bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the impact of Enhanced-Case-Finding on tuberculosis incidence and transmission in The Gambia using epidemiological and phylodynamic approaches
Authors: Gehre Florian , Oko Francis , Ofori-Anyinam Boatema , Meehan Conor J. , Windels Etthel M. , Joof Ken , Faal Tutty , Mendy Francis , Jobarteh Tijan , Gitteh Ensa , Riley Abi Janet , Sarr-Kuyateh Binta , Okoi Catherine , Demba Edward , Del-Alorse William , Mlaga Kodjovi , Sambou Basil , Kanuteh Fatoumatta , Lette Koduh , Muhammad Abdul Khalie , Agbla Shadrac , Mulders Wim , Donkor Simon , Jeffries David , Roca Anna , D’Alessandro Umberto , Antonio Martin , Adetifa Ifedayo , de Jong Bouke C. 
Published: May 2024

AbstractBackgroundMost tuberculosis (TB) cases in The Gambia are notified in the Greater Banjul Area (GBA). We conducted an Enhanced-Case-Finding (ECF) intervention in the GBA and determined its effect on TB incidence and ongoing TB transmission.MethodsThis was a cluster randomized trial in which randomly assigned intervention areas of grouped settlements received three rounds of an ECF strategy consisting of sensitization followed by auramine microscopy, whereas TB patients in control areas continued to be identified through passive case finding. The primary outcome was TB incidence rate. To exclude that an increase in notified cases, followed by a decrease in notified cases, would hide the future impact of the intervention, we tested for changes in transmission dynamics using both genetic clustering and phylodynamic methods.ResultsNo significant difference in TB incidence rates, transmission clustering or effective reproductive number was detected between intervention and control areas.ConclusionAlthough we did not find evidence for decreased TB incidence nor TB transmission through the ECF strategy used, this approach is an examplar of how both classical epidemiology and genomic phylodynamics approaches can be integrated to better assess public health intervention outcomes.
Diagnostics for detection and surveillance of priority epidemic-prone diseases in Africa: an assessment of testing capacity and laboratory strengthening needs
Authors: Ashenafi Aytenew , Sule Olajumoke , Peter Trevor , Mashate Silver , Otieno Osborn , Kebede Yenew , Oio John , Kao Kekeletso , Carter Jane , Whistler Toni , Ndlovu Nqobile , Kebede Yenew 
Published: May 2024

AbstractIn 2023, Africa experienced 180 public health emergencies, of which 90% were infectious diseases and 75% were related to zoonotic diseases. Testing capacity for epidemic-prone diseases is essential to enable rapid and accurate identification of causative agents, and for action to prevent disease spread. Moreover, testing is pivotal in monitoring disease transmission, evaluating public health interventions, and informing targeted resource allocation during outbreaks. An online, self-assessment survey was conducted in African Union Member States to identify major challenges in testing for epidemic-prone diseases. The survey assessed current capacity for diagnosing priority epidemic-prone diseases at different laboratory levels. It explored challenges in establishing and maintaining testing capacity to improve outbreak response and mitigate public health impact. Survey data analysed diagnostic capacity for priority infectious diseases, diagnostic technologies in use, existing surveillance programmes and challenges limiting diagnostic capacity, by country. The survey result from 15 Member States who responded to the survey, showed high variability in testing capacity and technologies across countries and diverse factors limiting testing capacity for certain priority diseases like dengue and Crimean-Congo haemorrhagic fever. At the same time, there is better diagnostic capacity for coronavirus disease 2019 (COVID-19), polio, and measles due to previous investments. Unfortunately, many countries are not utilising multiplex testing, despite its potential to improve diagnostic access. The challenges of limited laboratory capacity for testing future outbreaks are indeed significant. Recent disease outbreaks in Africa have underscored the urgent need to strengthen diagnostic capacity and introduce cost-effective technologies. Small sample sizes and differing disease prioritisation within each country limited the analysis. These findings suggest the benefits of evaluating laboratory testing capacity for epidemic-prone diseases and highlight the importance of effectively addressing challenges to detect diseases and prevent future pandemics.
Inferring causal cell types of human diseases and risk variants from candidate regulatory elements
Authors: Kim Artem , Zhang Zixuan , Legros Come , Lu Zeyun , de Smith Adam , Moore Jill E. , Mancuso Nicholas , Gazal Steven 
Published: May 2024

