bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial Cell Dysfunction and Retinal Arteriolar Narrowing in Young Adults With Elevated Blood Pressure
Authors: Tan Cheryl M. J. , Lewandowski Adam J. , Hanssen Henner , Streese Lukas , Huckstep Odaro J. , Fischer Roman , Alsharqi Maryam , Mohamed Afifah , Williamson Wilby , Leeson Paul , Bertagnolli Mariane 
Published: July 2024

ABSTRACTBackgroundYoung-adults with endothelial cell dysfunction are more likely to develop elevated blood pressure. We tested the hypothesis that this relates to development of structural microvascular impairments by studying associations between circulating endothelial colony-forming cell (ECFC) dysfunction and microvascular markers, as well as identifying related endothelial molecular mechanisms.MethodsPeripheral blood ECFCs were isolated from 32 subjects (53% men, 28±4 years old) using the Ficoll density gradient centrifugation method. Participants with blood pressure ≥120/80 mm Hg were included in the elevated blood pressure (BP) group, whereas ≤120/80 mm Hg were classed as normotensive. Retinal microvasculature was assessed by Static Retinal Vessel Analyzer (SVA-T).ResultsSubjects with elevated BP had impaired in vitro ECFC colony-forming growth, cell proliferation and angiogenesis assessed by tube formation potential. There was a graded inverse association between ECFC colony-forming capacity (days taken for ECFC colony growth) and retinal arteriolar diameter, as well as arteriolar/venular ratio. Proteomic analysis of ECFCs identified differences in extracellular matrix organization, blood coagulation, exocytosis and vesicle transport proteins in subjects with elevated blood pressure, revealing the adaptor protein GRB2 as a potential link between endothelial cell and microvascular abnormalities.ConclusionsEndothelial cell dysfunction associates with retinal arteriolar narrowing in men and women with elevated blood pressure. Endothelial molecular mechanisms linked to reduced adaptive postnatal angiogenesis capacity, rather than vascular development, may contribute to early microvascular changes.HIGHLIGHTSSubjects with elevated blood pressure had impaired in vitro endothelial cell growth and angiogenesis in comparison to normotensive subjects.There was an association between impaired endothelial cell growth capacity and reduced retinal arteriolar diameter.Different endothelial proteome signatures were identified, revealing the adaptor protein GRB2 as a potential link between endothelial and microvascular abnormalities in subjects with elevated blood pressure.GRAPHICAL ABSTRACT
Autoimmune Encephalitis, Neuromyelitis Optica Spectrum Disorder and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: Analysis of the Vaccine Adverse Event Reporting System (VAERS)
Authors: Garcia-Dominguez Maria A. , Kaur Taranjit , Kipkorir Vincent , Cheruto Doreen C. , Rugut Clinton , Udochukwu Anosike , Singh Harsimran , S. Srichawla Bahadar 
Published: July 2024

ABSTRACTIntroductionAutoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are complex and debilitating neurological disorders.MethodsThis study uses the Vaccine Adverse Event Reporting System (VAERS) to investigate the potential relationship between vaccinations and the incidence of NMOSD, AE, and MOGAD. Potential risk factors, such as age, sex, type of vaccine, and previous history of autoimmune diseases, were examined using multivariate logistic regression analysis.ResultsOur analysis included 161 cases: 72 NMOSD, 82 AE, and 7 MOGAD. The COVID-19 vaccine was implicated in 19/72 (26.3%) NMOSD, 43/82 (52.4%) of AE and 6/7 (85.7%) of MOGAD. The subacute temporal profile (OR 24.4, p = 0.004) and the presence of any comorbidity (OR 12.49, p = 0.004) were significantly associated with hospitalization for those with NMOSD. The subacute onset of symptoms and encephalopathy was statistically significant for hospitalization (OR 6.15, p = 0.048) and (OR 10.3, p = 0.005) respectively for patients with AE. Anti-NMDAR (N-methyl D-aspartate) antibodies were observed in 16/24 (66.7%) of AE. Treatment often involved high-dose corticosteroids or intravenous immunoglobulin (IVIG).ConclusionsMost cases of vaccine induced NMOSD, AE, and MOGAD occurred secondary to the SARS-CoV-2 vaccine. The subacute onset of symptoms and the presence of encephalopathy was most associated with hospitalization.
An epidemiological description of rabies outbreaks in Zambia from 2013 to 2023
Authors: Banda Humphrey , Hamukale Amos , Makungu Chitwambi , Ngoma Masuzyo , Chazya Ricky , Mataa Liywalii , Mulenga Chilufya , Banda James Blazer , Muleya Walter , Sialubanje Cephas , Banda Dabwitso , Sinyange Nyambe , Kachinda Wezi 
Published: July 2024

