bluuebunny/crossref_metadata_2025_split huggingface dataset:
Th2 cell extracellular vesicles promote eosinophil survival through the cytokine cargo IL-3 and prolong airway eosinophilia
Authors: Bunn Kaitlyn E. , Giese-Byrne Brenna G. , Pua Heather H. 
Published: July 2024

AbstractBackgroundExtracellular vesicles (EVs) mediate intercellular communication during immune responses. EVs are abundant in respiratory biofluids, and the composition of EVs in the lung changes during inflammation.ObjectiveWe aimed to quantify the contribution of T cells to airway EVs in allergic lung inflammation and ascertain their function during a type 2 inflammatory response.MethodsGenetic membrane tagging was combined with single vesicle flow cytometry to quantify T cell EVs in the airways of mice challenged with ovalbumin or house dust mite. EVs were purified from T helper type 2 (Th2) cell cultures and their functions on eosinophils assessed by flow cytometry and RNA sequencing. Th2 cell EVs were instilled into the lungs of mice to determine effects on lung eosinophilia. Finally, the function of an EV protein cargo was tested using inhibitors and blocking antibodies.ResultsT cell EVs are increased in the airways of mice with induced allergic inflammation. EVs secreted by Th2 cells inhibit apoptosis and induce activating pathways in eosinophilsin vitro.This effect depends on re-stimulation through the T cell receptor. Th2 cell EVs prolong eosinophiliain vivoduring allergic airway inflammation. Th2 cell EVs carry a potent form of the cytokine IL-3 on their surfaces, which inhibits apoptosis by activating Jak1/2-dependent pro-survival programs in eosinophils.ConclusionTh2 cell EVs promote eosinophil survival and prolong eosinophilia during allergic airway inflammation. This function depends on the EV cargo IL-3, supporting a role for EVs as vehicles of cytokine-based communication in lung inflammation.Key MessagesT cells secrete extracellular vesicles in the airway during allergic lung inflammation.Th2 cell extracellular vesicles inhibit eosinophil apoptosis and prolong airway eosinophilia during allergic lung inflammation.IL-3 carried on Th2 cell EVs is a functional cargo, supporting a role for cytokine-carrying EVs as drivers of type 2 inflammation.Capsule summaryThis study supports that T cell extracellular vesicles may be important drivers of eosinophilic inflammation through the cytokine cargo IL-3, offering new insights into pro-inflammatory signaling in the allergic lung of patients with asthma.
Towards a new standard in genomic data privacy: a realization of owner-governance
Authors: Zhang Jingcheng , Ren Yingxuan , Au Man Ho , Chow Ka-Ho , Zhou Yekai , Chen Lei , Zhao Yanmin , Su Junhao , Luo Ruibang 
Published: July 2024

AbstractWith the rapid developments in sequencing technologies, individuals now have unprecedented access to their genomic data. However, existing data management systems or protocols are inadequate for protecting privacy, limiting individuals’ control over their genomic information, hindering data sharing, and posing a challenge for biomedical research. To fill the gap, an owner-governed system that fulfills owner authority, lifecycle data encryption, and verifiability at the same time is prompted. In this paper, we realized Governome, an owner-governed data management system designed to empower individuals with absolute control over their genomic data during data sharing. Governome uses a blockchain to manage all transactions and permissions, enabling data owners with dynamic permission management and to be fully informed about every data usage. It uses homomorphic encryption and zero-knowledge proofs to enable genomic data storage and computation in an encrypted and verifiable form for its whole lifecycle. Governome supports genomic analysis tasks, including individual variant query, cohort study, GWAS analysis, and forensics. Query of a variant’s genotype distribution among 2,504 1kGP individuals in Governome can be efficiently completed in under 18 hours on an ordinary server. Governome is an open-source project available athttps://github.com/HKU-BAL/Governome.
Mechanisms of Anammox Adaptation to High Temperatures: Increased Cyclization of Ladderane Lipids and Proteomic Insights
Authors: Christina Karmann , Klára Navrátilová , Adam Behner , Tayyaba Noor , Stella Danner , Anastasia Majchrzak , Jiří Šantrůček , Tomáš Podzimek , Marco A. Marin Lopez , Jana Hajšlová , Petra Lipovová , Jan Bartáček , Vojtěch Kouba 
Published: July 2024

