bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beyond prescribed activities: examining passive postural sway and gait data in patients with multiple sclerosis
Authors: Meyer Brett M. , Agarwal Nishit , Gamboa Kevin Machado , O’Learly Aisling , Solomon Andrew J. , McGinnis Ryan S. , Ceruolo Melissa 
Published: November 2024

AbstractSymptoms of multiple sclerosis (MS) are highly variable and include impaired senses, instability, and fatigue, making persons with MS (PwMS) ill-suited for the traditional six-month office visit paradigm. Instead, PwMS are well suited for remote monitoring to capture their true impairment. The objective of this work is to investigate the value of free-living data compared to prescribed walking tasks. Wearable sensor data were utilized from six-weeks of data from 25 PwMS. Participants completed a daily 1-minute walk, 30-second standing task, and patient reported outcomes of balance confidence (ABC), fatigue (MFIS) and walking impairment (MSWS). We compared gait and sway, as well as correlated them to patient reported outcomes (PRO). Lastly, we used a regression to determine the variance accounted for (VAF) in each PRO by different data sources. Temporal gait features were moderately correlated (r=0.6 – 0.81) between passive and prescribed walking, however, no postural sway features were correlated with each other. Passive data was found to have greater clinical relevance in our sample of PwMS compared to prescribe tasks for both gait and sway analyses. Passive sway features were found to be moderately related to ABC, MFIS, and MSWS (r=0.42-0.74, VAF=0.42-0.7), while prescribe sway was only correlated to MFIS (r = 0.41, VAF = 0.44). Both passive and prescribed measures of gait were related to ABC and MSWS; stronger relationships were found in the passive data (r = 0.42-0.78, VAF = 0.64-0.78). Additionally, we found the performance increased for passive monitoring with a shorter monitoring duration – highlighting the need to properly match the monitoring and analysis duration to the population. Overall, our findings highlight the importance of including passive free-living analysis in future studies.
An accurate genetic colocalization method for the HLA locus
Authors: Butler-Laporte Guillaume , Lu Tianyuan , Morris Sam , Zhang Wenmin , Band Gavin , Hamilton Fergus , Chong Amanda , Lin Kuang , Nanjala Ruth , Brent Richards J , Lee Mei-Hsuan , Yang Ling , Yao Pang , Li Liming , Chen Zhengming , Luo Yang , Milwood Iona Y , Walters Robin G , Mentzer Alexander J 
Published: November 2024

AbstractGenetic colocalization analyses are frequently conducted to determine if causal signals at a genetic locus are shared between two phenotypes. However, colocalization is rarely undertaken at the HLA locus, due to its complex linkage disequilibrium (LD) and high polymorphism density. This lack of genetic causal inference method limits our ability to translate HLA associations into therapeutic targets. Here we present a method that uses HLA alleles, instead of nucleotide variants, to perform genetic colocalization of two traits at HLA genes. The method, which we call HLA-colocalization, works by controlling for LD using Bayesian variable selection, then performing Bayesian regression on the resulting posterior inclusion probabilities. We first show through simulation that the method correctly identifies truly colocalizing genes. We then test the method in two positive control scenarios, showing colocalization between hepatitis B and liver disease atHLA-DPB1, and between Epstein-Barr virus and multiple sclerosis atHLA-DRB1andHLA-DQB1. Lastly, we perform a large colocalization scan between multiple viruses and auto-immune diseases, demonstrating that the method is well calibrated, and uncovering multiple biologically plausible novel causal associations, such as cytomegalovirus and ulcerative colitis. To our knowledge, HLA-colocalization is the first accurate genetic colocalization method for the HLA locus (github:https://github.com/DrGBL/hlacoloc).
The impact of diabetes mellitus and HBV infection on major adverse cardiovascular events related to statin use for Chinese population with cardiovascular disease
Authors: Wu Qian , He Xiaoxuan , Tong Xiaoning , Li Ying , Wang Xiaoqin 
Published: November 2024

