bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Networks of Alzheimer’s Disease, Aging and Longevity in Humans
Authors: Balmorez Timothy , Sakazaki Amy , Murakami Shin 
Published: January 2023

AbstractHuman genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer’s disease (AD genes). Although the genetics of aging and longevity has been extensively studied, previous studies have focused on a specific set of genes that have been shown to contribute to or to be a risk factor for AD. Thus, the connections among the genes involved in AD, aging, and longevity are not well understood. Here, we identified the genetic interaction networks (referred to as pathways) of aging and longevity within the context of AD, using a gene set enrichment analysis by Reactome that cross-references more than 100 bioinformatic databases to allow interpretation of the biological functions of gene sets through a wide variety of gene networks. We validated the pathways with a threshold of p-value < 1.00E-05, using the databases to extract lists of 356 AD genes, 307 aging-related (AR) genes, and 357 longevity genes. There was a broad range of biological pathways involved in AR and Longevity genes shared with AD genes. AR genes identified 261 pathways within the threshold of p < 1.00E-05, of which 26 pathways (10% of AR gene pathways) were further identified by overlapping genes among AD and AR genes. The overlapped pathways included Gene Expression (p = 4.05E-11) including ApoE, SOD2, TP53 and TGFB1 (p = 2.84E-10); Protein Metabolism and SUMOylation including E3 ligases and target proteins (p = 1.08E-07), ERBB4 signal transduction (p = 2.69E-06), Immune System including IL-3 and IL-13 (p = 3.83E-06), Programmed Cell Death (p = 4.36E-06) and platelet degranulation (p = 8.16E-06) among others. Longevity genes identified 49 pathways within the threshold, of which 12 pathways (24% of Longevity gene pathways) were further identified by overlapping genes among AD and Longevity genes. They include the immune system including IL-3 and IL-13 (p = 7.64E-08), plasma lipoprotein assembly, remodeling and clearance (p < 4.02E-06), metabolism of fat-soluble vitamins (p = 1.96E-05). Thus, this study provides shared genetic hallmarks of aging, longevity, and AD backed up by statistical significance. We discuss significant genes involved in these pathways, including TP53, FOXO, Sumoylation, IL4, IL6, APOE, and CEPT, and suggest that mapping the gene network pathways provide a useful basis for further medical research, education, and community outreach.
“Novel Clinical Manifestations of Human Monkeypox Virus Infection and Current Therapeutic and Preventive Strategies: A Systematic Review “
Authors: Chenchula Santenna , Ghanta Mohan Krishna , Chavan Madhavrao , Amerneni Krishna Chaitanya , Padmavathi R , Gupta Rupesh 
Published: January 2023

AbstractThe escalating global monkeypox cases since early May 2022, acquired by the monkeypox virus (MPXV), a double-stranded DNA virus has been declared a public health emergency of international concern by the World Health Organization (WHO). Globally as of December 2022, the MPXV was transmitted to more than 100 countries with around 82,550 cases, among which 81577 cases from the 103 countries that are non-endemic to the MPXV with more than 50 deaths. The ripple effect of the Monkeypox outbreak in nonendemic countries globally could potentially bring significant challenges to worldwide health systems if the spread of the virus is not effectively controlled. In this urgent situation, only three antiviral drugs are in use against monkeypox infections and are not specific against monkeypox, hence the scientific communities across the world are in search to explore vaccines or therapeutic antiviral drugs selectively against the monkeypox virus. Here, in the present review, we discuss the clinical characteristics and treatment outcomes of the ongoing MPX outbreak of 2022 in nonendemic countries globally, from the published and grey literature in PubMed, Scopus and Google scholar. A total of 17 studies with 17,811 of MPX cases were found and included in the final qualitative analysis of the current systematic review.
The interplay between pre-season population susceptibility and the effectiveness of the rolled out vaccination control the timing and size of an emerging seasonal influenza wave in England
Authors: van Leeuwen E. , Panovska-Griffiths J. , Elgohari S. , Charlett A. , Watson C. 
Published: January 2023

