bluuebunny/crossref_metadata_2025_split huggingface dataset:
A force-sensitive adhesion GPCR is indispensable in normal equilibrioception
Authors: Yang Zhao , Zhou Shu-Hua , Zhang Qi-Yue , Song Zhi-Chen , Liu Wen-Wen , Sun Yu , Wang Ming-Wei , Fu Xiao-Long , Zhu Kong-Kai , Guan Ying , Qi Jie-Yu , Wang Xiao-Hui , Sun Yu-Nan , Lu Yan , Ping Yu-Qi , Xi Yue-Tong , Xu Zhi-Gang , Xiong Wei , Qin Wei , Yang Wei , Yi Fan , Yu Xiao , Chai Ren-Jie , Sun Jin-Peng 
Published: October 2023

AbstractEquilibrioception is essential for the perception and navigation of mammals in the three-dimensional world. A rapid mechanoelectrical transduction (MET) response in vestibular hair cells plays a critical role in positional and motional perception. Here, we identified that the G protein-coupled receptor LPHN2/ADGRL2, which is expressed in the apical membrane of utricular hair cells, is required for maintenance of normal balance. Hair cell-specific Lphn2 deficiency in mice impaired both balance behaviors and MET responses. Functional analyses usingPou4f3-CreER+/-;Lphn2fl/flmice and LPHN2-specific inhibitors revealed that LPHN2 regulated the tip link-independent MET current at the apical surface of the utricular hair cell by converting force stimuli into transmembrane channel-like protein 1 (TMC1) activity. Force sensation by LPHN2 also induced glutamate release and calcium signaling in utricular hair cells. Reintroduction of LPHN2 into the hair cells of Lphn2-deficient mice restored the vestibular functions and MET responses. Our data suggest an indispensable role for a mechanosensitive GPCR in equilibrioception.
Chemoproteomics identifies proteoform-selective caspase-2 inhibitors
Authors: Castellón José O. , Ofori Samuel , Armenta Ernest , Burton Nikolas , Boatner Lisa M. , Takayoshi Evan E. , Faragalla Marina , Zhou Annie , Tran Ky , Shek Jeremy , Yan Tianyang , Desai Heta S. , Backus Keriann M. 
Published: October 2023

ABSTRACTCaspases are a highly conserved family of cysteine-aspartyl proteases known for their essential roles in regulating apoptosis, inflammation, cell differentiation, and proliferation. Complementary to genetic approaches, small-molecule probes have emerged as useful tools for modulating caspase activity. However, due to the high sequence and structure homology of all twelve human caspases, achieving selectivity remains a central challenge for caspase-directed small-molecule inhibitor development efforts. Here, using mass spectrometry-based chemoproteomics, we first identify a highly reactive non-catalytic cysteine that is unique to caspase-2. By combining both gel-based activity-based protein profiling (ABPP) and atobacco etch virus(TEV) protease activation assay, we then identify covalent lead compounds that react preferentially with this cysteine and afford a complete blockade of caspase-2 activity. Inhibitory activity is restricted to the zymogen or precursor form of monomeric caspase-2. Focused analogue synthesis combined with chemoproteomic target engagement analysis in cellular lysates and in cells yielded both pan-caspase reactive molecules and caspase-2 selective lead compounds together with a structurally matched inactive control. Application of this focused set of tool compounds to stratify caspase contributions to initiation of intrinsic apoptosis, supports compensatory caspase-9 activity in the context of caspase-2 inactivation. More broadly, our study highlights future opportunities for the development of proteoform-selective caspase inhibitors that target non-conserved and non-catalytic cysteine residues.
Cortico-thalamic communication for action coordination in a skilled motor sequence
Authors: Li Yi , An Xu , Mulcahey Patrick J. , Qian Yongjun , Xu X. Hermione , Zhao Shengli , Mohan Hemanth , Suryanarayana Shreyas M. , Bachschmid-Romano Ludovica , Brunel Nicolas , Whishaw Ian Q. , Huang Z. Josh 
Published: October 2023