BACKGROUNDThe association between hepatitis B virus (HBV) infection, diabetes mellitus (DM) and cardiovascular disease (CVD) remains uncertain. This study was aimed to investigate the impact of HBV infection and DM on 13 major adverse cardiovascular events (MACEs) among CVD patients with or without statin use.METHODS AND RESULTSIn total, 45,013 individuals participated in the baseline survey between June 2020 and August 2023. The patients were categorized into two groups according to their surface antigen status. Finally, a sample size of 496 participants was included in the study: patients with coexisting CVD and HBV (n = 225) and patients with CVD alone (n = 271).The implementation of statins has demonstrated the potential to reduce the incidence of coronary heart disease (CHD) and angina pectoris (AP) in individuals with CVD who are also affected by HBV infection. The analysis of stratification, taking into account the presence of DM, has demonstrated a significant increased vulnerability to myocardial infarction (MI), acute myocardial infarction (AMI), and heart failure (HF) among individuals with HBV infection combined with CVD. DM and hemoglobin A1c (HBA1c) level of ≥ 6 are identified as risk factors for the development of CHD, MI, AP, and hypertension. Our study also suggests that statin therapy led to a dose-dependent decrease in liver fibrosis, as well as improvement of the atherogenicity index and systemic inflammatory response in patients with CVD.CONCLUSIONOur study indicates that CVD patients who also have HBV infection or DM may experience a reduction in MACEs when treated with statins. Furthermore, our research indicates that focusing on long-term glycemic control is essential in this patient population in order to enhance cardiovascular outcomes. The observed improvements in hepatic function, atherosclerotic burden, and systemic inflammation associated with statin therapy may contribute to the favorable cardiovascular outcomes among individuals with CVD.Clinical PerspectiveWhat Is New?This study investigates the association between statin therapy and major adverse cardiovascular events (MACEs) in Chinese patients with cardiovascular disease who have concurrent hepatitis B virus infection or diabetes mellitus.The findings suggest potential cardiovascular benefits of statin therapy in this specific patient population.The study explores the relationship between statin use and changes in hepatic function, atherosclerotic markers, and inflammatory parameters.What Are the Clinical Implications?The results provide evidence supporting statin use in cardiovascular disease patients with hepatitis B virus infection or diabetes mellitus.Glycemic control appears to be an important factor in optimizing cardiovascular outcomes in these patients.Regular monitoring of hepatic and inflammatory markers may be valuable in assessing treatment response.
Targeted H3K9 acetylation at lncSox1 promoter by cell type-specific epigenome editing promotes intermediate progenitor proliferation in developing mouse cortex
Authors: Sokpor Godwin , Ulmke Pauline Antonie , Nguyen Hoang Duy , Pham Linh , Kakani Princy , Chu Van Trung , Arnold Sebastian J. , Brand-Saberi Beate , Nguyen Huu Phuc , Tuoc Tran 
Published: November 2024

