bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Molecular Signature of Neuropathic Pain in a Human Model System
Authors: Sandy-Hindmarch Oliver P , Chang Pao-Sheng , Scheuren Paulina Simonne , De Schoenmacker Iara , Hubli Michèle , Loizou Constantinou , Wirth Stephan , Mahadevan Devendra , Wiberg Akira , Furniss Dominic , Denk Franziska , Baskozos Georgios , Schmid Annina 
Published: January 2024

AbstractPeripheral neuropathic pain remains challenging to treat, partly due to our limited understanding of the molecular mechanisms at play in humans. In this multicentre cohort study, we describe the local molecular signature of neuropathic pain at the lesion site, using peripheral nerves of patients with Morton’s neuroma as a human model system of neuropathic pain.Plantar tibial nerves were collected from 22 patients with Morton’s neuroma (18 female, median age 60.0 [IQR 16.0] years) and control nerves from 11 participants (4 females, 58.0 [21.0] years) without a nerve injury. Pre-surgery, we collected data on pain severity, duration and nature (e.g., neuropathic pain inventory, NPSI).RNA bulk sequencing of peripheral nerves identified 3349 genes to be differentially expressed between Morton’s neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses (WGCNA) revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed that the densities of macrophages as well as B-cells were higher in Morton’s neuroma than control samples. The findings for T-cells were inconclusive. Modules associated with defence response, neurogenesis and muscle system development correlated with paroxysmal and evoked pain in people with Morton’s neuroma. Macrophage cell populations identified by deconvolution analysis as well as single differentially expressed genes (MARCO, CD163, STAB1;indicating the presence of a specific M(GC) subset of macrophages) correlated with paroxysmal pain.Immunofluorescent analyses confirmed the presence of demyelination, higher densities of intraneural T-cells and CD163+MARCO+macrophage subsets in Morton’s neuroma compared to control nerves. Histological CD68+macrophage density correlated with burning pain. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO+subset implicated.
Redefining Clinical Hyperprogression: the Incidence, Clinical Implications, and Risk Factors of Hyperprogression in Non-Small Cell Lung Cancer Treated with Immunotherapy
Authors: Djunadi Trie Arni , Oh Youjin , Lee Jeeyeon , Yu Jisang , Chung Liam Il-Young , Lee Yeunho , Kim Leeseul , Hong Timothy , Lee Soowon , Shah Zunairah , Park Joo Hee , Yoon Sung Mi , Chae Young Kwang 
Published: January 2024

AbstractIntroductionImmune checkpoint inhibitors (ICIs) may be associated with hyperprogressive disease (HPD). However, there is currently no standardized definition of HPD, with its risk factors and clinical implications remaining unclear. We investigated HPD in lung cancer patients undergoing immunotherapy, aiming to redefine HPD, identify risk factors, and assess its impact on survival.MethodsClinical and radiologic data from 121 non-small cell lung cancer (NSCLC) patients with 136 immunotherapy cases were reviewed retrospectively. Three HPD definitions (Champiat et al., HPDc; Saâda-Bouzid et al., HPDs; and Ferrara et al., HPDf) were employed. Additionally, all new measurable lesions on the post-treatment CT scan were incorporated in measuring the sum of longest diameters (SLD) to define modified HPD (mHPD).ResultsAmong the 121 patients, 4 (3.3%) had HPDc, 11 (9.1%) had HPDs, and none had HPDf. Adding all new measurable lesions increased HPD incidence by 5%–10% across definitions. Multivariate analysis revealed significantly lower progression-free survival (PFS) and overall survival (OS) for patients with HPDc (HR 5.25, p=0.001; HR 3.75, p=0.015) and HPDs (HR 3.74, p<0.001; HR 3.46, p<0.001) compared to those without. Patients with mHPD showed similarly poor survival outcomes as HPD patients. Liver metastasis at diagnosis was associated with HPDs, and a high tumor burden correlated with HPDc.ConclusionsThe incidence and risk factors of HPD varied with different definitions, but mHPD identified more cases with poor outcomes. This comprehensive approach may enhance the identification of at-risk patients and lead to a better understanding of HPD in lung cancer during immunotherapy.
GM1 Gangliosidosis Type II: Results of a 10-Year Prospective Study
Authors: D’Souza Precilla , Farmer Cristan , Johnston Jean , Han Sangwoo T , Adams David , Hartman Adam L. , Zein Wadih , Huryn Laryssa A. , Solomon Beth , King Kelly , Jordan Christopher , Myles Jennifer , Nicoli Elena-Raluca , Rothermel Caroline E , Mojica Algarin Yoliann , Huang Reyna , Quimby Rachel , Zainab Mosufa , Bowden Sarah , Crowell Anna , Buckley Ashura , Brewer Carmen , Regier Deborah , Brooks Brian , Baker Eva , Vézina Gilbert , Thurm Audrey , Tifft Cynthia J 
Published: January 2024