SUMMARYThe coordination of forelimb and orofacial movements to compose an ethological reach-to-consume behavior likely involves neural communication across brain regions. Leveraging wide-field imaging and photo-inhibition to survey across the cortex, we identified a cortical network and a high-order motor area (MOs-c), which coordinate action progression in a mouse reach-and-withdraw-to-drink (RWD) behavior. Electrophysiology and photo-inhibition across multiple projection neuron types within the MOs-c revealed differential contributions of pyramidal tract and corticothalamic (CTMOs) output channels to action progression and hand-mouth coordination. Notably, CTMOsdisplay sustained firing throughout RWD sequence and selectively enhance RWD-relevant activity in postsynaptic thalamus neurons, which also contribute to action coordination. CTMOsreceive converging monosynaptic inputs from forelimb and orofacial sensorimotor areas and are reciprocally connected to thalamic neurons, which project back to the cortical network. Therefore, motor cortex corticothalamic channel may selectively amplify the thalamic integration of cortical and subcortical sensorimotor streams to coordinate a skilled motor sequence.
Systematic discovery of gene-environment interactions underlying the human plasma proteome in UK Biobank
Authors: Hillary Robert F. , Gadd Danni A. , Kuncheva Zhana , Mangelis Tasos , Lin Tinchi , Ferber Kyle , McLaughlin Helen , Runz Heiko ,   Biogen Biobank Team, Marioni Riccardo E. , Foley Christopher N. , Sun Benjamin B. 
Published: October 2023

AbstractUnderstanding how gene-environment interactions (GEIs) influence the circulating proteome could aid in biomarker discovery and validation. The presence of GEIs can be inferred from single nucleotide polymorphisms that associate with phenotypic variability - termed variance quantitative trait loci (vQTLs). Here, vQTL association studies are performed on plasma levels of 1,468 proteins in 53,752 UK Biobank participants. A set of 683 independent vQTLs are identified across 571 proteins, all of which are newly discovered. They include 65 variants that lack conventional additive main effects on protein levels. Over 1,400 GEIs are identified between 142 proteins and 101 lifestyle and metabolic exposures. GEI analyses uncover biological mechanisms that explain why 13/65 vQTL-only sites lack corresponding main effects. Stratified analyses also highlight how age, sex and genotype can interact to modify relationships between biomarkers and health-related traits. This study establishes the most comprehensive database yet of vQTLs and GEIs for the human proteome.
Analysis of Global Ischemic Heart Disease Burden from Multiple Perspectives
Authors: Wang Lian , Yan Xisheng , Xu Zhengwen 
Published: October 2023

AbstractBackgroundIschemic heart disease (IHD) is a prevalent cardiovascular condition that poses a significant risk to human health. It has become essential to update the global prevalence, incidence, and mortality of IHD to examine secular trends.MethodsThe prevalence, incidence, death rates, and disability-adjusted life years (DALYs) of IHD were obtained from the Global Burden of Disease Study 2019 to assess the disease burden. We used joinpoint regression analysis to detect temporal changes and estimate the annual percent of change (APC) of each trend segment. The annual percentage change (EAPC) to access the temporal trends of the disease burden of IHD. Additionally, an analysis of the associated risk factors for IHD was conducted.ResultsThe global number of IHD prevalence cases has increased from 96.90 million to 197.22 million, along with an increase in incidence, death, and DALYs from 1990 to 2019. After adjusting for age standardization, all indicators have shown a decrease. The decline was more pronounced among females. The number of IHD cases increased with age. In 1990 and 2019, the highest age-standardized prevalence rate (ASPR) of IHD was observed in North Africa, the Arabian Peninsula, and surrounding countries. The ASPR and age-standardized incidence rate (ASIR) of IHD were highest in low-middle SDI regions. High systolic blood pressure was the main driving force for IHD.ConclusionsIHD has shown a decline in morbidity and mortality worldwide, but is on the rise in some less developed regions. The risk of incidence and death from IHD is higher in males. Paying more attention to the occurrence of IHD in the elderly is key to prevention. There exists a strong correlation between social development and the rates of morbidity and mortality associated with IHD. The inequity in global health is especially apparent in the context of this disease.
Effects of Different Intensity of Work Physical Activity on Sleep Disorder in Patients with Cholesterol
Authors: Cao Yiwen , Feng Rui 
Published: October 2023

