bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants
Authors: Wu Jianbo , Chen Zhenguo , Gao Yidan , Wang Zegen , Wang Jiarong , Chiang Bing-Yu , Zhou Yunjiao , Han Yuru , Zhan Wuqiang , Xie Minxiang , Jiang Weiyu , Zhang Xiang , Hao Aihua , Xia Anqi , He Jiaying , Xue Song , Mayer Christian T. , Wu Fan , Wang Bin , Zhang Lunan , Sun Lei , Wang Qiao 
Published: December 2022

ABSTRACTStriking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.
Genome-wide association study of multiple neuropathology endophenotypes identifies novel risk loci and provides insights into known Alzheimer’s risk loci
Authors: Shade Lincoln M.P. , Katsumata Yuriko , Claas Steven A. , Ebbert Mark T. W. , Abner Erin L. , Hohman Timothy J. , Mukherjee Shubhabrata , Nho Kwangsik , Saykin Andrew J. , Bennett David A. , Schneider Julie A. ,   The Alzheimer’s Disease Genetics Consortium, Nelson Peter T. , Fardo David W. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundAlzheimer’s disease is highly heritable and exhibits neuropathological hallmarks of neurofibrillary tau tangles and neuritic amyloid plaques. Previous genome-wide association studies (GWAS) have identified over 70 genomic risk loci of clinically diagnosed Alzheimer’s disease. However, upon autopsy, many Alzheimer’s disease patients have multiple comorbid neuropathologies that may have independent or pleiotropic genomic risk factors. Autopsy data combined with GWAS provides the opportunity to study the genetic risk factors of individual neuropathologies.MethodsWe studied the genome-wide risk factors of eleven Alzheimer’s disease-related neuropathology endophenotypes. We used four sources of neuropathological data: National Alzheimer’s Coordinating Center, Religious Orders Study and Rush Memory and Aging Project, Adult Changes in Thought study, and Alzheimer’s Disease Neuroimaging Initiative. We used generalized linear mixed models to identify risk loci, followed by Bayesian colocalization analyses to identify potential functional mechanisms by which genetic loci influence neuropathology risk.ResultsWe identified two novel loci associated with neuropathology: onePIK3R5locus (lead variant rs72807981) with neurofibrillary pathology, and oneCOL4A1locus (lead variant rs2000660) with cerebral atherosclerosis. We also confirmed associations between known Alzheimer’s genes and multiple neuropathology endophenotypes, includingAPOE(neurofibrillary tangles, neuritic plaques, diffuse plaques, cerebral amyloid angiopathy, and TDP-43 pathology);BIN1(neurofibrillary tangles and neuritic plaques); andTMEM106B(TDP-43 pathology and hippocampal sclerosis). After adjusting forAPOEgenotype, we identified a locus nearAPOC2(lead variant rs4803778) associated with cerebral amyloid angiopathy that influences DNA methylation at nearby CpG sites in the cerebral cortex.Conclusionsrs2000660 is in strong linkage disequilibrium with a synonymous coding variant (rs650724) ofCOL4A1, providing a candidate functional variant. Two CpG sites affected by the cerebral amyloid angiopathy-associatedAPOC2locus were previously associated with dementia in an independent cohort, suggesting that the effect of this locus on disease may be mediated by DNA methylation.BIN1is associated with neurofibrillary tangles and neuritic plaques but not with amyloid pathology.TMEM106Bis associated with hippocampal sclerosis and TDP-43 pathology but not the canonical Alzheimer’s disease pathologies. These findings provide insights into known Alzheimer’s disease risk loci by refining the pathways affected by these risk genes.
Relationship between blood bone metabolic biomarkers and anemia in CKD patients
Authors: Li Fan , Yang Guang , Ye Xiaoxue , Zeng Ming , Huang Hui , Bian Anning , Xing Changying , Tang Shaowen , Zhang Jing , Jiang Yao , Chen Huimin , Yin Caixia , Zhang Lina , Wang Jing , Huang Yaoyu , Zhou Wenbin , Wan Huiting , Zha Xiaoming , Wang Ningning 
Published: December 2022

