bluuebunny/crossref_metadata_2025_split huggingface dataset:
hnRNPA1 RGG-box acts a ”catalyst” in UP1-induced destabilization of RNA and DNA telomeric G-Quadruplexes
Authors: Balasubramanian Sangeetha , Roy Irawati , Appadurai Rajeswari , Srivastava Anand 
Published: August 2023

AbstracthnRNPA1, a protein from the heterogeneous-nuclear ribonucleoprotein fam-ily, mediates cellular processes such as RNA metabolism and DNA telomere maintenance. Besides the folded RNA recognition motifs, hnRNPA1 has a ∼ 135 amino-acids long low-complexity domain (LCD) consisting of an RGG-rich region and a prion-like domain (PrLD). Biochemical data suggest that RGG-rich region modulates recognition of G-quadruplexes (GQs) in the telomeric repeats. Here, we utilize an in-house developed replica exchange technique (REHT) to generate the heterogeneous conformation ensemble of hnRNPA1-RGG and explore its functional significance in telomere maintenance. Single chain statistics and abundance of structural motifs, as well as consistency with experimentally reported struc-tural data, suggest faithful recapitulation of local interactions. We also introduce a protocol to generate functionally significant IDP-nucleic acid complex structures that corroborate well with the experimental knowledge of their binding. We find that RGG-box preferentially binds to the grooves and loops of GQs providing specificity towards certain GQ structures with its Phe, Tyr, and Asn residues forming essential hydrogen bonds and electrostatic interactions. Several of these residues were also identified as important by the reported HSQC chemical shift data. Our binding and simulations studies also revealed that a minor population of the RGG-box can destabilize telomeric GQs, thereby expediting the unfolding activities of hnRNPA1-UP1 at the telomeric end.
Spatiotemporal modelling of cholera and implications for its control, Uvira, Democratic Republic of the Congo
Authors: Ratnayake Ruwan , Knee Jacqueline , Cumming Oliver , Saidi Jaime Mufitini , Rumedeka Baron Bashige , Finger Flavio , Azman Andrew S. , Edmunds W. John , Checchi Francesco , Gallandat Karin 
Published: August 2023

ABSTRACTThe African Great Lakes region including Eastern Democratic Republic of the Congo is a hotspot for cholera transmission. We evaluated the local and global clustering of cholera using 5 years (2016—2020) of suspected cases positive by rapid diagnostic test in Uvira, South Kivu to detect spatiotemporal clusters and the extent of zones of increased risk around cases. We detected 26 clusters (mean radius 652m and mean duration 24.8 days) which recurred annually in three locations and typically preceded seasonal outbreaks. We found a 1100m zone of increased infection risk around cases during the 5 days following clinic attendance for the 2016—2020 period and a 600m radius risk zone for 2020 alone. These risk zone sizes correspond with the area typically used for targeted intervention in the Democratic Republic of the Congo. Our findings underscore the value of the site-specific evaluation of clustering to guide targeted control efforts.
Pathogenic paralogous variants can be used to apply the ACMG PS1 and PM5 variant interpretation criteria
Authors: Brünger Tobias , Ivaniuk Alina , Pérez-Palma Eduardo , Montanucci Ludovica , Cohen Stacey , Smith Lacey , Parthasarathy Shridhar , Helbig Ingo , Nothnagel Michael , May Patrick , Lal Dennis 
Published: August 2023

AbstractPurposeThe majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Broadening the evidence of the PS1 and PM5 criteria has the potential to increase conclusive variant interpretation.MethodsWe hypothesized that incorporation of pathogenic missense variants in conserved residues across paralogous genes can increase the number of variants where ACMG PS1/PM5 criteria can be applied. We mapped over 2.5 million pathogenic and general population variants from ClinVar, HGMD, and gnomAD databases onto 9,990 genes and aligned these by gene families. Subsequently, we developed a novel framework to extend PS1/PM5 by incorporating pathogenic paralogous variants annotations (para-PS1/PM5).ResultsWe demonstrate that para-PS1/PM5 criteria increase the number of classifiable amino acids 3.6-fold compared to PS1 and PM5. Across all gene families with at least two disease-associated genes, the calculated likelihood ratios suggest moderate evidence for pathogenicity. Moreover, for 36 genes, the extended para-PS1/PM5 criteria reach strong evidence level.ConclusionWe show that single pathogenic paralogous variants incorporation at paralogous protein positions increases the applicability of the PS1 and PM5 criteria, likely leading to a reduction of variants of uncertain significance across many monogenic disorders. Future iterations of the ACMG guidelines may consider para-PS1 and para-PM5.
Risk of long COVID and associated symptoms after acute SARS-COV-2 infection in ethnic minorities: a Danish nationwide cohort study
Authors: Mkoma George F. , Agyemang Charles , Benfield Thomas , Rostila Mikael , Cederström Agneta , Petersen Jørgen H. , Norredam Marie 
Published: August 2023

