bluuebunny/crossref_metadata_2025_split huggingface dataset:
JASPER: fast, powerful, multitrait association testing in structured samples gives insight on pleiotropy in gene expression
Authors: Mbatchou Joelle , McPeek Mary Sara 
Published: December 2023

AbstractJoint association analysis of multiple traits with multiple genetic variants can provide insight into genetic architecture and pleiotropy, improve trait prediction and increase power for detecting association. Furthermore, some traits are naturally high-dimensional, e.g., images, networks or longitudinally measured traits. Assessing significance for multitrait genetic association can be challenging, especially when the sample has population sub-structure and/or related individuals. Failure to adequately adjust for sample structure can lead to power loss and inflated type 1 error, and commonly used methods for assessing significance can work poorly with a large number of traits or be computationally slow. We developed JASPER, a fast, powerful, robust method for assessing significance of multitrait association with a set of genetic variants, in samples that have population sub-structure, admixture and/or relatedness. In simulations, JASPER has higher power, better type 1 error control, and faster computation than existing methods, with the power and speed advantage of JASPER increasing with the number of traits. JASPER is potentially applicable to a wide range of association testing applications, including for multiple disease traits, expression traits, image-derived traits and microbiome abundances. It allows for covariates, ascertainment and rare variants and is robust to phenotype model misspecification. We apply JASPER to analyze gene expression in the Framingham Heart Study, where, compared to alternative approaches, JASPER finds more significant associations, including several that indicate pleiotropic effects, some of which replicate previous results, while others have not previously been reported. Our results demonstrate the promise of JASPER for powerful multitrait analysis in structured samples.
Chemotherapy synergizes with cancer vaccines and expands stem-like TCF1+CD8+ T cells
Authors: Noblecourt Laurine , Wicki Amanda , Pereira-Almeida Vinnycius , McAuliffe James , Steffke Emily , Panetti Silvia , Ramirez-Valdez Ramiro A. , Chandrasekar Vineethkrishna , Jainarayanan Ashwin , Hill Adrian V.S. , Van den Eynde Benoit J. , Leung Carol Sze Ki 
Published: December 2023

SummaryTherapeutic cancer vaccines, whether based on neoantigens or shared antigens, will likely be given in the clinic together with the standard of care, which often comprises immune checkpoint blockade therapy and chemotherapy. It remains unclear, however, whether vaccines effectively synergize with chemotherapy. Here, we tested the combination of a heterologous prime-boost viral vector vaccine with chemotherapy (CarboTaxol) and anti-PD- 1. We show that this triple combination improves tumor control and survival in different murine tumor models. CarboTaxol, and also cyclophosphamide, acted as an immune adjuvant for the vaccines, enhancing tumor-specific CD8+ T-cell responses, irrespective of the presence of a tumor. These chemotherapies expanded stem-like T cell factor 1 (TCF1)+CD8+ T cells. Inhibition of the transcriptional activity of TCF1/β-catenin with a small molecule inhibitor abolished the immune adjuvant effect of CarboTaxol. This study sheds light on the new immunomodulatory roles of chemotherapies and holds promises for clinical testing of this combination strategy.HighlightsThe combination of CarboTaxol with viral vector cancer vaccines and anti-PD-1 promotes better tumor control, tumor clearance, and survivalCarboTaxol increases TCF1 expression in CD8+ T cells and expands stem-like TCF1+CD8+ T cellsCarboTaxol acts as an adjuvant for cancer vaccines irrespective of the presence of a tumor and this effect is mediated by TCF1/β-catenin activity
Genome-wide exploration of metabolic-based pyrethroid resistance mechanism inHelicoverpa armigera
Authors: Kim Juil , Rahman Md-Mafizur , Han Changhee , Jeon Jungwon , Kwon Min , Lee Si Hyeock , Omoto Celso 
Published: December 2023