AbstractIntroductionBlood bone metabolic biomarkers are non-invasive indexes for evaluating renal osteodystrophy (ROD). Here the relationships between blood bone metabolic biomarkers and anemia in chronic kidney disease (CKD) patients are investigated, the effects of parathyroidectomy (PTX) on above indices are analyzed.MethodsIn this cross-sectional study, 100 healthy controls and 239 CKD patients, including 46 secondary hyperparathyroidism (SHPT) subgroup with PTX, were enrolled. A prospective study with 28 PTX patients was followed up. The degree of anemia was classified as mild, moderate, and severe based on the tertiles of hemoglobin (Hb) levels of the anemic CKD patients, with cutoff values of 83g/L and 102g/L. Bone metabolic biomarkers, including calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF23) and α-klotho were tested.ResultsThe mean eGFR in CKD patients was 25.74±35.99 ml/min/1.73 m2and 84.10% patients had anemia. The baseline Hb levels in the mild, moderate, and severe anemia subgroups were 110.86±5.99g/L, 92.71±5.96g/L and 67.38±10.56g/L, respectively. CKD patients had higher adjusted Ca, P, ALP, iPTH and FGF23 levels, and lower α-klotho levels than controls. Baseline adjusted Ca, P, iPTH and α-klotho levels were associated with Hb in CKD patients. Blood adjusted Ca, P, iPTH levels were correlated with anemia severity. After PTX (median interval: 6.88 months), anemia and high blood adjusted Ca, P, iPTH and FGF23 levels were ameliorated, while α-klotho levels increased.ConclusionsBlood adjusted Ca, P, iPTH and α-klotho levels were correlated with Hb in CKD patients, correcting ROD is supposed to be therapeutic targets for anemia.
The effects of sleep disturbance on dyspnoea and impaired lung function following COVID-19 hospitalisation: a prospective multi-centre cohort study
Authors: Jackson C. , Stewart I. , Plekhanova T. , Cunningham P. , Hazel A. L. , Al-Sheklly B. , Aul R. , Bolton C. E. , Chalder T. , Chalmers J. D. , Chaudhuri N. , Docherty A. B. , Donaldson G. , Edwardson C. L. , Elneima O. , Greening N. J. , Hanley N. A. , Harris V. C. , Harrison E. M. , Ho L-P. , Houchen-Wolloff L. , Howard L. S. , Jolley C. J. , Jones M. G. , Leavy O. C. , Lewis K. E. , Lone N. I. , Marks M. , McAuley H. J. C. , McNarry M. A. , Patel B. , Piper-Hanley K. , Poinasamy K. , Raman B. , Richardson M. , Rivera-Ortega P. , Rowland-Jones S. , Rowlands A. V. , Saunders R. M. , Scott J. T. , Sereno M. , Shah A. , Shikotra A. , Singapuri A. , Stanel S. C. , Thorpe M. , Wootton D. G. , Yates T. , Jenkins R. G. , Singh S. , Man W. D-C. , Brightling C. E. , Wain L. V. , Porter J. C. , Thompson A. A. R. , Horsley A. , Molyneaux P. L. , Evans R. A. , Jones S. E. , Rutter M. K. , Blaikley J. F. 
Published: December 2022

