bluuebunny/crossref_metadata_2025_split huggingface dataset:
CH-related Mutant ASXL1 Promotes Atherosclerosis in Mice via Dysregulated Innate Immunity
Authors: Sato Naru , Goyama Susumu , Chang Yu-Hsuan , Fujino Takeshi , Denda Tamami , Asada Shuhei , Shikata Shiori , Liu Xiaoxiao , Yonezawa Taishi , Takeda Reina , Yamamoto Keita , Tanaka Yosuke , Honda Hiroaki , Ota Yasunori , Shibata Takuma , Sekiya Motohiro , Koide Shuhei , Lamagna Chrystelle , Masuda Esteban , Iwama Atsushi , Shimano Hitoshi , Inoue Jun-ichiro , Miyake Kensuke , Kitamura Toshio 
Published: August 2024

SummaryCertain somatic mutations confer a fitness advantage in hematopoietic stem and progenitor cells (HSPCs) over normal HSPCs, resulting in the clonal expansion of mutant blood cells1, otherwise known as clonal haematopoiesis (CH). CH is frequently observed among healthy elderly people and is closely associated with the risk of cardiovascular diseases (CVDs). The most frequently mutated genes of CH includeDNMT3A, TET2, andASXL12. Among them, even thoughASXL1mutations are clinically associated with the highest risk for developing CVDs, little is known whether and how the mutations contribute to CVDs. Here we show accelerated development of atherosclerosis and increased inflammatory monocytes in mice transplanted with the bone marrow cells (BMCs) from the mice expressing mutant ASXL1 (ASXL1-MT) selectively in hematopoietic cells. RNA sequencing analysis of the plaque-macrophages derived from BMCs expressing ASXL1-MT showed more inflammatory signatures than those from control BMCs. Mechanistically, wild-type ASXL1 inhibited innate immune signalling through direct interactions with IRAK1/TRAF6/TAK1 in the cytoplasm, while ASXL1-MT, which only interacted with TAK1, lost this regulatory function, leading to NF-κB activation. This mechanism is unique and distinct from those of CH withTet2orDnmt3amutations, where overactivation of the IL-1β/NLRP3 inflammasome plays critical roles3–5. Intriguingly, IRAK1/4 inhibition decreased the number of inflammatory monocytes and attenuated the development of atherosclerosis driven by ASXL1-MT. The present work connects the mutations of an epigenetic factor, ASXL1, with inflammation and CVDs and gives an indication for the prevention of CVDs in CH.
Social and health conditions that drive the need, demand, utilisation and expenditure on social care in the United Kingdom: a protocol for a systematic review
Authors: Amies-Cull Ben , Shepperd Sasha , Roberts Nia , Mason Anne , Bojke Laura , Clarkson Paul , Scott Anna Mae 
Published: August 2024

AbstractBackgroundSocial care is the personal and practical assistance provided to individuals in their daily activities, personalised around their circumstances to promote wellbeing. It is provided by formal and informal carers, with formal care supported by considerable public resources through the Adult Social Care function of local authorities. While it is a matter of great public and policy concern that the system better meet people’s needs and that public finances are not unsustainably strained, some key drivers of adult social care need, such as the relationships between age, social determinants, environmental conditions, and health status are not well understood at the system level. This is a protocol for a systematic review of the evidence to determine the health and social drivers that contribute to adults’ need and demand for and utilisation of social care in the UK, and how these interact.MethodsWe will include quantitative studies of any experimental, observational or simulation/modelling design with average participant age ≥60, that examine the relationships between health status and/or social conditions, and their impact on adult social care need, demand, utilisation and expenditure. Informal and formal domiciliary, residential and nursing care, professional social work and occupational therapy will be included.Medline, CINAHL, EconLit, ASSIA Campbell Collaboration and grey literature will be searched. A single reviewer will screen titles/abstracts for eligibility, and two reviewers will independently screen the full-text of studies initially considered eligible. 15% of the included studies will be double-extracted, and remainder single extracted with an accuracy check.Risk of bias will be assessed using Cochrane Risk of Bias 2 and ROBINS-I.The findings will be grouped by health condition(s), the type of determinant, outcome and will be presented in an evidence gap map. If three or more comparable studies are identified, we will consider calculating the effect size. We will use GRADE to assess the evidence certainty.DiscussionWe will detail the evidence on the relationships (to include an indication of their contribution) between health status and social conditions with the need, demand, utilisation and expenditure on adult social care in the UK, informing further analyses in key evidence gaps.
The potential clinical impact and cost-effectiveness of the updated COVID-19 mRNA Autumn 2024 vaccines in the United Kingdom
Authors: Kohli Michele A. , Maschio Michael , Lee Amy , Joshi Keya , Carroll Stuart , Balogh Orsolya , van de Velde Nicholas , Beck Ekkehard 
Published: August 2024