AbstractThe heritability of human diseases is extremely enriched in candidate regulatory elements (cRE) from disease-relevant cell types. Critical next steps are to infer which and how many cell types are truly causal for a disease (after accounting for co-regulation across cell types), and to understand how individual variants impact disease risk through single or multiple causal cell types. Here, we propose CT-FM and CT-FM-SNP, two methods that leverage cell-type-specific cREs to fine-map causal cell types for a trait and for its candidate causal variants, respectively. We applied CT-FM to 63 GWAS summary statistics (averageN= 417K) using nearly one thousand cRE annotations, primarily coming from ENCODE4. CT-FM inferred 81 causal cell types with corresponding SNP-annotations explaining a high fraction of trait SNP-heritability (∼2/3 of the SNP-heritability explained by existing cREs), identified 16 traits with multiple causal cell types, highlighted cell-disease relationships consistent with known biology, and uncovered previously unexplored cellular mechanisms in psychiatric and immune-related diseases. Finally, we applied CT-FM-SNP to 39 UK Biobank traits and predicted high confidence causal cell types for 2,798 candidate causal non-coding SNPs. Our results suggest that most SNPs impact a phenotype through a single cell type, and that pleiotropic SNPs target different cell types depending on the phenotype context. Altogether, CT-FM and CT-FM-SNP shed light on how genetic variants act collectively and individually at the cellular level to impact disease risk.
Identifying a Heterogeneous Effect of Atrial Fibrillation Screening in Older Adults: A Secondary Analysis of the VITAL-AF Trial
Authors: Shah Sachin J , Iyer Jay M. , Agha Leila , Chang Yuchiao , Ashburner Jeffrey M. , Atlas Steven J. , McManus David D. , Ellinor Patrick T. , Lubitz Steven A. , Singer Daniel E. 
Published: May 2024

ABSTRACTBackgroundOne-time atrial fibrillation (AF) screening trials have produced mixed results; however, it is unclear if there is a subset for whom screening is effective. Identifying such a subgroup would support targeted screening.MethodsWe conducted a secondary analysis of VITAL-AF, a randomized trial of one-time, single-lead ECG screening during primary care visits. We tested two approaches to identify a subgroup where screening is effective. First, we developed an effect-based model using a T-learner. Specifically, we separately predicted the likelihood of AF diagnosis under screening and usual care conditions; the difference in probabilities was the predicted screening effect. Second, we used a validated AF risk model to test for a heterogeneous screening effect. We used interaction testing to determine if observed AF diagnosis rates in the screening and usual care groups differed when stratified by decile of the predicted screening effect and predicted AF risk.ResultsBaseline characteristics were similar between the screening (n=15187) and usual care (n=15078) groups (mean age 74 years, 59% female). In the effect-based analysis, in the highest decile of predicted screening effectiveness (n=3026), AF diagnosis rates were higher in the screening group (6.50 vs. 3.06 per 100 person-years, rate difference 3.45, 95%CI 1.62 to 5.28). In this group, the mean age was 84 years and 68% were female. The risk-based analysis did not identify a subgroup where screening was more effective. Predicted screening effectiveness and predicted baseline AF risk were poorly correlated (Spearman coefficient 0.13).ConclusionsIn a secondary analysis of the VITAL-AF trial, we identified a small subgroup where one-time screening was associated with increased AF diagnoses using an effect-based approach. In this study, predicted AF risk was a poor proxy for predicted screening effectiveness. These data caution against the assumption that high AF risk is necessarily correlated with high screening effectiveness.
Oxygen-based autoregulation indices associated with clinical outcomes and spreading depolarization in aSAH
Authors: Carlson Andrew P , Jones Thomas , Zhu Yiliang , Desai Masoom , Alsarah Ali , Shuttleworth C. William 
Published: May 2024

