bluuebunny/crossref_metadata_2025 huggingface dataset:
A near-complete telomere-to-telomere genome assembly forBatrachochytrium dendrobatidisGPL JEL423 reveals a CBM18 gene family expansion and a M36 metalloprotease gene family contraction
Authors: Helmstetter Nicolas , Harrison Keith , Greggory Jack , Harrison Jamie , Ballou Elizabeth , Farrer Rhys A.
Published: October 2024

Batrachochytrium dendrobatidis(Bd) is responsible for mass extinctions and extirpations of amphibians, mainly driven by the Global Panzootic Lineage (BdGPL).BdGPL isolate JEL423 is a commonly used reference strain in studies exploring the evolution, epidemiology and pathogenicity of chytrid pathogens. These studies have been hampered by the fragmented, erroneous and incompleteB. dendrobatidisJEL423 genome assembly, which includes long stretches of ambiguous positions, and poorly resolved telomeric regions. Here we present and describe a substantially improved, near telomere-to-telomere genome assembly and gene annotation forB. dendrobatidisJEL423. Our new assembly is 24.5 Mb in length, ∼800 kb longer than the previously published assembly for this organism, comprising 18 nuclear scaffolds and 2 mitochondrial scaffolds and including an extra 839 kb of repetitive sequence. We discovered that the patterns of aneuploidy inB. dendrobatidisJEL423 have remained stable over approximately 5 years. We found that our updated assembly encodes fewer than half the number of M36 metalloprotease genes predicted in the previous assembly. In contrast, members of the crinkling and necrosis gene family were found in similar numbers to the previous assembly. We also identified a more extensive carbohydrate binding module 18 gene family than previously observed. We anticipate our findings, and the updated genome assembly will be a useful tool for further investigation of the genome evolution of the pathogenic chytrids.

Author Summary

B. dendrobatidisis a fungus that has been implicated in the extinctions and declines of dozens of amphibians globally. Here we describe a new genome assembly for the commonly usedB. dendrobatidisisolate JEL423, which is a substantial improvement from the previously used assembly. Compared with the previous assembly, we reveal that some gene families (such as carbohydrate binding module 18 genes) are more expanded than previously recognised, while others (such as the M36 metalloproteases) are more contracted than previously recognised. Our new genome assembly will be useful for future work exploring the pathogenicity, epidemiology and evolution of chytrid fungi.
MEDIAL FRONTAL THETA (MFT) AS A PREDICTOR OF ANXIETY SENSITIVITY TREATMENT RESPONSE
Authors: Ellis Jessica , Mello Glenda , Butler Devin , Schmidt N. B. , Bernat Edward
Published: October 2024

Despite various interventions for anxiety disorders, effects can take months and many individuals do not respond. Activity in the anterior cingulate cortex is a consistent predictor of treatment outcomes, and can be measured by medial frontal theta (MFT) event-related potentials. This study used task-based electroencephalography and MFT to predict anxiety sensitivity treatment response at mid-treatment, 1-week post-treatment, and 6 months post-treatment. Results indicated that lower medial to lateral prefrontal theta phase synchrony was associated with greater symptom improvement. This work represents a novel finding that may contribute to the improvement in treatment efficacy by serving as a target for future interventions and individualized treatment selection.
Dual-function logic gates based on CRISPRi
Authors: Yao Zhiwu , Guo Shaobin
Published: October 2024

Developing logic gate circuits that are programmable and reliable for specific functions is a central goal in synthetic biology. Traditional synthetic circuits often rely on protein regulators, which face scalability and resource burden limitations. To overcome these challenges, we introduce a novel approach utilizing dual-function and multi-level logic gates based on the CRISPRi system with dCas9 and sgRNA. This method, implemented in an in vitro transcription system, enables the rapid design and validation of complex logic gates. Our dual-function and multi-level design strategies achieve robust functionality in NOR, NAND, AND, and OR gates, allowing different logic outputs by altering only the inputs while reusing all other modules. This showcases significant advancements in efficiency and scalability for synthetic circuit construction. This work reduces development time and simplifies circuit design, paving the way for more efficient synthetic biology applications.
Auxin-salicylic acid seesaw regulates the age-dependent balance between plant growth and herbivore defense
Authors: Han Wen-Hao , Zhang Feng-Bin , Ji Shun-Xia , Liang Kai-Lu , Wang Jun-Xia , Fan Xiao-Ping , Liu Shu-Sheng , Wang Xiao-Wei
Published: October 2024

Plants must fine-tune their needs for growth and defense. According to the Plant Vigor Hypothesis, younger, more vigorous plants tend to be more susceptible to herbivores compared to older, mature plants, yet the molecular mechanisms underlying this dynamic remain elusive. Here, we uncover a hormonal crosstalk framework that orchestrates the age-related balance between plant growth and herbivore defense. We demonstrate that the accumulation of salicylic acid (SA), synthesized byNicotiana benthamianaphenylalanine ammonia-lyase 6 (NbPAL6), dictates insect resistance in adult plants. The expression ofNbPAL6is driven by the key transcription factor, NbMYB42, which is regulated by two interacting auxin response factors, NbARF18La/b. In juvenile plants, higher auxin levels activateNbmiR160c, a microRNA that simultaneously silencesNbARF18La/b, subsequently reducingNbMYB42expression, lowering SA accumulation, and thus weakening herbivore defense. Furthermore, excessive SA accumulation in juvenile plants enhances defense but antagonizes auxin signaling, impairing early growth. Our findings suggest a seesaw-like model that balances growth and herbivore defense depending on the plant’s developmental stage.
A unified framework for hydromechanical signaling: Do plant signals go with the flow?
Authors: Bacheva Vesna , Rockwell Fulton , Salmon Jean-Baptiste , Woodson Jesse , Frank Margaret , Stroock Abraham
Published: October 2024

