bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct Perception Mechanisms of BACH1 Quaternary Structure Degrons by Two F-box Proteins under Oxidative Stress
Authors: Cao Shiyun , Shi Huigang , Garcia Sheena Faye , Kito Yuki , Shi Hui , Goldberg Hailey V. , Ponce Jackeline , Ueberheide Beatrix , Lignitto Luca , Pagano Michele , Zheng Ning 
Published: June 2024

SUMMARYThe transcription factor BACH1 regulates heme homeostasis and oxidative stress responses and promotes cancer metastasis upon aberrant accumulation. Its stability is controlled by two F-box protein ubiquitin ligases, FBXO22 and FBXL17. Here we show that the homodimeric BTB domain of BACH1 functions as a previously undescribed quaternary structure degron, which is deciphered by the two F-box proteins via distinct mechanisms. After BACH1 is released from chromatin by heme, FBXO22 asymmetrically recognizes a cross-protomer interface of the intact BACH1 BTB dimer, which is otherwise masked by the co-repressor NCOR1. If the BACH1 BTB dimer escapes the surveillance by FBXO22 due to oxidative modifications, its quaternary structure integrity is probed by a pair of FBXL17, which simultaneously engage and remodel the two BTB protomers into E3-bound monomers for ubiquitination. By unveiling the multifaceted regulatory mechanisms of BACH1 stability, our studies highlight the abilities of ubiquitin ligases to decode high-order protein assemblies and reveal therapeutic opportunities to block cancer invasion via compound-induced BACH1 destabilization.
Loopsim: Enrichment Analysis of Chromosome Conformation Capture with Fast Empirical Distribution Simulation
Authors: Shaked Gideon , Zhang Haihan , Zhang Zhaolin , Gudjonsson Johann E. , Elder James T. , Patrick Matthew T. , Tsoi Lam C. 
Published: June 2024

AbstractSummaryGene regulation is intricately influenced by the three-dimensional organization of the genome. In particular, chromatin can exist in loop structures that enable long-range regulatory interactions. By utilizing chromosome conformation capture techniques such as Hi-C, valuable information regarding the organization of these loop structures in 3D space can be obtained. While functional/feature enrichment has become a standard downstream analysis for different genomic data to provide biological context, tools that developed specifically for high throughput assays capturing chromosome conformation are relatively limited. Here, we present Loopsim, a command-line application that performs enrichment analysis on Hi-C loop profiles against user-defined regions. Loopsim efficiently simulates a background distribution using a distinctive sampling approach that considers loop size, intervals, loop-loop distances, and structure; it then computes loop-level statistics based on the empirical null distribution.AvailabilityLoopsim is a Python package available via PyPI (https://pypi.org/project/loopsim) and the source code is available on GitHub (https://github.com/CutaneousBioinf/Loopsim) under the MIT license.
The TyphiNET data visualisation dashboard: UnlockingSalmonellaTyphi genomics data to support public health
Authors: Dyson Zoe A. , Cerdeira Louise , Sharma Vandana , Carey Megan E. , Holt Kathryn E. ,   Global Typhoid Genomics Consortium
Published: June 2024