AbstractBackgroundIn Zambia, a dog bite is the most common rabies exposure. There is limited information on rabies outbreaks in jackals in Zambia. We investigated all rabies cases in Zambia and narrowed down on jackal bites in Mungwi district to determine a temporal trend and buffer zones for rabies.MethodsThe risk of exposure included all humans and animals bitten by jackals, data were collected by interviewing jackal bite victims and collecting brain specimen samples from animals. Risk of spread was determined by estimating the distance jackals strayed into human population and the Rabies Vaccination Coverage (RVC) in the district. The RVC was determined by dividing vaccinated dogs by dog population. The incidence rate (IR) and a Sen’s slope was used to determine a trend of RVC and the rabies cases in Zambia. QGIS was used to produce a heatmap and rabies risk zones. Direct Fluorescent Antibody technique was used to test for rabies.ResultsZambia had recorded a total of 224 rabies cases with a mean (SD) of 22.4 (16) rabies cases and a positivity rate of 65.4% (25.7) per year from 2013 to 2022. Lusaka and Copperbelt provinces recorded the highest rabies cases. The rabies incidence rate was 2.3 rabies cases per 10,000 dogs in Zambia. The cases had reduced from 2013 to 2021 with a Sen’s slope of -0.74 (p = 0.02). At least 227 animal bites were recorded (two jackals and 225 dog bites) in Mungwi District. 94% (213) of the victims needed Post Exposure Prophylaxis. The victim’s median age was 20 (Interquartile range=12-38) years. The accumulative RVC from 2018-2022 (611/7777), was 0.11 (95% CI: −0.4-0.7, p=0.46) annual slope increase with 1.60% mean (Standard deviation = 0.34). One rabies heatmap and three risk-level zones (low, medium and high) were produced, and two jackals and one goat specimens were positive.ConclusionsA risk-based surveillance and enhanced vaccination of dogs in high-risk areas through a one health approach is critical for rabies control in Zambia.
Free energy profiles of temozolomide crossing brain plasma membranes
Authors: Ge Yanhong , Lu Huixia , Marti Jordi 
Published: July 2024

AbstractTemozolomide is an efficient small-molecule drug mostly employed for the treatment of glioblastoma, a tumor attacking both the spinal cord and the brain. Understanding the interactions of temozolomide with different lipids at the brain cell membrane can help elucidate how temozolomide permeates through cell membranes and its membrane-crossing ability. In the present work, we have constructed a simplified brain plasma membrane model to explore temozolomide’s microscopic structure and dynamics by means of all-atom microsecond scale molecular dynamics simulations. The preferential location of temozolomide is at the solvent-aqueous fluid surrounding the brain membrane, but it can access the interface with the membrane regularly, eventually binding to lipids of the choline and cerebroside classes. The free energy barriers of temozolomide related to brain-like plasma membrane crossing were investigated by adaptive biasing force methods, revealing values ranging from 18.5 to 66.5 kcal/mol at temperatures of 323 K and 310 K, respectively. Our results suggest that temozolomide cannot cross the membrane by pure diffusion at the normal human body temperature but that rising the temperature significantly increases the probability of barrier crossing. This fact is mainly due to the crucial role played by cholesterol and lipids of the cerebroside class. The findings reported in this work can be used to optimize the molecular design of temozolomide and to develop new analogs with better pharmacokinetic properties.Author summaryGlioblastoma is a devastating tumor affecting the brain and spinal cord, which has in the FDA-approved drug temozolomide its main clinical treatment. The present study explores how temozolomide interacts with several lipids in brain-like cell membranes. Our findings show that at normal body temperature temozolomide cannot cross the membrane by pure diffusion, but that higher temperatures significantly enhance its ability to cross the membrane by reducing the free energy barriers. Temozolomide interacts differently with several lipids and sterols depending on the temperature, which affects its permeability. This implies that temozolomide will cross the outer layer of the brain membrane only with the help of driving agents, such as intermembrane proteins. Our research suggests that temozolomide may be more effective at higher temperatures and cancer patients with fever might need a lower dose. Importantly, cholesterol plays a key role in blocking temozolomide from crossing brain-like membranes, so reducing dietary intake of cholesterol and cerebroside lipids could help modify brain cell membranes, making it easier for temozolomide to target cancer cells effectively and potentially reducing side effects.
Endomucin knockout leads to delayed retinal vascular development and reduced ocular pathological neovascularization
Authors: Hu Zhengping , Cano Issahy , Lennikov Anton , Wild Melissa , Gupta Urvi , Ng Yin Shan Eric , D’Amore Patricia A. 
Published: July 2024