Local wounding in plants triggers signals that travel locally within the wounded leaf or systemically through the vasculature to distal leaves. The transmission mechanisms of this ubiquitous class of signals remain poorly understood. Here, we develop a unifying framework based on poroelastic dynamics to study two coupled biophysical processes – propagation of pressure changes and transmission of chemical elicitors via mass flows driven by these pressure changes – as potential mechanisms for the initiation and propagation of wound-induced signals. We show that rapid pressure changes in the xylem can transmit mechanical information across the plant, while their coupling with neighboring non-vascular tissue drives swelling and mass flow that can transport chemical elicitors to distal leaves. We confront our model predictions with signaling dynamics measurements in several species, and show that the poroelastic model captures observed mechanical, biochemical, and electrophysiological signals. This framework provides a valuable foundation for assessing mechanisms of signal transmission and for designing future experiments to elucidate factors involved in signal initiation, propagation, and target elicitation.
Genetically-Encoded Fluorescence Barcodes for Single-Cell Analysis
Authors: Lu Xiaoming , Pritko Daniel J , Abravanel Megan E , Huggins Jonah R , Ogunleye Feranmi , Biswas Tirthankar , Ashy Katia C , Woods Semaj K , Livingston Mariclaire WT , Blenner Mark , Birtwistle Marc R
Published: October 2024

Genetically-encoded, single-cell barcodes are broadly useful for experimental tasks such as lineage tracing or genetic screens. For such applications, a barcode library would ideally have high diversity (many unique barcodes), non-destructive identification (repeated measurements in the same cells or population), and fast, inexpensive readout (many cells and conditions). Current nucleic acid barcoding methods generate high diversity but require destructive and slow/expensive readout, and current fluorescence barcoding methods are non-destructive, fast, and inexpensive to readout but lack high diversity. We recently proposed theory for how fluorescent protein combinations may generate a high-diversity barcode library with non-destructive, fast and inexpensive identification. Here, we present an initial experimental proof-of-concept by generating a library of ~150 barcodes from two-way combinations of 18 fluorescent proteins. We use a pooled cloning strategy to generate a barcode library that is validated to contain every possible combination of the 18 fluorescent proteins. Experimental results using single mammalian cells and spectral flow cytometry demonstrate excellent classification performance of individual fluorescent proteins, with the exception of mTFP1, and of most evaluated barcodes, with many true positive rates >99%. The library is compatible with genetic screening for hundreds of genes (or gene pairs) and lineage tracing hundreds of clones. This work lays a foundation for greater diversity libraries (potentially ~105and more) generated from hundreds of spectrally-resolvable tandem fluorescent protein probes.
Unc-51-like Kinase 1 (ULK1) Regulates Bacterial Ubiquitylation and p62 Recruitment during Xenophagic Clearance ofListeria monocytogenes
Authors: Siqueira MS , Farias TSM , Ribeiro RM , Ribeiro JS , Pereira TD , Carneiro LAM , Travassos LH
Published: October 2024

Autophagy is an essential cellular homeostatic process, that also serves as an innate immune mechanism against intracellular bacterial pathogens, through a highly selective form of autophagy known as xenophagy. Despite advances in understanding how bacteria are targeted for autophagic degradation, the specific regulatory mechanisms that drive the initial steps and ensure bacterial selection remain incompletely defined. Our study uncovers a pivotal role for Unc-51-like kinase 1 (ULK1) in the xenophagic clearance of the intracellular bacterial pathogenListeria monocytogenes. We observed that ULK1 is essential for the efficient ubiquitylation of bacteria and subsequent recruitment of the autophagic adaptor protein p62 to the bacterial surface. Furthermore, we show that the impact of ULK1 deficiency in these early events - reduction in bacterial ubiquitylation followed by impaired p62 targeting – later result in diminished formation of bacteria-targeted autophagosomes. Notably, phosphorylation of p62 at the S409 residue, which is known to enhance its affinity for ubiquitin, is necessary for its recruitment and effective bacterial clearance, highlighting the regulatory role of ULK1 in this process. These findings unveil a previously unrecognized function of ULK1 in modulating early xenophagy steps, contributing to the autophagic control of intracellular pathogens. Our findings offer new perspectives into the manipulation of ULK1activity for therapeutic interventions against infectious diseases.