AbstractBackgroundSalmonella entericasubspeciesentericaserovar Typhi (abbreviated as ‘Typhi’) is the bacterial agent of typhoid fever. Effective antimicrobial therapy reduces complications and mortality; however, antimicrobial resistance (AMR) is a major problem in many endemic countries. Prevention through vaccination is possible through recently-licensed Gavi-supported typhoid conjugate vaccines (TCVs), and national immunisation programs are currently being considered or deployed in several countries where AMR prevalence is known to be high. Pathogen whole genome sequence data are a rich source of information on Typhi variants (genotypes or lineages), AMR prevalence, and mechanisms. However, this information is currently not readily accessible to non-genomics experts, including those driving vaccine implementation or empirical therapy guidance.ResultsWe developed TyphiNET (https://www.typhi.net), an interactive online dashboard for exploring Typhi genotype and AMR distributions derived from publicly available pathogen genome sequences. TyphiNET allows users to explore country-level summaries such as the frequency of pathogen lineages, temporal trends in resistance to clinically relevant antimicrobials, and the specific variants and mechanisms underlying emergent AMR trends. User-driven plots and session reports can be downloaded for ease of sharing. Importantly, TyphiNET is populated by high-quality genome data curated by the Global Typhoid Pathogen Genomics Consortium, analysed using the Pathogenwatch platform, and identified as coming from non-targeted sampling frames that are suitable for estimating AMR prevalence amongst Typhi infections (no personal data is included in the platform). As of February 2024, data from a total of n=11,836 genomes from 101 countries are available in TyphiNET. We outline case studies illustrating how the dashboard can be used to explore these data and gain insights of relevance to both researchers and public health policy-makers.ConclusionsThe TyphiNET dashboard provides an interactive platform for accessing genome-derived data on pathogen variant frequencies to inform typhoid control and intervention strategies. The platform is extensible in terms of both data and features, and provides a model for making complex bacterial genome-derived data accessible to a wide audience.
Amygdala circuit mechanisms underlying alcohol seeking
Authors: Suh Junghyup , Pasqualini Amanda L. , Zambrano Maria A. , Ressler Kerry J. 
Published: June 2024

AbstractAlcohol seeking during abstinence is mediated in part by strong associations between the pharmacological effects of alcohol and the environment within which alcohol is administered. The amygdala, particularly the basolateral amygdala (BLA), is a key neural substrate of environmental cue and reward associations since it is involved in associative learning and memory recall. However, we still lack a clear understanding of how the activity of molecularly distinct BLA neurons is affected by alcohol and encodes information that drives environmental cue-dependent, alcohol-related behaviors. We previously demonstrated that a subset of BLA neurons which express the CaMKII and Thy1 markers project preferentially to the nucleus accumbens (NAcc), rather than the central amygdala; and these neurons mediate fear inhibition rather than fear acquisition or expression, suggesting a specific role in positive valence processing. We now demonstrate that Pavlovian conditioning with alcohol administration increases the activity of these Thy1-expressing (Thy1+) excitatory neurons in mouse BLA, which is necessary for the conditioned appetitive response.In vivocalcium imaging indicates that the temporal activity profile of these neurons is also correlated with alcohol seeking behavior in response to environmental cues. Optogenetic inhibition of BLA Thy1+ neuronal activity disrupts both the formation and recall of alcohol conditioned place preference. Furthermore, selective axonal inhibition of BLA-Thy1+ neurons reveals that the activity of their NAcc and prefrontal cortex (PFC) projections are differentially necessary for alcohol cueassociationvs.recall, respectively. Together, these findings provide insights into a molecularly distinct subset of BLA neurons that regulates environmental cue-reward associations and drives alcohol seeking behaviors in a projection-specific manner.DisclosuresKJR has received consulting income from Acer, Bionomics, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, the Brain and Behavior Research Foundation, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. None of this work is directly related to the work presented here.
DICE: Fast and Accurate Distance-Based Reconstruction of Single-Cell Copy Number Phylogenies
Authors: Weiner Samson , Bansal Mukul S. 
Published: June 2024

AbstractSomatic copy number alterations (sCNAs) are valuable phylogenetic markers for inferring evolutionary relationships among tumor cell subpopulations. Advances in single-cell DNA sequencing technologies are making it possible to obtain such sCNAs datasets at ever-larger scales. However, existing methods for reconstructing phylogenies from sCNAs are often too slow for large datasets. Moreover, the accuracies of many existing methods are highly sensitive to error and other features of the analyzed datasets.In this work, we propose two new distance-based approaches for reconstructing single-cell tumor phylogenies from sCNA data. The new methods,DICE-barandDICE-star, are based on novel, easy-to-compute distance measures and drastically outperform the current state-of-the-art in terms of both accuracy and scalability. Using carefully simulated datasets, we find that DICE-bar and DICE-star significantly improve upon the accuracies of existing methods across a wide range of experimental conditions and error rates while simultaneously being orders of magnitude faster. Our experimental analysis also reveals how noise/error in copy number inference, as expected for real datasets, can drastically impact the accuracies of many existing methods. We apply DICE-star, the most accurate method on error-prone datasets, to two real single-cell breast cancer datasets and find that it helps identify previously unreported rare cell populations.
Genomic regions of current low hybridisation mark long-term barriers to gene flow in scarce swallowtail butterflies
Authors: Ebdon Sam , Laetsch Dominik R. , Vila Roger , Baird Stuart J.E. , Lohse Konrad 
Published: June 2024