AbstractAimsTo estimate the potential clinical impact and cost-effectiveness of a United Kingdom (UK) Autumn 2024 vaccination campaign with an updated Moderna COVID-19 vaccine in adults ≥65 years and eligible persons 6 months to 64 years of age over a 1-year time horizon (September 2024-August 2025).Materials and methodsA compartmental Susceptible-Exposed-Infected-Recovered model was adapted to reflect COVID-19 cases in the UK. Numbers of symptomatic infections, COVID-19– related hospitalizations and deaths, costs, and quality-adjusted life-years (QALYs) were predicted using a decision tree. The incremental cost-effectiveness ratio (ICER) of an updated Moderna mRNA vaccine (Moderna Autumn 2024 Campaign) was compared to no Autumn 2024 vaccine and to an updated Pfizer-BioNTech mRNA Autumn 2024 vaccine, from a healthcare perspective.ResultsThe Moderna Autumn 2024 Vaccination Campaign is predicted to decrease the expected 8.3 million symptomatic infections with no vaccination by 19% to 6.7 million. Hospitalizations, long COVID cases, and deaths are expected to decline by 27,000 (−38%), 59,000 (−19%), and 6000 (−43%), respectively. The Moderna Autumn 2024 Campaign will increase QALYs by 78,000 and costs by £665 million, yielding an ICER of £8500/QALY gained. Sensitivity analyses suggest that vaccine effectiveness (VE) and waning, symptomatic infection incidence, hospitalization rates, and mortality rates drive cost-effectiveness. Vaccination remains cost-effective when lowering the target population to ≥50 years. Use of the Moderna vaccine is expected to prevent 8000 more hospitalizations and 1700 more deaths than the updated Pfizer-BioNTech vaccine.ConclusionsVaccination of the eligible population would contribute to significant reductions in hospitalizations, deaths, and long COVID in the UK in the 2024-2025 season. Expanding the target population continues to be cost-effective. Use of the Moderna Autumn 2024 Campaign is predicted to reduce SARS-CoV-2 infections and associated outcomes in a cost-effective manner and will contribute to a more resilient healthcare system in the UK.
Predicting the impact of non-pharmaceutical interventions against COVID-19 onMycoplasma pneumoniaein the United States
Authors: Park Sang Woo , Noble Brooklyn , Howerton Emily , Nielsen Bjarke F , Jiudice Sarah S , Ambroggio Lilliam , Dominguez Samuel , Messacar Kevin , Grenfell Bryan T 
Published: August 2024

AbstractThe introduction of non-pharmaceutical interventions (NPIs) against COVID-19 disrupted circulation of many respiratory pathogens and eventually caused large, delayed outbreaks, owing to the build up of the susceptible pool during the intervention period. In contrast to other common respiratory pathogens that re-emerged soon after the NPIs were lifted, longer delays (>3 years) in the outbreaks ofMycoplasma pneumoniae(Mp), a bacterium commonly responsible for respiratory infections and pneumonia, have been reported in Europe and Asia. As Mp cases are continuing to increase in the US, predicting the size of an imminent outbreak is timely for public health agencies and decision makers. Here, we use simple mathematical models to provide robust predictions about a large upcoming Mp outbreak in the US. Our model further illustrates that NPIs and waning immunity are important factors in driving long delays in epidemic resurgence.
Uncovering immune characteristics of neurons in the context of multiple sclerosis and experimental autoimmune encephalomyelitis
Authors: Mohammadnia Abdulshakour , Drake Sienna Sage , Zandee Stephanie E.J. , Gosselin David , Antel Jack P. , Prat Alexandre , Fournier Alyson 
Published: August 2024