AbstractBackgroundHigh cholesterol level is an important risk factor for cardiovascular disease. We believe that it is important to improve sleep disorders in patients with hyperlipidemia by exploring the effects of different intensities of physical activity on patients with hyperlipidemia.ObjectiveThe purpose of this study is to explore the relationship between sleep disorder and different intensity of work physical activity in patients with high cholesterol.Method and MaterialsThis study used a randomly selected American population from the National Health and Nutrition Survey (NHANES) from 2017 to 2018 as the survey sample, consisting of 1515 individuals (770 males and 745 females, with an average age of 60.53 ± 14.232 years). The Categorical variable uses the Chi-squared test, and the measurement variable uses the rank sum test to calculate the test statistics, which is considered statistically significant (two-sided test) with P<0.05. After single factor analysis, we take physical activity at work as independent variable, take statistically significant variables in Demography (gender, race, marital status, income poverty ratio, physical activity, current health status) as covariates, and take sleep disorder as dependent variable to conduct binary logistic regression analysis.ResultsAfter excluding all the confounding factors, there was a significant correlation between work physical activity and sleep disorder (P<0.001), and the OR was 1.251 (95% Cl: 1.096-1.429).ConclusionPhysical activity at work is a risk factor for sleep disorder in patients with high cholesterol, and the increased risk of sleep disorder caused by intense physical activity at work is particularly obvious.
Online trend estimation and detection of trend deviations in sub-sewershed time series of SARS-CoV-2 RNA measured in wastewater
Authors: Ensor Katherine B. , Schedler Julia , Sun Thomas , Schneider Rebecca , Mulenga Anthony , Wu Jingjing , Stadler Lauren B. , Hopkins Loren 
Published: October 2023

AbstractWastewater surveillance has proven a key public health tool to understand a wide range of community health diseases and has proven to be especially critical to health departments throughout the SARS CoV-2 pandemic. The size of the population served by a wastewater treatment plant (WWTP) may limit the targeted insight about community disease dynamics. To investigate this concern, samples of wastewater were obtained at lift stations upstream of WWTPs within the sewer network. First, an online, semi-automatic time series model is fitted to the weekly measurements of WWTP samples to estimate the viral trend for the community and compared to the time series observations from the lift stations. Second, deviations from the WWTP trend are identified using an Exponentially Weighted Moving Average (EWMA) control chart. The analysis reveals that the lift stations display slightly different dynamics than the larger WWTP, highlighting the more granular insight gleaned from sampling sites which represent smaller populations. Discussion focuses on the use of our methods to support rapid public health decision-making based on additional, targeted samples in times of concern.
Cumulative Remnant Cholesterol as a causal risk factor for Ischemic Heart Disease: A Prospective Cohort Study
Authors: Zhao Xuemei , Wang Yifei , Li Wei , Gao Haibo , Wu Haotian , Yu Jiaxin , Wang Guiping , Wu Shouling , Liu Xiaokun 
Published: October 2023

AbstractBackgroundWhile previous studies have established a significant correlation between baseline remnant cholesterol (RC) and ischemic heart disease (IHD), the enduring impact of RC on incident IHD remains to be elucidated. This study aimed to investigate the association between cumulative remnant cholesterol(cumRC) and IHD susceptibility.MethodsParticipating from the Kailuan Study (2006-2010) were enrolled, excluding those with prior myocardial infarction, coronary artery revascularization and cancer across three consecutive examinations. The cumRC derived by multiplying the average RC with the interval between the two consecutive assessments. Participants were segmented into quartiles based on cumRC levels: Q1 (cumRC<2.69mmol/l); Q2 (2.69≤cumRC<4.04mmol/l); Q3(4.04≤cumRC<5.65mmol/l) and Q4 (cumRC≥5.65mmol/l). The correlation between cumRC and IHD risk was ascertained by using multivariable Cox proportional hazard models.ResultThe analysis encompassed 42,639 participants. Over an average tracking period of 9.97 years, 1,205 instances of IHD were identified. IHD susceptibility augmented with rising cumRC quartiles. After adjusting for potential confounders, the hazard ratios for IHD events were 1.06 (0.88-1.29) for Q2, 1.30 (1.08-1.56) for Q3 and 1.69 (1.42-2.01) for Q4, relative to Q1. Elevated cumRC was significantly associated with a heightened IHD risk, a trend consistent in both subgroup and sensitivity analyses.ConclusionElevated cumRC significantly correlates with a higher risk of IHD, suggesting that consistent monitoring and regulation of RC might be instrumental in IHD prevention.
Turn-On Protein Switches for Controlling Actin Binding in Cells
Authors: Effiong Unyime M. , Khairandish Hannah , Ramirez-Velez Isabela , Wang Yanran , Belardi Brian 
Published: October 2023