AbstractBackgroundSleep disturbance is common following hospitalisation both for COVID-19 and other causes. The clinical associations are poorly understood, despite it altering pathophysiology in other scenarios. We, therefore, investigated whether sleep disturbance is associated with dyspnoea along with relevant mediation pathways.MethodsSleep parameters were assessed in a prospective cohort of patients (n=2,468) hospitalised for COVID-19 in the United Kingdom in 39 centres using both subjective and device-based measures. Results were compared to a matched UK biobank cohort and associations were evaluated using multivariable linear regression.Findings64% (456/714) of participants reported poor sleep quality; 56% felt their sleep quality had deteriorated for at least 1-year following hospitalisation. Compared to the matched cohort, both sleep regularity (44.5 vs 59.2, p<0.001) and sleep efficiency (85.4% vs 88.5%, p<0.001) were lower whilst sleep period duration was longer (8.25h vs 7.32h, p<0.001). Overall sleep quality (effect estimate 4.2 (3.0–5.5)), deterioration in sleep quality following hospitalisation (effect estimate 3.2 (2.0–4.5)), and sleep regularity (effect estimate 5.9 (3.7–8.1)) were associated with both dyspnoea and impaired lung function (FEV1and FVC). Depending on the sleep metric, anxiety mediated 13–42% of the effect of sleep disturbance on dyspnoea and muscle weakness mediated 29-43% of this effect.InterpretationSleep disturbance is associated with dyspnoea, anxiety and muscle weakness following COVID-19 hospitalisation. It could have similar effects for other causes of hospitalisation where sleep disturbance is prevalent.FundingUK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.
The genomic and epidemiological virulence patterns ofSalmonella entericaserovars in the United States
Authors: Fenske Gavin J. , Pouzou Jane G. , Pouillot Régis , Taylor Daniel D. , Costard Solenne , Zagmutt Francisco J. 
Published: December 2022

AbstractThe serovars ofSalmonella entericadisplay dramatic differences in pathogenesis and host preferences. We developed a process (patent pending) for groupingSalmonellaisolates and serovars by their public health risk to provide better Salmonellacontrol targets along the food chain. We collated a curated set of 12,337S. entericaisolate genomes from human, beef, and bovine sources in the US. After annotating a virulence gene catalog for each isolate, we used unsupervised random forest methods to estimate the proximity (similarity) between isolates based upon the genomic presentation of putative virulence traits We then grouped isolates (virulence clusters) using hierarchical clustering (Ward’s method), used non-parametric bootstrapping to assess cluster stability, and externally validated the virulence clusters against epidemiological virulence measures from FoodNet, the National Outbreak Reporting System (NORS), and US federal sampling of beef products. We identified five stable virulence clusters ofS. entericaserovars. Cluster 1 (higher virulence) serovars yielded an annual incidence rate of domestically acquired sporadic cases roughly one and a half times higher than the other four clusters combined (Clusters 2-5, lower virulence). Compared to other clusters, cluster 1 also had a higher proportion of infections leading to hospitalization and was implicated in more foodborne and beef-associated outbreaks, despite being isolated at a similar frequency from beef products as other clusters. We also identified subpopulations within 11 serovars. Remarkably, we foundS.Infantis andS.Typhimurium subpopulations that significantly differed in genome length and clinical case presentation. Further, we found that the presence of the pESI plasmid accounted for the genome length differences between theS.Infantis subpopulations. Our results demonstrate thatS. entericastrains with the highest incidence of human infections share a common virulence repertoire. This work could be used in combination with foodborne surveillance information to best target serovars of public health concern.
Label-free digital holotomography reveals ibuprofen-induced morphological changes to red blood cells
Authors: Bergaglio Talia , Bhattacharya Shayon , Thompson Damien , Nirmalraj Peter Niraj 
Published: December 2022

