bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Prospective Observational Study to Assess the Impact of Pharmacogenetics on Outcomes in Vascular Surgery (PROSPER)
Authors: Burke Kerry A , Mirza Selman , Wright Stuart J , Greaves Nicholas S , Newman William G , McDermott John H 
Published: May 2024

AbstractIntroductionPatients with chronic limb threatening ischaemia (CLTI) are often prescribed clopidogrel in order to reduce their risk of major adverse limb and cardiovascular events. Clopidogrel is metabolised by the CYP2C19 enzyme, and genetics variations inCYP2C19are common. These variants can influence an individual’s ability to metabolise clopidogrel to its active metabolite. This work aims to establish the relationship between patient genotype and outcomes after revascularisation in patients with CLTI who are prescribed clopidogrel. It will consider whether pharmacogenetics can be used to ensure patients are prescribed effective medications to optimise their outcomes.Methods and analysisThis is a prospective observational cross-sectional study of patients undergoing lower limb surgical, endovascular or hybrid revascularisation for CLTI. Patients taking clopidogrel post-procedure, as well as those prescribed a non-clopidogrel based medication regimen, will be recruited prior to or shortly after revascularisation. Patients will undergoCYP2C19genotyping and will be followed-up using online records.Ethics and disseminationManchester University Research Ethics Committee approval as obtained was part of the Implementing Pharmacogenetics to Improve Prescribing (IPTIP) trial process (IRAS 305751). The results of the study will be published in a peer-review journal and presented at international conferences.RegistrationThis work is a sub-protocol for the IPTIP study which is registered asISRCTN14050335.
Host blood protein biomarkers to screen for Tuberculosis disease: a systematic review and meta-analysis
Authors: Gaeddert Mary , Glaser Kerstin , Chendi Bih H. , Sultanli Ayten , Koeppel Lisa , MacLean Emily L. , Broger Tobias , Denkinger Claudia M. 
Published: May 2024

AbstractIntroductionNon-sputum tests are needed to improve TB diagnosis and close the diagnostic gap. The World Health Organization target product profile (TPP) for point-of-care (POC) screening tests requires minimum sensitivity 90% and specificity 70%. Our objective was to identify host blood protein biomarkers meeting TPP criteria.MethodsA systematic review was conducted and reported following PRISMA guidelines. Data extraction and quality assessment with QUADAS-2 were completed for included studies. Heterogeneity was assessed. For biomarkers reporting sensitivity and specificity in at least four studies, a random-effects meta-analysis was performed for biomarkers with similar cut-offs.ResultsWe screened 4,651 citations and included 65 studies that enrolled 16,010 participants and evaluated 156 host proteins. Most (47/65) studies enrolled adult pulmonary TB (PTB), with 15 studies in adult extra-pulmonary TB and 5 in children. Small early-stage discovery studies with case-control design were common (24/65) and had high risk of bias. For adult PTB, CRP, IP-10, NCAM-1, and SAA met TPP criteria in high-quality studies. There was a high degree of heterogeneity in biomarker cut-offs and study design. CRP at 10mg/L cut-off was meta-analyzed from 10 studies; pooled sensitivity 86% (95% CI: 80-95) and pooled specificity 67% (95% CI: 54-79). In people living with HIV (6 studies) CRP pooled sensitivity was 93% (95% CI: 90-95) and pooled specificity 59% (95% CI: 40-78).DiscussionWe identified promising biomarkers that performed well in high-quality studies. Data overall are limited and highly heterogenous. Further standardized validation across subgroups in prospective studies is needed before translating into POC assays.
BMP signaling promotes heart regeneration via alleviation of replication stress
Authors: Vasudevarao Mohan Dalvoy , Pena Denise Posadas , Ihle Michaela , Bongiovanni Chiara , Maity Pallab , Redaelli Simone , Happ Kathrin , Geissler Dominik , Mohammadi Hossein Falah , Rall-Scharpf Melanie , Wu Chi-Chung , Beisaw Arica , Scharffetter-Kochanek Karin , D’Uva Gabriele , Wiesmüller Lisa , Weidinger Gilbert 
Published: May 2024