1.AbstractRelaxing social distancing measures and reduced level of influenza over the last two seasons may lead to a winter 2022 influenza wave in England. We used an established model for influenza transmission and vaccination to evaluate the rolled out influenza immunisation programme over October to December 2022. Specifically, we explored how the interplay between pre-season population susceptibility and influenza vaccine efficacy control the timing and the size of a possible winter influenza wave. Our findings suggest that susceptibility affects the timing and the height of a potential influenza wave, with higher susceptibility leading to an earlier and larger influenza wave while vaccine efficacy controls the size of the peak of the influenza wave. With pre-season susceptibility higher than pre-COVID-19 levels, under the planned vaccine programme an early influenza epidemic wave is possible, its size dependent on vaccine effectiveness against the circulating strain. If pre-season susceptibility is low and similar to pre-COVID levels, the planned influenza vaccine programme with an effective vaccine could largely suppress a winter 2022 influenza outbreak in England.
Patient perspectives and hospital pay-for-performance: A qualitative study from Lebanon
Authors: Khalife Jade , Ekman Björn , Ammar Walid , El-Jardali Fadi , Halabi Abeer Al , Barakat Elise , Emmelin Maria 
Published: January 2023

AbstractBackgroundPatient perspectives have received increasing importance within health systems over the past four decades. Measures of patient experience and satisfaction are commonly used. However, these do not capture all the information available through patient engagement. An improved understanding of the various types of patient perspectives and the distinctions between them is needed. The lack of such knowledge limits the usefulness of including patient perspectives as components within pay-for-performance initiatives. This study was aimed to identify and explore patient perspectives on hospital care in Lebanon, and to describe how they relate to the national pay-for-performance initiative.MethodsWe conducted a qualitative study using focus group discussions with persons recently discharged after hospitalization under the coverage of the Lebanese Ministry of Public Health. This study was implemented in 2017 and involved 42 participants across eight focus groups. Qualitative content analysis was used to analyze the information provided by participants.ResultsFive overall themes supported by 17 categories were identified, capturing the meaning of the informants’ perspectives: health is everything; being turned into second class citizens; money and ‘wasta’ (personal connections) make all the difference; wanting to be treated with dignity and respect; and tolerating letdown, for the sake of right treatment. The most frequently prioritized statement in a ranking exercise regarding patient satisfaction was regular contact with one’s doctor.ConclusionsPatient perspectives include more than what is traditionally incorporated in measures of patient satisfaction and experience. Patient valuing of health and their perceptions on each of the health system, and access and quality of care should also be taken into account. Hospital pay-for-performance initiatives can be made more responsive through a broader consideration of these perspectives. More broadly, health systems would benefit from wider engagement of patients. We propose a framework relating patient perspectives to value-based healthcare and health system performance.
Joint estimation and imputation of variant functional effects using high throughput assay data
Authors: Yu Tian , Fife James D. , Adzhubey Ivan , Sherwood Richard , Cassa Christopher A. 
Published: January 2023

SummaryDeep mutational scanning assays enable the functional assessment of variants in high throughput. Phenotypic measurements from these assays are broadly concordant with clinical outcomes but are prone to noise at the individual variant level. We develop a framework to exploit related measurements within and across experimental assays to jointly estimate variant impact. Drawing from a large corpus of deep mutational scanning data, we collectively estimate the mean functional effect per AA residue position within each gene, normalize observed functional effects by substitution type, and make estimates for individual allelic variants with a pipeline called FUSE (FunctionalSubstitutionEstimation). FUSE improves the correlation of functional screening datasets covering the same variants, better separates estimated functional impacts for known pathogenic and benign variants (ClinVarBRCA1, p=2.24×10−51), and increases the number of variants for which predictions can be made (2,741 to 10,347) by inferring additional variant effects for substitutions not experimentally screened. For UK Biobank patients who carry a rare variant inTP53, FUSE significantly improves the separation of patients who develop cancer syndromes from those without cancer (p=1.77×10−6). These approaches promise to improve estimates of variant impact and broaden the utility of screening data generated from functional assays.Graphical AbstractHighlightsUses functional assay data collectively to improve the estimation of allelic variant effectsInfers the impact of variants not experimentally screened, broadening the utility of assaysImproves the discrimination of clinically actionable variants within ClinVarSignificantly separates patients at risk for cancer syndromes in the UK Biobank
Multi-scale transcriptome unveils spatial organisation and temporal dynamics ofBacillus subtilisbiofilms
Authors: Dergham Yasmine , Coq Dominique Le , Nicolas Pierre , Deschamps Julien , Huillet Eugénie , Sanchez-Vizuete Pilar , Hamze Kassem , Briandet Romain 
Published: January 2023