AbstractPurposeGM1 gangliosidosis (GM1) is an ultra-rare lysosomal storage disease caused by pathogenic variants in galactosidase beta 1 (GLB1; NM_000404), primarily characterized by neurodegeneration, often in children. There are no approved treatments for GM1, but clinical trials using gene therapy (NCT03952637,NCT04713475) and small molecule substrate inhibitors (NCT04221451) are ongoing. Understanding the natural history of GM1 is essential for timely diagnosis, facilitating better supportive care, and contextualizing the results of therapeutic trials.MethodsForty-one individuals with type II GM1 (n=17 late infantile and n=24 juvenile onset) participated in a single-site prospective observational study. Here, we describe the results of extensive multisystem assessment batteries, including clinical labs, neuroimaging, physiological exams, and behavioral assessments.ResultsClassification of 37 distinct variants in this cohort was performed according to ACMG criteria and resulted in the upgrade of six and the submission of four new variants to pathogenic or likely pathogenic. In contrast to type I infantile, children with type II disease exhibited normal or near normal hearing and did not have cherry red maculae or significant hepatosplenomegaly. Some older children with juvenile onset developed thickened aortic and/or mitral valves with regurgitation. Serial MRIs demonstrated progressive brain atrophy that were more pronounced in those with late infantile onset. MR spectroscopy showed worsening elevation of myo-inositol and deficit ofN-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale and progress more rapidly in late infantile than juvenile onset disease.ConclusionThe comprehensive serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies some common misconceptions about type II patients. Findings from this 10-year endeavor are a pivotal step toward more timely diagnosis and better supportive care for patients. The wealth of data amassed through this effort will serve as a robust comparator for ongoing and future therapeutic trials.
Characterising and differentiating cognitive and motor speed in older adults: a longitudinal birth cohort study
Authors: Bundil Indra , Baltruschat Sabina , Zhang Jiaxiang 
Published: January 2024