AbstractOne hallmark of aging is a decline in tissue regeneration, which can be caused by DNA replication stress. Whether highly regenerative species like zebrafish are immune from such hindrances to replication is unknown. In contrast to most mammals, adult zebrafish achieve complete heart regeneration via cell cycle entry and proliferation of mature cardiomyocytes. We found that cycling cardiomyocytes experience replication stress, which is induced by the demands of regeneration, but does not occur during physiological heart growth. Since zebrafish cardiomyocyte regeneration is remarkably efficient, heart regeneration appears to depend on elevated capabilities to overcome replication stress. Indeed, pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for heart regeneration. Using inducible overexpression of ligands and inhibitors of the Bone Morphogenetic Protein (BMP)-Smad pathway, combined with analysis of genetic mutants, we found that BMP signaling alleviates cardiomyocyte replication stress. In the absence of BMP signaling, cardiomyocytes become arrested in the S-phase of the cell cycle, which prevents progression to mitosis and results in heart regeneration failure. Interestingly, BMP signaling can also rescue neonatal mouse cardiomyocytes and human fibroblasts from hydroxyurea-induced replication stress. DNA fiber spreading assays in human cancer cells and human hematopoietic stem and progenitor cells (HSPCs) indicate that BMP signaling acts directly on replication dynamics by accelerating DNA replication fork progression and by facilitating their re-start after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated heart regeneration capacity in zebrafish. Notably, the conserved capability of BMP signaling to promote stress-free DNA replication might unlock new avenues towards anti-aging and pro-regenerative applications in humans.
Mild hyperthermia-induced thermogenesis in the endoplasmic reticulum defines stress response mechanisms
Authors: Dukic Barbara , Ruppert Zsófia , Tóth Melinda E. , Hunya Ákos , Czibula Ágnes , Bíró Péter , Tiszlavicz Ádám , Péter Mária , Balogh Gábor , Erdélyi Miklós , Timinszky Gyula , Vígh László , Gombos Imre , Török Zsolt 
Published: May 2024

AbstractPrevious studies reported that a mild, non-protein denaturing, fever-like temperature increase induced the unfolded protein response (UPR) in mammalian cells. Our dSTORM super-resolution microscopy experiments revealed that the master regulator of the UPR, the IRE1 (inositol-requiring enzyme 1) protein is clustered as a result of UPR activation in a human osteosarcoma cell line (U2OS) upon mild heat stress. Using ER thermo yellow, a temperature-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we detected significant intracellular thermogenesis in mouse embryonic fibroblast (MEF) cells. Temperatures reached at least 8°C higher than the external environment (40°C), resulting in exceptionally high ER temperatures similar to those previously described for mitochondria. Mild heat-induced thermogenesis in the ER of MEF cells was likely due to the uncoupling of the Ca2+/ATPase (SERCA) pump. The high ER temperatures initiated a pronounced cytosolic heat shock response in MEF cells, which was significantly lower in U2OS cells in which both the ER thermogenesis and SERCA pump uncoupling were absent. Our results suggest that, depending on intrinsic cellular properties, mild hyperthemia-induced intracellular thermogenesis defines the cellular response mechanism, and determines the outcome of hyperthermic stress.
Ccrk-Mak/Ick kinase signaling axis is a ciliary transport regulator essential for retinal photoreceptor maintenance
Authors: Chaya Taro , Maeda Yamato , Tsutsumi Ryotaro , Ando Makoto , Ma Yujie , Kajimura Naoko , Tanaka Teruyuki , Furukawa Takahisa 
Published: May 2024

AbstractPrimary cilia are microtubule-based sensory organelles whose dysfunction leads to ciliopathies in humans. The formation, function, and maintenance of primary cilia depend crucially on intraflagellar transport (IFT); however, the regulatory mechanisms of IFT and their physiological roles are poorly understood. In the current study, we screened and identified that the ciliopathy kinase Mak is a ciliary tip-localized IFT regulator that cooperatively acts with the ciliopathy kinase Ick, an IFT regulator. Simultaneous disruption ofMakandIckresulted in loss of photoreceptor ciliary axonemes and severe degeneration in the mouse retina. Mak overexpression restored ciliary defects caused byIckdeficiency in cultured cells. Gene delivery ofIckand pharmacological inhibition of FGF receptors, negative regulators of Ick, ameliorated retinal degeneration inMak−/−mice. In addition, we identified that Ccrk kinase is an upstream activator of Mak and Ick in retinal photoreceptor cells. Furthermore, overexpression of Mak, Ick, and Ccrk and pharmacological inhibition of FGF receptors suppressed ciliopathy-related phenotypes caused by cytoplasmic dynein inhibition in cultured cells. Collectively, our results show that the Ccrk-Mak/Ick axis is an essential IFT regulator crucial for retinal photoreceptor maintenance. This study sheds light on pathological mechanisms underlying retinitis pigmentosa caused by mutations in the humanMAKgene and presents activation of Ick as a potential therapeutic approach for this retinal degenerative disease.
Modular Design and Scaffold-Synthesis of Multi-Functional Fluorophores for Targeted Cellular Imaging and Pyroptosis
Authors: Li Yuanyuan , Wang Chunhui , Wang Haiyang , Sun Kunhui , Lu Siyu , Wang Yahui , Zhang Lei , Jing Su , Cordes Thorben 
Published: May 2024