ABSTRACTBacillus subtilishas been extensively used to study the molecular mechanisms behind the development and dispersal of surface bacterial multicellular communities. Well-structured spatially organised communities (colony, pellicle, and submerged biofilm) share some similarities, but also display considerable differences at the structural, chemical and biological levels. To unveil the spatial transcriptional heterogeneity between the different communities, we analysed by RNA-seq nine spatio-physiological populations selected from planktonic and spatially organised communities. This led to a global landscape characterisation of gene expression profiles uncovering genes specifically expressed in each compartmental population. From this mesoscale analysis and using fluorescent transcriptional reporter fusions, 17 genes were selected and their patterns of expression reported at single cell scale with time-lapse confocal laser scanning microscopy (CLSM). Derived kymographs allowed to emphasise spectacular mosaic gene expression patterns within a biofilm. A special emphasis on oppositely regulated carbon metabolism genes (gapAandgapB) permitted to pinpoint the coexistence of spatially segregated bacteria under either glycolytic or gluconeogenic regime in a same biofilm population. Altogether, this study gives novel insights on the development and dispersal ofB. subtilissurface-associated communities.
A strongly improved assembly of the pearl millet reference genome using Oxford Nanopore long reads and optical mapping
Authors: Salson Marine , Orjuela Julie , Mariac Cédric , Zekraouï Leïla , Couderc Marie , Arribat Sandrine , Rodde Nathalie , Faye Adama , Kane Ndjido A. , Tranchant-Dubreuil Christine , Vigouroux Yves , Berthouly-Salazar Cécile 
Published: January 2023

AbstractPearl millet (Pennisetum glaucum(L.)) R. Br. syn.Cenchrus americanus(L.) Morrone) is an important crop in South Asia and sub-Saharan Africa which contributes to ensure food security. Its genome has an estimated size of 1.76 Gb and displays a high level of repetitiveness above 80%. A first assembly was previously obtained for the Tift 23D2B1-P1-P5 cultivar genotype using short-read sequencing technologies. This assembly is however incomplete and fragmented with around 200 Mb unplaced on chromosomes. We report here an improved quality assembly of the pearl millet Tift 23D2B1-P1-P5 cultivar genotype obtained with an approach combining Oxford Nanopore long reads and Bionano Genomics optical maps. This strategy allowed us to add around 200 Mb at the chromosome-level assembly. Moreover we strongly improved continuity in the order of the contigs and scaffolds wihtin the chromosomes, particularly in the centromeric regions. Notably, we added more than 100 Mb around the centromeric region on chromosome 7. This new assembly also displayed a higher gene completeness with a complete BUSO score of 98.4% using the Poales database. This more complete and higher quality assembly of the Tift 23D2B1-P1-P5 genotype now available to the community will help in the development of research on the role of structural variants, and more broadly in genomics studies and the breeding of pearl millet.
Myddosome clustering in IL-1 receptor signaling regulates the formation of an NF-kB activating signalosome
Authors: Cao Fakun , Deliz-Aguirre Rafael , Gerpott Fenja H. U. , Ziska Elke , Taylor Marcus J. 
Published: January 2023

