bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of microglial morphological complexity in adult mouse brain samples using 2-dimensional and 3-dimensional image analysis tools
Authors: Murray Colin J. , Tunderman Eva D. , Vecchiarelli Haley A. , González Ibáñez Fernando , Tremblay Marie-Ève 
Published: October 2024

AbstractCharacterizing cell morphology has been an essential aspect of neuroscience for over a century to provide essential insights into cellular function and dysfunction. Microglia, the resident innate immune cells of the central nervous system, undergo drastic changes in morphology in response to various stimuli, with many classifications proposed in recent years. Increased availability of advanced analysis software to study microglial morphology represents a step forward in the field. However, whether the use of advanced analysis tools provides equivalent or varied outcomes remains undetermined. This study re-analyzed raw data, previously processed using a standard 2D microglial morphology analysis method, using 3D analysis methods. The published article observed significant changes in microglial morphology in the mouse ventral hippocampus after administration of a ketogenic diet and exposure to repeated social defeat stress in young adult male mice. Overall, we observed different statistical outcomes in the 3D dataset compared to the previously published 2D results, with both maintained and new findings. This may indicate that the 3D analysis method is better able to capture minute changes in morphology. However, overall conclusions on microglial morphology changes remain consistent between methods. Lastly, we highlight the difference between a nested statistical design, which considers within animal variability, and a non-nested design. Overall, we highlight and discuss differences between 2D and 3D microglial morphology analysis and explore the contribution of individual cell and animal variability to statistical outcomes.Main Points3D analysis method generates similar and novel results compared to a 2D method.verall microglial morphological changes to stimuli are comparable between methods.nested statistical design produces distinct significant differences.
Autophagic enhancer rescues Tau accumulation in a stem cell model of frontotemporal dementia
Authors: Mirfakhar Farzaneh S. , Marsh Jacob A. , Minaya Miguel A. , Pak Stephen C. , Silverman Gary A. , Perlmutter David H. , Macauley Shannon L. , Karch Celeste M. 
Published: October 2024

AbstractTau degradation is disrupted in neurodegenerative tauopathies, such as frontotemporal dementia (FTD), which may contribute to Tau aggregation. The prevailing hypothesis has been that Tau degradation is stymied due to an imbalance in proteostasis that occurs with age. Here, we used Airyscan super resolution imaging to illustrate that a pathogenic FTD mutation in theMAPTgene, which encodes Tau, is sufficient to alter multiple steps of the autophagy lysosomal pathway and impair Tau degradation. We discovered lysosomes clogged with both Tau and phosphorylated Tau, stalled lysosome motility, disrupted molecular motors, enhanced autophagic flux, and slowed cargo degradation in mutant Tau neurons. Treatment of mutant Tau neurons with a small molecule autophagy enhancer drug increases autophagic flux and cargo degradation, reduces phospho-Tau levels, and reduces Tau accumulation in lysosomes without restoring defects in lysosomal motility. This study reveals novel effects of mutant Tau and provides a window through which therapeutic treatments targeting autophagy may promote Tau homeostasis.
Increased CPT1a expression is a critical cardioprotective response to pathological stress that suppresses gene programs for remodeling and enables rescue by gene transfer
Authors: Carley Andrew N. , Maurya Santosh K. , Maurya Chandan K. , Wang Yang , Webb Amy , Challa Azariyas A. , Zhang Zhentao , Zhu Hua , Heydemann Ahlke , Bedi Kenneth C. , Kyriakopoulos Christos P. , Selzman Craig H. , Drakos Stavros G. , Margulies Kenneth B , Lewandowski E. Douglas 
Published: October 2024