AbstractMultiple sclerosis (MS) is an immune-mediated disease characterized by chronic inflammation and damage to the central nervous system, and substantial characterization of molecular signatures of glial and immune cells in the disease has been conducted. However, comparatively less well characterized is the molecular signature of pathologically inflamed neurons. Here, we accessed multi-omic high-throughput transcriptomic and epigenomic data to investigate the molecular signature of neurons from progressive MS patients and from mice subjected to experimental autoimmune encephalomyelitis (EAE). Our results indicate a shared and consistent neuronal gene expression signature in MS and EAE samples including a notable upregulation of immune system related genes and processes. Analysis of immune-enriched pathways in retinal ganglion cells (RGCs) and motor neurons from mice subjected to EAE revealed enrichment for the major histocompatibility complex class I pathway and interferon response genes in both types of neurons, and ATAC-seq analysis confirmed the accessibility of these genes. Parallel analyses of neurons from MS patients identified a signature of 48 commonly upregulated immune genes in neurons. Prediction of transcriptional regulators of these genes identified key upstream regulators including signal transducer and activation of transcription 1 (STAT1) and interferon response factor 5 (IRF5), highly involved in immune-related processes, with significant gene expression changes in both RGCs and motor neurons. Protein-protein interaction analyses among the transcriptional regulators unveiled intricate interactions among transcription factors, especially from the IRF and STAT families, suggesting their importance in regulating immune gene expression in inflamed neurons. Small molecule inhibition of IRF5 in inflamed neuronsin vitropromoted cell survival and reduced the expression of the immune gene signature, supporting the biological relevance of IRF5 in mediating the neuronal inflammatory response. Together, this study identifies regulated immune processes in neurons from EAE mice and from MS patient samples suggesting potential roles for neuronal immune molecules in disease progression, as revealed by transcriptomic, epigenomic, and experimental approaches. Further, the results strongly implicate active interferon signaling in neurons driving immune related changes in gene expression through IRF5 and STAT1 transcription factor activity, potentially impacting downstream neuronal survival through IRF5 activity.
Acute inhibition of iron-sulfur cluster biosynthesis disrupts metabolic flexibility in mice
Authors: Molenaars Marte , Mir Hannan , Alvarez Samantha W. , Arivazhagan Lakshmi , Rosselot Carolina , Zhan Di , Park Christopher Y , Garcia-Ocana Adolfo , Schmidt Ann Marie , Possemato Richard 
Published: August 2024

SummaryIron-sulfur clusters (ISCs) are cell-essential cofactors present in ∼60 proteins including subunits of OXPHOS complexes I-III, DNA polymerases, and iron-sensing proteins. Dysfunctions in ISC biosynthesis are associated with anemias, neurodegenerative disorders, and metabolic diseases. To assess consequences of acute ISC inhibition in a whole body setting, we developed a mouse model in which key ISC biosynthetic enzyme NFS1 can be acutely and reversibly suppressed. Contrary to in vitro ISC inhibition and pharmacological OXPHOS suppression, global NFS1 inhibition rapidly enhances lipid utilization and decreases adiposity without affecting caloric intake and physical activity. ISC proteins decrease, including key proteins involved in OXPHOS (SDHB), lipoic acid synthesis (LIAS), and insulin mRNA processing (CDKAL1), causing acute metabolic inflexibility. Age-related metabolic changes decelerate loss of adiposity substantially prolonged survival of mice with NFS1 inhibition. Thus, the observation that ISC metabolism impacts organismal fuel choice will aid in understanding the mechanisms underlying ISC diseases with increased risk for diabetes.Graphical abstractHighlights-Acute ISC inhibition leads to rapid loss of adiposity in mice-Multi-metabolic pathway disruption upon ISC deficiency blocks energy storage-Nfs1 inhibition induces glucose dyshomeostasis due to ISC deficiency in β-cells-Energy distress caused by inhibition of ISC synthesis is attenuated in aged mice
Multimodal imaging reveals multiscale mechanical interplay in vertebral endplate microarchitecture during intervertebral disc loading
Authors: Parmenter Alissa L. , Newham Elis , Sharma Aikta , Disney Catherine M. , Deyhle Hans , Bosi Federico , Terrill Nick J. , Bay Brian K. , Pitsillides Andrew A. , Gupta Himadri S. , Lee Peter D. 
Published: August 2024