AbstractSignaling pathways can produce digital invariant outputs and analog outputs that scale with the amount of stimulation. In IL-1 receptor (IL-1R) signaling both types of outputs require the Myddosome, a multi-protein complex. The Myddosome is required for polyubiquitin chain formation and NF-kB signaling. However, the ways in which these signals are spatially and temporally regulated to drive switch-like and proportional outcomes is not understood. We find that during IL-1R signaling, Myddosomes dynamically re-organize into large, multi-Myddosome clusters at the cell membrane. Blockade of Myddosome clustering using nanoscale extracellular barriers reduces NF-kB activation. We find that Myddosomes function as a scaffold that assembles an NF-kB signalosome consisting of E3-ubiquitin ligases TRAF6 and LUBAC, K63/M1-linked polyubiquitin chains, phospho-IKK, and phospho-p65. This signalosome preferentially assembles at regions of high Myddosome density, which enhances the recruitment of TRAF6 and LUBAC. Extracellular barriers that restrict Myddosome clustering perturbed the recruitment of both ligases. We found that LUBAC was especially sensitive to clustering with a sevenfold lower recruitment to single Myddosomes than clustered Myddosomes. This data reveals that the clustering behavior of Myddosome provides the basis for digital and analog IL-1R signaling.
Thermodynamic limitations on brain oxygen metabolism: physiological implications
Authors: Buxton Richard B. 
Published: January 2023

AbstractA recent hypothesis is that maintaining the brain tissue ratio of O2to CO2is critical for preserving the entropy increase available from oxidative metabolism of glucose, with a fall of that available entropy leading to a reduction of the phosphorylation potential and impairment of brain energy metabolism. The hypothesis suggests that physiological responses under different conditions can be understood as preserving tissue O2/CO2. To test this idea, a mathematical model of O2and CO2transport was used to calculate how well different physiological responses maintain tissue O2/CO2, showing good agreement with reported experimental measurements for increased neural activity, hypercapnia and hypoxia. The results highlight the importance of thinking about brain blood flow as a way to modulate tissue O2/CO2, rather than simply in terms of O2delivery to the capillary bed. The hypoxia modeling focused on humans at high altitude, including acclimatized lowlanders and adapted populations, with a primary finding that decreasing CO2by increasing ventilation rate is much more effective for preserving tissue O2/CO2than increasing blood hemoglobin content. The modeling provides a new framework and perspective for understanding how blood flow and other physiological factors support energy metabolism in the brain under a wide range of conditions.Key points summaryRecent thermodynamic modeling suggests that preserving the O2/CO2ratio in brain tissue is critical for preserving the entropy change available from the oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism.The hypothesis tested is that normal physiological responses (notably blood flow changes) often act to preserve this ratio under changing conditions.Using a detailed model to calculate tissue O2/CO2we found good agreement with the predictions of the hypothesis and reported experimental results during hypoxia, hypercapnia and increased oxygen metabolic rate in response to increased neural activity.For the hypoxia modeling we considered high altitude acclimatization and adaptation in humans, showing the critical role of reducing CO2in preserving tissue O2/CO2.The tissue O2/CO2hypothesis provides a useful perspective for understanding the function of observed physiological responses under different conditions in terms of preserving brain energy metabolism, although the mechanisms underlying these functions are not well understood.
RabbitVar: ultra-fast and accurate somatic small-variant calling on multi-core architectures
Authors: Zhang Hao , Song Honglei , Yin Zekun , Chang Qixin , Wei Yanjie , Niu Beifang , Schmidt Bertil , Liu Weiguo 
Published: January 2023

AbstractThe continuous development of next-generation sequencing (NGS) technology has led to extensive and frequent use of genomic analysis in cancer research. The associated production of large-scale NGS datasets establishes the need for high-precision somatic variant calling methods that are highly optimized on commonly used hardware platforms. We present RabbitVar (https://github.com/LeiHaoa/RabbitVar), a scalable variant caller that can detect small somatic variants from paired tumor/normal NGS data on modern multi-core CPUs. Our approach combines candidate-finding and machine-learning-based filtering strategies with optimized data structures and multi-threading to achieve both high accuracy and efficiency. We have compared the performance of RabbitVar to leading state-of-the-art callers (Strelka2, Mutect2, NeuSomatic, VarDict, VarScan2) on real-world HCC1395 breast cancer datasets under different sequencing conditions and contamination rates. The evaluation results demonstrate that RabbitVar achieves highly competitive F1-scores when calling SNVs. Moreover, when calling the more challenging indel variants, it consistently achieves the highest F1-scores. RabbitVar is able to process a paired tumor and normal whole human genome sequencing datasets with 80x depth in less than 20 minutes on a 48-core workstation outperforming all other tested variant callers in terms of efficiency.
Somatostatin-expressing neurons in the ventral tegmental area innervate specific forebrain regions and are involved in the stress response
Authors: Nagaeva Elina , Schäfer Annika , Linden Anni-Maija , Elsilä Lauri V. , Ryazantseva Maria , Umemori Juzoh , Egorova Ksenia , Korpi Esa R. 
Published: January 2023