AbstractModified commercial fluorophores are essential tools for optical imaging and biomedical research. Their synthetic modification to incorporate new functions, however, remains a challenging task. Conventional strategies rely on linear synthesis in which a parent framework is gradually extended. We here designed and synthesized a versatile library of functional fluorophores via a scaffold-based Ugi four-component reaction (U-4CR). The adaptability of the scaffold is achieved through modification of starting materials. This allows to use a small range of starting materials for the creation of fluorogenic probes that can detect reactive-oxygen species and where the localization into subcellular organelles or membranes can be controlled. We present reaction yields ranging from 60% to 90% and discovered that some compounds can even function as imaging and therapeutic agents via Fenton chemistry inducing pyroptosis in living cancer cells. Our study underlines the potential of scaffold-based synthesis for versatile creation of functional fluorophores and their applications.
Characterization of sleep in a mouse model of CLN3 disease revealed sex-specific sleep disturbances
Authors: Kane Kelby M. , Iradukunda Diane , McLouth Christopher J. , Guo Landys Z. , Wang Jun , Subramoniam Anjana , Huffman Dillon , Donohue Kevin , O’Hara Bruce F. , Sunderam Sridhar , Wang Qing Jun 
Published: May 2024

AbstractThe neuronal ceroid lipofuscinoses (NCLs) are a group of recessively inherited neurodegenerative diseases characterized by lysosomal storage of fluorescent materials. CLN3 disease, or juvenile Batten disease, is the most common NCL that is caused by mutations in theCeroid Lipofuscinosis, Neuronal 3(CLN3) gene. Sleep disturbances are among the most common symptoms associated with CLN3 disease, yet this is understudied and has not been delineated in an animal model of the disease. The current study utilized a non-invasive, automated piezoelectric motion sensing system (PiezoSleep) to classify sleep and wakefulness in aCln3ϕ..ex1–6/ϕ..ex1–6(Cln3KO) mouse model and age- and sex-matched wild-type (WT) controls. The sleep-wake classification by PiezoSleep was found to be about 90% accurate when validated against simultaneous gold standard polysomnographic recordings including electroencephalography (EEG) and electromyography (EMG) in a small cohort of WT andCln3KO mice. Our large cohort PiezoSleep study reveals sleep abnormalities during the light period (LP) in maleCln3KO mice compared to WT male, and more subtle differences inCln3KO female mice throughout the dark period (DP) compared to WT female, recapitulating sleep abnormalities seen in CLN3 disease patients. Our characterization of sleep in a mouse model of CLN3 disease contributes to a better understanding of the sleep disturbances commonly reported for CLN3 disease and other NCLs, which will facilitate the development of new disease treatment and management strategies.
A fully synthetic three-dimensional human cerebrovascular model based on histological characteristics to investigate the hemodynamic fingerprint of the layer BOLD fMRI signal formation
Authors: Báez-Yáñez Mario Gilberto , Schellekens Wouter , Bhogal Alex A. , Roefs Emiel C.A. , van Osch Matthias J.P. , Siero Jeroen C.W. , Petridou Natalia 
Published: May 2024

ABSTRACTRecent advances in functional magnetic resonance imaging (fMRI) at ultra-high field (≥7 tesla), novel hardware, and data analysis methods have enabled detailed research on neurovascular function, such as cortical layer-specific activity, in both human and nonhuman species. A widely used fMRI technique relies on the blood oxygen level-dependent (BOLD) signal. BOLD fMRI offers insights into brain function by measuring local changes in cerebral blood volume, cerebral blood flow, and oxygen metabolism induced by increased neuronal activity. Despite its potential, interpreting BOLD fMRI data is challenging as it is only an indirect measurement of neuronal activity.Computational modeling can help interpret BOLD data by simulating the BOLD signal formation. Current developments have focused on realistic 3D vascular models based on rodent data to understand the spatial and temporal BOLD characteristics. While such rodent-based vascular models highlight the impact of the angioarchitecture on the BOLD signal amplitude, anatomical differences between the rodent and human vasculature necessitate the development of human-specific models. Therefore, a computational framework integrating human cortical vasculature, hemodynamic changes, and biophysical properties is essential.Here, we present a novel computational approach: a three-dimensional VAscular MOdel based on Statistics (3D VAMOS), enabling the investigation of the hemodynamic fingerprint of the BOLD signal within a model encompassing a fully synthetic human 3D cortical vasculature and hemodynamics. Our algorithm generates microvascular and macrovascular architectures based on morphological and topological features from the literature on human cortical vasculature. By simulating specific oxygen saturation states and biophysical interactions, our framework characterizes the intravascular and extravascular signal contributions across cortical depth and voxel-wise levels for gradient-echo and spin-echo readouts. Thereby, the 3D VAMOS computational framework demonstrates that using human characteristics significantly affects the BOLD fingerprint, making it an essential step in understanding the fundamental underpinnings of layer-specific fMRI experiments.
APP-KI mice do not display the hallmark age-dependent cognitive decline of amyloid diseases
Authors: Blackmer-Raynolds Lisa , Lipson Lyndsey D. , Fraccaroli Isabel , Krout Ian N. , Chang Jianjun , Sampson Timothy Robert 
Published: May 2024