Text AbstractBackgroundCarnitine palmitoyl transferase 1 (CPT1) is a rate-limiting enzyme for long chain fatty acid oxidation (FAO) in cardiac mitochondria. In adult hearts, CPT1b predominates, while CPT1a is co-expressed at lower levels. Pathological stress on the heart induces greater CPT1a expression, and this coincides with a reduction in FAO, yet the role of CPT1a in pathological cardiac remodeling is unknown.MethodsCPT1 isoform expression was assayed in myocardium of human heart failure (HF) patients with nonischemic cardiomyopathy (NICM) and a preclinical mouse model of heart failure. To explore the role of CPT1a upregulation in response to pathological stress, mice were subjected to afterload stress via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, AAV9-mediated CPT1a overexpression (AAV9.cTNTN.Cpt1a), versus empty virus or PBS infusions as controls. MiR370, known to suppress hepatic CPT1a, was assayed and overexpressed to determine if miR370 regulates cardiac CPT1a expression.ResultsCPT1a protein was elevated and miR370 reduced in myocardium of male and female NICM patients (204% vs. non-failing unused donor hearts), as well as in failing mouse hearts. AAV mediated miR370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac specific CPT1a knockout mice (csCPT1a ko) exacerbated adverse remodeling, causing severe dysfunction and increased mortality. In contrast, CPT1a overexpression (2.8 fold), attenuated impaired ejection fraction (EF, by 54%) and fractional shortening (FS, 65%) vs. PBS-infused TAC hearts (p<0.05). Delivery of AAV9.cTnT.Cpt1a 4 wks after TAC surgery, led to significant rescue of EF and FS vs. animals receiving empty virus and mitigated the exacerbated dysfunction of csCPT1a ko hearts at 4 wks TAC. RNA-seq and reverse transcription-quantitative PCR revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic and cell death gene programs in both sham and TAC hearts, irrespective of changes in FAO.ConclusionsThe effects of CPT1a in the heart extend beyond FAO and include a non-canonical regulation of cardiac gene programs. In addition to an animal model of HF, CPT1a upregulation occurs in NICM, and is a critical cardioprotective adaptation to pathological stress.
The expression alteration ofGolim4(Gpp130) and its prognostic value in epithelial ovarian cancer
Authors: Sheida Sadaf Valeh , Gholipour Akram , Bayat Varchaghi Hossein , Mowla Seyed Javad 
Published: October 2024

AbstractBackgroundAmong common cancers in women, ovarian cancer has the lowest incidence; however, mortality rates are more than other gynecological cancers due to the lack of specific symptoms during early stages and absence of diagnostic markers. Golgi integral membrane protein 4 (GOLIM4) is a member of transporter complex which is located to the cis/medial of Golgi, and its role in tumor is unknown. In this study we aimed to assess the expression ofGolim4(GPP130) in epithelial ovarian cancer (EOC) patients.MethodsThe expression levels ofGolim4in 58 malignant EOC specimens and 11 benign and normal control tissues were determined by real-time RT-PCR. Clinicopathological characteristics were analyzed. Non-parametric survival analysis was estimated by using Kaplan-Meier and log-rank test. Parametric survival analysis was evaluated through multivariate Cox regression analysis and generalized Gamma survival model.ResultOur findings showed thatGolim4was significantly down-regulated in Serous Papillary type of EOC tissue specimens than in non-cancerous tissues (P<0.001); however; the expression ofGolim4in total EOC tissue specimens revealed non-significant up-regulation. Kaplan-Meier analysis and log-rank test have suggested that EOC patients with lowGolim4expression have shorter overall survival when compared with patients with other expression groups (log-rank test P<0.05). Semi-parametric Cox proportional hazards model indicated that the status ofGolim4were independent predictor of overall survival in patients with EOC. Correlation analysis has been done by Spearman Rank correlation coefficient.
Solid-state esophageal pressure sensor for the estimation of pleural pressure: a bench and first-in-human validation study
Authors: van Oosten Julien P. , Goedendorp Nico , Mousa Amne , Flink Rutger , Schaart Rik , Flinsenberg Merel , Somhorst Peter , Gommers Diederik A.M.P.J. , Heunks Leo , Jonkman Annemijn H. 
Published: October 2024