AbstractUnderstanding the dose-dependent effect of over-the-counter drugs on red blood cells (RBCs) is crucial for hematology and digital pathology. Yet, it is challenging to continuously record the real-time, drug-induced nanoscopic shape changes of RBCs in a label-free manner. Here, we demonstrate digital holotomography (DHTM) enabled real-time, label-free concentration-dependent and time-dependent monitoring of ibuprofen on RBCs from a healthy donor. The RBCs are segmented based on 3D and 4D refractive index tomograms and their morphological and chemical parameters are retrieved with their shapes classified using machine learning. We directly observed the formation and motion of spicules on the RBC membranes when aqueous solutions of ibuprofen were drop cast on wet blood, creating rough-membraned echinocyte forms. At low concentrations of 0.25-0.50 mM, the ibuprofen-induced morphological change was transient but at high concentrations (1.5-3 mM) the spiculated RBC remained over a period of up to 1.5 hours. Molecular simulations confirmed that aggregates of ibuprofen molecules at high concentrations significantly disrupted the RBC membrane structural integrity and lipid order, but produced negligible effect at low ibuprofen concentrations. Control experiments on the effect of urea, hydrogen peroxide and aqueous solutions on RBCs showed zero spicule formation. Our work elucidates the dose-dependent chemical effects on RBCs using label-free microscopes that can be deployed for the rapid detection of overdosage of over-the-counter and prescribed drugs.SignificanceThe interaction between drugs and blood cells is an important field of study in order to understand the risk for drug-induced haematological adverse effects. Using digital holo-tomographic microscopy (DHTM), we can resolve the real-time effect of medications on the morphological and chemical properties of red blood cells with high spatial and temporal resolution and in a label-free manner. We show that our approach can be used as a haematology platform for the diagnosis of blood disorders and for monitoring the dose-dependent effect of prescribed and over-the-counter medications in a cost-effective manner, with significant implications for its applicability in resource-limited settings and in the field of personalized medicine.
Bacterial colonizers ofNematostella vectensisare initially selected by the host before interactions between bacteria determine further succession
Authors: Domin H , Zimmermann J , Taubenheim J , Fuentes Reyes G , Saueressig L , Prasse D , Höppner M , Schmitz RA , Hentschel U , Kaleta C , Fraune S 
Published: December 2022

AbstractThe microbiota of multicellular organisms undergoes considerable changes during development but the general mechanisms that control community assembly and succession are poorly understood. Here, we use bacterial recolonization experiments inNematostella vectensisas a model to understand general mechanisms determining bacterial establishment and succession. We compared the dynamic establishment of the microbiome on the germfree host and on inert silica. Following the dynamic reconstruction of microbial communities on both substrates, we show that the initial colonization events are strongly influenced by the host but not by the tube, while the subsequent bacteria-bacteria interactions are the main cause of bacterial succession. Interestingly, the recolonization pattern on adult hosts resembles the ontogenetic colonization succession. This process occurs independently of the bacterial composition of the inoculum and can be followed at the level of individual bacteria, suggesting that priority effects are neglectable for early colonization events inNematostella. To identify potential metabolic traits associated with initial colonization success and potential metabolic interactions among bacteria associated with bacterial succession, we reconstructed the metabolic networks of bacterial colonizers based on their genomes. These analyses revealed that bacterial metabolic capabilities reflect the recolonization pattern, and the degradation of chitin might be a selection factor during early colonization of the animal. Concurrently, transcriptomic analyses revealed thatNematostellapossesses two chitin synthase genes, one of which is upregulated during early recolonization. Our results show that early colonization events are strongly controlled by the host while subsequent colonization depends on metabolic bacteria-bacteria interactions largely independent of host development.
Mechanistic dissection of alga recognition and uptake in coral-algal endosymbiosis
Authors: Hu Minjie , Bai Yun , Zheng Xiaobin , Zheng Yixian 
Published: December 2022

AbstractMany corals form a mutually beneficial relationship with the dinoflagellate algae calledSymbiodiniaceae. Cells in the coral gastrodermis recognize, phagocytose, and house the algae in an organelle called symbiosome, which supports algae photosynthesis and nutrient exchange with corals1–3. Rising ocean temperature disrupts this endosymbiotic relationship, leading to alga loss, coral bleaching and death, and the degradation of marine ecosystems4–6. Mitigation of coral death requires a mechanistic understanding of coral-algal endosymbiosis. We have developed genomic resources to enable the use of a soft coralXenia speciesas a model to study coral-algal endosymbiosis7. Here we report an effective RNA interference (RNAi) method and its application in the functional studies of genes involved in early steps of endosymbiosis. We show that an endosymbiotic cell marker called LePin (for itsLectin and kazalProteaseinhibitor domains) is a secreted lectin that binds to algae to initiate the formation of alga-containing endosymbiotic cells. The evolutionary conservation of LePin among marine endosymbiotic anthozoans suggests a general role in coral-algal recognition. Coupling bioinformatics analyses with RNAi and single cell (sc)-RNA-seq, we uncover three gene expression programs (GEP) influenced by LePin during the early and middle stages of endosymbiotic lineage development. Further studies of genes in these GEPs lead to the identification of two scavenger receptors that support the formation of alga-containing endosymbiotic cells, most likely by initiating phagocytosis and modulating coral immune response. We also identify two actin regulators for endosymbiosis, which shed light on the phagocytic machinery and a possible mechanism for symbiosome formation. Our findings should usher in an era of mechanistic studies of coral-algal endosymbiosis.
Combined administration of novobiocin and apomorphine mitigates cholera toxin mediated cellular toxicity
Authors: Bhalerao Sonali Eknath , Sen Himanshu , Raychaudhuri Saumya 
Published: December 2022