AbstractBackgroundImpairment in cerebral autoregulation has been proposed as a potentially targetable factor in patients with aneurysmal subarachnoid hemorrhage (aSAH), however there are different continuous measures that can be used to calculate the state of autoregulation. In addition, it has previously been proposed that there may be an association of impaired autoregulation with the occurrence of spreading depolarization (SD) events.MethodsSubjects with invasive multimodal monitoring and aSAH were enrolled in an observational study. Autoregulation indices were prospectively calculated from this database as a 10 second moving correlation coefficient between various cerebral blood flow (CBF) surrogates and mean arterial pressure (MAP). In subjects with subdural ECoG (electrocorticography) monitoring, SD was also scored. Associations between clinical outcomes using the mRS (modified Rankin Scale) and occurrence of either isolated or clustered SD was assessed.Results320 subjects were included, 47 of whom also had ECoG SD monitoring. As expected, baseline severity factors such as mFS and WFNS (World Federation of Neurosurgical Societies scale) were strongly associated with the clinical outcome. SD probability was related to blood pressure in a triphasic pattern with a linear increase in probability below MAP of ∼100mmHg.Autoregulation indices were available for intracranial pressure (ICP) measurements (PRx), PbtO2 from Licox (ORx), perfusion from the Bowman perfusion probe (CBFRx), and cerebral oxygen saturation measured by near infrared spectroscopy (OSRx). Only worse ORx and OSRx were associated with worse clinical outcomes. ORx and OSRx also were found to both increase in the hour prior to SD for both sporadic and clustered SD.ConclusionsImpairment in autoregulation in aSAH is associated with worse clinical outcomes and occurrence of SD when using ORx and OSRx. Impaired autoregulation precedes SD occurrence. Targeting the optimal MAP or cerebral perfusion pressure in patients with aSAH should use ORx and/or OSRx as the input function rather than intracranial pressure.
Microbial education plays a crucial role in harnessing the beneficial properties of microbiota for infectious disease protection inCrassostrea gigas
Authors: Dantan Luc , Carcassonne Prunelle , Dégremont Lionel , Morga Benjamin , Travers Marie-Agnès , Petton Bruno , Mege Mickael , Maurouard Elise , Allienne Jean-François , Courtay Gaëlle , Romatif Océane , Pouzadoux Juliette , Lami Raphaël , Intertaglia Laurent , Gueguen Yannick , Vidal-Dupiol Jeremie , Toulza Eve , Cosseau Céline 
Published: May 2024

AbstractBackgroundRecently, the frequency and severity of marine diseases have increased in association with global changes, and molluscs of economic interest are particularly concerned. Among them, the Pacific oyster (Crassostrea gigas) production faces challenges from several diseases such as the Pacific Oyster Mortality Syndrome (POMS) or vibriosis. Various strategies such as genetic selection or immune priming have been developed to fight some of these infectious diseases. The microbial education, which consist of exposing the host immune system to beneficial microorganisms during early life stages is a promising approach against diseases. This study explores the concept of microbial education using controlled and pathogen-free bacterial communities and assesses its protective effects against POMS andVibrio aestuarianusinfections, highlighting potential applications in oyster production.ResultsWe demonstrate that it is possible to educate the oyster immune system by adding microorganisms during the larval stage. Adding culture based bacterial mixes to larvae protects only against the POMS disease while adding whole microbial communities from oyster donors protects against both POMS and vibriosis. The efficiency of the immune protection depends both on oyster origin and on the composition of the bacterial mixes used for exposure. No preferential protection was observed when the oysters were stimulated with their sympatric strains. We further show that the added bacteria were not maintained in the oyster microbiota after the exposure, but this bacterial addition induced long term changes in the microbiota composition and oyster immune gene expression.ConclusionOur study reveals successful immune system education of oysters by introducing beneficial micro-organisms during the larval stage. We improved the long-term resistance of oysters against critical diseases (POMS disease andVibrio aestuarianusinfections) highlighting the potential of microbial education in aquaculture.
A benchmark comparison of CRISPRn guide-RNA design algorithms and generation of small single and dual-targeting libraries to boost screening efficiency
Authors: Lukasiak Sebastian , Kalinka Alex , Gupta Nikhil , Papadopoulos Angelos , Saeed Khalid , McDermott Ultan , Hannon Gregory J , Ross-Thriepland Douglas , Walter David 
Published: May 2024