ABSTRACTBackgroundAdvanced respiratory monitoring through the measurement of esophageal pressure (Pes) as a surrogate of pleural pressure helps guiding mechanical ventilation in ICU patients. Pes measurement with an esophageal balloon catheter, the current clinical reference standard, needs complex calibrations and a multitude of factors influence its reliability. Solid-state pressure sensors might be able to overcome these limitations.ObjectivesTo evaluate the accuracy of a new solid-state Pes transducer (Pessolid). We hypothesized that measurements are non-inferior to those obtained with a properly calibrated balloon catheter (Pesbal).MethodsAbsolute and relative solid-state sensor Pes measurements were compared to a reference pressure in a 5-day bench setup, and to simultaneously placed balloon catheters in 15 spontaneously breathing healthy volunteers and in 16 mechanically ventilated ICU patients. Bland-Altman analysis was performed with nonparametric bootstrapping to estimate bias and upper and lower limits of agreement (LoA).ResultsBench study: Solid-state pressure transducers had a positive bias (Psolid– Pref) of around 1 cmH2O for the absolute minimal and maximum pressures, and no bias for pressure swings. Healthy volunteers: the solid-state transducer revealed a bias (Pessolid–Pesbal) [upper LoA; lower LoA] of 1.58 [8.19; −5.03], −2.37 [3.96; −8.69] and 3.94 [11.09; −3.20] cmH2O for end-expiratory, end-inspiratory and ΔPes values, respectively. ICU patients: the solid-state transducer showed a bias (Pessolid–Pesbal) [upper LoA; lower LoA] during controlled / assisted ventilation of: −0.15 [1.39; −1.70] / −0.20 [5.02; −5.41], 0.32 [3.35; −2.72] / −0.54 [4.60; −5.68] and 0.47 [3.79; −2.85] / 0.35 [3.88; −3.18] cmH2O for end-expiratory, end-inspiratory and ΔPes values, respectively. LoA were <2cmH2O for static measurements on controlled ventilation.ConclusionsThe novel solid-state pressure transducer showed good accuracy on the bench, in healthy volunteers and in ventilated ICU-patients. This could contribute to the implementation of Pes as advanced respiratory monitoring technique.Trial registrationClinicaltrials.govidentifier:NCT05817968(patient study). Registered on 18 April 2023.
Information processing speed modulation by electrical brain stimulation in multiple sclerosis: Towards individually-tailored protocols
Authors: Riemann Steffen , Mittelstädt Michel , Glatzki Maurice , Zilges Carlotta , Wolff Clara , Niemann Filip , Roheger Mandy , Flöel Agnes , Grothe Matthias , Meinzer Marcus 
Published: October 2024

AbstractInformation processing speed (IPS) is a core cognitive process, highly relevant in everyday-life and the most frequent and disabling cognitive symptom in patients with Relapsing Multiple Sclerosis (pwRMS). By using region-specific focalized transcranial direct current stimulation (tDCS) in healthy individuals and pwRMS, we provide causal evidence for superior parietal lobe (SPL) involvement in IPS and identified a clinical predictor of tDCS-response in pwRMS. The study employed a registered, randomized, sham-tDCS controlled, three-way blinded, cross-over trial and a mixed-factors design with eight arms [between-subjects: group (pwRMS, controls); tDCS-polarity (excitatory, inhibitory); within-subjects: stimulation (active-, sham-tDCS)]. Concurrently with tDCS, participants completed a computerized version of the Symbol-Digit-Modalities-Test (SDMT), the current gold standard for quantifying IPS impairment in pwRMS. Bayesian modeling with generalized linear mixed models provided strong evidence for polarity specific modulation of IPS by SPL-tDCS and a double-dissociation of stimulation response in pwRMS and controls. Healthy individuals showed the canonical pattern of significantly enhanced and reduced processing speed during excitatory or inhibitory tDCS. In pwRMS, a reversed pattern was found and tDCS-response was predicted by baseline SDMT performance; i.e., more or less impaired patients benefited from inhibitory or excitatory tDCS, respectively. Our results provide direct causal evidence for SPL involvement in IPS in health and disease and suggest that the degree of IPS impairment in pwRMS reflects compensatory or dysfunctional neuroplastic processes that can be counteracted in a polarity specific way. Identified standardized transition scores for the effectiveness of excitatory or inhibitory tDCS will inform future individually-tailored stimulation protocols in pwRMS.One Sentence SummaryPolarity-specific modulation of information processing speed in multiple sclerosis.
Determinants of acute malnutrition among children under five in arid regions, Kenya
Authors: Amugsi Dickson A , Sidze Estelle , Thuita Faith , Flax Valerie L. , Wilunda Calistus , Adair Linda , Mwangi Bonventure , Anono Esther , Odhiambo Hazel , Ekiru Stephen , Chepkwony Gillian , Albert Webale , Ng’ang’a Monica , Miller Joshua D. , Sagara Bradley , Kimani-Murage Elizabeth , Lutter Chessa 
Published: October 2024