AbstractBackgroundEthnic minorities living in high-income countries have been disproportionately affected by COVID-19 in terms of infection rates and hospitalisations; however, less is known about long COVID in this population. Our aim was to examine the risk of long COVID and associated symptoms among ethnic minorities.Methods and FindingsA Danish nationwide register-based cohort study of individuals diagnosed with COVID-19 aged ≥18 years (n=2 334 271) between January 2020 and August 2022. We calculated the risk of long COVID diagnosis and long COVID symptoms among ethnic minorities compared with native Danes using multivariable Cox proportional hazard regression and logistic regression, respectively.Ethnic minorities from North Africa (adjusted hazard ratio [aHR] 1.41; 95% CI 1.12–1.79), Middle East (aHR 1.38; 95% CI 1.24–1.55), Eastern Europe (aHR 1.35; 95% CI 1.22–1.49), and Asia (aHR 1.23; 95% CI 1.09–1.40) had significantly greater risk of long COVID diagnosis than native Danes in both unadjusted and adjusted models. In the analysis by largest countries of origin, the greater risks of long COVID diagnosis were found in Iraqis (aHR 1.56; 95% CI 1.30– 1.88), Turks (aHR 1.42; 95% CI 1.24–1.63), and Somalis (aHR 1.42; 95% CI 1.07–1.91) after adjustment for confounders. Significant factor associated with an increased risk of long COVID diagnosis was COVID-19 hospitalisation. Furthermore, the odds of reporting cardiopulmonary symptoms (including dyspnoea, cough, and chest pain) andanylong COVID symptoms were higher among North African, Middle Eastern, Eastern European, and Asian than among native Danes in both unadjusted and adjusted models.ConclusionsBelonging to an ethnic minority group was significantly associated with an increased risk of long COVID indicating the need to better understand long COVID drivers and address care and treatment strategies in this population.
Sex differences in the diagnosis of advanced cancer and subsequent outcome in people with chronic kidney disease: an analysis of a national population cohort
Authors: Shemilt R , Sullivan MK , Hanlon P , Jani B , De La Mata N , Rosales B , Elyan BMP , Wyld M , Hedley JA , Cutting R , McAllister DA , Webster AC , Mark PB , Lees JS 
Published: August 2023