AbstractExpanding knowledge about the cellular composition of subcortical brain regions demonstrates large heterogeneity and differences from the cortical architecture. Recently, we described three subtypes of somatostatin-expressing (Sst) neurons in the mouse ventral tegmental area (VTA) and showed their local inhibitory action on the neighbouring dopaminergic neurons (Nagaeva et al., 2020). Here, we report that VTA Sst neurons especially from the anterolateral part also project far outside the VTA and innervate several forebrain regions that are mainly involved in the regulation of emotional behaviour. Deletion of these VTA Sst neurons affected several behaviours and drug responses, such as home cage activity, sensitization of locomotor activity to morphine, fear conditioning responses, and reactions to inescapable stress of forced swimming, often in a sex-dependent manner. Together, these data demonstrate that VTA Sst neurons have selective projection targets, which are distinct from the main targets of VTA dopamine neurons and involved in the regulation of a variety of behaviours mostly associated with the stress response. This, makes Sst neurons a meaningful addition to the remote VTA circuit and stress-related neuronal network.
Mechanistic insight into substrate specificity of plant glucosinolate transporters
Authors: Kanstrup Christa , Wulff Nikolai , Peña-Varas Carlos , Jørgensen Morten Egevang , Bang-Sørensen Rose , Crocoll Christoph , Jørgensen Flemming Steen , Ramírez David , Dreyer Ingo , Mirza Osman , Nour-Eldin Hussam H. 
Published: January 2023

AbstractPlants depend on transport processes for correct allocation of specialized metabolites. This is important for optimal defense, avoidance of autotoxicity, connecting compartmented biosynthetic modules and more. Transport of a wide variety of specialized metabolites is mediated by transporters from the Nitrate and Peptide transporter Family (NPF), which belongs to the Major Facilitator Superfamily (MFS). However, the mechanism by which NPF members recognize and transport specialized metabolites remains unknown.Here we mutate eight residues to reciprocally swap the substrate-preference of two closely related glucosinolate transporters (GTRs). Seven of these residues assemble in a ring-like structure in all conformations of the transporters. We labeled the ring-like structure a selectivity filter and based on docking studies, we propose that the interaction between the selectivity filter and the glucosinolate side chain determines whether a given glucosinolate is recognized as a substrate. Besides partly explaining the distinct substrate preference of GTR1 (NPF2.10) and GTR3 (NPF2.9), this study proposes fundamental principles of substrate recognition in the NPF and establishes the GTR subclade as a novel model system for studying structure function relationships in the NPF.
RBM43 links adipose inflammation and energy expenditure through translational regulation of PGC1α
Authors: Dumesic Phillip A. , Wilensky Sarah E. , Bose Symanthika , Van Vranken Jonathan G. , Gygi Steven P. , Spiegelman Bruce M. 
Published: January 2023

ABSTRACTAdipose thermogenesis involves specialized mitochondrial function that counteracts metabolic disease through dissipation of chemical energy as heat. However, inflammation present in obese adipose tissue can impair oxidative metabolism. Here, we show that PGC1α, a key governor of mitochondrial biogenesis and thermogenesis, is negatively regulated at the level of mRNA translation by the little-known RNA-binding protein RBM43.Rbm43is expressed selectively in white adipose depots that have low thermogenic potential, and is induced by inflammatory cytokines. RBM43 suppresses mitochondrial and thermogenic gene expression in a PGC1α-dependent manner and its loss protects cells from cytokine-induced mitochondrial impairment. In mice, adipocyte-selectiveRbm43disruption increases PGC1α translation, resulting in mitochondrial biogenesis and adipose thermogenesis. These changes are accompanied by improvements in glucose homeostasis during diet-induced obesity that are independent of body weight. The action of RBM43 suggests a translational mechanism by which inflammatory signals associated with metabolic disease dampen mitochondrial function and thermogenesis.