AbstractGenome-wide CRISPR sgRNA libraries have emerged as transformative tools to systematically probe gene function. While these libraries have been iterated over time to be more efficient, their large size limits their use in some applications. Here, we benchmarked publicly available genome-wide single-targeting sgRNA libraries and evaluated dual targeting as a strategy for pooled CRISPR loss-of-function screens. We leveraged this data to design two minimal genome-wide human CRISPR-Cas9 libraries that are 50% smaller than other libraries and that preserve specificity and sensitivity, thus enabling broader deployment at scale.
Machine Learning and Directed Evolution of Base Editing Enzymes
Authors: Perrotta Ramiro M. , Vinke Svenja , Ferreira Raphaël , Moret Michaël , Mahas Ahmed , Chiappino-Pepe Anush , Riedmayr Lisa M. , Mehra Anna-Thérèse , Lehmann Louisa S. , Church George M. 
Published: May 2024

AbstractAs we enter the era of CRISPR medicines, base editors (BEs) emerged as one of the most promising tools to treat genetic associated diseases. However, unintended bystander editing beyond the target nucleotide poses a challenge to their translation into effective therapies. While many efforts have been made in the design of a universal enzyme with minimal bystander editing, the context dependent activity represents a major challenge for base editing-based therapies. In this work, we designed a sequence-specific guide RNA library with 3’-extensions and detected guides that were able to reduce bystander and increase editing efficiency in a context dependent manner. The best candidate was later used for phage assisted non-continuous evolution to find a new generation of precise base editors. Simultaneously, we use protein language models trained on massive protein sequence datasets to find the evolutionarily plausible mutational patterns that can improve deaminase activity and precision. Both strategies provide a collection of precise TadA variants that not only drastically reduced bystander edits, but also was not in detriment of on-target activity. Our findings introduce a guide/enzyme parallel engineering pipeline, which lays the foundation for the development of new personalized genome editing strategies, ultimately enhancing the safety and precision of this groundbreaking technology.
Phase synchrony between prefrontal noradrenergic and cholinergic signals indexes inhibitory control
Authors: Liu Yuxiang (Andy) , Nong Yuhan , Feng Jiesi , Li Guochuan , Sajda Paul , Li Yulong , Wang Qi 
Published: May 2024

AbstractInhibitory control is a critical executive function that allows animals to suppress their impulsive behavior in order to achieve certain goals or avoid punishment. We investigated norepinephrine (NE) and acetylcholine (ACh) dynamics and population neuronal activity in the prefrontal cortex (PFC) during inhibitory control. Using fluorescent sensors to measure extracellular levels of NE and ACh, we simultaneously recorded prefrontal NE and ACh dynamics in mice performing inhibitory control tasks. The prefrontal NE and ACh signals exhibited strong coherence at 0.4-0.8 Hz. Although inhibition of locus coeruleus (LC) neurons projecting to the PFC impaired inhibitory control, inhibiting LC neurons projecting to the basal forebrain (BF) caused a more profound impairment, despite an approximately 30% overlap between LC neurons projecting to the PFC and BF, as revealed by our tracing studies. The inhibition of LC neurons projecting to the BF did not diminish the difference in prefrontal NE/ACh signals between successful and failed trials; instead, it abolished the difference in NE-ACh phase synchrony between successful and failed trials, indicating that NE-ACh phase synchrony is a task-relevant neuromodulatory feature. Chemogenetic inhibition of cholinergic neurons that project to the LC region did not impair inhibitory control, nor did it abolish the difference in NE-ACh phase synchrony between successful or failed trials, further confirming the relevance of NE-ACh phase synchrony to inhibitory control. To understand the possible effect of NE-ACh synchrony on prefrontal population activity, we employed Neuropixels to record from the PFC during inhibitory control. The inhibition of LC neurons projecting to the BF not only reduced the number of prefrontal neurons encoding inhibitory control, but also disrupted population firing patterns representing inhibitory control, as revealed by a demixed principal component (dPCA) analysis. Taken together, these findings suggest that the LC modulates inhibitory control through its collective effect with cholinergic systems on population activity in the prefrontal cortex. Our results further indicate that NE-ACh phase synchrony is a critical neuromodulatory feature with important implications for cognitive control.
Cryo-EM structures of a bathy phytochrome histidine kinase reveal a unique light-dependent activation mechanism
Authors: Bódizs Szabolcs , Mészáros Petra , Grunewald Lukas , Takala Heikki , Westenhoff Sebastian 
Published: May 2024