AbstractMany closely related species continue to hybridise after millions of generations of divergence. However, the extent to which current patterning in hybrid zones connects back to the speciation process remains unclear: does evidence for current multilocus barriers support the hypothesis of speciation due to multilocus divergence? We analyse whole-genome sequencing data to investigate the speciation history of the scarce swallowtailsIphiclides podaliriusandI. feisthamelii, which abut at a narrow (∼25 km) contact zone north of the Pyrenees. We first quantify the heterogeneity of effective migration rate under a model of isolation with migration, using genomes sampled across the range to identify long-term barriers to gene flow. Secondly, we investigate the recent ancestry of individuals from the hybrid zone using genome polarisation and estimate the coupling coefficient under a model of a multilocus barrier. We infer a low rate of long-term gene flow fromI. feisthameliiintoI. podaliriusthe direction of which matches the admixture across the hybrid zone and complete reproductive isolation across≈33% of the genome. Our contrast of recent and long-term gene flow shows that regions of low recent hybridisation are indeed enriched for long-term barriers which maintain divergence between these hybridising sister species. This paves the way for future analysis of the evolution of reproductive isolation along the speciation continuum.Author summaryEfforts to understand how new species evolve typically approach the problem through either: 1) investigating patterns of genetic exchange across ’hybrid zones’ — where closely related species interbreed — or 2) modelling the demographic history of closely related species. Both approaches are capable of quantifying variation in genetic exchange, or ’gene flow’, along the genome to identify regions of reproductive isolation; yet they leverage genetic signatures across vastly different timescales. The former exploits very recent signatures, while the latter averages long-term signatures over the history of divergence. Hence, we can contrast the genomic distribution of barriers acting on these very different timescales to test how patterns of gene flow change across the speciation continuum. Here we use this strategy to capture the speciation dynamics of a pair of hybridising papilionid butterflies. Our results show that not only are these species continuing to produce hybrids after more than a million years since the onset of divergence, but there is a significant degree of concordance between patterns of gene flow observed along the genome across time scales.
QTL mapping in field plant populations reveals a genetic basis for frequency- and spatially-specific fungal pathosystem resistance
Authors: Baraniecka Patrycja , Gase Klaus , Pradhan Maitree , Baldwin Ian T. , McGale Erica , Valim Henrique F. 
Published: June 2024

AbstractFungal pathogens pose significant challenges to agro-ecosystem productivity. The wild tobacco,Nicotiana attenuata, has been grown for over two decades at an experimental field station in its native habitat, leading to the emergence of a high-mortality sudden wilt disease caused by aFusarium-Alternariapathosystem. By using an Advanced Intercross Recombinant Inbred Line (AI-RIL) mapping population ofN. attenuataplanted in the infected field site, we found two significant loci associated with plant susceptibility to the fungi. A functional characterization of several genes in these loci identifiedRLXL(intracellular ribonuclease LX-like) as an important factor underlying plant pathogen resistance. Virus-induced silencing ofRLXLreduced leaf wilting in plants inoculated with anin vitroculture ofFusariumspecies. Assessing the significance of theRLXL-associated allele in mixed field populations indicated that, among 4-plant subpopulations, those harboring a single plant with theRLXL-deficiency allele exhibited the highest survival rates. Within these populations, a livingRLXL-deficient plant improved the survival ofRLXL-producing plants located diagonally, while the mortality of the adjacent plants remained as high as in all other subpopulations. Taken together, these findings provide evidence for the genetic basis for a frequency- and spatially-dependent population pathogen resistance mechanism.Significance statementPlant pathogen resistance studies predominantly focus on single genes that reduce pathogenicity in individual plants, aiming to apply these findings to agricultural monocultures. On the other hand, ecologists have observed for decades that greater diversity drives plant population resistance and resilience to pathogens. More studies are needed to identify and characterize loci with positive effects conferred through their frequency in plant populations. We combine quantitative genetics, molecular techniques, and ecologically-informed mixed field populations to identify a novel intracellular ribonuclease LX-like (RLXL) gene with a frequency- and position-dependent effect for plant resistance. To our knowledge, this is the first detailed link between plant population protection and various percentages of plants with an allele representingRLXLpresence or absence.
A new level of RNA-based plant protection - dsRNAs designed from functionally characterized siRNAs highly effective against Cucumber Mosaic Virus
Authors: Knoblich Marie , Gursinsky Torsten , Gago-Zachert Selma , Weinholdt Claus , Grau Jan , Behrens Sven-Erik 
Published: June 2024

