bluuebunny/crossref_metadata_2025_split huggingface dataset:
BOLD Amplitude Correlates of Preclinical Alzheimer’s Disease
Authors: Hrybouski Stanislau , Das Sandhitsu R. , Xie Long , Brown Christopher A. , Flamporis Melissa , Lane Jacqueline , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Wolk David A. 
Published: October 2024

ABSTRACTAlzheimer’s disease (AD) is characterized by a long preclinical stage during which molecular markers of amyloid beta and tau pathology rise, but there is minimal neurodegeneration or cognitive decline. Previous literature suggests that measures of brain function might be more sensitive to neuropathologic burden during the preclinical stage of AD than conventional measures of macrostructure, such as cortical thickness. However, among studies that used resting-state functional Magnetic Resonance Imaging (fMRI) acquisitions with Blood Oxygenation Level Dependent (BOLD) contrast, most employed connectivity-based analytic approaches, which discard information about the amplitude of spontaneous brain activity. Consequently, little is known about the effects of amyloid and tau pathology on BOLD amplitude. To address this knowledge gap, we characterized the effects of preclinical and prodromal AD on the amplitude of low-frequency fluctuations (ALFF) of the BOLD signal both at the whole-brain level and, at a more granular level, focused on subregions of the medial temporal lobe. We observed reduced ALFF in both preclinical and prodromal AD. In preclinical AD, amyloid positivity was associated with a spatially diffuse ALFF reduction in the frontal, medial parietal, and lateral temporal association cortices, while tau pathology was negatively associated with ALFF in the entorhinal cortex. These ALFF effects were observed in the absence of observable macrostructural changes in preclinical AD and remained after adjusting for structural atrophy in prodromal AD, indicating that ALFF offers additional sensitivity to early disease processes beyond what is provided by traditional structural imaging biomarkers of neurodegeneration. We conclude that ALFF may be a promising imaging-based biomarker for assessing the effects of amyloid-clearing immunotherapies in preclinical AD.
NAD+- and EVA1-C-dependent reversal of neurological deficits is mediated by differential alternative RNA splicing in tauopathic animal models
Authors: Ai Ruixue , Mao Lipeng , Jin Xurui , Zhang Shi-qi , Pan Junping , Lagartos Maria Jose Donate , Cao Shu-Qin , Yang Guang , Xie Chenglong , Kang Xiongbin , Wang Pingjie , Hu Yang , Bergersen Linda Hildegard , Storm-Mathisen Jon , Kuroyanagi Hidehito , Doncel Beatriz Escobar , González Noemí Villaseca , Chaudhry Farrukh Abbas , Wang Zeyuan , Zhang Qiang , Niu Zhangming , Chen Guobing , Luo Oscar Junhong , Fang Evandro Fei 
Published: October 2024

AbstractAberrant alternative splicing (ASEs) is an aging hallmark to Alzheimer’s Disease (AD). Although NAD+and related metabolites can slow down AD, NAD+on ASEs in AD remain unclear. Mouse transcriptomic data revealed NR-induced ASEs, focusing on the Eva1-C locus. AI-based algorithms predicted EVA1-C protein structures and protein-protein interactions. AD postmortem brain samples and tauopathy models including transgenic mice and worm was used for validation. NAD+abundance/metabolic status modulates ASEs and the expression of EVA1-C isoforms, which in turn regulate the interaction with BAG-1 and HSP70 proteins. Importantly, EVA1-C is dramatically reduced in 20 Braak 5/6 AD patients compared to cognitive normal humans in different brain regions. NAD+metabolism modulates abundance of specific mRNA isoforms, and that ASEs influence disease progression in model tauopathies and potentially AD. These results could facilitate future development of NAD+-based splice-switching therapeutics for AD.TeaserUnveiling the Link Between NAD+Metabolism and Alzheimer’s Disease: Discovering the Role of Alternative RNA Splicing in Disease Progression and Potential Therapeutic Targets
Evaluation of Tumor-colonizingSalmonellaStrains using the Chick Chorioallantoic Membrane Model
Authors: Mon Khin K. Z. , Kenney Linda J. 
Published: October 2024