AbstractAPP knock-in (KI) mice serve as an exciting new model system to understand amyloid beta (Aβ) pathology, overcoming many of the limitations of previous overexpression-based model systems. The APPSAAmouse model (containing the humanized APP with three familial Alzheimer’s disease mutations) and the APPWTcontrol are the first commercially available APP KI mice within the United States. While APPSAAmice have been shown to develop progressive Aβ pathology and neuroinflammation, behavioral changes, particularly in cognitive functions, have yet to be described. Therefore, we performed an in-depth longitudinal study over 12 months, assessing cognition in these two strains, as well as assessments of motor and GI function. We surprisingly note no overt, progressive cognitive impairment or motor deficits. However, we do observe a significant increase in fecal output in APPSAAmice compared to APPWTat 12 months old. These data provide a baseline for these models’ behavioral attributes.HighlightsAPPSAAand APPWTknock-in mice do not display age related cognitive declineFecal output appears altered by APP genotype, but no other measure of GI function is impacted.Both genotypes behave equally in motor function tests
The UFMylation pathway is impaired in Alzheimer’s disease
Authors: Yan Tingxiang , Heckman Michael G. , Craver Emily C. , Liu Chia-Chen , Rawlinson Bailey D. , Wang Xue , Murray Melissa E. , Dickson Dennis W. , Ertekin-Taner Nilufer , Lou Zhenkun , Bu Guojun , Springer Wolfdieter , Fiesel Fabienne C. 
Published: May 2024

ABSTRACTBackgroundAlzheimer’s disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. This UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet.MethodsHere we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9.ResultsCompared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling.ConclusionsThere are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.
Feedback control of recurrent dynamics constrains learning timescales during motor adaptation
Authors: Gurnani Harsha , Liu Weixuan , Brunton Bingni W. 
Published: May 2024

AbstractLatent dynamical models of the primary motor cortex (M1) have revealed fundamental neural computations underlying motor control; however, such models often overlook the impact of sensory feedback, which can continually update cortical dynamics and correct for external perturbations. This suggests a critical need to model the interaction between sensory feedback and intrinsic dynamics. Such models would also benefit the design of brain-computer interfaces (BCIs) that decode neural activity in real time, where both user learning and proficient control require feedback. Here we investigate the flexible feedback modulation of cortical dynamics and demonstrate its impact on BCI task performance and short-term learning. By training recurrent network models with real-time sensory feedback on a simple 2D reaching task, analogous to BCI cursor control, we show how previously reported M1 activity patterns can be reinterpreted as arising from feedback-driven dynamics. Next, by incorporating adaptive controllers upstream of M1, we make a testable prediction that short-term learning for a new BCI decoder is facilitated by plasticity of inputs to M1, including remapping of sensory feedback, beyond the plasticity of recurrent connections within M1. This input-driven dynamical structure also determines the speed of adaptation and learning outcomes, and explains a continuous form of learning variability. Thus, our work highlights the need to model input-dependent latent dynamics for motor control and clarifies how constraints on learning arise from both the statistical characteristics and the underlying dynamical structure of neural activity.
Angiogenesis in the mature mouse cortex is governed in a region specific and Notch1 dependent manner
Authors: Raudales Alejandra , Schager Ben , Hancock Dominique , Sharma Sorabh S. , Narayana Kamal , Reeson Patrick , Cheema Manjinder , Körbelin Jakob , Brown Craig E. 
Published: May 2024

AbstractCerebral angiogenesis is well appreciated in development and after injury, but the extent to which it occurs across cortical regions in normal adult mice and underlying mechanisms, is incompletely understood. Usingin vivoimaging, we show that angiogenesis in anterior-medial cortical regions (retrosplenial and sensorimotor cortex), was exceptionally rare. By contrast, angiogenesis was significantly elevated in posterior-lateral regions such as visual cortex, primarily within 200µm of the cortical surface. There were no regional differences in vessel pruning or sex effects except for the length and depth of new capillaries. To understand mechanisms, we surveyed gene expression and found Notch related genes were enriched in ultra-stable retrosplenial versus visual cortex. Using endothelial specific knockdown of Notch1, cerebral angiogenesis was significantly increased along with genes implicated in angiogenesis (Apln, Angpt2, Cdkn1a). Our study shows that angiogenesis is regionally dependent and manipulations of Notch1 signaling could unlock the angiogenic potential of the mature vasculature.