AbstractRNA-mediated crop protection increasingly becomes a viable alternative to agrochemicals that threaten biodiversity and human health. Pathogen-derived double-stranded dsRNAs are processed into small interfering RNAs (siRNAs), which can then induce silencing of target RNAs,e.g.viral genomes. However, with currently used dsRNAs, which largely consist of undefined regions of the target RNAs, silencing is often ineffective: processing generates siRNA pools that contain only a few functionally effective siRNAs (here calledesiRNAs). Using a recently developedin vitroscreen that reliably identifiesesiRNAs from siRNA pools, we identifiedesiRNAs against Cucumber Mosaic Virus (CMV), a devastating plant pathogen. Topical application ofesiRNAs to plants resulted in highly effective protection against massive CMV infection. However, optimal protection was achieved with newly designed multivalent “effective dsRNAs” (edsRNAs), which contain the sequences of severalesiRNAs and are preferentially processed into precisely theseesiRNAs. TheesiRNA components can attack one or more target RNAs at different sites, be active in different silencing complexes and provide cross-protection against different viral variants, important properties for combating rapidly mutating pathogens such as CMV.esiRNAs andedsRNAs have thus been established as a new class of “RNA actives” that significantly increase the efficacy and specificity of RNA-mediated plant protection.
Florfenicol administration in piglets co-selects for multiple antimicrobial resistance genes
Authors: Holman Devin B. , Gzyl Katherine E. , Kommadath Arun 
Published: June 2024

AbstractFlorfenicol is a broad-spectrum phenicol antibiotic used in swine for various indications. However, information regarding its effect on the pig gut microbiome and resistome is lacking. Therefore, this study investigated those effects by treating piglets with an intramuscular injection of florfenicol at 1 and 7 days of age. Fecal samples were collected from treated (n =30) and untreated (n = 30) pigs at nine different time points up until 140 days of age and their microbiomes were profiled using both 16S rRNA gene and shotgun metagenomic sequencing. The gut microbiomes of the two groups of piglets were most dissimilar in the immediate period following florfenicol administration. These differences were driven in part by an enrichment inClostridium scindens,Enterococcus faecalis, andEscherichiaspp. in the florfenicol-treated piglets andFusobacteriumspp.,Pauljensenia hyovaginalis,andRuminococcus gnavusin the control piglets. In addition to florfenicol resistance genes includingfloR,fexA, andfexB, florfenicol also selected for genes conferring resistance to the aminoglycosides, beta-lactams, peptides, or sulfonamides up until weaning at 21 days of age. Florfenicol-resistantEscherichia coliisolated from these piglets were found to carry a plasmid with afloR, alongtet(A),aph(6)-Id,aph(3’’)-Ib,sul2, andblaTEM-1/blaCMY-2. A plasmid carryingfexBandpoxtAwas identified in florfenicol-resistantEnterococcus avium,Enterococcus faecium, andE.faecalisisolates from the treated piglets. This study highlights the potential for co-selection and perturbation of the gut microbial community in pre-weaned piglets administered florfenicol.ImportanceAntimicrobial use and resistance remain a serious challenge in food-animal production systems. Understanding how specific antimicrobials affect the gut microbiome and resistome is an important step in reducing antimicrobial use and resistance. Florfenicol is an antimicrobial used in swine production, yet very little is known about its effect on the pig gut microbiome and resistome. In this study, we administered florfenicol to piglets at 1 and 7 days of age and characterized their fecal metagenomes through to 140 days of age. Florfenicol altered the fecal microbiome and selected for many unrelated antimicrobial resistance genes up until weaning at 21 days of age. Part of this co-selection process appeared to involve anEscherichia coliplasmid carrying a florfenicol resistance gene along with genes conferring resistance to at least four other antimicrobial classes. These results demonstrate the potential for certain antimicrobials to co-select for multiple, unrelated antimicrobial resistance genes in pigs.
Antigen specificity shapes antibody functions in tuberculosis
Authors: Miles Joshua R. , Lu Pei , Bai Shuangyi , Aguillón-Durán Genesis P. , Rodríguez-Herrera Javier E. , Gunn Bronwyn M. , Restrepo Blanca I. , Lu Lenette L. 
Published: June 2024