IMPORTANCE

Autophagy is a vital process in eukaryotic cells that enables them to digest intracellular components, helping them respond to various stresses, including starvation, the accumulation of dysfunctional organelles, and infections. While the autophagic flux has been extensively studied over the past few decades, some key mechanisms remain poorly understood. In our research, we aimed to clarify one such mechanism: the way the autophagic machinery specifically targets intracellular bacteria. We identified a novel role for the protein ULK1 in this process, demonstrating that ULK1 is essential for marking bacteria within the cell and recruiting the protein p62. This marking and recruitment of p62 are critical steps for effective bacterial clearance. This underscores the pivotal role of ULK1 in initiating the cellular defense against bacterial infections. Our findings could pave the way for new therapeutic strategies aimed at enhancing the body’s capacity to combat bacterial infections.
Duplex PCR assay to determine sex and mating status ofIxodes scapularis(Acari: Ixodidae), vector of the Lyme disease pathogen
Authors: Ronai Isobel , Frederick Julia C. , Thompson Alec T. , Sharma Prisha , Yabsley Michael J. , Pal Utpal , Extavour Cassandra G. , Glenn Travis C.
Published: October 2024

Ticks are a major health threat to humans and other animals, through direct damage, toxicoses, and transmission of pathogens. An estimated half a million people are treated annually in the United States of America for Lyme disease, a disease caused by the bite of a black-legged tick (Ixodes scapularisSay) infected with the bacterial pathogenBorrelia burgdorferi. This tick species also transmits another six human-disease causing pathogens, for which vaccines are currently unavailable. WhileI.scapularisare sexually dimorphic at the adult life stage, the DNA sequence differences between male and femaleI.scapularisthat could be used as a sex-specific marker have not yet been established. We determine the sex-specific DNA sequences forI.scapularis(male heterogametic system with XY), using whole-genome resequencing and restriction site-associated DNA sequencing. Then we identify a male-specific marker that we use as the foundation of a molecular sex identification method (duplex PCR) to differentiate the sex of anI.scapularistick. In addition, we provide evidence that this molecular sexing method can establish the mating status of adult females that have been mated and inseminated with male-determining sperm. Our molecular tool allows the characterization of mating and sex-specific biology across development forI.scapularis, a major pathogen vector, which is crucial for a better understanding of their biology and controlling tick populations.
A general model for the seasonal to decadal dynamics of leaf area
Authors: Zhou Boya , Cai Wenjia , Zhu Ziqi , Wang Han , Harrison Sandy P. , Prentice I. Colin
Published: October 2024

Leaf phenology, represented at ecosystem scale by the seasonal dynamics of leaf area index (LAI), is a key control on the exchanges of CO2, energy and water between the land and atmosphere. Robust simulation of leaf phenology is thus important for both dynamic global vegetation models (DGVMs) and land-surface representations in climate and Earth System models. There is no general agreement on how leaf phenology should be modelled. However, a recent theoretical advance posits a universal relationship between the time course of “steady-state” gross primary production (GPP) and LAI – that is, the mutually consistent LAI and GPP that would pertain if weather conditions were held constant. This theory embodies the concept that leaves should be displayed when their presence is most beneficial to plants, combined with the reciprocal relationship of LAI and GPP via (a) the Beer’s law dependence of GPP on LAI, and (b) the requirement for GPP to support the allocation of carbon to leaves. Here we develop a global prognostic leaf phenology model, combining this theoretical approach with a parameter-sparse terrestrial GPP model (the P model) that achieves good fit to GPP derived from flux towers in all biomes, and a scheme based on the P model that predicts seasonal maximum LAI as the lesser of an energy-limited rate (maximizing GPP) and a water-limited rate (maximizing the use of available precipitation). The exponential moving average method is used to represent the time lag between leaf allocation and modelled steady-state LAI. The model captures satellite-derived LAI dynamics across biomes at both site and global levels. Since this model outperforms the 15 DGVMs used in the TRENDY project, it could provide a basis for improved representation of leaf-area dynamics in vegetation and climate models.
Global identification of AGO3–RNA interactions inChlamydomonasreveals the small RNA–mediated regulation of nuclear and chloroplast gene expression
Authors: Murakami Suzuna , Takahashi Hiroki , Shimizu Kaede , Yamasaki Tomohito
Published: October 2024

MicroRNAs (miRNAs) form complexes with Argonaute (AGO) proteins and bind to mRNAs with complementary sequences to repress their expression. Organisms typically possess several hundred miRNAs regulating diverse biological processes. Although the roles of miRNAs have been well elucidated in multicellular organisms, they remain largely unexplored in unicellular organisms. In the green algaChlamydomonas reinhardtii, the first unicellular organism in which miRNAs were discovered, identifying miRNA target genes remains challenging. Here, we report the high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) to generate global AGO3–RNA interaction maps, identifying 131 mRNAs derived from nuclear genes. We also detected mRNAs from two chloroplast genes, suggesting that AGO3 may also influence chloroplast gene expression. Our findings indicate thatChlamydomonassmall RNAs repress nuclear and chloroplast gene expression. Furthermore, HITS-CLIP analyses are now feasible for any RNA-binding protein inChlamydomonas, offering new opportunities to uncover the functions of RNA-binding proteins of interest.
Impulsivity Facets and Substance Use Involvement: Insights from Genomic Structural Equation Modeling
Authors: Vilar-Ribó Laura , Hatoum Alexander S , Grotzinger Andrew D , Mallard Travis T ,   23andMe Research Team, Elson Sarah , Fontanillas Pierre , Palmer Abraham A , Gustavson Daniel E , Sanchez-Roige Sandra
Published: October 2024

Background

Impulsivity is a multidimensional trait associated with substance use disorders (SUDs), but the relationship between distinct impulsivity facets and stages of substance use involvement remains unclear.

Methods

We used genomic structural equation modeling and genome-wide association studies (N=79,729-903,147) based on individuals of European ancestry to examine the latent genetic architecture of impulsivity and substance use behaviors. We included GWAS data from nine impulsivity traits and seven substance use (SU) and SUD traits.