ABSTRACTObjectivesInformation processing speed (IPS) has been proposed to be a key component in healthy ageing and cognitive functioning. Yet, current studies lack a consistent definition and specific influential characteristics. This study aimed at investigating IPS as a multifaceted concept by differentiating cognitive and motor IPS.Design, setting and participantsA retrospective data analysis using data from the Medical Research Council National Survey of Health and Development (MRC NSHD; a population-based cohort of UK adults born in 1946) at childhood (ages 8, 11, and 15) and adulthood (ages 60-64 and 68-70). Using structural equation modelling, we constructed two models of IPS with 2124 and 1776 participants, respectively.Outcome measuresMeasures of interest included IPS (i.e., letter cancellation, simple and choice reaction time), intelligence (i.e., childhood intelligence and NART), verbal memory, socio-economic status (SES) and cognitive functions measured by the Addenbrooke’s Cognitive Examination III, as well as a variety of health indexes.ResultsWe found distinct predictors for cognitive and motor IPS and how they relate to other cognitive functions in old age. In our first model, SES and anti-psychotic medication usage emerged as significant predictors for cognitive IPS, intelligence and smoking as predictors for motor IPS, while both share sex, memory, and anti-epileptic medication usage as common predictors. Notably, all differences between both IPS types ran in the same direction except for sex differences, with women performing better than men in cognitive IPS and vice versa in motor IPS. The second model showed that both IPS measures, as well as intelligence, memory, anti-psychotic and sedative medication usage explain cognitive functions later in life.ConclusionTaken together, these results shed further light on IPS as a whole by showing there are distinct types and that these measures directly relate to other cognitive functions.STRENGTH & LIMITATIONSA large longitudinal cohort data set with different measurements of information processing speed that are widely usedInformation processing speed is not only related to variables measured at the same time but also to childhood and premorbid intelligence and cognitive functions in later lifeLimitations of the cohort dataset include different response rates between waves, thus some variables were not available for all individuals at certain time points, and IPS scores were derived from a small number of trialsThe study involved self-reported measures which might have increased the proportion of misclassification
The Post-Septic Peripheral Myeloid Compartment Reveals Unexpected Diversity in Myeloid-Derived Suppressor Cells
Authors: Barrios Evan L. , Leary John , Darden Dijoia B. , Rincon Jaimar C. , Willis Micah , Polcz Valerie E. , Gillies Gwendolyn S. , Munley Jennifer A. , Dirain Marvin L. , Ungaro Ricardo , Nacionales Dina C. , Gauthier Marie-Pierre L. , Larson Shawn D. , Morel Laurence , Loftus Tyler J. , Mohr Alicia M. , Maile Robert , Kladde Michael P. , Mathews Clayton E. , Brusko Maigan A. , Brusko Todd M. , Moldawer Lyle L. , Bacher Rhonda , Efron Philip A. 
Published: January 2024

AbstractSepsis engenders distinct host immunologic changes that include the expansion of myeloid-derived suppressor cells (MDSCs). These cells play a physiologic role in tempering acute inflammatory responses but can persist in patients who develop chronic critical illness. The origins and lineage of these MDSC subpopulations were previously assumed to be discrete and unidirectional; however, these cells exhibit a dynamic phenotype with considerable plasticity. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing followed by transcriptomic analysis, we identify a unique lineage and differentiation pathway for MDSCs after sepsis and describe a novel MDSC subpopulation. Additionally, we report that the heterogeneous response of the myeloid compartment of blood to sepsis is dependent on clinical outcome.
Unveiling the oncogenic significance of thymidylate synthase in human cancers
Authors: Geng Yibo , Xie Luyang , Wang Yang , Wang Yan 
Published: January 2024

AbstractBackgroundThymidylate synthase (TYMS) constitutes a pivotal and potent target in the context of chemoresistance. However, the oncogenic role of TYMS has received insufficient attention.MethodsLeveraging data from the Cancer Genome Atlas and various public databases, we conducted an extensive investigation into the oncogenic role of TYMS across 33 cancer types.ResultsTYMS exhibited pronounced expression across a spectrum of cancers and demonstrated associations with clinical outcomes in diverse cancer patient cohorts. Furthermore, genetic alterations were identified as potential influencers of overall survival in specific tumor types. Notably, the expression of thymidylate synthase correlated with tumor-infiltrating CD4+ cells in select cancers. Additionally, the functional mechanism of TYMS encompassed nucleotidase activity, chromosome segregation, and DNA replication progress.ConclusionsThis study furnishes a comprehensive understanding of the oncogenic role played by TYMS in human tumors.
Atherogenic sdLDL-cholesterol and resistin association with vitamin B12 in relation to Body Mass Index
Authors: Ashfaq Fauzia , Haji Alhaji Jwaher , Alharbi Mohammed Salem , Khatoon Fahmida , Alhatlani Nayef Hamad E , Mari Alkhamisi Fahad Ayash , Alshuwaier Ghareeb O. , Khan Mohammad Idreesh , Beg Mirza Masroor Ali 
Published: January 2024