AbstractWithin a shared cytoplasm, filamentous actin (F-actin) plays numerous and critical roles across the cell body. Cells rely on actin-binding proteins (ABPs) to organize F-actin and to integrate its polymeric characteristics into diverse cellular processes. Yet, the multitude of ABPs that engage with and shape F-actin make studying a single ABP’s influence on cellular activities a significant challenge. Moreover, without a means of manipulating actin-binding subcellularly, harnessing the F-actin cytoskeleton for synthetic biology purposes remains elusive. Here, we describe a suite of designed proteins, Controllable Actin-binding Switch Tools (CASTs), whose actin-binding behavior can be controlled with external stimuli. CASTs were developed that respond to different external inputs, providing options for turn-on kinetics and enabling orthogonality. Being genetically encoded, we show that CASTs can be inserted into native protein sequences to control F-actin association locally and engineered into new structures to control cell and tissue shape and behavior.
Biosynthesis- and Metabolomics-guided discovery of antimicrobial cyclopeptides against drug-resistant clinical isolates
Authors: Cheng Zhuo , He Bei-Bei , Lei Kangfan , Gao Ying , Shi Yuqi , Zhong Zheng , Liu Hongyan , Liu Runze , Zhang Haili , Wu Song , Zhang Wenxuan , Tang Xiaoyu , Li Yong-Xin 
Published: October 2023

AbstractAntimicrobial resistance remains a significant global threat, contributing significantly to mortality rates worldwide. Ribosomally synthesized and post-translationally modified peptides (RiPPs) have emerged as a promising source of novel peptide antibiotics due to their diverse chemical structures. Here, we reported the discovery of new Avi(Me)Cys-containing cyclopeptide antibiotics through a synergistic approach that combines rule-based genome mining, automated metabolomic analysis, and heterologous expression. We first bioinformatically identified 1,172 RiPP biosynthetic gene clusters (BGCs) responsible for Avi(Me)Cys-containing cyclopeptides from a vast pool of over 50,000 bacterial genomes. Subsequently, we successfully established the connection between three newly identified BGCs and the synthesis of five new peptide antibiotics. Notably, massatide A displayed excellent activity against a spectrum of gram-positive pathogens, including drug-resistant clinical isolates like linezolid-resistantS. aureusand methicillin-resistantS. aureus, with a minimum inhibitory concentration (MIC) of 0.25 μg/mL. The remarkable performance of massatide A in an animal infection model, coupled with a low risk of resistance and favorable safety profile, positions it as a promising candidate for antibiotic development. Our study highlights the potential of Avi(Me)Cys-containing cyclopeptides in expanding the arsenal of antibiotics against multi-drug-resistant bacteria, offering promising drug leads in the ongoing battle against infectious diseases.
Is developmental plasticity triggered by DNA methylation changes in the invasive cane toad (Rhinella marina)?
Authors: Yagound Boris , Sarma Roshmi R. , Edwards Richard J. , Richardson Mark F. , Lopez Carlos M. Rodriguez , Crossland Michael R. , Brown Gregory P. , DeVore Jayna L. , Shine Richard , Rollins Lee A. 
Published: October 2023

AbstractMany organisms can adjust their development according to environmental conditions, including the presence of conspecifics. Although this developmental plasticity is common in amphibians, its underlying molecular mechanisms remain largely unknown. Exposure during development to either ‘cannibal cues’ from older conspecifics, or ‘alarm cues’ from injured conspecifics, causes reduced growth and survival in cane toad (Rhinella marina) tadpoles. Epigenetic modifications, such as changes in DNA methylation patterns, are a plausible mechanism underlying these developmental plastic responses. Here we tested this hypothesis, and asked whether cannibal cues and alarm cues trigger the same DNA methylation changes in developing cane toads. We found that exposure to both cannibal cues and alarm cues induced local changes in DNA methylation patterns. These DNA methylation changes affected genes putatively involved in developmental processes, but in different genomic regions for different conspecific-derived cues. Genetic background explained most of the epigenetic variation among individuals. Overall, the molecular mechanisms triggered by exposure to cannibal cues seem to differ from those triggered by alarm cues. Studies linking epigenetic modifications to transcriptional activity are needed to clarify the proximate mechanisms that regulate developmental plasticity in cane toads.
AToxoplasma gondiiO-glycosyltransferase that modulates bradyzoite cyst wall rigidity is structurally and functionally distinct from host homologues
Authors: Kumar Pranav , Tomita Tadakimi , Gerken Thomas A. , Ballard Collin J. , Lee Yong Sok , Weiss Louis M. , Samara Nadine L. 
Published: October 2023