Results

We found that the SU and SUD factors were strongly genetically inter-correlated (rG=0.77) but their associations with impulsivity factors differed. Lack of premeditation, negative and positive urgency were equally positively genetically correlated with both the SU (rG=.0.30-0.50) and SUD (rG=0.37-0.47) factors; sensation seeking was more strongly genetically correlated with the SU factor (rG=0.27 vs.rG=0.10); delay discounting was more strongly genetically correlated with the SUD factor (rG=0.32 vs.rG=0.21); and lack of perseverance was only weakly genetically correlated with the SU factor (rG=0.09). After controlling for the genetic correlation between SU/SUD, we found that lack of premeditation and positive urgency were independently genetically associated with both the SU (β=0.39, β=0.28, respectively) and SUD factors (β=0.28, β=0.19, respectively); sensation seeking and lack of perseverance were independently genetically associated with the SU factor (β=0.46, β=0.19, respectively); and negative urgency and delay discounting were independently genetically associated with the SUD factor (β=0.34, β=0.39, respectively).

Conclusions

Our findings show that specific impulsivity facets confer risk for distinct stages of substance use involvement, with potential implications for SUDs prevention and treatment.
Public reporting guidelines for outbreak data: Enabling accountability for effective outbreak response by developing standards for transparency and uniformity
Authors: Grégoire Vanessa , Zhu Alex W. , Brown Catherine M. , Brownstein John S. , Cardo Denise , Cumming Fergus , Danila Richard , Donnelly Christl A. , Duchin Jeffrey S. , Fill Mary-Margaret A. , Fraser Christophe , Fullerton Katie , Funk Sebastian , George Dylan , Hopkins Susan , Kraemer Moritz U.G. , Layton Marcelle , Lessler Justin , Lynfield Ruth , McCaw James M. , McPherson Tristan D. , Moore Zack , Morgan Oliver , Riley Steven , Rosenfeld Roni , Samoff Erika , Schaffner William , Shaffner Julie , Sturm Roberta , Terashita Dawn , Walke Henry , Washington Raynard E. , Rivers Caitlin M.
Published: October 2024

Currently, there are few standards for what essential information about an infectious disease outbreak should be reported to the public and when. The content and timeliness of public reporting (e.g. situation reports) is at the discretion of the jurisdiction overseeing the outbreak response, resulting in a substantial heterogeneity in available information. To address this problem, we undertook a consensus process to develop recommendations for what epidemiological information public health authorities should report to the public during an outbreak, including the administrative level and frequency of reporting. We first assembled a steering committee of nine experts representing federal public health, state public health, academia, and international partners to develop a candidate list of reporting items. We then invited 45 experts, 35 of whom agreed to participate in a Delphi panel. Of those, 25 participated in voting in the first round, 25 participated in voting in the second round, and 25 participated in voting in the third round, demonstrating consistent engagement in the consensus-building process. The final stage of the Delphi process consisted of a hybrid consensus meeting to finalize the voting items. This resulted in a final list of nine reporting items representing the minimum set of information to include in publicly available situation reports: Numbers of new confirmed cases, new hospital admissions, new deaths, cumulative confirmed cases, cumulative hospital admissions, and cumulative deaths, each reported weekly and at Administrative level 1 (typically state or province), and stratified by sex, age group, and race/ethnicity. This minimum reporting standard creates a strong framework and guidance for uniform sharing of outbreak information and promotes consistency of data between jurisdictions to enable prompt and effective response.
Pain Among US Adults Before, During, and After the COVID-19 Pandemic: A Repeated Cross-Sectional Study using the 2019-2023 National Health Interview Survey
Authors: Zajacova Anna , Grol-Prokopczyk Hanna , Nahin Richard L.
Published: October 2024

Importance

Chronic pain (CP) is a major public health problem in the US. The COVID-19 pandemic led to widespread disruptions in the US and it is important to monitor changes in pain during and after the pandemic.

Objective

To determine prevalence of chronic pain (CP) and high-impact chronic pain (HICP) before, during, and after the COVID-19 pandemic and identify potential contributing factors.

Methods

We analyze a nationally representative sample of 88,469 community-dwelling Americans aged 18 and older from three cross-sectional waves of the National Health Interview Survey before (2019), during (2021), and after (2023) the COVID-19 pandemic.

Year of interview is the exposure. All regression models control for age and sex; fully controlled models include 19 additional covariates (demographics, socioeconomic status, health behaviors, health conditions, mental health, and health insurance type); analyses also explore the role of long COVID. Outcomes are CP and HICP using measures proposed by the US National Pain Strategy; we also present findings for six site-specific pain measures.

Results

Between 2019 and 2023, CP and HICP prevalence increased by 18% and 13%, respectively. Specifically, CP prevalence was 20.6% (95%CI: 19.9-21.2%) in 2019, 20.9%(20.3-21.6%) in 2021, and 24.3% (23.7-25.0%) in 2023. HICP prevalence declined from 7.5% (7.1-7.8%) in 2019 to 6.9% (6.6-7.3%) in 2021, before rising sharply to 8.5% (8.1-8.9%) in 2023. The increases occurred in all examined body sites except for tooth/jaw pain, and in all major population groups. Approximately 13% of the increase in CP and HICP was attributable to long COVID.