SUMMARYThe distribution and level of epigenetic (chromatin) marks have implications for differential regulatory effects at specific gene loci. Herein, we applied a protocol which combinesin vivoelectroporation and a CRISPR-dead (d)Cas9 system to probe and edit a specific chromatin mark in the epigenome of intermediate progenitor cells (IPCs) in developing mouse cortex. We found that the promoter oflncSox1, a long non-coding gene, is a key genomic locus for H3K9 acetylation (H3K9ac) during IPC amplification. CRISPR-dCas9–mediated addition of H3K9ac atlncSox1promoter resulted in lncSox1 upregulation, with attendant increase in IPC pool and augmented neurogenesis. Thus, we have identified dynamic regulation of lncSox1 as a major downstream target of H3 acetylation, and as part of an epigenetic mechanism involved in IPC proliferation during neocortex expansion. This finding is a proof-of-concept that our epigenome editing-based method can be used for manipulating specific epigenetic effectors to determine their (neuro)biological significance.MOTIVATIONThe abundance of basal progenitors is critical for cortical neurogenesis during brain development. There is growing interest in identifying how specific epigenetic factors regulate the genesis and expansion of basal progenitor cell sub-populations, including intermediate progenitor cells. We established a protocol that allowed us to identify the involvement of a long non-coding RNA (lncSox1) in regulating the proliferation of intermediate progenitor cells under the influence of H3K9 acetylation (H3K9ac). By enhancing H3K9ac at the promoter region oflncSox1using a CRISPR-dCas9–mediated gene-editing tool, we were able to determine that lncSox1 upregulation is a downstream effect of H3K9ac acetylation and is necessary for intermediate progenitor pool amplification during cortical development.Highlights–Identification of H3 acetylation-dependent expression of ncRNAs in developing cortex.–Establishment of cell Cre/LoxP and CRISPR-dCas9-dependent H3K9ac epigenome editing.–CRISPR-dCas9–mediated addition of H3K9ac at lncSox1 promoter resulted in lncSox1 upregulation.–H3K9 acetylation at lncSox1 promoter enhances proliferation of TBR2-expressing IPCs.–Targeted epigenome editing revealed lncSox1 as a key regulator of cortical development.
Development of an AAV Vector System for Highly Specific and Efficient Gene Expression in Microglia
Authors: Aoki Ryo , Konno Ayumu , Hosoi Nobutake , Kawabata Hayato , Hirai Hirokazu 
Published: November 2024

AbstractMicroglia play a critical role in diseases such as Alzheimer’s and stroke, making them a significant target for therapeutic intervention. However, due to their immune functions in detecting and combating viral invasion, efficient gene delivery to microglia remains challenging. We achieved specific and efficient gene delivery to microglia using an adeno- associated virus (AAV) vector designed for this purpose. This microglia-targeting AAV vector includes the mouse microglia/macrophage-specific ionized calcium-binding adaptor molecule 1 (mIba1) promoter, green fluorescent protein (GFP), microRNA target sequences (miR.Ts), woodchuck hepatitis virus posttranscriptional regulatory element (WPRE), and polyadenylation (polyA) signal, positioned between inverted terminal repeats. When miR.Ts were placed downstream of WPRE (between WPRE and polyA), gene expression occurred not only in microglia but also in a substantial number of neurons. However, when miR.Ts were positioned upstream of WPRE (between GFP and WPRE) or on both sides of WPRE, neuronal expression was significantly suppressed, resulting in selective GFP expression in microglia. Notably, positioning miR.Ts on both sides of WPRE achieved over 90% specificity and more than 60% efficiency in transgene expression in microglia three weeks after viral administration. This vector also enabled GCaMP expression in microglia, facilitating real-time monitoring of calcium dynamics and microglial process activity in the cortex. Additionally, intravenous administration of this vector with the blood-brain barrier-penetrant AAV-9P31 capsid variant resulted in extensive GFP expression selectively in microglia throughout the brain. These findings establish this AAV vector system as a robust tool for long-term, specific, and efficient gene expression in microglia.
Unraveling eye movement-related eardrum oscillations (EMREOs): how saccade direction and tympanometric measurements relate to their amplitude and time course
Authors: Sotero Silva Nancy , Kayser Christoph , Bröhl Felix 
Published: November 2024

AbstractEye movement-related eardrum oscillations (EMREOs) reflect movements of the tympanic membrane that scale with the magnitude and direction of saccades. EMREOs have been consistently described in humans and non-human primates, yet many questions regarding this phenomenon remain unresolved. Based on bilateral in-ear recordings in human participants we here explore several properties of these EMREOs in order to improve our understanding of this signal’s origin and functional significance. Our data support that the EMREO time course is comparable between the left and right ears, and between paradigms guiding saccades by visual and auditory target stimuli. However, the precise amplitude time course differs significantly between ipsi-and contralateral saccades in addition to the previously known phase-inversion described for saccades in opposing directions. Finally, our data suggest that the EMREO amplitude is negatively related to the compliance of the tympanic membrane as established by tympanometry. Collectively, these results support the notion that EMREOs reflect motor-related top-down signals relayed to the ear from yet-to-be-resolved sources, and fuel the speculation that EMREOs may be generated by the middle ear muscles in a differential operation similar to the execution of ipsi-and contralateral saccades.
The phosphatase PP2C12 is a negative player in LRX-RALF-FER-mediated cell wall integrity sensing
Authors: Hou Xiaoyu , Bender Kyle W. , Kadler Gabor , Gupta Shibu , Häfliger Mona , Guérin Amandine , Diet Anouck , Roffler Stefan , Campanini Daniela , Wicker Thomas , Zipfel Cyril , Ringli Christoph 
Published: November 2024