AbstractEndomucin (EMCN), an endothelial-specific glycocalyx component highly expressed in capillary and venous endothelium, plays a critical role in regulating VEGF receptor 2 (VEGFR2) endocytosis and downstream VEGF signaling. Using the first global EMCN knockout mouse model, we investigated the effects of EMCN deficiency on retinal vascularization during development and pathological angiogenesis. We found relatively high expression of EMCN in choroidal capillaries and retinal vasculature. Emcn-/-mice exhibited delayed retinal vascularization at postnatal day 5, with fewer tip cells and reduced vessel density. Ultrastructural examination revealed disrupted and reduced fenestrations in choroidal capillary endothelium. In an oxygen-induced retinopathy model, while Emcn-/-mice showed no significant difference in avascular area compared to Emcn+/+mice at postnatal day 12, there was a significant reduction in neovascular tufts in Emcn-/-mice at postnatal day 17. Similarly, in a laser-induced choroidal neovascularization model, Emcn-/-mice showed a significant reduction in vascular leakage and lesion size. These findings suggest that EMCN plays a critical role in both vascular development and pathological neovascularization, highlighting its potential as a target for anti-angiogenic therapies.
Social odors drive hippocampal CA2 place cell responses to social stimuli
Authors: Robson Emma , Donahue Margaret M. , Mably Alexandra J. , Demetrovich Peyton G. , Hewitt Lauren T. , Colgin Laura Lee 
Published: July 2024

AbstractHippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.
Deletion of the endothelial glycocalyx component endomucin leads to impaired glomerular structure and function
Authors: Hu Zhengping , Cano Issahy , Lei Fengyang , Liu Jie , Ramos Ramon Bossardi , Gordon Harper , Paschalis Eleftherios I. , Saint-Geniez Magali , Ng Yin Shan Eric , D’Amore Patricia A. 
Published: July 2024