Conclusions and Relevance

Pain among US adults was high before and during the pandemic but has surged substantially since. In 2023, an unprecedented 60 million Americans had chronic pain and 21 million had high-impact chronic pain.
Extreme weather events and dengue in Southeast Asia: a regionally-representative analysis of 291 locations from 1998 to 2021
Authors: Ith Sophearen , Seposo Xerxes , Phy Vitou , Tantrakarnapa Kraichat , Apostol Geminn Louis C. , Dhewantara Pandji Wibawa , Hod Rozita , Hassan Mohd Rohaizat , Othman Hidayatulfathi , Sahani Mazrura , Lim Jue Tao , Nhung Ha Hong , Tuan Nguyen Hai , Nghia Ngu Duy , Takemura Taichiro , Nouhak Inthavong , Carlos Chua Paul Lester , Cook Alex R , Colón-González Felipe J , Hashizume Masahiro
Published: October 2024

Background

Climate change, leading to more frequent and intense extreme weather events (EWEs), could significantly impact dengue transmission. However, the associations between EWEs and dengue remains underexplored in the Southeast Asia (SEA) region. We investigated the association between selected EWEs (i.e. heatwaves, extremely wet, and drought conditions) and dengue in the SEA region.

Methods and Findings

Monthly dengue case reports were obtained from 291 locations across eight SEA countries between 1998 and 2021. Heatwaves are defined as the monthly total number of days where temperatures exceed the 95th percentile for at least two consecutive days. Droughts and extremely wet conditions are defined by a self-calibrating Palmer Drought Severity Index (scPDSI). We implemented a generalized additive mixed model coupled with a distributed lag non-linear model to estimate the association between each EWE and dengue. Months with fewer than 12 heatwave days increased dengue risk with delayed effect after two months lag, compared with months without any heatwave. Highest dengue risk is at 7 heatwave days (RR=1·28; 95%CI: 1·19,1·38). Compared to normal conditions (i.e. scPDSI=0), drought conditions (i.e. scPDSI=–4) were positively associated with dengue risk (RR=1·85; 95%CI: 1·73,1·99), while extremely wet conditions (i.e. scPDSI=4) have reduced dengue risk (RR=0·89; 95%CI: 0·87,0·91). Although the findings of this study are significant, its limitations arise from the inconsistency of dengue case reporting, which might complicate dengue risk estimation.

Conclusions

This study shows that the delayed effect of heatwaves and drought conditions magnifies the risk of dengue in the SEA region. Our findings offer stakeholders sizeable amount of time to organize and implement public health interventions in minimizing the prospective dengue risk, posed by EWEs in the context of climate change in SEA. Future research may focus on factors associated with dengue risk variations within SEA region to facilitate the development of location-based, tailor-fit mitigation and preventative interventions.
Changing patterns of heart failure in China from 1990 to 2021: a secondary analysis of the Global Burden of Disease study 2021
Authors: Yang Qiwen , Zhuang Rui , Lyu Diyang , Xue Donghua , Niu Chaofeng , Shi Yujie , Li Meng , Zhang Lijing
Published: October 2024

Background

Heart failure is a leading public health issue in China, with a steadily increasing burden. This study aims to assess the changing patterns of heart failure in China from 1990 to 2021, providing evidence for informed healthcare strategies.

Methods

Data on prevalence, years lived with disability (YLDs), and their corresponding 95% uncertainty intervals (UI) were obtained from the Global Burden of Disease (GBD) Study 2021. The joinpoint regression model was used to identify both overall and localized trends of heart failure burden, and the age-period-cohort model served to analyze the contributions of age, period, and birth cohort separately. We further utilized the autoregressive integrated moving average (ARIMA) model to predict future trends of heart failure in the next 10 years.

Results

In 2021, 13099727 (95% UI, 11320895 to 15376467) individuals lived with heart failure and this illness accounted for 1290810 (95% UI, 865894 to 1775731) YLDs in China. The burden of heart failure is more pronounced in males and the elderly, and ischemic heart disease has become the leading cause since 2002. The age-standardized rates of prevalence and YLDs increased at average annual percentage changes of 0.23% (95% CI, 0.20 to 0.26) and 0.25% (95% CI, 0.23 to 0.27) respectively. The curve of local drift showed a downward trend with age. Both the period and cohort rate ratios have increased significantly over the last 30 years. By 2031, the age-standardized rates of prevalence will decrease to 678.69 (95% CI, 640.75 to 716.63), while the age-standardized rates of YLDs will increase to 69.19 (95% CI, 66.95 to 71.43).

Conclusions

The burden of heart failure in China remains concerning. The implementation of comprehensive strategies should be taken into consideration, including strengthening primary healthcare system, enhancing public awareness, and promoting cardiac rehabilitation.

Clinical Perspective

What Is New?

This is the first study of the Global Burden of Disease (GBD) 2021 that comprehensively analyzes the burden of heart failure in China over the past 30 years.

What Are the Clinical Implications?

The burden of heart failure in China remains concerning.