AbstractIntroductionObesity is a known risk factor for many chronic diseases and is a growing global health concern and poor health outcomes have consistently been linked to body mass index (BMI). Small dense low-density lipoprotein (sdLDL) changes brought on by obesity may increase the likelihood of endothelium penetration and subsequent atherogenesis. Numerous tissues’ metabolic and secretory functions are altered by obesity, which may also increase the serum resistin level.MethodsPresent study included 300 participants with diffent BMI among them sdLDL and resistin was evaluated. HbA1c was analysed by whole blood of EDTA and the serum were thawed sample was used for lipid parameters (TG, cholesterol, HDL, LDL, VLDL and sdLDL) and vitamin B12 analysis as well as resistin level was analysed by ELISA.ResultsStudy observed higher HbA1c (%, p=0.0004), LDL (mg/dl) (<0.0001), TG (mg/dl) (<0.0001), Cholesterol (mg/dl) (<0.0001), VLDL (mg/dl) (<0.0001) in obese compared to overweight, normal BMI, except HDL. Smokers and hypertensive participants had higher sdLDL (p=0.03, p=0.0001) and resistin level (p=0.03, p<0.0001). Obese participants had high amount of sdLDL (p<0.0001, p<0.0001) and resistin level (p<0.0001, p<0.0001) compared to overweight and normal BMI. SdLDL and resistin were found to be positively correlated as well as correlation analysis of sdLDL and resistin level was observed to be significantly correlated with BMI, systolic, TG, cholesterol, VLDL, LDL while negative correlation with HDL level. ROC analysis showed that sdLDL and resistin could be used as prognostic factor for overweight/obesity at cutoff value of 18.55 mg/dl (sdLDL) and 750 pg/ml (resistin). It was also observed that the participant with normal BMI had 389.6 pmol/L while overweight participant had 300.6 pmol/L (p<0.0001) and obese had 291.0 pmol/L (p<0.0001).ConclusionStudy concluded that the obese participants had higher TG, cholesterol, VLDL, LDL and lower HDL level. The most importantly, higher sdLDL level and resistin level was observed in obese participants as well as higher sdLDL and resistin could influence the higher lipid parameters (TG, cholesterol, VLDL, LDL) and lower HDL level. It was also observed that obese participants had lower vitamin B12 level and could lead to other metabolic error.
An internally controlled system to study microtubule network diversification links tubulin evolution to the use of distinct microtubule regulators
Authors: Kennard Andrew S. , Velle Katrina B. , Ranjan Ravi , Schulz Danae , Fritz-Laylin Lillian K. 
Published: January 2024

SUMMARYDiverse eukaryotic cells assemble microtubule networks that vary in structure and composition. While we understand how cells build microtubule networks with specialized functions, we do not know how microtubule networks diversify across deep evolutionary timescales. This problem has remained unresolved because most organisms use shared pools of tubulins for multiple networks, making it impossible to trace the evolution of any single network. In contrast, the amoeboflagellateNaegleriauses distinct tubulin genes to build distinct microtubule networks: whileNaegleriabuilds flagella from conserved tubulins during differentiation, it uses divergent tubulins to build its mitotic spindle. This genetic separation makes for an internally controlled system to study independent microtubule networks in a single organismal and genomic context. To explore the evolution of these microtubule networks, we identified conserved microtubule binding proteins and used transcriptional profiling of mitosis and differentiation to determine which are upregulated during the assembly of each network. Surprisingly, most microtubule binding proteins are upregulated during only one process, suggesting thatNaegleriauses distinct component pools to specialize its microtubule networks. Furthermore, the divergent residues of mitotic tubulins tend to fall within the binding sites of differentiation-specific microtubule regulators, suggesting that interactions between microtubules and their binding proteins constrain tubulin sequence diversification. We therefore propose a model for cytoskeletal evolution in which pools of microtubule network components constrain and guide the diversification of the entire network, so that the evolution of tubulin is inextricably linked to that of its binding partners.
Low parental conflict, no endosperm hybrid barriers, and maternal bias in genomic imprinting in selfingDrabaspecies
Authors: Alling Renate M. , Bjerkan Katrine N. , Bramsiepe Jonathan , Nowak Michael D. , Gustafsson A. Lovisa S. , Brochmann Christian , Brysting Anne K. , Grini Paul E. 
Published: January 2024