ABSTRACTThe chick embryo chorioallantoic membrane (CAM) tumor model is a valuable preclinical model for studying the tumor colonizing process ofSalmonella entericaserovar Typhimurium. It offers advantages such as cost-effectiveness, rapid turnaround, reduced engraftment issues, and ease of observation. In this study, we explored and validated the applicability of the partially immune-deficient CAM tumor model. Herein, we demonstrate thatSalmonellapreferentially colonizes tumors and directly causes tumor cell death. Bacterial migration, tumor colonization, and intra-tumor distribution did not require flagellar-mediated motility. The vast majority ofSalmonellathat colonized the CAM tumor were extracellular. Thus, tumor invasion was independent of both SPI1– and SPI2-encoded type three secretion systems. Surprisingly, the extracellular residence ofSalmonellaon CAM tumors did not require biofilm formation. We evaluated our wild-type parental strain compared to the attenuated clinical strain VNP20009 and discovered a reduced tumor colonization capability of VNP20009. The inability to effectively colonize CAM tumors potentially explains the reduced anti-tumor efficacy of VNP20009. Our work establishes the xenograft CAM model as an informative and predictive screening platform for studying tumor-colonizingSalmonella.IMPORTANCECancer has a major impact on society, as it poses a significant health burden to human populations worldwide.SalmonellaTyphimurium has demonstrated promise in cancer treatment by exerting direct tumoricidal effects and enhancing host-mediated anti-tumor immunity in xenograft mouse studies. A general understanding of its pathogenesis and the relative ease of genetic manipulation support the development of attenuated strains for therapeutic use. Alternativein ovomodels such as the CAM tumor model present a suitable screening platform to accelerate the development of therapeutic strains. It allows for rapid evaluation ofSalmonellastrains to assess their efficacy and potential as oncolytic agents. The present study establishes that thein ovotumor model can be utilized as a preclinical tool for evaluating oncolyticSalmonella, bridging the gap betweenin vitroandin vivoscreening.
The Role of Ethics in Physiotherapy: A Scoping Review Protocol
Authors: Bertoni Gianluca , Patuzzo Manzati Sara , Pagani Federica , Testa Marco , Battista Simone 
Published: October 2024

AbstractBackground and aimsEthical considerations play a crucial role in physiotherapy, influencing patient care, professional conduct, and clinical decision-making. Despite its significance, there is a limited comprehensive understanding of how ethical principles are applied in physiotherapy practice. The evolving nature of the field, alongside advancements in treatment approaches, presents new ethical challenges that require systematic investigation. This scoping review aims to map the existing literature on ethical issues within physiotherapy, identify research methodologies, and highlight knowledge gaps.MethodThis review will follow the methodological framework proposed by the Joanna Briggs Institute (JBI) for scoping reviews and will be reported following the PRISMA for Scoping Reviews guidelines. A comprehensive search will be conducted on PubMed, Medline, Embase, CINAHL, PsychInfo, Cochrane Central, and Pedro. The gray literature will be consulted. Studies involving physiotherapists and those addressing ethical issues in physiotherapy practice will be included. Data extraction will be based on a standardized form, and a narrative synthesis will categorize the ethical issues and principles.DiscussionThe review will provide a broad overview of ethical issues and principles in physiotherapy. It will inform future research priorities, guide ethical training for practitioners, and support the development of policies and guidelines to improve ethical shared decision-making in physiotherapy practice.
How the COVID-19 pandemic affected lifestyle and wellbeing factors associated with dementia risk in older adults with Subjective Cognitive Decline and Mild Cognitive Impairment participating in the APPLE-Tree (Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce) in England
Authors: Wright Annie Mae , Demnitz-King Harriet , Burton Alexandra , Morse Rachel M. , Alberts Sweedal , Kenten Charlotte , Jeraldo Rosario Isabel Espinoza , Poppe Michaela , Barber Julie , Cooper Claudia 
Published: October 2024