ABSTRACTTo elucidate the deltamethrin resistance mechanism inHelicoverpa armigera, we explored mutations at the deltamethrin target site, genomic level variations between insecticide-susceptible and -resistant strains, and differences in gene expression patterns between the strains. Known pyrethroid resistance-associated point mutations within the voltage-gated sodium channel were undetected in the cDNA and gDNA of resistant strains or field populations. The whole-genomede novoassembly of a Korean resistant strain was performed (GCA_026262555.1), and 13 genomes of susceptible and resistant individuals were re-sequenced using field populations. Approximately 3,369,837 variants (SNPs and indels) were compared with our referenceH. armigeragenome, and 1,032,689 variants were identified from open reading frames. A resistance-specific CYP3 subfamily gene with five variants (CYP321A1v1–v5) was identified in the resistant strains, indicating the potential role of these variants in resistance. RNA-seq analysis identified 36,720 transcripts from 45 Illumina RNA-seq datasets of the fat body, gut, and the rest of the body. Differential gene expression analysis revealed some differently overexpressed detoxification enzyme genes in the resistant strains, particularly cytochrome P450 genes. This finding was consistent with the results of bioassay tests using PBO-based synergists, further supporting the role of detoxification enzymes in resistance. Therefore,H. armigeramay acquire deltamethrin resistance through a combination of actions, including the overexpression of various detoxification enzymes, such as CYP3 subfamilies (CYP321A5) and cuticular proteins. The five variants of CYP321A subfamily identified in this study may serve as a basis for understanding insecticide resistance at the molecular level and can be applied as diagnostic markers for resistance.Key MessagesKnown resistance-related mutations were undetected in all the resistant strains or field populations.No specific resistance-associated variations were identified at the genomic level.The expression pattern of the CYP3 subfamily genes was strongly correlated with the level of resistance.Genes other than CYP337B3 are also involved in the development of high-level resistance.Resistance developed as a result of changes in the expression of detoxification genes rather than target site modification through mutation.
An approach to characterize mechanisms of action of anti-amyloidogenic compoundsin vitroandin situ
Authors: Stalder P. , Serdiuk T. , Ghosh D. , Fleischmann Y. , Malinovska L. , Davranche A. , Haenseler W. , Boudou C. , Tsika E. , Ouared A. , Stöhr J. , Melki R. , Riek R. , de Souza N. , Picotti P. 
Published: December 2023

AbstractAggregation of amyloidogenic proteins is associated with neurodegenerative disease and its modulation is a focus of drug development efforts. However, the physicochemical properties and structural heterogeneity of amyloidogenic proteins hinder the mechanistic understanding of anti- amyloidogenic compounds. Further, modes of interaction with amyloidogenic proteins are often probedin vitrousing purified protein samples, even though these models may not capturein vivoprotein structures and do not enable identification of off-target effects. We have developed a modular structural proteomic pipeline based on limited proteolysis coupled to mass spectrometry (LiP-MS) with improved, amino acid level-resolution, to probe the mechanism of action of anti- amyloidogenic compounds. We demonstrate our approach by analysing the interactions of six known or putative anti-amyloidogenic compounds and the amyloid binder Thioflavin T (ThT) with different structural forms of the amyloidogenic Parkinson’s disease (PD) protein α-Synuclein. Our approach enables determination of putative interaction sites, identification of whether interactions are covalent or non-covalent, and crucially, can probe for interactions of compounds with physiological structures of α-Synuclein in complex cell and tissue extracts and identify off-targets.In vitroanalyses with our pipeline showed that the green tea polyphenol EGCG induces an N- and C-terminus- dependent compaction of the unstructured α-Synuclein monomer, detected preferential interactions of ThT with the N-terminus of α-Synuclein fibrils compared to the amyloid core, and showed that the most potent inhibitors of aggregation in our study (EGCG, baicalein and AC Immune compound #2) induced similar non-fibrillar end structures despite different interactions with α-Synuclein monomers. Importantly, in mammalian cell lysates, α-Synuclein was either a low-affinity target (for EGCG and Baicalein) or did not show evidence of compound interaction (for ThT and doxycycline) in our experimental conditions, despite both monomeric and fibrillar forms interacting with these compoundsin vitro. For EGCG, we validated this result in postmortem brain homogenates from PD patients. Thesein situanalyses identified many additional putative cellular targets of Doxycycline, EGCG, Baicalein and ThT, suggesting that their effects in cellular or animal models of neurodegeneration are likely due to interactions with proteins other than α-Synuclein and showing that anti-amyloidogenic compounds should be analyzedin situas well asin vitro. Our modular pipeline will enablein situscreening of drugs and PET tracers for amyloid aggregates of interest as well as detailed mechanistic studies of compound actionin vitro.
Mussels on the move: new records of the invasive non-native quagga mussel (Dreissena rostriformis bugensis) in Great Britain using eDNA and a new probe-based qPCR assay
Authors: Peixoto Sara , Blackman Rosetta C. , Porter Jonathan , Wan Alan , Gerrard Chris , Aston Ben , Handley Lori Lawson 
Published: December 2023