AbstractBackgroundIn the general population, advanced cancer stage at presentation is associated with poorer health outcomes. People with chronic kidney disease (CKD) have increased incidence and mortality from most cancer types. We sought to determine whether people with CKD were more likely to present with advanced stage cancer, whether this was associated with survival, and whether these associations varied by sex.MethodsData were from Secure Anonymised Information Linkage Databank (SAIL), a Welsh primary care database with linkage to cancer and death registries. We included patients with a de- novo cancer diagnosis (2011-2017), and at least two kidney function tests in the two years prior to diagnosis. Estimated glomerular filtration rate based on serum creatinine (eGFRcr) was calculated using the CKD-EPI 2009 equation (mL/min/1.73m2). Logistic regression models determined odds of presenting with advanced cancer (stage 3 or 4 at diagnosis) by different values of eGFRcr at baseline. Cox proportional hazards models tested associations between eGFRcr at baseline and all-cause mortality risk (reference eGFR 75 to <90).FindingsThere were 66,128 patients: 30,857 (46.7%) were female, mean age was 69.1 (standard deviation [SD] 13.8) years in females and 70.6 (SD 11.1) years in males; median eGFRcr at baseline was 78 (interquartile range [IQR] 63 – 90) mL/min/1.73m2in both females and males. Over a median follow-up time of 3.1 (IQR 0.5 – 5.7) years in females and 2.9 (IQR 0.5-5.5) years in males, there were 17,303 deaths in females and 20,855 in males. An eGFRcr <30 was associated with higher odds of presenting with advanced cancer in males (OR 1.33 95% CI 1.09-1.62), but not in females (OR 1.17 95% CI 0.92-1.50); positive associations were primarily driven by prostate and breast cancers. With lower eGFRcr, hazards of cancer death increased in both sexes, but lower eGFRcr was associated with greater hazards of cancer death in females (eGFRcr <30: HR 1.71, 95% CI 1.56-1.88, p<0.001; male versus female comparison HR 0.88, 95% CI 0.78-0.90; p=0.037).InterpretationCKD was not associated with substantially higher odds of presenting with advanced cancer across most cancer sites (except prostate and breast), but was associated with reduced survival. Despite an initial survival advantage compared to males, females with CKD had disproportionately higher hazards of death. Though potential explanations for reduced survival after a cancer diagnosis are manifold, scrutiny of access to, efficacy, and safety of cancer treatments in people with CKD – particularly females with CKD – are warranted.FundingChief Scientist Office (Scotland) Postdoctoral Lectureship (PCL/20/10) and University of Sydney/University of Glasgow Office of Global Engagement Collaboration Partnership (9241562498).
Administration of vaccine-boosted COVID-19 convalescent plasma to SARS-CoV-2 infected hamsters decreases virus replication in lungs and hastens resolution of the infection despite transiently enhancing disease and lung pathology
Authors: Carroll Timothy D. , Wong Talia , Morris Mary Kate , Germanio Clara Di , Ma Zhong-min , Stone Mars , Ball Erin , Fritts Linda , Rustagi Arjun , Simmons Graham , Busch Michael , Miller Christopher J. 
Published: August 2023

AbstractThe utility of COVID-19 convalescent plasma (CCP) for treatment of immunocompromised patients who are not able to mount a protective antibody response against SARS-CoV-2 and who have contraindications or adverse effects from currently available antivirals remains unclear. To better understand the mechanism of protection in CCP, we studied viral replication and disease progression in SARS-CoV-2 infected hamsters treated with CCP plasma obtained from recovered COVID patients that had also been vaccinated with an mRNA vaccine, hereafter referred to as Vaxplas. We found that Vaxplas dramatically reduced virus replication in the lungs and improved infection outcome in SARS-CoV-2 infected hamsters. However, we also found that Vaxplas transiently enhanced disease severity and lung pathology in treated animals likely due to the deposition of immune complexes, activation of complement and recruitment of increased numbers of macrophages with an M1 proinflammatory phenotype into the lung parenchyma.
Cerebral perfusion alterations in temporal lobe epilepsy: Structural underpinnings and network disruptions
Authors: Ngo Alexander , Royer Jessica , Rodríguez-Cruces Raúl , Xie Ke , DeKraker Jordan , Auer Hans , Tavakol Shahin , Lam Jack , Schrader Dewi , Dudley Roy W. R. , Bernasconi Andrea , Bernasconi Neda , Frauscher Birgit , Larivière Sara , Bernhardt Boris C. 
Published: August 2023

AbstractObjectiveNeuroimaging has been the prevailing method to study brain networks in temporal lobe epilepsy (TLE), showing widespread alterations beyond the mesiotemporal lobe. Despite the critical role of the cerebrovascular system in maintaining whole-brain structure and function, changes in cerebral blood flow (CBF) remain incompletely understood in the disease.MethodsWe studied 24 individuals with pharmaco-resistant TLE and 38 healthy adults using multimodal 3T magnetic resonance imaging. We compared regional CBF changes in patients relative to controls and related our perfusion findings to morphological and microstructural metrics. We further probed inter-regional vascular networks in TLE, using graph theoretical CBF covariance analysis. Finally, we assessed the effects of disease duration to study progressive changes.ResultsCompared to controls, individuals with TLE showed widespread CBF reductions, predominantly in fronto-temporal regions, with 83% of patients showing more marked decreases ipsilateral than contralateral to the seizure focus. Parallel structural profiling and network-based models showed that cerebral hypoperfusion may be partly constrained by grey and white matter changes and topologically segregated from whole-brain perfusion networks. Negative effects of progressive disease duration further targeted regional CBF profiles in patients. Findings were confirmed in a subgroup of patients who remained seizure-free after surgery.InterpretationOur multimodal findings provide insights into vascular contributions to TLE pathophysiology and highlight their clinical potential in seizure lateralization.
Single-molecule analysis reveals the phosphorylation of FLS2 governs its spatiotemporal dynamics and immunity
Authors: Cui Yaning , Qian Hongping , Yin Jinhuan , Xu Changwen , Luo Pengyun , Zhang Xi , Yu Meng , Su Bodan , Li Xiaojuan , Lin Jinxing 
Published: August 2023