ABSTRACTBackgroundEndomucin (EMCN), an endothelial-specific glycocalyx component, was found to be highly expressed by the endothelium of the renal glomerulus. We reported an anti-inflammatory role of EMCN and its involvement in the regulation of vascular endothelial growth factor (VEGF) activity through modulating VEGF receptor 2 (VEGFR2) endocytosis. The goal of this study is to investigate the phenotypic and functional effects of EMCN deficiency using the first global EMCN knockout mouse model.MethodsGlobal EMCN knockout mice were generated by crossing EMCN-floxed mice with ROSA26-Cre mice. Flow cytometry was employed to analyze infiltrating myeloid cells in the kidneys. The ultrastructure of the glomerular filtration barrier was examined by transmission electron microscopy, while urinary albumin, creatinine, and total protein levels were analyzed from freshly collected urine samples. Expression and localization of EMCN, EGFP, CD45, CD31, CD34, podocin, albumin, and α-smooth muscle actin were examined by immunohistochemistry. Mice were weighed regularly, and their systemic blood pressure was measured using a non-invasive tail-cuff system. Glomerular endothelial cells and podocytes were isolated by fluorescence-activated cell sorting for RNA-seq. Transcriptional profiles were analyzed to identify differentially expressed genes in both endothelium and podocytes, followed by gene ontology analysis of up- and down-regulated genes. Protein levels of EMCN, albumin, and podocin were quantified by Western blot.ResultsEMCN-/-mice were viable with no gross anatomical defects in kidneys. The EMCN-/-mice exhibited increased infiltration of CD45+cells, with an increased proportion of Ly6GhighLy6Chighmyeloid cells and higher VCAM-1 expression. EMCN-/-mice displayed albuminuria with increased albumin in the Bowman’s space compared to the EMCN+/+littermates. Glomeruli in EMCN-/-mice revealed fused and effaced podocyte foot processes and disorganized endothelial fenestrations. We found no significant difference in blood pressure between EMCN knockout mice and their wild-type littermates. RNA-seq of glomerular endothelial cells revealed downregulation of cell-cell adhesion and MAPK/ERK pathways, along with glycocalyx and extracellular matrix remodeling. In podocytes, we observed reduced VEGF signaling and alterations in cytoskeletal organization. Notably, there was a significant decrease in both mRNA and protein levels of podocin, a key component of the slit diaphragm.ConclusionOur study demonstrates a critical role of the endothelial marker EMCN in supporting normal glomerular filtration barrier structure and function by maintaining glomerular endothelial tight junction and homeostasis and podocyte function through endothelial-podocyte crosstalk.
Probability of Lateral Instability While Walking on Winding Paths
Authors: Render Anna C. , Cusumano Joseph P. , Dingwell Jonathan B. 
Published: July 2024

ABSTRACTPeople with balance impairments often struggle performing turns or lateral maneuvers, which can increase risk of falls and injuries. Here we asked how people’s mediolateral balance is impacted when walking on non-straight winding paths. Twenty-four healthy adults (12F/12M; 25.8±3.5 yrs) participated. Each walked on each of six paths projected onto a treadmill, comprised of three pseudo-random path oscillation frequency combinations (straight, slowly-winding, quickly-winding), each presented at either wide or narrow width. We quantified stepping errors as the percent of steps taken off each path. We quantified minimum mediolateral Margin of Stability (MoSL) at each step and calculated means (μ) and standard deviations (σ) for each trial. We calculated lateral Probability of Instability (PoIL) as participants’ statistical risk of taking unstable (MoSL< 0) steps. Onnarrowerpaths, participants made more stepping errors and walked with smallerμ(MoSL) on all paths (p < 0.001), and exhibited increasedPoILon the straight and slowly-winding paths (p < 0.001). Onwindingpaths, participants made progressively more stepping errors and walked with smallerμ(MoSL) for increasingly sinuous narrow paths (all p < 0.001) and wide quickly-winding paths (all p < 0.001). They also consistently walked with largerσ(MoSL), and increasedPoILon higher sinuosity paths of both widths (all p < 0.001). Though many took numerous unstable steps, no participantfell. Our results demonstrate healthy adults’ ability both to trade off increased risk of lateral instability for greater maneuverability, and to employ highly-versatile stepping strategies to maintain balance while walking.
Pathogenic LRRK2 causes age-dependent and region-specific deficits in ciliation, innervation and viability of cholinergic neurons
Authors: Brahmia Besma , Naaldijk Yahaira , Sarkar Pallabi , Parisiadou Loukia , Hilfiker Sabine 
Published: July 2024