AbstractInvasive non-native species (INNS) pose a worldwide environmental threat, negatively impacting invaded ecosystems on an ecological and economical scale. In recent decades, quagga mussels (Dreissena rostriformis bugensis) have successfully invaded several countries in Western Europe from the Ponto-Caspian region, being recorded for the first time in Great Britain (GB) in 2014, in Wraysbury, near London. In recent years, environmental DNA (eDNA) analysis has proven to be a sensitive and effective method for early detection and monitoring of a number of INNS. Previously, a dye-based quantitative PCR (qPCR) assay was developed for the detection of quagga mussels from eDNA samples. Here, a target-specific probe was designed to further increase the specificity of this assay and used to obtain an updated distribution of this species in GB. Twenty-four sites were sampled, including sites with established populations near London and sites spread across the East Midlands and East Anglia regions. Positive detections were obtained for 11 of the 24 sites, and these were widely spread, as far as Nottingham (East Midlands) and Norfolk (East Anglia). Detection rates were 100% at the three sites with known established populations, while rates were lower (3-50% of positive replicates) in the eight newly-identified sites, consistent with an early stage of invasion. Of particular concern was the detection of quagga mussels in major waterways and in popular recreational sites, highlighting urgent measures are needed to control pathways and spread. Our study demonstrates that quagga mussels are considerably more widespread in GB than previously thought and provides a much-needed step towards operational use of eDNA for monitoring quagga mussels.
The dynamics of oligodendrocyte populations following permanent ischemia promotes long-term spontaneous remyelination of damaged area
Authors: Martín-Lopez Gerardo , Mallavibarrena Paula R. , Villa-Gonzalez Mario , Vidal Noemi , Pérez-Alvarez Maria José 
Published: December 2023

AbstractStroke is a major public health concern, whit limited clinically approved interventions available to enhance sensorimotor recovery beyond reperfusion. Remarkably, spontaneous recovery is observed in certain stroke patients, suggesting the existence of a self-brain repair mechanism not yet fully understood. In a rat model of permanent cerebral ischemia, we described an increase in oligodendrocytes expressing 3RTau in damaged area. Considering that restoration of myelin integrity ameliorates symptoms in many neurodegenerative diseases, here we hypothesize that this cellular response could trigger remyelination. Our results revealed after ischemia an early recruitment of OPCs to damaged area, followed by their differentiation into 3RTau+pre-myelinating cells and subsequent into remyelinating oligodendrocytes. Using rat brain slices and mouse primary culture we confirmed the presence of 3RTau in pre-myelinating oligodendrocytes and a subset of mature. The myelin status analysis confirmed long-term remyelination in the damaged area. Postmortem samples from stroke subjects showed a reduction in oligodendrocytes, 3RTau+cells, and myelin complexity in subcortical white matter. In conclusion, the dynamics of oligodendrocytes populations after ischemia reveals a spontaneous brain self-repair mechanism which restores the functionality of neuronal circuits long-term by remyelination of damage area. This is evidenced by the improvement of sensorimotor functions in ischemic rats. A deep understanding of this mechanism could be valuable in the search for alternative oligodendrocyte-based, therapeutic interventions to reduce the effects of stroke.
Missense mutations in CMS22 patients reveal that PREPL has both enzymatic and non-enzymatic functions
Authors: Monnens Yenthe , Theodoropoulou Anastasia , Rosier Karen , Bhalla Kritika , Mahy Alexia , Vanhoutte Roeland , Meulemans Sandra , Cavani Edoardo , Antanasijevic Aleksandar , Lemmens Irma , Lee Jennifer A. , Spellicy Catherin J. , Schroer Richard J. , Maselli Richardo A. , Laverty Chamindra G. , Agostinis Patrizia , Pagliarini David J. , Verhelst Steven , Marcaida Maria J. , Rochtus Anne , Peraro Matteo Dal , Creemers John W.M. 
Published: December 2023