Comprehensive strategies prioritizing primary healthcare system, public awareness, and cardiac rehabilitation could be effective to mitigate the burden of heart failure.
Evaluation of Machine Learning-Assisted Directed Evolution Across Diverse Combinatorial Landscapes
Authors: Li Francesca-Zhoufan , Yang Jason , Johnston Kadina E. , Gürsoy Emre , Yue Yisong , Arnold Frances H.
Published: October 2024

Various machine learning-assisted directed evolution (MLDE) strategies have been shown to identify high-fitness protein variants more efficiently than typical wet-lab directed evolution approaches. However, limited understanding of the factors influencing MLDE performance across diverse proteins has hindered optimal strategy selection for wet-lab campaigns. To address this, we systematically analyzed multiple MLDE strategies, including active learning and focused training using six distinct zero-shot predictors, across 16 diverse protein fitness landscapes. By quantifying landscape navigability with six attributes, we found that MLDE offers a greater advantage on landscapes which are more challenging for directed evolution, especially when focused training is combined with active learning. Despite varying levels of advantage across landscapes, focused training with zero-shot predictors leveraging distinct evolutionary, structural, and stability knowledge sources consistently outperforms random sampling for both binding interactions and enzyme activities. Our findings provide practical guidelines for selecting MLDE strategies for protein engineering.
A new screening assay reveals that aminoglycoside antibiotics interfere with the Tau/MDM2 interaction
Authors: Sola Martina , Ciccaldo Matteo , Paganetti Paolo , Papin Stéphanie
Published: October 2024

MAPTgene mutations cause some neurodegenerative tauopathies and theMAPT-encoded protein Tau is deposited in neurofibrillary tangles, hallmarks of this disease family. In addition to its canonical function in regulating microtubule dynamics, Tau modulates chromatin compaction, gene expression, and the cellular response to DNA damage. During the DNA damage response, Tau positively modulates P53 by binding to MDM2 thereby preventing P53 inactivation and degradation. The aberrant presence of both MDM2 associated to neurofibrillary tangles and of P53 misfolding in brains affected by neurodegenerative diseases suggests that the sequestration of MDM2 may prevent P53 clearance in tauopathies and so contribute to progressive neuronal dysfunction and death. Following this evidence, a pharmacological inhibition of the Tau/MDM2 interaction may represent a viable strategy to reduce P53-dependent cell damage in brain disorders. With the screening FDA-approved drugs and natural compounds, we discovered that members of the aminoglycoside antibiotic family antagonize the Tau/MDM2 interaction. The use of these reagents may advance the understanding of the implication of the Tau/MDM2/P53 axis in neurodegeneration models. However, their unfavorable pharmacokinetic properties may limit their systemic use when targeting the brain.
GABAergic neurons can facilitate the propagation of cortical spreading depolarization: experiments in mouse neocortical slices and a novel neural field computational model
Authors: Baspinar Emre , Simonti Martina , Srour Hadi , Desroches Mathieu , Avitabile Daniele , Mantegazza Massimo
Published: October 2024

Cortical spreading depolarization (CSD) is a wave of depolarization with local onset and extended propagation implicated in several pathological conditions. Its mechanisms have been extensively investigated, including our recent studies showing with experimental and computational approaches that the hyperactivity of GABAergic neurons can initiate migraine-related CSD because of spiking-generated extracellular potassium (K+) build-up. However, less is known about the role played by GABAergic neurons in CSD propagation. Here we studied mechanisms of CSD propagation, focusing on the role of GABAergic neurons, with experiments performed in mouse brain slices and with a new spatially extended neural field computational model. Experimentally, we induced CSD by applying brief puffs of potassium chloride (KCl) in somatosensory cortex slices from wild type and VGAT-ChR2-tdtomato mice, which specifically express the excitatory opsin channelrhodopsin (ChR2) in GABAergic neurons. We evaluated the role of GABAergic neurons in CSD propagation by modulating their activity with optogenetic illumination and their synaptic connections with pharmacological tools. We have developed the computational model to obtain realistic simulations of both initiation and propagation of CSD. It includes large populations of interconnected excitatory and inhibitory neurons, as well as the effect of extracellular ion concentrations on their features. We found that the decrease of the synaptic activity of GABAergic neurons can enhance CSD propagation, because of the reduction of the inhibitory synaptic weight, whereas their spiking activity can enhance CSD propagation because of extracellular K+upload. However, differently from for CSD initiation, the latter effect is normally hidden by the action of GABAergic synaptic transmission. A reduction of GABAergic synaptic transmission, which can be observed in pathological states, can reveal the potentiating effect of the K+upload induced by GABAergic activation. The neural field model that we implemented can generate accurate simulations of CSD, providing testable hypotheses on mechanisms, and can also be used for modeling other (patho)-physiological activities of neuronal networks.
Nanoparticles with Curcumin and Piperine Modulate Steroid Biosynthesis in Prostate Cancer
Authors: Yakubu Jibira , Natsaridis Evangelos , du Toit Therina , Barata Isabel Sousa , Tagit Oya , Pandey Amit V.
Published: October 2024

