenes responsible for peroxisomal formation. Impaired peroxisome assembly causes severe multisystemic failure with patient phenotypes ranging from epilepsy, liver disease, feeding issues, biochemical abnormalities, and neurodegeneration. Variants in the samePEXgene can produce wide differences in severity, ranging from individuals with death in the first year of life to adults with milder complications. To study this strong genotype-phenotype correlation, we selected specific humanPEXgene mutations and utilizedDrosophilaas a model organism. We generated flies replacing the coding sequence of ourPexgene of interest with aKozakGAL4 (KZ)promoter trap sequence. These cassettes simultaneously knock-out of thePexgene and knock-in aGAL4driver, ideal for making “humanized” flies in which the humanPEXgene can replace the fly loss. We assessedPex2KZandPex16KZlines in lifespan, bang sensitivity, and climbing assays and confirmed that these are strong loss-of-function alleles. In parallel, we generated human reference and variant UAS-cDNA lines ofPEX2andPEX16variants inDrosophila. We observed nearly complete phenotypic rescue ofDrosophila Pex2andPex16loss when humanPEX2ReforPEX16Ref, respectively, were expressed. We also provide evidence for an allele severity spectrum inPEX2andPEX16in which some missense alleles, such asPEX2C247R, are equally severe as early truncations, such asPEX2R119*. We also observed that alleles associated with mild PBD, such asPEX2E55K, show variability depending on the assay but do not fully rescue. Finally, alleles associated with atypical ataxia phenotypes, such asPEX16F332Del, can perform as well asPEX16Ref, depending on the assay. Altogether, theseDrosophilalines effectively model the range of severity of peroxisomal biogenesis disorders.
Steric Repulsion Counteracts ER-to-Lipid Droplet Protein Movement
Authors: Damm Alicia , Stojanović Ozren , Esch Bianca M. , Carpentier Maxime , Omrane Mohyeddine , Forêt Lionel , Fröhlich Florian , Klemm Robin , Thiam Abdou Rachid 
Published: November 2024

AbstractLipid droplets (LDs) are uniquely shaped organelles consisting of a neutral lipid core surrounded by a phospholipid monolayer, continuous with the cytosolic leaflet of the endoplasmic reticulum (ER). The dynamics and function of LDs are closely tied to their proteome composition, which is subject to dynamic remodeling. Key proteins essential for LD biology relocate from the ER to LDs, yet the mechanisms governing their movement and accumulation in LDs remain poorly understood. Here, we developed an innovative ex vivo tool to quantify and classify ER proteins based on their affinity for LDs. We found a broad spectrum of ER-to-LD partitioning affinities. We identified steric hindrance as a key factor in regulating ER-to-LD protein transfer, where proteins with only slightly higher LD affinity can effectively displace those with lower affinity from the LD surface. Consistent with this model, we observed that differentiation of 3T3 pre-adipocytes into adipocytes involves extensive remodeling of ER proteins targeting LDs, with Plin1—a high-affinity LD protein—becoming predominantly recruited and excluding other ER proteins. These findings highlight lateral protein-protein exclusion as a fundamental mechanism in shaping the LD proteome, providing new insights into LD biogenesis and function.
Amphipathic helices sense the inner nuclear membrane environment through lipid packing defects
Authors: Lee Shoken , Le Roux Anabel-Lise , Mors Mira , Vanni Stefano , Roca-Cusachs Pere , Bahmanyar Shirin 
Published: November 2024

SummaryAmphipathic helices (AHs) are ubiquitous protein motifs that modulate targeting to organellar membranes by sensing differences in bulk membrane properties. However, the adaptation between membrane-targeting AHs and the nuclear membrane environment that surrounds the genome is poorly understood. Here, we computationally screened for candidate AHs in a curated list of characterized and putative human inner nuclear membrane (INM) proteins. Cell biological andin vitroexperimental assays combined with computational calculations demonstrated that AHs detect lipid packing defects over electrostatics to bind to the INM, indicating that the INM is loosely packed under basal conditions. Membrane tension resulting from hypotonic shock further promoted AH binding to the INM, whereas cell-substrate stretch did not enhance recruitment of membrane tension-sensitive AHs. Together, our work demonstrates the rules driving lipid-protein interactions at the INM, and its implications in the response of the nucleus to different stimuli.
The effects of soleus push up on glucose tolerance among individuals with prediabetes
Authors: Elek Dávid , Tóth Miklós , Sonkodi Balázs , Ács Pongrác , Kovács Gábor L. , Melczer Csaba 
Published: November 2024

SUMMARYThe objective of this study was to assess the efficacy of a previously invented soleus-dominant exercise in reducing postprandial blood glucose levels in individuals with prediabetes and to evaluate the feasibility of incorporating this soleus push up exercise into their daily routine. It seems that performing the mostly soleus-involved activity in a sitting position during the oral glucose tolerance test results in ∼32% lower postprandial glucose excursion than the control results. This effect is also present in the absence of electromyographic feedback. Hereby we conclude that performing this repetitive prolonged contractile muscle activity may help metabolic regulation even in prediabetic people without the need of a laboratory setting. Therefore soleus push up is a potent exercise method that can be effectively completed in a home setting or work environment. However, further validation of this treatment method should be studied in a larger sample size.