ABSTRACTThe optimal biomechanical function of the spine depends on hierarchical structures spanning the whole joint to molecular scales. The vertebral endplates experience complex, location specific loading from the intervertebral discs, and their biomechanical behaviour is governed by the microarchitecture, mineralisation, and prestrain of their constituent bone and cartilage. Here we use a combination of synchrotron X-ray tomography, digital volume correlation, and wide-angle X-ray diffraction to investigate relationships between microstructure and mechanics, nanoscale mineral structure, and molecular level prestrain in murine vertebral endplates. Our results show radial variation in endplate structure and local mechanical strain, revealing tensile and shear strains as potential drivers of the cartilage to bone transition. Bone contained narrower mineral crystallites under greater compressive prestrain when compared to calcified cartilage. This multiscale structural adaptation supports load resistance adjacent to the annulus fibrosus and elastic deformation below the nucleus pulposus. Our findings reveal the multiscale mechanics of these mineralised tissues, and the methods presented here have the potential to enhance our understanding of biomechanics in health, disease, and aging.
Fast implicit and slow explicit learning of temporal context in cortico-cerebellar loops
Authors: Mangili Luca , Wissing Charlotte , Narain Devika 
Published: August 2024

AbstractOne is seldom aware of the anticipatory and preemptive feats that the eyeblink systems achieves in daily life but it frequently protects the eye from projectiles gone awry and insects on apparent collision courses. This poor awareness is why predictive eyeblinks are considered a form of implicit learning. In motor neuroscience, implicit learning is considered to be slow and, eyeblink conditioning, in particular, is believed to be a rigid and inflexible cerebellar-dependent behavior. In cognitive neuroscience, however, implicit and automatic processes are thought to be rapidly acquired. Here we show that the eyeblink system is, in fact, capable of remarkable cognitive flexibility and can learn on more rapid timescales than previously expected. In a task where we yoked contextual learning of predictive eyeblinks and manual responses in humans, well-timed eyeblink responses flexibly adjusted to external context on each trial. The temporal precision of the predictive eyeblinks exceeded that of manual response times. Learning of the well-timed eyeblink responses was also more rapid than that for the manual response times. This pattern persevered with the use of a cognitive strategy, which seemed to accelerate both types of learning. These results suggest that behaviors associated with the cerebellar cortex that were previously believed to be inflexible and largely implicit, can demonstrate rapid and precise context-dependent temporal control.
Malnutrition drives infection susceptibility and dysregulated myelopoiesis that persists after refeeding intervention
Authors: Sukhina Alisa , Queriault Clemence , Hall Elise , Rome Kelly , Aggarwal Muskaan , Nunn Elizabeth , Weiss Ashley , Nguyen Janet , Bailis Will 
Published: August 2024

AbstractUndernutrition is one of the largest persistent global health crises, with nearly 1 billion people facing severe food insecurity. Infectious disease represents the main underlying cause of morbidity and mortality for malnourished individuals, with infection during malnutrition representing the leading cause of childhood mortality worldwide. In the face of this complex challenge, simple refeeding protocols have remained the primary treatment strategy. Although an association between undernutrition and infection susceptibility has been appreciated for over a century, the underlying mechanisms remain poorly understood and the extent to which refeeding intervention is sufficient to reverse nutritionally acquired immunodeficiency is unclear. Here we investigate how malnutrition leads to immune dysfunction and the ability of refeeding to repair it. We find that chronic malnutrition severely impairs the ability of animals to control a sub-lethal bacterial infection. Malnourished animals exhibit blunted immune cell expansion, impaired immune function, and accelerated contraction prior to pathogen clearance. While this defect is global, we find that myelopoiesis is uniquely impacted, resulting in in reduced neutrophil and monocyte numbers prior to and post-infection. Upon refeeding, we observe that animals recover body mass, size, cellularity across all major immune organs, the capacity to undergo normal immune cell expansion in response to infection, and a restoration in T cell responses. Despite this broad improvement, refed animals remain susceptible to bacterial infection, uncoupling global lymphoid atrophy from immunodeficiency. Mechanistically, we find peripheral neutrophil and monocyte numbers fail to fully recover and refed animals are unable to undergo normal emergency myelopoiesis. Altogether, this work identifies a novel cellular link between prior nutritional state and immunocompetency, highlighting dysregulated myelopoiesis as a major driver. We believe these findings illustrate how exposure to food scarcity is an immunologic variable, even post-recovery, which should be accounted for in patient medical history and current global public health policy.
CCCTC-binding Factor (CTCF) N-terminal Domain Regulates Clustered Protocadherin Gene Expression by Enhancing Cohesin Processivity
Authors: Zhang Yijun , Wu Qiang 
Published: August 2024

