bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication
Authors: Xie Ling , Sheehy Ryan N. , Xiong Yan , Muneer Adil , Wrobel John A. , Park Kwang-Su , Velez Julia , Liu Jing , Luo Yan-Jia , Li Ya-Dong , Quintanilla Luis , Li Yongyi , Xu Chongchong , Deshmukh Mohanish , Wen Zhexing , Jin Jian , Song Juan , Chen Xian 
Published: October 2023

AbstractCurrent amyloid beta-targeting approaches for Alzheimer’s disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects.One-Sentence Summary:A brain-penetrant inhibitor of G9a methylase blocks G9a translational mechanism to reverse Alzheimer’s disease related proteome for effective therapy.
Changes in sleep duration during the long-lasting COVID-19 pandemic: individual and regional disparities
Authors: Min Jieun , Oh Jieun , Lee Whanhee 
Published: October 2023

AbstractThe adequate quality and quantity of sleep are related to maintaining the immune system and mental well-being; therefore, it is necessary to evaluate sleep duration during COVID-19. This study aimed to investigate the changes in sleep duration during the long-lasting COVID-19 period (2020 and 2021) in South Korea, and to examine the individual and regional disparities. The study population comprised 1,143,460 adults aged ≥19 years who participated in the 2017– 2021 Korea Community Health Survey excluding those who did not respond to the daily sleep duration questionnaire. For statistical analysis, we first conducted a multiple regression model for 229 districts to estimate the district-specific changes in sleep duration. We then applied a meta-analysis to pool the 229 estimates and a meta-regression to examine the association between changes in sleep duration and regional characteristics. The sleep duration increased by 9.66 (95% CI: 8.53, 10.80) min in 2020 and 3.66 (95% CI: 2.09, 5.22) min in 2021 compared to the pre-pandemic period (2017–2019). The increase was more prominent in males, younger adults, employed individuals, and those with a high socioeconomic status compared to the general population. Communities with a higher proportion of apartments, lower normalized difference vegetation index in summer, and lower practice rate of moderate exercise were associated with a higher increase in sleep duration during the pandemic. The sleep duration increased during the COVID-19 pandemic, and the increase decreased as the COVID-19 lasted longer. The findings of our study highlight that preventive measures to manage sleep health during a pandemic should be framed in consideration of individual and regional characteristics.
Drivers of geographic patterns in outpatient antibiotic prescribing in the United States
Authors: Kissler Stephen M. , Roster Kirstin I. Oliveira , Petherbridge Rachel , Mehrotra Ateev , Barnett Michael L. , Grad Yonatan H. 
Published: October 2023

AbstractAntibiotic prescribing rates vary dramatically across regions in the United States, but the relative importance in prescribing practices versus per capita visit rates in driving this variation remain unclear. Quantifying their relative importance can aid in reducing antibiotic use. Using US medical claims data from 2015-2018 covering over 15 million privately insured adults, we conducted a regression analysis to estimate the relative contribution of outpatient visit rates and per-visit prescribing in explaining variation in outpatient antibiotic prescribing rates across metropolitan statistical areas. Variation in visit rates per capita explained more of the geographic variation in outpatient antibiotic prescribing rates than per-visit prescribing for conditions with high prescribing volume. Efforts to reduce antibiotic use may benefit from addressing the factors driving higher rates of outpatient visits, in addition to continued focus on stewardship.
A model for angiogenesis suppression via SERPINF1 in the surrounding pro-acinar microenvironment during human fetal pancreas development
Authors: Mehta Pratik Nailesh , Giardina Charles 
Published: October 2023

AbstractPancreas hormone-producing endocrine cell islets are integrated with the blood supply, whereas pancreatic digestive-enzyme producing acini are not. The functional result is that pancreatic acinar cells release their digestive enzymes into the ductal system and the duodenum to aid in digestion, while pancreatic hormone-producing endocrine cells release their hormones, such as insulin and glucagon, into the bloodstream. Despite this understanding, the mechanism for how acinar cells are free of vascularization is not completely clear. Based on an analysis of publicly available single cell RNA-sequencing data (GSE110154) of the human fetal pancreas during gestational weeks 12 through 22, a model is proposed that draws upon the anti-angiogenic properties of SERPINF1. This model envisions +PTF1A/+SOX9/+CPA1 pancreatic pro-acinar tip progenitor and +COL1A2/+PDGFRA pancreatic stromal fibroblast cell populations that surround the developing acini secreting SERPINF1 (PEDF) to inhibit angiogenesis and endothelial cell generation. This secretion could maintain an acinar microenvironment that is free from robust vascularization and integration of blood vessels as seen in mature pancreatic islet of Langerhans/endocrine cells.
Application of nanopore sequencing to identify antimicrobial resistance genes, mobile genetic elements and virulence factors in clinical isolates
Authors: Kimani Rachel , Musundi Sebastian , Wakaba Patrick , Mbogo David , Essuman Suliman , Kanoi Bernard N. , Gitaka Jesse 
Published: October 2023