AbstractThe COVID-19 pandemic negatively affected known dementia risk factors and cognition in older adults. We invited adults with mild cognitive concerns without dementia, aged ≥60 years participating in a randomised controlled trial of a psychosocial, secondary dementia prevention intervention, to complete a co-designed, semi-structured qualitative survey, regarding how the pandemic impacted their lifestyle and wellbeing in areas relevant to dementia risk: social connections, activities, diet, mental and physical health, community and family support. Data was collected between October 2020 and December 2022; we conducted manifest content analysis.551/746 trial participants completed the survey. Most (n=530, 96%) described pandemic-related changes to lifestyle or wellbeing; two thirds (n=369/545, 67.7%) reported less activities. A quarter (n=145, 26.8%) identified no change in social connections, with others reporting less in-person meetings (n=139, 25.7%) or speaking to less people (n=99; 18.2%); a minority engaged in compensatory online activities (n=31, 5.7%) and online (n=63, 11.6%) or phone (n=90, 16.6%) social contact. Relatively few reported weight gain (n=22, 4.0%); two-thirds reported no change in their diet (n=360, 66.1%), with others eating more unhealthy food (n=31, 4.8%), more food (n=21, 3.9%) and/or snacks (n=11, 2.0%); others reporting more healthy eating (n=26, 4.8%) and/or more home cooking (n=57, 10.5%). Modes of support changed, with reliance on food parcels, online services and shopping by neighbours. Over half reported (almost exclusively negative) mental health pandemic-related changes (n=307, 56.9%), including depression, stress, fear and loneliness; many reported declines in physical health (n=153, 28.1%) and/or fitness (n=70, 12.8%).Stoical accounts of adaptation and resilience, enabled by technology and community support predominated, but were not possible for all. Reducing the digital divide, tackling loneliness and developing inclusive online/in-person support programmes that are more resilient in future lockdowns could protect cognitively frail people now and in any future pandemic, and contribute to national dementia prevention strategy.Trial registration:ISRCTN17325135;https://doi.org/10.1186/ISRCTN17325135(27.11.19)
Disentangling the relationship between fibromyalgia and insomnia: A bidirectional two-sample Mendelian random analysis
Authors: Gao Jin , Pan Liangke , Pan Zhenglun 
Published: October 2024

ObjectiveFibromyalgia (FM) and insomnia frequently coexist, but whether FM is an independent causal risk factor for insomnia, and/or vice versa, remains unclear. We investigated the bidirectional causal relationship between FM and insomnia.MethodsGenome-wide association studies (GWAS) summary statistics on FM [sample size = 416,757 (2689 cases; 299,606 controls) (FinnGen)] and insomnia [sample size = 462,341 (UK Biobank)] were used. The possible causal relationships were assessed by bi-directional MR analysis. The major analysis method of MR was performed using inverse-variance weighted (IVW), supplemented by MR-Egger, weighted median, weighted mode and simple mode approaches. In addition, sensitivity analyses including Cochran’s Q test, MR-Egger intercept test, and the leave-one-out test were conducted to ensure the stability of the results.ResultsThere was strong evidence to suggest insomnia is a risk factor for FM (odds ratio (OR) 7.65, 95% confidence interval (CI) 3.17-18.45, p = 5.85E-06). We found no evidence that genetic liability to FM increases insomnia (OR = 1.00, 95% CI 0.99-1.01, p = 0.99)ConclusionsThis study provides evidence in support of a causal relationship between insomnia and increased risk of FM, whilst overcoming the major limitations of previous epidemiological studies. Interventions for insomnia may be an effective strategy to prevent or reduce the burden of FM. Extended study needs to be performed with multi-center, large-scale GWAS cohort studies to re-evaluate the association between FM and insomnia in future.
Genome Analyses of A Worldwide Multisource Collection ofKlebsiella variicolaReveal Adaptation Relevant for Human Infection
Authors: Wang Jiayu , Coipan Claudia E. , Franz Eelco , Kuiper Ed , Wessels Els , Gally David L. , Vasudevan Karthick , Veerarhagavan Balaji , Farzana Refath , Holden Nicola , Zadoks Ruth , Higgins Paul G. , Schneiders Thamarai 
Published: October 2024

AbstractKlebsiella variicola(K.var), part of theKlebsiella pneumoniae(K.pne) species complex, is an emerging human pathogen originally associated with plants. Phylogenomic analyses of a global dataset of isolates categorised as human, animal, plant, or environmental strains suggest thatK.varare broadly disseminated regardless of hosts or habitats and exhibit genomic variability that is relevant for occupying and transmitting within and across multiple sources. Ancestral state analyses confirm thatK.varare originally derived from non-human sources. Genome-wide association analyses of human versus non-human isolates ofK.varindicate isolates from human origins are linked to the loss of cold-shock response genes such aslpxPandcspB. Importantly, humanK.varisolates also showed enriched antimicrobial resistance gene content and diversity acquired through mobile genetic elements, horizontal gene transfer and mutations within the chromosomal loci which underscore the impact of antimicrobial exposure and proximity to antibiotic resistantK.pnein nosocomial environments. Capsular profiles ofK.varsuggest high levels of variability in gene composition and indicate that gene functionality forwcaJin capsule formation differs betweenK.varandK.pne. Although capsular specialisation was not observed in a host/habitat or lineage-dependent manner, human isolates harbour, on average, a higher siderophore gene content in addition tomrkDmutations which impact on fimbriae and biofilm formation. There is limited evidence of any specificK.varlineages exhibiting convergence of both virulence and antimicrobial resistance genotypes which suggest that these attributes are evolving independently in clinical strains. Our work highlights that gene attrition and acquisition provide a basis for adaptation ofK.varas human pathogens. The broad distribution and evolution ofK.varhighlight the need for improved diagnostic precision and surveillance under a One Health framework.
Operate a Cell-Free Biofoundry using Large Language Models
Authors: Hérisson J. , Hoang A. N. , El-Sawah A. , Khalil M. M. , Faulon J.-L. 
Published: October 2024