SummaryPhytochromes are photoreceptor proteins in plants, fungi and bacteria. They can adopt two photochromic states with differential biochemical responses. The structural changes transducing the signal from the chromophore to the biochemical output modules are poorly understood due to challenges in capturing structures of the dynamic, full-length protein. Here, we present the first cryo-electron microscopy structures of the phytochrome fromPseudomonas aeruginosa(PaBphP) in its resting Pfr and photoactivated Pr state. The kinase-active Pr state has an asymmetric, dimeric structure, whereas the kinase-inactive Pfr state opens up. This behaviour is different from other known phytochromes and we explain it with the unusually short connection between the photosensory and output modules. Multiple sequence alignment of this region suggests evolutionary optimisation for different modes of signal transduction in sensor proteins. The results establish a new mechanism for light-sensing by phytochrome histidine kinases and provide input for the design of optogenetic phytochrome variants.
Epigenetic delineation of the earliest cardiac lineage segregation by single-cell multi-omics
Authors: Xie Peng , Jiang Xu , He Jingjing , Pan Qingyun , Yang Zhongzhou , Zheng Yanying , Fan Wenli , Wu Chen , Zheng Weiheng , Fang Ke , Si Shuhan , Zhu Shiqi , Yang Yi , Zhong Tao P. , Yang Zhongzhou , Wei Ke , Xie Wei , Jing Naihe , Luo Zhuojuan , Lin Chengqi 
Published: May 2024

AbstractThe mammalian heart is formed from multiple mesoderm-derived cell lineages. However, it remains largely unknown when and how the specification of mesoderm towards cardiac lineages is determined. Here, we systematically depict the transcriptional trajectories toward cardiomyocyte in early mouse embryo, and characterize the epigenetic landscapes underlying the early mesodermal lineage specification by single-cell multi-omics analyses. The analyses also reveal distinct core regulatory networks (CRN) in controlling specification of mesodermal lineages. We further demonstrate the essential role HAND1 and FOXF1 in driving the earliest cardiac progenitors specification. These key transcription factors occupy at distinct enhancers, but function synergistically and hierarchically to regulate the expression of cardiac-specific genes. In addition, HAND1 is required for exiting from the nascent mesoderm program, while FOXF1 is essential for driving cardiac differentiation during MJH specification. Our findings establish transcriptional and epigenetic determinants specifying the early cardiac lineage, providing insights for the investigation of congenital heart defects.
Mechanism of TAX1BP1 recruitment in aggrephagy to switch from cargo collection to sequestration
Authors: Bauer Bernd , Idinger Jonas , Schuschnig Martina , Ferrari Luca , Martens Sascha 
Published: May 2024

AbstractAutophagy mediates the degradation of harmful material within lysosomes. In aggrephagy, the pathway mediating the degradation of aggregated, ubiquitinated proteins, this cargo material is collected in larger condensates prior to its sequestration by autophagosomes. In this process, SQSTM1/p62 and NBR1 drive cargo condensation, while TAX1BP1, which binds to NBR1 recruits the autophagy machinery to facilitate autophagosome biogenesis at the condensates. The mechanistic basis for the TAX1BP1 mediated switch from cargo collection to its sequestration is unclear. Here we show that TAX1BP1 is not a constitutive component of the condensates. Its recruitment correlates with the induction of autophagosome biogenesis. TAX1BP1 is sufficient to recruit the TBK1 kinase via the SINTBAD adapter. We define the NBR1 - TAX1BP1 binding site, which is adjacent to the GABARAP/LC3 interaction site and demonstrate that the recruitment of TAX1BP1 to cargo mimetics can be enhanced by an increased ubiquitin load. Our study suggests that autophagosome biogenesis is initiated once sufficient cargo is collected in the condensates.