SummaryTheArabidopsis thalianaFLAGELLIN-SENSITIVE2 (FLS2), a typical receptor kinase, recognizes the conserved 22 amino acid sequence in the N-terminal region of flagellin (flg22) to initiate plant defense pathways, which was intensively studied in the past decades. However, the dynamic regulation of FLS2 phosphorylation at the plasma membrane after flg22 recognition needs further elucidation. Through single-particle tracking, we demonstrated that upon flg22 treatment, the phosphorylation of Ser-938 in FLS2 impacts its spatiotemporal dynamics and lifetime. Following förster resonance energy transfer-fluorescence lifetime (FRET-FLIM) imaging microscopy and protein proximity indexes (PPI) assays revealed that flg22 treatment increased the co-localization of GFP-tagged FLS2/FLS2S938Dbut not FLS2S938Awith AtRem1.3-mCherry, a sterol-rich lipid marker, indicating that the phosphorylation of FLS2S938affects FLS2 sorting efficiency to AtRem1.3-associated nanodomains. Importantly, we found that the phosphorylation of Ser-938 enhanced flg22-induced FLS2 internalization and immune responses, demonstrating that the phosphorylation may activate flg22-triggered immunity through partitioning FLS2 into functionalAtRem1.3-associated nanodomains, which fills the gap between the FLS2S938phosphorylation and FLS2-mediated immunity.
Meta-omic profiling reveals ubiquity of genes encoding for the high value nitrogen rich biopolymer cyanophycin in activated sludge microbiomes
Authors: Farmer McKenna , Raj Rashmi , Tarpeh Will , Tyo Keith , Wells George 
Published: August 2023

AbstractRecovering nitrogen (N) from municipal wastewater is a promising approach to prevent nutrient pollution, reduce energy use, and transition towards a circular N bioeconomy, but remains a technologically challenging endeavor. Existing N recovery techniques are optimized for high-strength, low-volume wastewater. Therefore, developing methods to concentrate dilute N from mainstream wastewater will bridge the gap between existing technologies and practical implementation. The N-rich biopolymer cyanophycin is a promising candidate for N bioconcentration and recovery due to its solubility characteristics and potential for high levels of accumulation in a limited number of bacterial isolates. However, the cyanophycin synthesis pathway is poorly explored in natural and engineered microbiomes. In this study, we analyzed over 3700 publicly available metagenome assembled genomes (MAGs) and found that the cyanophycin synthesis genecphAwas ubiquitous across common activated sludge bacteria. Surprisingly, we found thatcphAwas present in all analyzed genomes of the common phosphorus accumulating organisms (PAO)Ca. ‘Accumulibacter’ andTetrasphaera, suggesting potential for simultaneous N and P bioconcentration in the same organisms. Using metatranscriptomic data, we also confirmed the expression ofcphAin lab-scale bioreactors enriched with PAO. Our findings suggest that cyanophycin synthesis is a ubiquitous metabolic pathway in activated sludge microbiomes and therefore may have potential for integration in existing biological nutrient removal and recovery processes. We anticipate this work to be a starting point for future evaluations of combined N and P bioaccumulation, with the ultimate goal of advancing widespread adoption of nutrient recovery from municipal wastewater.
scCancer2: data-driven in-depth annotations of the tumor microenvironment at single-level resolution
Authors: Chen Zeyu , Miao Yuxin , Tan Zhiyuan , Hu Qifan , Wu Yanhong , Guo Wenbo , Gu Jin 
Published: August 2023