AbstractIn flowering plants, a distinct post-zygotic hybridization barrier between closely related species can arise during seed maturation, resulting in embryo lethality due to abnormal endosperm development. The endosperm initially works as a nutrient sink, acquiring nutrients from adjacent tissues, but later undergoes cellularization, switching to serve as a nutrient source. In hybrid seeds, this cellularization switch can be hampered if the endosperm genomic ratio is imbalanced. Disruption in the genomic ratio can be caused when species of different ploidy are crossed, but also by crosses between species with identical ploidy, if the effective ploidy differs. One factor proposed to influence effective ploidy is the epigenetic phenomenon genomic imprinting, the parent-of-origin specific expression of alleles inherited either maternally or paternally. It has been proposed that outbreeding species exhibit higher effective ploidy compared to selfing species, as a consequence of parental conflict in resource allocation to the developing progenies. This suggests a low anticipation of endosperm-based post-zygotic hybridization barriers between selfing species of similar ploidy. Here, we show that in crosses between the diploid selfing arctic speciesDraba fladnizensis,D. nivalisandD. subcapitata, the endosperm-based post-zygotic hybridization barrier is absent, supporting low parental conflict. To investigate parent-of-origin allele specific expression, we conducted a genomic imprinting study inD. nivalisand compared to previous studies in other Brassicaceae species. We report a high number of maternally expressed genes (MEGs) and concomitantly low numbers of paternally expressed genes (PEGs). Our results suggest rapid evolution of MEGs and loss of PEGs in a mating system with low parental conflict, proposing that selfing arctic species may exhibit a generally stronger maternal expression bias as an adaptive mechanism to efficiently cope with an extreme environment.
Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in Amyotrophic Lateral Sclerosis
Authors: Wong Julian P. H. , Blazev Ronnie , Ng Yaan-Kit , Goodman Craig A. , Montgomery Magdalene K. , Watt Kevin I. , Carl Christian S. , Watt Matthew J. , Voldstedlund Christian T. , Richter Erik A. , Crouch Peter J. , Steyn Frederik J , Ngo Shyuan T , Parker Benjamin L. 
Published: January 2024

ABSTRACTArginine methylation is a protein post-translational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with amyotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show thatin vivooverexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and non-methylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.
A comparative study of influenza A M2 protein conformations in DOPC/DOPS liposomes and in nativeE. colimembranes
Authors: Sanders Griffin , Borbat Peter P. , Georgieva Elka R. 
Published: January 2024

ABSTRACTWe compared the conformations of the transmembrane domain (TMD) of influenza A M2 (IAM2) protein reconstituted at pH 7.4 in DOPC/DOPS bilayers to those in isolatedE. colimembranes, having preserved its native proteins and lipids. IAM2 is a single-pass transmembrane protein known to assemble into homo-tetrameric proton channel. To represent this channel, we made a construct containing the IAM2’s TMD region flanked by the juxtamembrane residues. The single cysteine substitute, L43C, of leucine located in the bilayer polar region was paramagnetically tagged with a methanethiosulfonate nitroxide label for the ESR (electron spin resonance) study. We compared the conformations of the spin-labeled IAM2 residing in DOPC/DOPS and nativeE. colimembranes using continuous-wave (CW) ESR and double electron-electron resonance (DEER) spectroscopy. The total protein-to-lipid molar ratio spanned the range from 1:230 to 1:10,400. The CW ESR spectra corresponded to a nearly rigid limit spin label dynamics in both environments. In all cases, the DEER data were reconstructed into the distance distributions showing well-resolved peaks at 1.68 nm and 2.37 nm. The peak distance ratio was 1.41±0.2 and the amplitude ratio was 2:1. This is what one expects from four nitroxide spin-labels located at the corners of a square, indicative of an axially symmetric tetramer.Distance modeling of DEER data with molecular modeling software applied to the NMR molecular structures (PDB: 2L0J) confirmed the symmetry and closed state of the C-terminal exit pore of the IAM2 tetramer in agreement with the NMR model. Thus, we can conclude that IAM2 TMD has similar conformations in model and nativeE. colimembranes of comparable thickness and fluidity, notwithstanding the complexity of theE. colimembranes caused by their lipid diversity and the abundance of integral and peripheral membrane proteins.