AbstractIn this paper, we present a novel approach to optimizing cell-free protein synthesis (CFPS) systems using artificial intelligence (AI), specifically leveraging ChatGPT-4 for code generation and active learning (AL). This study aims to automate and enhance the process of producing antimicrobial proteins, namely colicin M and colicin E1, in CFPS systems. We developed an automated workflow that employs an iterative Design-Build-Test-Learn (DBTL) cycle, integrating a newly implemented AL method with cluster margin (CM) selection to efficiently explore experimental conditions. The workflow components, including modules for sampling, plate design, instruction generation, and data analysis, were coded using ChatGPT-4 without further human modification. By employing this automated approach, significant improvements in protein yields were achieved, with a 9-fold increase for colicin M and a 3-fold increase for colicin E1 compared to standard buffer compositions. The use of LLMs in conjunction with AL demonstrated the potential of AI-driven methodologies to accelerate the optimization of complex biological processes and reduce manual intervention. The study also discusses limitations such as variability in CFPS and suggests future improvements in automation, reproducibility, and integration of diverse liquid handling systems to further enhance the scalability and efficiency of cell-free biofoundries.
Soluble guanylyl cyclase, the NO-receptor, regulates endothelium-dependent vascular relaxation via its transnitrosation activity
Authors: Younis Waqas , Cui Chuanlong , Sadeghian Tanaz , Burboa Pia , Shu Ping , Qin Yong , Xie Lai-Hua , Gallardo Mauricio Lillo , Beuve Annie 
Published: October 2024

AbstractWe previously demonstrated that the NO-receptor soluble guanylyl cyclase (GC1) has the ability to transnitrosate other proteins in a reaction that involves, in some cases, oxidized Thioredoxin 1 (oTrx1). This transnitrosation cascade was establishedin vitroand we identified by mass spectrometry and mutational analysis Cys 610 (C610) of GC1 α-subunit as a major donor of S-nitrosothiols (SNO). To assay the relevance of GC1 transnitrosation under physiological conditions and in oxidative pathologies, we studied a knock-in mouse in which C610 was replaced with a serine (KI αC610S) under basal or angiotensin II (Ang II)–treated conditions. Despite similar GC1 expression and NO-stimulated cGMP-forming activity, the Ang II-treated KI mice displayed exacerbated oxidative pathologies including higher mean arterial pressure and more severe cardiac dysfunctions compared to the Ang II-treated WT. These phenotypes were associated with a drastic decrease in global S-nitrosation and in levels of SNO-Trx1 and SNO-RhoA in the KI mice. To investigate the mechanism underlying the dysregulation of blood pressure despite an intact NO-cGMP axis, pressure myography andin vivointravital microscopy were conducted to analyze the vascular resistance tone. Both approaches indicated that, even in the absence of oxidative stress, the single mutation C610S led to a significant deficiency in acetylcholine-induced vasorelaxation while smooth muscle relaxation in response to NO remained unchanged. These findings indicate that the C610S mutation uncoupled the two NO signaling pathways involved in the endothelium and smooth muscle vasorelaxation and suggest that GC1-dependent S-nitrosation is a key player in endothelium-derived hyperpolarization.
Frem2Knockout Mice Exhibit Fraser Syndrome Phenotypes and Neonatal Lethality Due to Bilateral Renal Agenesis
Authors: Simikyan Rubina G. , Zhang Xinyuan , Strelkova Olga , Li Nathan , Zhu MengYu , Eckhard Andreas , Baranov Petr Y. , Wu Xudong , Richey Lauren , Indzhykulian Artur A. 
Published: October 2024