Endogenous androgens are pivotal in the development and progression of prostate cancer (PC). We investigated nanoparticle formulations of curcumin and piperine in modulating steroidogenesis within PC cells. Using multiple PC cell lines (LNCaP, VCaP, DU145 and PC3) we studied the effects of curcumin, piperine, and their nanoparticle formulations—curcumin nanoparticles, piperine nanoparticles, and curcumin-piperine nanoparticles (CPN)—on cell viability, migration, and steroid biosynthesis. Curcumin and its nanoparticle formulations significantly reduced cell viability in PC cells, with curcumin-piperine nanoparticles showing the highest efficacy. These treatments also inhibited cell migration, with CPN exhibiting the most pronounced effect. In assays for steroid biosynthesis, curcumin and its nanoparticle formulations, as well as piperine and its nanoparticles, selectively inhibited 17α-hydroxylase and 17,20-lyase activities of cytochrome P450 17A1 (CYP17A1). Abiraterone, a CYP17A1 inhibitor, displayed a broader inhibition of steroid metabolism including cytochrome P450 21-hydroxylase activity, whereas curcumin and piperine provided a more targeted inhibition profile. Analysis of steroid metabolites by liquid chromatography-mass spectrometry revealed that CPN caused significant reduction of androstenedione and cortisol, suggesting potential synergistic effects. In conclusion, nanoformulations co-loaded with curcumin and piperine offer an effective approach to targeting steroidogenesis and could be promising candidates for therapies aimed at managing androgen-dependent PC.
FtsK is Critical for the Assembly of the Unique Divisome Complex of the FtsZ-lessChlamydia trachomatis
Authors: Harpring McKenna , Lee Junghoon , Zhong Guangming , Ouellette Scot P. , Cox John V.
Published: October 2024

Chlamydia trachomatisserovar L2(Ct),an obligate intracellular bacterium that does not encode FtsZ, divides by a polarized budding process. In the absence of FtsZ, we show that FtsK, a chromosomal translocase, is critical for divisome assembly inCt. Chlamydial FtsK forms discrete foci at the septum and at the base of the progenitor mother cell, and our data indicate that FtsK foci at the base of the mother cell mark the location of nascent divisome complexes that form at the site where a daughter cell will emerge in the next round of division. The divisome inCthas a hybrid composition, containing elements of the divisome and elongasome from other bacteria, and FtsK is recruited to nascent divisomes prior to the other chlamydial divisome proteins assayed, including the PBP2 and PBP3 transpeptidases, and MreB and MreC. Knocking down FtsK prevents divisome assembly inCtand inhibits cell division and septal peptidoglycan synthesis. We further show that MreB does not function like FtsZ and serve as a scaffold for the assembly of theCtdivisome. Rather, MreB is one of the last proteins recruited to the chlamydial divisome, and it is necessary for the formation of septal peptidoglycan rings. Our studies illustrate the critical role of chlamydial FtsK in coordinating divisome assembly and peptidoglycan synthesis in this obligate intracellular bacterial pathogen.
Effect of cysteine oxidation in SARS-CoV-2 Spike protein on its conformational changes: insights from atomistic simulations
Authors: Ghasemitarei Maryam , Taeb Hoda , Ghorbi Tayebeh , Yusupov Maksudbek , Ala-Nissila Tapio , Bogaerts Annemie
Published: October 2024

This study investigates the effect of cysteine (Cys) oxidation on the conformational changes of the SARS-CoV-2 Spike (S) protein, a critical factor in viral attachment and entry into host cells. Using targeted molecular dynamics (TMD) simulations, we explore the conformational transitions between the down (inaccessible) and up (accessible) states of the SARS-CoV-2 S protein in both its native and oxidized forms. Our findings reveal that oxidation significantly increases the energy barrier for these transitions, as indicated by the work required to move from the down to the up conformation and vice versa. Specifically, in the oxidized system compared to the native system, the energy required to transition from the down to the up conformation increases by approximately 131 ± 1 kJ.mol -1 , while the energy required for the reverse transition increases by about 223 ± 6 kJ.mol -1 . This is due to the stabilizing effect of oxidation on the conformation of the SARS-CoV-2 S protein. Analysis of hydrogen bond and salt bridge formation before and after oxidation provides additional insights into the stabilization mechanisms, showing an increase in salt bridge formation that contributes to conformational stabilization. These results underscore the potential of targeting translational modifications to hamper viral entry or enhance susceptibility to neutralization, offering a novel perspective for antiviral strategy development against SARS-CoV-2. This study adds important knowledge to the field of viral protein dynamics and highlights the critical role of structural and computational biology in uncovering new therapeutic avenues.
TIR signaling activates caspase-like immunity in bacteria
Authors: Rousset François , Osterman Ilya , Scherf Tali , Falkovich Alla H. , Leavitt Azita , Amitai Gil , Shir Sapir , Malitsky Sergey , Itkin Maxim , Savidor Alon , Sorek Rotem
Published: October 2024

Proteases of the caspase family, as well as Toll/Interleukin-1 Receptor (TIR)-domain proteins, have central roles in innate immunity and regulated cell death in humans. In this study we describe a bacterial immune system comprising both a caspase-like protease and a TIR-domain protein. We found that the TIR protein, once it recognizes phage invasion, produces the previously unknown immune signaling molecule ADP-cyclo[N7:1′′]-ribose (N7-cADPR). This molecule specifically activates the bacterial caspase-like protease which then indiscriminately degrades cellular proteins to halt phage replication. The TIR-caspase defense system, which we denote as type IV Thoeris, is abundant in bacteria and efficiently protects against phage propagation. Our study highlights the diversity of TIR-produced immune signaling molecules and demonstrates that cell death regulated by proteases of the caspase family is an ancient mechanism of innate immunity.
Virulence regulates and boosts CRISPR-Cas9 immunity in Group BStreptococcus
Authors: Pastuszka Adeline , Mazzuoli Maria-Vittoria , Crestani Chiara , Deborde Léonie , Sismeiro Odile , Lemaire Coralie , Rong Vanessa , Gominet Myriam , Jacquemet Elise , Legendre Rachel , Lanotte Philippe , Firon Arnaud
Published: October 2024