AbstractPlants have evolved an elaborate cell wall integrity (CWI) sensing system to monitor and modify cell wall formation. LRR-extensins (LRXs) are cell wall-anchored proteins that bind RAPID ALKALINIZATION FACTOR (RALF) peptide hormones and induce compaction of cell wall structures. At the same time, LRXs form a signaling platform with RALFs and the transmembrane receptor kinase FERONIA (FER) as a means to relay changes in CWI to the protoplast.LRX1ofArabidopsis thalianais predominantly expressed in root hairs andlrx1mutants develop defective root hairs. Here, we identify a regulator of LRX1-RALF-FER signaling as a suppressor of thelrx1root hair phenotype. Therepressor of lrx1_23(rol23) gene encodes PP2C12, a type 2C phosphatase of clade H that interacts with FER and dephosphorylates Thr696 in the FER activation loopin vitro. The LRX1-related function of PP2Cs appears clade H-specific and was not observed for other PP2Cs investigated. Collectively, our data suggest that LRX1 acts upstream of the RALF1-FER signaling module and PP2C12 has an inhibitory activity via modulating FER activity to fine-tune CWI signaling.
Microglia modulate cerebral blood flow and neurovascular coupling through ectonucleotidase CD39
Authors: Fu Zhongxiao , Ganesana Mallikarjunarao , Hwang Philip , Tan Xiao , Kinkaid Melissa Marie , Sun Yu-Yo , Bian Emily , Weybright Aden , Sol-Church Katia , Eyo Ukpong B. , Pridans Clare , Quintana Francisco J. , Robson Simon C. , Kumar Pankaj , Venton B. Jill , Schaefer Anne , Kuan Chia-Yi 
Published: November 2024

AbstractMicroglia and the border-associated macrophages (BAMs) contribute to the modulation of cerebral blood flow (CBF), but the mechanisms have remained ill-defined. Here, we show that microglia regulate the CBF baseline and upsurges after whisker stimulation or intracisternal magna injection of adenosine triphosphate (ATP). Genetic or pharmacological depletion of microglia reduces the activity-dependent hyperemia but not the cerebrovascular responses to adenosine stimulation. Notably, microglia repopulation corrects these CBF reactivity deficits. The microglial-dependent regulation of CBF requires the ATP-sensing P2ry12 receptor and the ectonucleotidase CD39 that initiates the breakdown of extracellular ATP. Pharmacological inhibition or microglia-specific deletion of CD39 simulates the CBF anomalies detected in microglia-deficient mice and reduces the rise of extracellular adenosine after whisker stimulation. Together, these results suggest that the microglial CD39-initiated conversion of extracellular ATP to adenosine is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity.
Oral Boldine Administration Attenuates Glia Activation and Prevents Neuropathic Pain in a Murine Spared Nerve Injury Model
Authors: Pan Jiangping , Duarte Yorley , Chow Christine , Toro Carlos A. , Sáez Juan C. , Cardozo Christopher P. , Zhao Wei 
Published: November 2024