AbstractAcute malnutrition, defined as a weight-for-height Z-score below -2 standard deviations of the WHO growth standards, is prevalent among children in low- and middle-income countries. Our study aimed to identify immediate, underlying, and basic determinants of acute malnutrition among children in Turkana and Samburu, two arid and semi-arid regions in Kenya. Data are from a longitudinal study that recruited children under 3 years of age, with follow-up every 4 months over six waves. Generalized estimating equations were used to assess risk factors of acute malnutrition in this population. Among immediate factors, children who recently experienced diarrhea had 19% and 23% higher odds of acute malnutrition and those who consumed animal-source foods had 12% and 22% lower odds of acute malnutrition in Turkana and Samburu, respectively. Among underlying factors, children in Turkana whose caregivers used alcohol had 32% higher odds of acute malnutrition. Among basic factors, children in Turkana whose caregivers had 3-5 or 6 or more children had 39% and 70% higher odds, whereas those in female-headed households had 34% and 81% higher odds of acute malnutrition in Turkana and Samburu, respectively. Children in Turkana’s fisherfolk communities had 36% higher odds of acute malnutrition compared with those in urban or peri-urban areas. Key risk factors for acute malnutrition included child diarrhea, caregiver’s use of alcohol (in Turkana), caregiver’s number of children, female-headed households, and fisherfolk livelihood (in Turkana), while consuming animal-source foods was associated with lower risk. Interventions should target these intersecting factors to reduce acute malnutrition in these counties.Key messagesAcute malnutrition in children under 5 years is persistent in East Africa’s arid and semi-arid lands.Among immediate factors, children who had diarrhea were more likely to have acute malnutrition, while those who consumed animal-source foods were less likely to have acute malnutrition in both counties.Among underlying factors, children whose caregivers used alcohol were more likely to have acute malnutrition in Turkana only. Household food insecurity and water, sanitation, and hygiene were not directly associated with acute malnutrition.A variety of basic factors were associated with a higher likelihood of acute malnutrition, including number of children in the household, the household being headed by a female, and fisherfolk livelihood (in Turkana).
Interpreting Health Differences between Self-reported Black and White Children in U.S.: Insights from a Methodological Perspective
Authors: Yang Fan Nils , Duyn Jeff H. , Xie Weizhen 
Published: October 2024

AbstractUnderstanding health differences among racial groups in child development is crucial for addressing inequalities that may affect various aspects of a child’s life. However, factors such as household and neighborhood socioeconomic status (SES) often covary with health differences between races, making it challenging to accurately reveal these differences using conventional covariate-control methods such as multiple regression. Alternative methods, such as Propensity Score Matching (PSM), may provide better covariate control. Supporting this notion, we found that PSM is more sensitive than regression-based methods in detecting health differences between self-reported Black and White children across a wide range of behavioral and neural measurements in the ABCD (5636 White, 1350 Black). Puberty status, an index of physical maturation, emerged as the largest difference between races and mediated the health differences between races on the majority of behavioral and neural variables. These findings highlight the importance of controlling for pubertal status and using more effective covariate-control methods to accurately represent health differences between Black and White children.
Rare pathogenic variants in G-protein coupled receptor genes involved in gut-to- host communication are associated with cardiovascular disease risk
Authors: Tavares Leticia Camargo , Muralitharan Rikeish R. , Snelson Matthew , Marques Francine Z. 
Published: October 2024

BackgroundGut microbial metabolites called short-chain fatty acids (SCFA) confer protective effects against cardiovascular disease and high blood pressure. Proposed mechanisms include anti-inflammatory signalling mediated by SCFA-sensing G-protein-coupled receptors (GPCR), particularly GPR41, GPR43, and GPR109a, as suggested by knockout mouse models. We aimed to determine if rare pathogenic variants (RPVs) affecting GPCR genes in humans increase the risk of hypertension (HTN) and major adverse cardiac events (MACEs), including acute coronary syndrome, heart failure, and ischemic stroke.MethodsUsing UK Biobank whole-exome sequencing data from 393,649 European participants, we identified rare (minor allele frequency <1%) pathogenic variants with predicted high-impact functional consequences in GPCR genes, based on Ensembl Variant Effect Predictor annotations. For missense variants, pathogenicity likelihood scores from AlphaMissense, Mendelian Clinically Applicable Pathogenicity, and Combined Annotation Dependent Depletion were assessed. Multivariable logistic regression models, adjusted for age, sex, BMI, genetic ancestry, and other potential confounders, were conducted to compare RPV prevalence between cases and controls.ResultsWe identified a total of 158 RPVs in SCFA-sensing GPCR genes. The prevalence of RPV carriers was significantly higher in patients with HTN (OR=1.12, P=0.014) and MACEs (OR=1.18, P=0.009) than controls. In single GPCR gene analyses, RPVs in the FFAR2 gene (encoding GPR43) were associated with an increased risk of HTN (OR=1.23, P=0.005). RPVs in the HCAR2 gene (encoding GPR109A) were associated with a markedly increased risk of heart failure (OR=1.57, P=0.012).ConclusionsThese findings confirm and extend previous results from knockout animal models in a large population-based cohort, highlighting the potential of GPCRs as therapeutic targets for HTN and cardiovascular diseases in humans.
Gut microbiota and type 2 diabetes associaction: A meta-analysis of 16S studies and their methodological challenges
Authors: Picanço Machado Jéssica Lígia , Schaan Ana Paula , Mamede Izabela , Fernandes Gabriel da Rocha 
Published: October 2024