AbstractThe global health challenge posed by the emergence of antibiotic resistance pathogen is further exacerbated in African countries by the indiscriminate use of antibiotics, poor surveillance and lack of stewardship programs. To address this issue, we employed the Oxford Nanopore Technologies (ONT) to sequence 17 clinical isolates from a referral hospital in Kenya. Our comprehensive bioinformatics approach facilitated the assembly, identification of sequence types and prediction of antimicrobial resistance genes, mobile genetic elements (plasmids and integrons) and virulence genes. Of the 17 isolates, five wereA. baumannii, fourE. coli, threeS. haemolyticus, three wereE. cloacae,whileS. aureusandE. faecaliswere single isolates. For the detection of AMR genes,A. baumanniiisolates harbored genes such asblaOXA-23which mediates resistance to carbapenems,E. coliandE. cloacaecarriedblaCTX-M-15which confers resistance to cephalosporins andS. haemolyticusharboredblaZ,responsible for resistance againstpenicillins.S. aureusco-habouredmecAandblaZ genes.In addition,, various other different AMR genes to chloramphenicol, macrolides, aminoglycosides, tetracycline were also observed. For plasmid replicons,E. colicarried the most number of plasmids and shared ColRNAI_1 and IncFIB(pB171)_1_pB171 withA. baumanniiand IncR_1 withE. cloacae.Many genes encoding various virulence factors includingfimA-Iand ompA, senBwere identified inE. coli, hlgA-Candhla/hly, hlb, hldinS. aureusandefaA,ebpA-CinE. faecalis.In conclusion, most isolates contained a combination of different AMR genes harbored in plasmids and integrons and virulence genes. This study provides significant information on genetic determinants of antibiotic resistant pathogens in clinical isolates and could assist in developing strategies that improve patient treatment.Author SummaryAntimicrobial resistance remains a major health challenge across the globe. The continued misuse and lack of proper monitoring has worsened the problem of antibiotic resistant infections. In this study, we sought to use nanopore sequencing to identify antibiotic resistance genes, mobile genetic elements and virulence factors from clinical isolates which showed resistance against commonly used antibiotics. We found the presence of resistance genes to multiple different antibiotics including beta-lactams, macrolides, tetracycline and aminoglycosides across multiple bacterial species. We also identified plasmid replicons and class I integrons which facilitate the spread of antimicrobial resistant genes. Furthermore, several virulence factors that help resistant bacteria to survive were identified. Overall, this study highlights the widespread issue of antibiotic resistance, factors contributing to its persistence in clinical isolates and utility of nanopore sequencing for monitoring genetic determinants of antimicrobial resistance.
Homologs of SD6 and ICE2 from rice may be involved in regulation of ABA in woody perennial buds
Authors: Shi Zhaowan , Pandey Sonika , Halaly-Basha Tamar , Galbraith David W. , Or Etti 
Published: October 2023

ABSTRACTThe availability of ABA, a central component in the regulation of the dormancy cycle in grapevine buds, is controlled by coordinated and opposite regulation of NCED and ABA8OX expression, as shown during natural dormancy release and following treatment with Hydrogen Cyanamide (HC). This implies the existence of a shared regulatory entity, which serves as an upstream switch.A molecular switch for integrated and opposite regulation of NCED and ABA8OX was recently described in rice, involving a pair of bHLH transcription factors (OsSD6-OsICE2) that directly regulate ABA8OX3 expression and indirectly regulate NCED2 expression, by direct regulation of the expression of the NCED repressor OsbHLH048.Here, we tested whether expression of theVitishomologs of the rice SD6 and ICE2 are regulated by dormancy release stimuli, and whether the direction of regulation agrees with that ofABA8OX.Treatment with two independent stimuli of bud break (HC and hypoxia), as well as natural dormancy release, resulted in upregulation of OsSD6 homologs and down regulation of OsICE2 homologs, in agreement with the rice model. In unexpected contrast, the homolog of OsbHLH048 was down-regulated.Our results suggest a grapevine model in which (1) the homologs ofOsSD6andOsICE2act as direct activators and repressors ofABA8OX3expression, as for rice, (2) they have opposed effects on the expression of an OsbHLH048 homolog, which serves as direct activator of NCED expression, as for Arabidopsis, and (3) together they act as a switch that allows removal of ABA repression, followed by meristem reactivation and bud break.HIGHLIGHTA molecular switch for integrated and opposite regulation of NCED and ABA8OX in rice seeds, operated by three bHLH transcription factors, is conserved in grapevine buds and regulates dormancy release
Noradrenergic alpha-2a Receptor Stimulation Enhances Prediction Error Signaling in Anterior Cingulate Cortex and Striatum
Authors: Hassani Seyed A. , Womelsdorf Thilo 
Published: October 2023