AbstractCTCF (CCCTC-binding factor) instructs three-dimensional (3D) genome folding by anchoring or forestalling cohesin loop extrusion, but the exact mechanism remains obscure. Here, using clustered protocadherins (cPcdh) as model genes, we report that CTCF assists or facilitates cohesin loop extrusion by enhancing its processivity. Specifically, we show that, compared with thePcdh αandγgene clusters, thePcdhβcluster is greatly affected upon CTCFY226A/F228Amutation in the N-terminal domain. Given the long-range distance of thePcdhβcluster from the distal enhancer, this finding has interesting implications in CTCF regulation of cohesin processivity along the linear chromatin during DNA loop extrusion. In particular, the effect on cohesin processivity upon CTCFY226A/F228Amutation is conspicuously similar to that of WAPL overexpression, suggesting that, in addition to the general view of blocking or forestalling cohesin, CTCF may actually enhance or facilitate cohesin loop extrusion during 3D genome folding. We conclude that CTCF enhances cohesin enrichments via the N-terminal YDF motif in clustered protocadherin genes in a genomic-distance biased manner.
Computational Simulations of Hyoid Bone Position and Tracheal Displacement: Effects on Upper Airway Patency and Tissue Mechanics
Authors: Bekdache Dana , Amatoury Jason 
Published: August 2024

ABSTRACTSurgical hyoid repositioning (HR) improves upper airway (UA) patency. Tracheal displacement (TD) is likely to impact HR outcomes, and vice versa, due to hyoid-trachea connections. This study used computational modeling to investigate the influence of TD and HR on UA outcomes and examine the impact of a more caudal baseline hyoid position (OSA phenotype).MethodsA 2D finite element model of the rabbit UA was used to simulate TD and HR (in different directions), separately and combined. Model outcomes included UA closing pressure (Pclose), area, anteroposterior diameter (APD) and soft tissue mechanics (stress/strain). Simulations were repeated with a more caudal baseline hyoid position.ResultsCompared to baseline (TD=HR=0mm), TD alone reduced Pclose by −34%, increased area by 21% and APD by up to 18%. HR alone (except caudal) improved outcomes, particularly anterior-cranial HR which decreased Pclose by −106%, increased area by 32% and APD by up to 107%. TD+HR (except caudal) enhanced these outcomes, with TD+anterior-cranial HR further decreasing Pclose (−131%) and increasing area (55%) and APD (128%). A more caudal baseline hyoid position reduced the effect of TD+anterior-cranial HR on Pclose (−43%), area (49%) and APD (115%).ConclusionThe combination of TD and HR (except caudal) improved UA outcomes even further than when either intervention was applied alone. A more caudal baseline hyoid position reduced the overall impact of each intervention. This study suggests that considering the baseline hyoid position, the degree of TD, and the extent/direction of surgical HR could be crucial in optimizing OSA treatment outcomes.Key points summarySurgical hyoid repositioning can improve upper airway patency and is a treatment for obstructive sleep apnea (OSA).Tracheal displacement, also critical to upper airway function, likely influences hyoid repositioning outcomes due to hyoid-trachea connections.This study used a computational model of the upper airway to simulate tracheal displacement and hyoid repositioning in various directions and magnitude, assessing their impact on upper airway collapsibility, size, and soft tissue mechanics. The influence of a more caudal baseline hyoid position, like in OSA, was also simulated.Combining tracheal displacement with anterior-based hyoid repositioning, in particular, resulted in greater improvements in upper airway outcomes compared to tracheal displacement and hyoid repositioning alone.A more caudal baseline hyoid position diminished the upper airway improvements with both interventionsOptimizing OSA treatment outcomes with hyoid surgeries may require considering the baseline hyoid position, the degree of tracheal displacement, and the direction/magnitude of surgical hyoid repositioning.