AbstractCongenital myasthenic syndrome-22 (CMS22) is a rare genetic disorder caused by mutations in the prolyl endopeptidase-like (PREPL) gene. Since previous reports only described patients with deletions and nonsense mutations inPREPL, nothing is known about the effect of missense mutations in the pathology of CMS22. In this study, we have characterized missense mutations inPREPLin three CMS22 patients, all with hallmark phenotypes. Biochemical evaluation revealed that these missense mutations do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria. Structural analysis shows that the mutations affect regions most likely involved in intra-protein or protein-protein interactions. Indeed, binding to a selected group of known interactors was differentially reduced for the three mutants. The importance of non-hydrolytic functions of PREPL was investigated in catalytically inactive PREPL p.Ser559Ala cell lines which showed that hydrolytic activity of PREPL is needed for normal mitochondrial function but not for regulating AP1-mediated transport in the trans-Golgi network. In conclusion, these studies show that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense mutations that do not necessarily result in a loss of hydrolytic activity of PREPL.Graphical abstract
Toxoplasma gondiiF-Box Protein L2 Silences Feline-Restricted Genes Necessary for Sexual Commitment
Authors: Baptista Carlos G. , Hosking Sarah , Gas-Pascual Elisabet , Ciampossine Loic , Abel Steven , Hakimi Mohamed-Ali , Jeffers Victoria , Roch Karine Le , West Christopher M. , Blader Ira J. 
Published: December 2023

ABSTRACTToxoplasma gondiiis a foodborne pathogen that can cause severe and life-threatening infections in fetuses and immunocompromised patients. Felids are its only definitive hosts, and a wide range of animals, including humans, serve as intermediate hosts. When the transmissible bradyzoite stage is orally ingested by felids, they transform into merozoites that expand asexually, ultimately generating millions of gametes for the parasite sexual cycle. However, bradyzoites in intermediate hosts differentiate exclusively to disease-causing tachyzoites, which rapidly disseminate throughout the host. Though tachyzoites are well-studied, the molecular mechanisms governing transitioning between developmental stages are poorly understood. Each parasite stage can be distinguished by a characteristic transcriptional signature, with one signature being repressed during the other stages. Switching between stages requires substantial changes in the proteome, which is achieved in part by ubiquitination. F-box proteins mediate protein poly-ubiquitination by recruiting substrates to SKP1, Cullin-1, F-Box protein E3 ubiquitin ligase (SCF-E3) complexes. We have identified an F-box protein namedToxoplasma gondiiF-Box Protein L2 (TgFBXL2), which localizes to distinct nuclear sites. TgFBXL2 is stably engaged in an SCF-E3 complex that is surprisingly also associated with a COP9 signalosome complex that negatively regulates SCF-E3 function. At the cellular level, TgFBXL2-depleted parasites are severely defective in centrosome replication and daughter cell development. Most remarkable, RNA seq data show that TgFBXL2 conditional depletion induces the expression of genes necessary for sexual commitment. We suggest that TgFBXL2 is a latent guardian of sexual stage development inToxoplasmaand poised to remove conflicting proteins in response to an unknown trigger of sexual development.AUTHOR SUMMARYToxoplasma gondiiis a protozoan parasite that replicates sexually in felids and asexually in nearly all other mammals with each life stage having a specific transcriptional profile. When life stage specific transcription is not properly controlled, the parasite dies and therefore it’s important to understand what inhibits expression of sexual stage genes during asexual growth and vice versa. Here we identify a ubiquitin E3 ligase complex that inhibits sexual stage gene expression during asexual growth.
Integration of Unpaired and Heterogeneous Clinical Flow Cytometry Data
Authors: Phuycharoen Mike , Kaestele Verena , Williams Thomas , Lin Lijing , Hussell Tracy , Grainger John , Rattray Magnus 
Published: December 2023