AbstractDiabetes mellitus is a prevalent chronic non-communicable disease, and recent studies have explored the link between gut microbiota and its development. Despite some evidence suggesting an association, the influence of gut microbiota on type 2 diabetes DM2 remains unclear. A systematic search of PubMed Janeiro 2016– 10 December 2023 using the keywords “16S” and “diabetes” or “DM2” and “gut microbiota” and “diabetes” or “DM2”. The studies included compared gut microbiome diversity between diabetic and non-diabetic adults using 16S rRNA sequencing, excluding children, interventions, and type 1 diabetes. Alpha diversity indices and bacterial mean abundance were analyzed, with statistical assessments using a random-effects model and I2for heterogeneity. Thirteen studies met the criteria, with the Shannon index being the most commonly used measure. Results showed significant heterogeneity I2>75% and no notable differences between diabetic and non-diabetic groups. Other indices, such as Chao1 and phylogenetic whole tree, similarly showed no consistent differences. Taxonomic analysis also failed to find phyla consistently correlated with DM2, with variability across studies. The relationship between gut microbiota and diabetes remains uncertain due to technical and biological factors that are often overlooked. The inconsistencies across studies highlight the low reproducibility common in microbiota research.
Changes in Myofibril Size, Shape, and Network Connectivity in Aging Muscle
Authors: Ajayi Peter T. , Vue Zer , Hinton Antentor O. , Glancy Brian 
Published: October 2024

ABSTRACTAcross normal aging, striated muscles undergo structural remodeling associated with loss of force production. However, it is unknown how the organization of contractile myofibrillar networks, linked to their efficiency, is modified during aging. Using serial block-face scanning electron microscopy (SBF-SEM), we assess myofibril size, shape, and connectivity across different muscle types in young and geriatric mice and humans. Regardless of skeletal muscle fiber type in mice, age was associated with increased myofibrillar connectivity, with 24 months of age, as compared to 3 months, displaying more sarcomere branches. Distinctive age-related trends in myofibril size and shape were observed among each muscle type. Notably, there was a decrease in myofibril circularity from 3 months of age to 24 months of age in the gastrocnemius muscles of mice, contrasting with an increase in circularity in the soleus muscles during the same time frame. Additionally, while the soleus myofibrils in an aged cohort had a higher cross-sectional area, a reduction was observed in the gastrocnemius muscles. Cardiac muscles displayed no changes in sarcomere connectivity from 3 months to 24 months, although myofibril circularity and cross-sectional area were increased during this time. In human vastus lateralis muscles, sarcomere branching was positively correlated with advanced age. However, there were no consistent changes in myofibril size or shape across a wide age range from 16 to 68 years old. Overall, these data suggest that aging is associated with increased connectivity of the contractile networks within mammalian skeletal muscle.Graphical Abstract
Super-Resolution Axial Imaging for Quantifying Piconewton Traction Forces in Live-cells
Authors: Wang Dong-Xia , Kong De-Ming , Enderlein Jörg , Chen Tao 
Published: October 2024

AbstractCell mechanics play a pivotal role in regulating numerous biological processes. While super-resolution microscopy enables the imaging of cellular forces in the lateral dimension with sub-10-nanometer resolution, achieving comparable resolution along the axial dimension remains a significant challenge. In this study, we combine metal-induced energy transfer (MIET) imaging with novel DNA-hairpin-based molecular tension probes (MIET-MTP) to map integrin-mediated mechanical forces with nanometer precision in the axial direction. MIET-MTP allows for the simultaneous observation of both the plasma membrane and forceexerting molecules in the axial dimension. Using this approach, we mapped axial integrin tension in focal adhesions and podosomes, alongside their corresponding plasma membrane height profiles, offering detailed insights into the structures involved in force transmission.