AbstractInfection with the Apicomplexan protozoanToxoplasma gondiican be life-threatening in immunocompromised hosts. Transmission frequently occurs through the oral ingestion ofT. gondiibradyzoite cysts, which transition to tachyzoites, disseminate, and then form cysts containing bradyzoites in the central nervous system, resulting in latent infection. There are currently no effective treatments to cure latent infection. Bradyzoites are encapsulated by a cyst wall that is critical for immune evasion, survival, and transmission. Cyst wall rigidity is influenced by the O-glycosylation of the mucin domain of the cyst wall protein CST1 by mucin-type O-glycosyltransferases (GalNAc-Ts). Here, we report the first structures of a protozoan GalNAc-T,T.gondii-GalNAc-T3 in the apo state and in complex with glycopeptide substrates. The structures reveal features that are strictly conserved in Apicomplexan homologues ofT.gondii-GalNAc-T3, including a unique 2ndmetal binding site that is coupled to substrate binding and enzymatic activityin vitroand cyst wall O-glycosylation inT. gondii. Additional structural features illustrate the divergence of GalNAc-Ts from parasite to host and highlight multiple druggable sites inT.gondii-GalNAc-T3 and its homologues in Apicomplexa that are responsible for a wide range of parasitic diseases.
KIF1C activates and extends dynein movement through the FHF cargo adaptor
Authors: Ali Ferdos Abid , Zwetsloot Alexander J. , Stone Caroline E. , Morgan Tomos E. , Wademan Richard F. , Carter Andrew P. , Straube Anne 
Published: October 2023

ABSTRACTCellular cargos move bidirectionally on microtubules due to the presence of opposite polarity motors dynein and kinesin. Many studies show these motors are co-dependent, whereby one requires the activity of the other, although the mechanism is unknown. Here, using in vitro motility assays, we show that the kinesin-3 KIF1C acts both as an activator and a processivity factor for dynein. Activation only requires a fragment of the non-motor tail of KIF1C (KIF1C-stalk) to bind the cargo adaptor HOOK3. Cryo-EM, crosslinking mass spectrometry and AlphaFold2 predictions reveal this binding site to be separate from that of two constitutive factors (FTS and FHIP), which link HOOK3 to small G-proteins on cargos. We provide a structural model for how the FTS-HOOK3-FHIP1B (FHF) complex is auto-inhibited and explain how the KIF1C-stalk relieves this inhibition. Collectively, our work provides a molecular explanation for co-dependency by revealing that the mutual activation of dynein and kinesin is mediated through their shared adaptor. Many adaptors bind both dynein and kinesins, suggesting this mechanism could be generalised to other bidirectional complexes.
RpoS activates formation ofSalmonellaTyphi biofilms and drives persistence in the gall bladder
Authors: Desai Stuti K. , Zhou Yiyang , Dilawari Rahul , Routh Andrew L. , Popov Vsevolod , Kenney Linda J. 
Published: October 2023

AbstractThe development of strategies for targeting the asymptomatic carriage ofSalmonellaTyphi in chronic typhoid patients has suffered owing to our basic lack of understanding of the molecular mechanisms that enable the formation ofS.Typhi biofilms. Traditionally, studies have relied on cholesterol-attached biofilms formed by a closely related serovar, Typhimurium, to mimic multicellular Typhi communities formed on human gallstones. In long-term infections,S.Typhi adopts the biofilm lifestyle to persist in vivo and survive in the carrier state, ultimately leading to the spread of infections via the fecal-oral route of transmission. In the present work, we studiedS.Typhi biofilms directly, applied targeted as well as genome-wide genetic approaches to uncover unique biofilm components that do not conform to the CsgD-dependent pathway established inS.Typhimurium. We undertook a genome-wideTn5mutation screen in H58, a clinically relevant multidrug resistance strain ofS.Typhi, in gallstone-mimicking conditions. We generated New Generation Sequencing libraries based on the ClickSeq technology to identify the key regulators, IraP and RpoS, and the matrix components Sth fimbriae, Vi capsule and lipopolysaccharide. We discovered that the starvation sigma factor, RpoS, was required for the transcriptional activation of matrix-encoding genes in vitro, and forS.Typhi colonization in persistent infections in vivo, using a heterologous fish larval model. AnrpoSnull mutant failed to colonize the gall bladder in chronic zebrafish infections. Overall, our work uncovered a novel RpoS-driven, CsgD-independent paradigm for the formation of cholesterol-attached Typhi biofilms, and emphasized the role(s) of stress signaling pathways for adaptation in chronic infections. Our identification of the biofilm regulators inS.Typhi paves the way for the development of drugs against typhoid carriage, which will ultimately control the increased incidence of gall bladder cancer in typhoid carriers.