AbstractTuberculosis (TB) is the number one infectious disease cause of death worldwide due to an incomplete understanding of immunity. Emerging data highlight antibody functions mediated by the Fc domain as immune correlates. However, the mechanisms by which antibody functions impact the causative agentMycobacterium tuberculosis (Mtb)are unclear. Here, we examine how antigen specificity determined by the Fab domain shapes Fc effector functions againstMtb.Using the critical structural and secreted virulence proteinsMtbcell wall and ESAT-6 & CFP-10, we observe that antigen specificity alters subclass, antibody post-translational glycosylation, and Fc effector functions in TB patients. Moreover,Mtbcell wall IgG3 enhances disease through opsonophagocytosis of extracellularMtb. In contrast, polyclonal and a human monoclonal IgG1 we generated targeting ESAT-6 & CFP-10 inhibit intracellularMtb. These data show that antibodies have multiple roles in TB and antigen specificity is a critical determinant of the protective and pathogenic capacity.
PP2C phosphatase Pic14 negatively regulates tomato Pto/Prf-triggered immunity by inhibiting MAPK activation
Authors: Chakraborty Joydeep , Sobol Guy , Xia Fan , Zhang Ning , Martin Gregory B. , Sessa Guido 
Published: June 2024

SUMMARYType 2C protein phosphatases (PP2Cs) are emerging as important regulators of plant immune responses, although little is known about how they might impact nucleotide-binding, leucine-rich repeat (NLR)-triggered immunity (NTI). We discovered that expression of the PP2C-immunity associated candidate 14 gene (Pic14) is induced upon activation of the Pto/Prf-mediated NTI response in tomato. Pto/Prf recognize the effector AvrPto translocated into plant cells by the pathogenPseudomonas syringaepv.tomato(Pst) and activate a MAPK cascade and other responses which together confer resistance to bacterial speck disease.Pic14encodes a PP2C with an N-terminal kinase-interacting motif (KIM) and a C-terminal phosphatase domain. Upon inoculation withPst-AvrPto, Pto/Prf-expressing tomato plants with loss-of-function mutations inPic14developed less speck disease, specifically in older leaves, compared to wild-type plants. Transient expression of Pic14 in leaves ofNicotiana benthamianaand tomato inhibited cell death typically induced by Pto/Prf and the MAPK cascade members M3Kα and Mkk2. The cell death-suppressing activity of Pic14 was dependent on the KIM and the catalytic phosphatase domain. Pic14 inhibited M3Kα- and Mkk2-mediated activation of immunity-associated MAPKs and Pic14 was shown to be an active phosphatase that physically interacts with and dephosphorylates Mkk2 in a KIM-dependent manner. Together, our results reveal Pic14 as an important negative regulator of Pto/Prf-triggered immunity by interacting with and dephosphorylating Mkk2.SIGNIFICANCE STATEMENTPlant intracellular immune receptors, typically nucleotide-binding, leucine-rich repeat proteins (NLRs) such as the tomato Prf protein activate NLR-triggered immunity (NTI) in response to specific pathogen virulence proteins. This paper reveals how a protein phosphatase interacts with and dephosphorylates a key signaling component acting downstream of Pto/Prf, likely to moderate negative effects of NTI on growth or other plant processes.