AbstractThe noradrenergic system is implicated to support behavioral flexibility by increasing exploration during periods of uncertainty and by enhancing working memory for goal-relevant stimuli. Possible sources mediating these pro-cognitive effects are α2A adrenoceptors (α2AR) in prefrontal cortex or the anterior cingulate cortex facilitating fronto-striatal learning processes. We tested this hypothesis by selectively stimulating α2ARs using Guanfacine during feature-based attentional set shifting in nonhuman primates. We found that α2A stimulation improved learning from errors and facilitates updating the target feature of an attentional set. Neural recordings in the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex (dlPFC), and the striatum showed that α2A stimulation selectively enhanced the neural representation of negative reward prediction errors in neurons of the ACC and of positive prediction errors in the striatum, but not in dlPFC. This modulation was accompanied by enhanced encoding of the feature and location of the attended target across the fronto-striatal network. Enhanced learning was paralleled by enhanced encoding of outcomes in putative fast-spiking interneurons in the ACC, dlPFC, and striatum but not in broad spiking cells, pointing to an interneuron mediated mechanism of α2AR action. These results illustrate that α2A receptors causally support the noradrenergic enhancement of updating attention sets through an enhancement of prediction error signaling in the ACC and the striatum.
The essential chaperone DNAJC17 activates HSP70 to coordinate RNA splicing and G2-M progression
Authors: Allegakoen David V. , Kwong Kristen , Morales Jacqueline , Bivona Trever G. , Sabnis Amit J. 
Published: October 2023

AbstractMolecular chaperones including the heat-shock protein 70-kilodalton (HSP70) family and the J-domain containing protein (JDP) co-chaperones maintain homeostatic balance in eukaryotic cells through regulation of the proteome. The expansive JDP family helps direct specific HSP70 functions, and yet loss of single JDP-encoding genes is widely tolerated by mammalian cells, suggesting a high degree of redundancy. By contrast, essential JDPs might carry out HSP70-independent functions or fill cell-context dependent, highly specialized roles within the proteostasis network.Using a genetic screen of JDPs in human cancer cell lines, we found the RNA recognition motif (RRM) containingDNAJC17to be pan-essential and investigated the contribution of its structural domains to biochemical and cellular function. We found that the RRM exerts an auto-inhibitory effect on the ability of DNAJC17 to allosterically activate ATP hydrolysis by HSP70. The J-domain, but neither the RRM nor a distal C-terminal alpha helix are required to rescue cell viability after loss of endogenousDNAJC17. Knockdown ofDNAJC17leads to relatively few conserved changes in the abundance of individual mRNAs, but instead deranges gene expression through exon skipping, primarily of genes involved in cell cycle progression. Concordant with cell viability experiments, the C-terminal portions ofDNAJC17are dispensable for restoring splicing and G2-M progression.Overall, our findings identify essential cellular JDPs and suggest that diversification in JDP structure extends the HSP70-JDP system to control divergent processes such as RNA splicing. Future investigations into the structural basis for auto-inhibition of the DNAJC17 J-domain and the molecular regulation of splicing by these components may provide insights on how conserved biochemical mechanisms can be programmed to fill unique, non-redundant cellular roles and broaden the scope of the proteostasis network.
fhl2bexpression ameliorates muscular dystrophy
Authors: Dennhag Nils , Kahsay Abraha , Nissen Itzel , Chermenina Maria , Nord Hanna , Liu Jiao , Arner Anders , Liu Jing-Xia , Backman Ludvig J , Remeseiro Silvia , von Hofsten Jonas , Domellöf Fatima Pedrosa 
Published: October 2023

AbstractIn muscular dystrophies, muscle fibers loose integrity and die, leading to significant suffering and a shorter life. Strikingly, the extraocular muscles (EOMs), controlling eye movements, are spared and function well despite the disease progression. Although EOMs have been shown to have important differences compared to body musculature the mechanisms underlying this inherent resistance to muscle dystrophies remain largely unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscle in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is upregulated in response to knockout ofdesmin,plectinandobscurin, intermediate filament proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression offhl2bcan partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy modelsapje, significantly improving their survival rate. Therefore,fhl2is a protective agent and a candidate target gene for therapy of muscle dystrophies.
Universal inverse modelling of point spread functions for SMLM localization and microscope characterization
Authors: Liu Sheng , Chen Jianwei , Hellgoth Jonas , Müller Lucas-Raphael , Ferdman Boris , Karras Christian , Xiao Dafei , Lidke Keith A. , Heintzmann Rainer , Shechtman Yoav , Li Yiming , Ries Jonas 
Published: October 2023