AbstractPathogenic activating point mutations in the LRRK2 kinase cause autosomal-dominant familial Parkinsońs disease (PD). In cultured cells, mutant LRRK2 causes a deficit inde novocilia formation and also impairs ciliary stability. In brain, previous studies have shown that in PD patients due to the G2019S-LRRK2 mutation as well as in middle-aged G2019S-LRRK2 knockin mice, striatal cholinergic interneurons show a deficit in primary cilia. Here, we show that cilia loss in G2019S-LRRK2 knockin mice is not limited to cholinergic striatal interneurons but common to cholinergic neurons across distinct brain nuclei. The lack of cilia in cholinergic forebrain neurons is accompanied by the accumulation of LRRK2-phosphorylated Rab12 GTPase and correlates with the presence of dystrophic cholinergic axons. Those deficits are already evident in young adult mutant LRRK2 mice. In contrast, the age-dependent loss of cilia in brainstem cholinergic neurons correlates with an age-dependent loss of cholinergic innervation derived from this brain area. Strikingly, we find cholinergic cell loss in mutant LRRK2 mice that is age-dependent, cell type-specific and disease-relevant. The age-dependent loss of a subset of cholinergic neurons mimics that observed in sporadic PD patients, highlighting the possibility that these particular neurons may require functional cilia for long-term cell survival.
Visual cues for moisture perception of facial skin: Enhancing high-frequency components of skin lightness increases perceived dryness
Authors: Hasegawa Yuya , Tamura Hideki , Kanematsu Tama , Yamada Yuzuka , Ishiguro Yohei , Nakauchi Shigeki , Minami Tetsuto 
Published: July 2024

AbstractFacial skin texture provides crucial visual cues that reflect an individual’s impressions and health conditions. In this study, we focused on the texture attribute of “moisture” and investigated which visual cues influenced skin moisture perception. The stimuli consisted of images from three facial areas (the whole face, cheek, and eyebrow areas) with and without makeup under two lighting directions. The participants rated the presented stimuli on the three texture attributes (moisture, glossiness, and attractiveness) using a five-point scale. The results from Experiment 1 revealed correlations between the ratings and histogram statistics of each channel in the CIELAB color space, with variations depending on the conditions and facial regions. A negative correlation was observed between the cheek moisture perception and the variance in theL*channel. We subsequently obtained similar ratings by enhancing the high-frequency components of skin lightness for artificially dried stimuli (Experiment 2) and for images depicting different skin conditions due to various types of makeup (Experiment 3). Both experiments confirmed a decrease in moisture and attractiveness and an increase in glossiness; these were correlated with the degree of artificial drying. These findings indicated that the high-frequency components of skin lightness could be visual cues for determining the perceived dryness.
Alternative splicing in mechanically stretched podocytes as a model of glomerular hypertension
Authors: Mattias Francescapaola , Tsoy Olga , Hammer Elke , Gress Alexander , Simm Stefan , Lio Chit Tong , Ameling Sabine , Amann Kerstin , Dreher Leonie , Wenzel Ulrich , Kacprowski Tim , List Markus , Kalinina Olga , Endlich Karlhans , Baumbach Jan , Völker Uwe , Endlich Nicole , Kliewe Felix 
Published: July 2024

AbstractBackgroundAlterations in pre-mRNA splicing play an important role in disease pathophysiology. However, the role of alternative splicing (AS) for podocytes in hypertensive nephropathy (HN) has not been investigated. The purpose of the Sys_CARE project was to identify AS events that play a role in the development and progression of HN.MethodsMurine podocytes were exposed to mechanical stretch, after which proteins and mRNA were analyzed by proteomics, RNA-Seq and several bioinformatic AS tools.ResultsBased on transcriptomics and proteomics analysis we could observe significant changes in gene expression and abundance of proteins under mechanical stretch compared to unstretched conditions. By RNA-Seq, we identified over 3,000 alternative spliced genes after mechanical stretch, including all types of AS events. We found 17 genes that showed an AS event in four different splicing analysis tools. From these, we focused onMyl6, a component of the myosin protein complex, andShroom3, an actin-binding protein crucial for podocyte function. We found twoShroom3isoforms that showed significant changes in expression upon mechanical stretch, which was verified by qRT-PCR andin situhybridization. Furthermore, we observed an expression switch of twoMyl6isoforms after mechanical stretch. This switch is accompanied by a change in a C-terminally located amino acid sequence.ConclusionsIn summary, mechanical stretch of cultured podocytes is an excellent model to simulate hypertensive nephropathy. In depth RNA-Seq analysis disclosed alternative splicing events, such as inShroom3andMyl6, which may play a crucial role in the pathophysiology of hypertension-induced nephropathy.