CRISPR-Cas9 immune systems protect bacteria from foreign DNA. However, immune efficiency is constrained by Cas9 off-target cleavages and toxicity. How bacteria regulate Cas9 to maximize protection while preventing autoimmunity is not understood. Here, we show that the master regulator of virulence, CovR, regulates CRISPR-Cas9 immunity against mobile genetic elements inStreptococcus agalactiae, a pathobiont responsible for invasive neonatal infections. We show that CovR binds to and represses a distal promoter of thecasoperon, integrating immunity within the virulence regulatory network. The CovR-regulated promoter provides a controlled increase in off-target cleavages to counteract mutations in the target DNA, restores the potency of old immune memory, and stimulates the acquisition of new memory in response to recent infections. Regulation of Cas9 by CovR is conserved at the species level, with lineage specificities suggesting different adaptive trajectories. Altogether, we describe the coordinated regulation of immunity and virulence that enhances the bacterial immune repertoire during host-pathogen interaction.
Oncogenic Alterations, Race, and Survival in US Veterans with Metastatic Prostate Cancer Undergoing Somatic Tumor Next Generation Sequencing
Authors: Valle Luca F. , Li Jiannong , Desai Heena , Hausler Ryan , Haroldsen Candace , Chatwal Monica , Ojo Matthias , Kelley Michael J. , Rebbeck Timothy , Rose Brent S. , Rettig Matthew B. , Nickols Nicholas G. , Garraway Isla P. , Yamoah Kosj , Maxwell Kara N.
Published: October 2024

Purpose

National guidelines recommend next generation sequencing (NGS) of tumors in patients diagnosed with metastatic prostate cancer (mPCa) to identify potential actionable alterations. We sought to describe the spectrum and frequency of alterations in PCa-related genes and pathways, as well as associations with self-identified race/ethnicity, and overall survival in US Veterans.

Patients and Methods

This retrospective cohort study included Non-Hispanic Black (NHB) and Non-Hispanic white (NHW) Veterans with mPCa who obtained NGS through the Veterans Affairs National Precision Oncology Program. 45 genes in seven canonical or targetable mPCa pathways were evaluated in addition to TMB and MSI status. Multivariable logistic regression evaluated associations between race/ethnicity and genomic alteration frequencies. Cox proportional hazards models were used to determine associations between race/ethnicity, specific gene/pathway alteration, and overall survival.

Results

5,015 Veterans with mPCa who had NGS conducted were included (1,784 NHB, 3,231 NHW). NHB Veterans were younger, had higher PSA at diagnosis, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods compared to NHW Veterans. Nine of the top ten most commonly altered genes were the same in NHB v NHW Veterans; however, the frequencies of alterations varied by race/ethnicity. NHB race/ethnicity was associated with higher odds of genomic alterations inSPOP(OR 1.7 [1.2-2.6]) as well as immunotherapy targets (OR 1.7 [1.1-2.7]) including MSI high status (OR 3.1 [1.1-9.4]).

Furthermore, NHB race/ethnicity was significantly associated with lower odds of genomic alterations in the AKT/PI3K pathway (OR 0.6 [0.4-0.7]), AR axis (OR 0.7 [0.5-0.9]), and tumor suppressor genes (OR 0.7 [0.5-0.8]). Cox proportional hazards modelling stratified by race/ethnicity demonstrated alterations in tumor suppressor genes includingTP53were associated with shorter OS in both NHB (HR 1.54 [1.13-2.11] and NHW individuals (HR 1.52 [1.25-1.85]).

Conclusion

In the equal access VA healthcare setting, Veterans undergoing NGS for mPCa exhibited differences in alteration frequencies in both actionable and non-actionable pathways that may be associated with survival. This analysis affirms the utility of genomic testing for identifying candidates irrespective of race/ethnicity for precision oncology treatments, which could contribute to equitable outcomes in patients with mPCa.
A framework for target discovery in rare cancers
Authors: Li Bingchen , Sadagopan Ananthan , Li Jiao , Wu Yuqianxun , Cui Yantong , Konda Prathyusha , Weiss Cary N. , Choueiri Toni K. , Doench John G. , Viswanathan Srinivas R.
Published: October 2024

While large-scale functional genetic screens have uncovered numerous cancer dependencies, rare cancers are poorly represented in such efforts and the landscape of dependencies in many rare cancers remains obscure. We performed genome-scale CRISPR knockout screens in an exemplar rare cancer,TFE3-translocation renal cell carcinoma (tRCC), revealing previously unknown tRCC-selective dependencies in pathways related to mitochondrial biogenesis, oxidative metabolism, and kidney lineage specification. To generalize to other rare cancers in which experimental models may not be readily available, we employed machine learning to infer gene dependencies in a tumor or cell line based on its transcriptional profile. By applying dependency prediction to alveolar soft part sarcoma (ASPS), a distinct rare cancer also driven byTFE3translocations, we discovered and validated thatMCL1represents a dependency in ASPS but not tRCC. Finally, we applied our model to predict gene dependencies in tumors from the TCGA (11,373 tumors; 28 lineages) and multiple additional rare cancers (958 tumors across 16 types, including 13 distinct subtypes of kidney cancer), nominating potentially actionable vulnerabilities in several poorly-characterized cancer types. Our results couple unbiased functional genetic screening with a predictive model to establish a landscape of candidate vulnerabilities across cancers, including several rare cancers currently lacking in potential targets.