AbstractWe introduce the Unbiasing Variational Autoencoder (UVAE), a novel computational framework developed for the integration of unpaired biomedical data streams, with a particular focus on clinical flow cytometry. UVAE effectively addresses the challenges of batch effect correction and data alignment by training a semi-supervised model on partially labeled datasets. This approach enables the simultaneous normalisation and integration of diverse data within a shared latent space. The frame-work is implemented in Python with a descriptive interface for the specification and incorporation of multiple, partially overlapping data series. UVAE employs a probabilistic model for batch effect normalisation, with a generative capacity for unbiased data reconstruction and inference from heterogeneous samples. Its training process strategically balances class contents during various stages, ensuring accurate representation in statistical analyses. The model’s convergence is achieved through a stable, non-adversarial training mechanism, complemented by an automated selection of hyper-parameters via Bayesian optimization. We quantitatively validate the performance of UVAE’s constituent components and apply it to the problem of integrating heterogeneous clinical flow cytometry data collected from COVID-19 patients. We show that the alignment process enhances the statistical signal of cell types associated with severity and enables clustering of subpopulations without the impediment of batch effects. Finally, we demonstrate that homogeneous data generated by UVAE can be used to improve the performance of longitudinal regression for predicting peak disease severity from temporal patient samples.Availability: Framework:https://github.com/mikephn/UVAE. Training and benchmarking code:https://github.com/mikephn/UVAE-COVID19-codebase. Data and model files will be made available upon completing peer review.
Covalent Targeting of Splicing in T Cells
Authors: Scott Kevin A. , Kojima Hiroyuki , Ropek Nathalie , Warren Charles D. , Zhang Tiffany L. , Hogg Simon J. , Webster Caroline , Zhang Xiaoyu , Rahman Jahan , Melillo Bruno , Cravatt Benjamin F. , Lyu Jiankun , Abdel-Wahab Omar , Vinogradova Ekaterina V. 
Published: December 2023

SummaryDespite significant interest in therapeutic targeting of splicing, few chemical probes are available for the proteins involved in splicing. Here, we show that elaborated stereoisomeric acrylamide chemical probe EV96 and its analogues lead to a selective T cell state-dependent loss of interleukin 2-inducible T cell kinase (ITK) by targeting one of the core splicing factors SF3B1. Mechanistic investigations suggest that the state-dependency stems from a combination of differential protein turnover rates and availability of functional mRNA pools that can be depleted due to extensive alternative splicing. We further introduce a comprehensive list of proteins involved in splicing and leverage both cysteine- and protein-directed activity-based protein profiling (ABPP) data with electrophilic scout fragments to demonstrate covalent ligandability for many classes of splicing factors and splicing regulators in primary human T cells. Taken together, our findings show how chemical perturbation of splicing can lead to immune state-dependent changes in protein expression and provide evidence for the broad potential to target splicing factors with covalent chemistry.
Variability of morphology-performance relationships under acute exposure to different temperatures in three strains of zebrafish
Authors: Miller Christina L , Dugand Robert J , McGuigan Katrina 
Published: December 2023

AbstractLocomotion is thermally sensitive in ectotherms and therefore it is typically expressed differently among thermally heterogenous environments. Locomotion is a complex function, and while physiological and behavioural traits that influence locomotor performance may respond to thermal variation throughout life, other contributing traits, like body shape, may have more restricted responses. How morphology affects locomotor performance under variable temperature conditions is unknown. Here, we investigated three genetically distinct strains of zebrafish (AB, WIK, and Tu) with a shared multi-generational history at 28°C. After rearing fish at a constant 28°C, we measured prolonged swimming speed (Ucrit) at each of six temperatures (between 16°C and 34°C). Speed was strongly positively correlated among temperatures, resulting in most among-individual variation being temperature-independent (i.e., fish were relatively fast or slow across all temperatures). However, we also detected significant variation along two axes reflecting temperature-dependent variation, including one reflecting differences among individuals consistent with a hotter-colder tradeoff (i.e., individuals that were relatively fast at cooler temperatures were relatively slow at hotter temperatures and vice versa). Although strains differed in mean swimming performance, within strain (among-individual) patterns of speed variation were markedly consistent. Body shape and size explained significant variation among individuals in both temperature-independent and temperature-dependent axes of swimming speed variation. Notably, morphological traits that were most strongly associated with temperature-independent performance variation (i.e., faster-slower) differed from those associated with temperature-dependent (i.e., hotter-colder) variation. Further, there were significant differences among strains in both the direction and strength of association for specific morphological traits. Our results suggest that thermally heterogenous environments could have complex effects on the evolution of traits that contribute to whole organism performance traits.