AbstractThe point spread function (PSF) of a microscope describes the image of a point emitter. Knowing the accurate PSF model is essential for various imaging tasks, including single molecule localization, aberration correction and deconvolution. Here we present uiPSF (universal inverse modelling of Point Spread Functions), a toolbox to infer accurate PSF models from microscopy data, using either image stacks of fluorescent beads or directly images of blinking fluorophores, the raw data in single molecule localization microscopy (SMLM). The resulting PSF model enables accurate 3D super-resolution imaging using SMLM. Additionally, uiPSF can be used to characterize and optimize a microscope system by quantifying the aberrations, including field-dependent aberrations, and resolutions. Our modular framework is applicable to a variety of microscope modalities and the PSF model incorporates system or sample specific characteristics, e.g., the bead size, depth dependent aberrations and transformations among channels. We demonstrate its application in single or multiple channels or large field-of-view SMLM systems, 4Pi-SMLM, and lattice light-sheet microscopes using either bead data or single molecule blinking data.
Tumor-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism
Authors: Agca Samet , Domaniku Waraich Aylin , Bilgic Sevval Nur , Sucuoglu Melis , Dag Meric , Dogan Sukru Anil , Kir Serkan 
Published: October 2023

SummaryTumor-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. We investigated muscle gene expression at single nucleus level in cachectic mice and revealed distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Notably, atrophy-related genes, includingAtrogin1,MuRF1andEda2rwere upregulated in these myonuclei, emphasizing their crucial role in muscle wasting. Activation of the Ectodysplasin A2 Receptor (EDA2R) pathway suppressed gene sets related to muscle contraction and oxidative metabolism, indicating its involvement in transcriptional reprogramming. Our study also highlighted the negative impact of tumors on oxidative metabolism in muscle tissue and their influence on the transcriptomes of mononuclear cells in skeletal muscle. These findings contribute to a deeper understanding of the molecular mechanisms underlying cancer cachexia.
A Protein Blueprint of the Diatom CO2-Fixing Organelle
Authors: Nam Onyou , Musial Sabina , Demulder Manon , McKenzie Caroline , Dowle Adam , Dowson Matthew , Barrett James , Blaza James N. , Engel Benjamin D. , Mackinder Luke C. M. 
Published: October 2023

AbstractDiatoms are central to the global carbon cycle. At the heart of diatom carbon fixation is an overlooked organelle called the pyrenoid, where concentrated CO2is delivered to densely packed Rubisco. Diatom pyrenoids fix approximately one-fifth of global CO2, but virtually nothing is known about this organelle in diatoms. Using large-scale fluorescence protein tagging and affinity purification-mass spectrometry, we generate a high-confidence spatially-defined protein-protein interaction network for the diatom pyrenoid. Within our pyrenoid interaction network are 10 proteins with no known function. We show that six of these form a static shell encapsulating the Rubisco matrix of the pyrenoid, with the shell critical for pyrenoid structural integrity, shape, and function. Although not conserved at a sequence level, the diatom pyrenoid shares some architectural similarities to prokaryotic carboxysomes. Collectively, our results support the convergent evolution of pyrenoids across the two main plastid lineages and uncover a major structural and functional component of global CO2fixation.
An improved high-dimensional Kriging modeling method utilizing maximal information coefficient
Authors: Zhai Qiangqiang , Liu Zhao , Song Zhouzhou , Zhu Ping 
Published: October 2023

PurposeKriging surrogate model has demonstrated a powerful ability to be applied to a variety of engineering challenges by emulating time-consuming simulations. However, when it comes to problems with high-dimensional input variables, it may be difficult to obtain a model with high accuracy and efficiency due to the curse of dimensionality. To meet this challenge, an improved high-dimensional Kriging modeling method based on maximal information coefficient (MIC) is developed in this work.Design/methodology/approachThe hyperparameter domain is first derived and the dataset of hyperparameter and likelihood function is collected by Latin Hypercube Sampling. MIC values are innovatively calculated from the dataset and used as prior knowledge for optimizing hyperparameters. Then, an auxiliary parameter is introduced to establish the relationship between MIC values and hyperparameters. Next, the hyperparameters are obtained by transforming the optimized auxiliary parameter. Finally, to further improve the modeling accuracy, a novel local optimization step is performed to discover more suitable hyperparameters.FindingsThe proposed method is then applied to five representative mathematical functions with dimensions ranging from 20 to 100 and an engineering case with 30 design variables.Originality/valueThe results show that the proposed high-dimensional Kriging modeling method can obtain more accurate results than the other three methods, and it has an acceptable modeling efficiency. Moreover, the proposed method is also suitable for high-dimensional problems with limited sample points.