ABSTRACTFraser syndrome is a rare autosomal recessive disorder characterized by multiple congenital malformations, including cryptophthalmos, syndactyly, and renal agenesis, which can lead to severe complications beginning at the embryonic stage. Mutations in genes encoding extracellular matrix proteins such as FRAS1, FREM1, FREM2, and the associated trafficking protein GRIP1, are implicated in Fraser syndrome. These proteins are critical for maintaining epithelial integrity during embryogenesis, with deficiencies leading to tissue detachment and blistering phenotypes in mouse models. The FREM2 protein is a single-pass membrane protein of 3169 amino acids. While FREM2-deficient mouse models encoding missense variants found in patients, or a truncated FREM2 protein product were previously reported, it has not been studied in a constitutive knockout (KO) mouse model.Here, we developed constitutiveFrem2-KOmice exhibiting neonatal lethality, mainly due to bilateral renal agenesis, along with blood-filled blisters, cryptophthalmos, and syndactyly. Only one mouse survived to adulthood exhibiting unilateral renal agenesis and Fraser syndrome-like phenotypes. These findings confirm FREM2’s crucial role in the development of the kidneys, skin, and eyes and provide an animal model for further studies of FREM2-related developmental disorders.
Combinatorial effector targeting (COMET) for transcriptional modulation and locus-specific biochemistry
Authors: Wilson Caroline M. , Pommier Greg C. , Richman Daniel D. , Sambold Nicholas , Hussmann Jeffrey A. , Weissman Jonathan S. , Gilbert Luke A. 
Published: October 2024

SUMMARYUnderstanding how human gene expression is coordinately regulated by functional units of proteins across the genome remains a major biological goal. Here, we present COMET, a high-throughput screening platform forcombinatorialeffector targeting for the identification of transcriptional modulators. We generate libraries of combinatorial dCas9-based fusion proteins, containing two to six effector domains, allowing us to systematically investigate more than 110,000 combinations of effector proteins at endogenous human loci for their influence on transcription. Importantly, we keep full proteins or domains intact, maintaining catalytic cores and surfaces for protein-protein interactions. We observe more than 5800 significant hits that modulate transcription, we demonstrate cell type specific transcriptional modulation, and we further investigate epistatic relationships between our effector combinations. We validate unexpected combinations as synergistic or buffering, emphasizing COMET as both a method for transcriptional effector discovery, and as a functional genomics tool for identifying novel domain interactions and directing locus-specific biochemistry.
Reduced Folate Carrier 1 (RFC1/Slc19a1) Suppression Exacerbates Blood-Brain Barrier Breakdown in Experimental Ischemic Stroke in Adult Mice
Authors: Gurler Gokce , Bozanoglu Dilan , Leon Christelle , Belder Nevin , Bahcekapili Melike Sever , Bolbos Radu , Karatas Hulya , Wiart Marlene , Chauveau Fabien , Yemisci Muge 
Published: October 2024

ABSTRACTThe Reduced Folate Carrier 1 (RFC1), also called solute carrier family 19 member 1 (SLC19A1/SLC19a1), is recognized for transporting folates across the blood-brain barrier (BBB). RFC1 has recently been defined as a hypoxia-immune related gene whose expression levels were induced by acute retinal ischemia, suggesting that RFC1 may have a role in the response of the brain to ischemic injury. Despite a recent human meta-analysis suggesting an association between certain RFC1 polymorphisms and the risk of silent brain infarctions, preclinical evidence concerning the potential role of RFC1 in acute ischemic stroke has yet to be presented. To investigate this, we first characterized RFC1 protein expression in mouse microvessels and pericytes which play significant roles in stroke pathophysiology. Then, we examined the temporal (1-h, 24-h, and 48-h) and spatial (infarct, periinfarct, contralateral) expression of RFC1 protein in the intraluminal transient middle cerebral artery occlusion mouse model. Finally, we knocked down RFC1 protein with RFC1-siRNA in the potential periinfarct region before induction of ischemia and investigated BBB integrity and infarct sizein vivovia 7T-MRI. Moreover, we utilized a pharmacological modulation-methotrexate, a non-covalent inhibitor of RFC1- to further investigate the role of RFC1 in maintaining BBB integrity. Our study revealed that, i) RFC1 protein levels were dynamic throughout the acute phases of ischemic stroke, ii) RFC1 suppression aggravated the BBB leakage during ischemia. These results emphases the role of RFC1 in the pathophysiology of ischemic stroke and supports the evidence from human studies.