AbstractChronic pain is present in about 20% of the population and is a major burden to the health care system. About 30-40% of these patients report neuropathic pain. Neuropathic pain is defined as pain caused by injury or disease of the somatosensory nervous system. Current available treatments for neuropathic pain have limited efficacy and substantial side effects. To address the need for more effective and safer treatments for neuropathic pain, this study aimed to test whether boldine, a naturally occurring alkaloid, could attenuate neuropathic pain in a murine model of spared nerve injury (SNI). We found that oral administration of boldine at 50 mg/kg body weight/day resulted in significant reduction of SNI-induced mechanical and thermal hypersensitivity. Boldine also corrected SNI-induced weight bearing deficits, which are an indication of spontaneous pain. Boldine significantly inhibited SNI-induced peripheral inflammation as indicated by reduced levels of inflammatory cytokines/chemokines in the serum. Immunofluorescence studies revealed that boldine reduced the number of reactive astrocytes and inhibited microglia activation in the dorsal horn of lumbar spinal cord. Boldine also reduced the mRNA level of pro-inflammatory markers including IL-1β and TNF-α in the lumbar spinal cord after SNI. Quantitative PCR showed that boldine inhibited the lipopolysaccharide-induced overexpression of inflammatory markers in primary mouse astrocytes and in BV-2 microglial cells. Our findings suggest that boldine may be a promising therapeutic candidate for the treatment of neuropathic pain, possibly through inhibition of glia activation and neuroinflammation.
PgtE protease enables virulentSalmonellato evade C3-mediated serum and neutrophil killing
Authors: Lee Michael H. , Perez-Lopez Araceli , Knodler Leigh A. , Nguyen Grace , Walker Gregory T. , Behnsen Judith , Silva Steven , Celli Jean , Tamin Melissa A. , Liang Michael H. , Melchior Karine , Argueta Felix A. , Nuccio Sean-Paul , Raffatellu Manuela 
Published: November 2024

ABSTRACTNon-typhoidalSalmonellaserovars, such asSalmonella entericaserovar Typhimurium (STm), are a leading cause of inflammatory diarrhea in otherwise healthy individuals. Among children, the elderly, and immunocompromised individuals, STm can spread to systemic sites and cause potentially lethal bacteremia. Phagocytic cells and the immune complement system are pivotal to preventing the dissemination of STm. PgtE, an STm outer membrane protease, has been previously described to cleave over a dozen mammalian protein substratesin vitro, including complement protein C3. However, these activities have mostly been observed with mutant, avirulent strains with a truncated O-antigen that renders bacteria sensitive to complement killing. Here, we report that virulent STm utilizes PgtE to evade complement-mediated killingin vivo. The wild-type pathogen increasespgtEexpression and PgtE proteolytic function within macrophages and in macrophage-likein vitrogrowth conditions, concomitant with physiologic O-antigen shortening in these environments. Furthermore, we found that wild-type STm’s resistance to complement-mediated serum and neutrophil killing is PgtE-dependent. We propose that PgtE promotes the systemic spread of STm by acting as a second line of defense against complement when STm escapes from a macrophage.
Ecological Determinants of Altruism in Prokaryote Antivirus Defense
Authors: Biba Dmitry A. , Makarova Kira S. , Wolf Yuri I. , Waldron Levi , Koonin Eugene V. , Rochman Nash D. 
Published: November 2024

AbstractProkaryote evolution is driven in large part by the incessant arms race with viruses. Genomic investments in antivirus defense can be coarsely classified into two categories, immune systems that abrogate virus reproduction resulting in clearance, and altruistic programmed cell death (PCD) systems. Prokaryotic defense systems are enormously diverse, as revealed by an avalanche of recent discoveries, but the basic ecological determinants of defense strategy remain poorly understood. Through mathematical modeling of defense against lytic virus infection, we identify two principal determinants of optimal defense strategy and, through comparative genomics, we test this model by measuring the genomic investment into immunity vs PCD among diverse bacteria and archaea. First, as viral pressure grows, immunity becomes the preferred defense strategy. Second, as host population size grows, PCD becomes the preferred strategy. We additionally predict that, although optimal strategy typically involves investment in both PCD and immunity, overinvestment in immunity can result in system antagonism, increasing the probability a PCD-competent cell will lyse due to infection. Together these findings indicate that, generally, PCD is preferred at low multiplicity of infection (MOI) and immunity is preferred at high MOI, and that the landscape of prokaryotic antivirus defense is substantially more complex than previously suspected.