AbstractCholera is a dreadful disease. The scourge of this deadly disease is still evident in the developing world. Though several therapeutic strategies are in practice to combat and contain the disease, there is still a need for new drugs to control the disease safely and effectively. Keeping in view the concern, we screened a small molecule library against a yeast model of cholera toxin A subunit. Our effort resulted in the discovery of a small molecule, apomorphine effective in reducing the lethality of toxic subunit in yeast model. In addition, novobiocin, an inhibitor of ADP ribosylation process, a key biochemical event through which cholera toxin exerts its action on host, was also found to rescue yeast cells from cholera toxin A subunit mediated toxicity. Finally, both molecules prevented cholera toxin mediated cellular toxicity on HT29 intestinal epithelial cells. We also observed that combined administration of both drug molecules worked better than single drug in countering toxin driven lethality.
Interplay of physical and cognitive performance using hierarchical continuous-time dynamic modelling and a dual-task training regime in Alzheimer’s patients
Authors: Schwarck S. , Voelkle M. C. , Becke A. , Busse N. , Glanz W. , Düzel E. , Ziegler G. 
Published: December 2022

AbstractBackgroundTraining studies typically investigate the cumulative rather than the analytically challenging immediate effect of exercise on cognitive outcomes.MethodsWe investigated the dynamic interplay between single-session exercise intensity and time-locked cognition in older adults with suspected Alzheimer’s dementia (N = 17) undergoing a 24-week dual-task regime. We specified a state of the art hierarchical Bayesian continuous- time dynamic model with fully connected state variables to analyze the bidirectional effects between physical and cognitive performance over time.ResultsHigher physical performance was dynamically linked to improved memory recognition (-1.335,SD= 0.201, 95 BCI [-1.725, -0.954]). The effect was short-term, lasting up to five days (-0.368, SD = 0.05, 95 BCI [-0.479, -0.266]). Clinical scores supported the validity of the model and observed temporal dynamics.ConclusionHigher physical performance predicted improved memory recognition in a day- by-day manner, providing a proof-of-concept for the feasibility of linking exercise training and cognition in patients with Alzheimer’s dementia.HighlightsHierarchical Bayesian continuous-time dynamic modelling approach72 repeated physical exercise (PP) and cognitive (COG) performance measurementsPP is dynamically linked to session-to-session variability of COGHigher PP improved COG in subsequent sessions in subjects with Alzheimer’s dementiaShort-term effect: lasting up to four days after training sessionResearch in ContextSystematic review:Training-induced effects on cognitive outcomes in Alzheimer’s dementia and/or associated dynamic Bayesian modelling approaches were reviewed. Although studies showed exercise-induced cognitive improvements or maintenance, most of these studies fail to capture the dynamic nature of the change and interplay of physical (PP) and cognitive (COG) performance.Interpretation:Using a sophisticated hierarchical Bayesian continuous-time dynamic modelling approach, a fully connected state variable model was specified. PP is dynamically linked to COG, i.e. higher PP predicted improved COG in subsequent sessions. This effect was rather short term, lasting for up to five days.Future direction:Our results support exercise-induced effects on cognition. The cognitive system was still able to fluctuate and change favourably even in a sample with Alzheimer’s dementia. Further studies using dynamic modelling are necessary to replicate findings and examine other contributors to cognitive volatility in dementia.