AbstractSingle-cell RNA-seq (scRNA-seq) is a powerful technique for decoding the complex cellular compositions in the tumor microenvironment (TME). As previous studies have defined many meaningful cell subtypes in several tumor types, there is a great need to computationally transfer these labels to new datasets. Also, different studies used different approaches or criteria to define the cell subtypes for the same major cell lineages. The relationships between the cell subtypes defined in different studies should be carefully evaluated. In this updated package scCancer2, designed for integrative tumor scRNA-seq data analysis, we developed a supervised machine learning framework to annotate TME cells with annotated cell subtypes from 15 scRNA datasets with 594 samples in total. Based on the trained classifiers, we quantitatively constructed the similarity maps between the cell subtypes defined in different references by testing on all the 15 datasets. Secondly, to improve the identification of malignant cells, we designed a classifier by integrating large-scale pan-cancer TCGA bulk gene expression datasets and scRNA-seq datasets (10 cancer types, 159 samples, 652,160 cells). This classifier shows robust performances when no internal confidential reference cells are available. Thirdly, this package also integrated a module to process the seq-based spatial transcriptomic data and analyze the spatial features of TME. Software availability:http://lifeome.net/software/sccancer2/.
Frontal hip exoskeleton assistance does not appear promising for reducing the metabolic cost of walking: A preliminary experimental study
Authors: Kim Jinsoo , Raitor Michael , Liu C. Karen , Collins Steven H. 
Published: August 2023

AbstractBackgroundDuring walking, humans exert a substantial hip abduction moment to maintain balance and prevent pelvic drop. This significant torque requirement suggests that assisting the frontal hip muscles could be a promising strategy to reduce the energy expenditure associated with walking. A previous musculoskeletal simulation study also predicted that providing hip abduction assistance through an exoskeleton could potentially result in a large reduction in whole-body metabolic rate. However, to date, no study has experimentally assessed the metabolic cost of walking with frontal hip assistance.MethodsIn this case study involving a single subject (N = 1), a tethered hip exoskeleton emulator was used to assess the feasibility of reducing metabolic expenditure through frontal-plane hip assistance. Human-in-the-loop optimization was conducted separately under torque and position control to determine energetically optimal assistance parameters for each control scheme.ResultsThe optimized profiles in both control schemes did not reduce metabolic rate compared to walking with assistance turned off. The optimal peak torque magnitude was found to be close to zero, suggesting that any hip abduction torque would increase metabolic rate. Both bio-inspired and simulation-inspired profiles substantially increased metabolic cost.ConclusionFrontal hip assistance does not appear to be promising in reducing the metabolic rate of walking. This could be attributed to the need for maintaining balance, as humans may refrain from relaxing certain muscles as a precaution against unexpected disturbances during walking. An investigation of different control architectures is needed to determine if frontal-plane hip assistance can yield successful results.
Promotion of tumor angiogenesis and growth induced by low-dose antineoplastic agentsviabone-marrow-derived cells
Authors: You Huining , Zhao Peipei , Zhao Xue , Cheng Kai , Li Min , Kou Jianrong , Feng Weiyi 
Published: August 2023

AbstractMore research is needed to solidify the basis for reasonable metronomic chemotherapy regimens due to the inconsistent clinical outcomes from studies on metronomic chemotherapy with antineoplastic agents, along with signs of a nonlinear dose–response relationship at low doses. The present study therefore explored the dose–response relationships of representative antineoplastic agents in low dose ranges and their underlying mechanisms. Cyclophosphamide (CPA) and 5-fluorouracil (5-Fu) were employed to observe the effects of the frequent administration of low-dose antineoplastic agents on tumor growth, tumor angiogenesis, and bone-marrow-derived cell (BMDC) mobilization in mouse models. The effects of antineoplastic agents on tumor and endothelial cell functions with or without BMDCs were analyzedin vitro. Tumor growth and metastasis were significantly promoted after the administration of CPA or 5-Fu at certain low dose ranges, and were accompanied by enhanced tumor angiogenesis and proangiogenic factor expression in tumor tissues, increased proangiogenic BMDC release in the circulating blood, and augmented proangiogenic BMDC retention in tumor tissues. Low concentrations of CPA or 5-Fu were found to significantly promote tumor cell migration and invasion, and enhance BMDC adhesion to endothelial cellsin vitro. These results suggest that there are risks in empirical metronomic chemotherapy using low-dose antineoplastic agents.