AbstractAbstract FigureGraphical abstractAlthough anammox-based processes have been widely applied in mesophilic conditions of reject water and recently in mainstream conditions, the potential of their implementation in high-temperature wastewaters remains largely unexplored. Therefore, this study investigated the operation parameters for the successful adaptation of anammox bacteria and the mechanisms involved on the proteomic and cellular level including unique ladderane lipids. For this purpose, the enrichment of ‘CandidatusBrocadia’ was cultivated in two fed-batch reactors (FBRs) at a lab scale. The temperature of one FBR was gradually increased from 30 to 40 °C while the other FBR was maintained at 30 °C with four consecutive replicates of this experiment. For this adaptation to be successful, the original loading rate had to be at least halved, or ideally maintained below half the value of the specific anammox activity at the time. The most notable adaptation mechanisms included: (1) upregulation of chaperones and (2) doubled ladderane cyclization via the replacement of non-ladderane fatty acid by a ladderane fatty acid in ladderane lipids (p-value 0.005). To our best knowledge, this is the first study to describe the novel mechanism of ladderane cyclization which together with other adaptation strategies presents crucial indicators in anammox adaptation to high-temperature wastewaters.
Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma
Authors: Tandukar Bishal , Deivendran Delahny , Chen Limin , Cruz-Pacheco Noel , Sharma Harsh , Xu Albert , Bandari Aravind K. , Chen Daniel B. , George Christopher , Marty Annika , Cho Raymond J. , Cheng Jeffrey , Saylor Drew , Gerami Pedram , Arron Sarah T. , Bastian Boris C. , Shain A. Hunter 
Published: July 2024

AbstractWe performed multi-omic profiling of epidermal keratinocytes, precancerous actinic keratoses, and squamous cell carcinomas to understand the molecular transitions during skin carcinogenesis. Single-cell mutational analyses of normal skin cells showed that most keratinocytes have remarkably low mutation burdens, despite decades of sun exposure, however keratinocytes withTP53orNOTCH1mutations had substantially higher mutation burdens. These observations suggest that wild-type keratinocytes (i.e. without pathogenic mutations) are able to withstand high dosages of cumulative UV radiation, but certain pathogenic mutations break these adaptive mechanisms, priming keratinocytes for transformation by increasing their mutation rate. Mutational profiling of squamous cell carcinomas adjacent to actinic keratoses revealedTERTpromoter andCDKN2Amutations emerging in actinic keratoses, whereas additional mutations inactivatingARID2and activating the MAPK-pathway delineated the transition to squamous cell carcinomas. Surprisingly, actinic keratoses were often not related to their neighboring squamous cell carcinoma, indicating that collisions of unrelated neoplasms are common in the skin. Spatial variation in gene expression patterns was common in both tumor and immune cells, with high expression of checkpoint molecules at the invasive front of tumors. In conclusion, this study catalogues the key events during the evolution of cutaneous squamous cell carcinoma.
Beware of Data Leakage from Protein LLM Pretraining
Authors: Hermann Leon , Fiedler Tobias , Nguyen Hoang An , Nowicka Melania , Bartoszewicz Jakub M. 
Published: July 2024

AbstractPretrained protein language models are becoming increasingly popular as a backbone for protein property inference tasks such as structure prediction or function annotation, accelerating biological research. However, related research oftentimes does not consider the effects of data leakage from pretraining on the actual downstream task, resulting in potentially unrealistic performance estimates. Reported generalization might not necessarily be reproducible for proteins highly dissimilar from the pretraining set. In this work, we measure the effects of data leakage from protein language model pretraining in the domain of protein thermostability prediction. Specifically, we compare two different dataset split strategies: a pretraining-aware split, designed to avoid similarity between pretraining data and the held-out test sets, and a commonly-used naive split, relying on clustering the training data for a downstream task without taking the pretraining data into account. Our experiments suggest that data leakage from language model pretraining shows consistent effects on melting point prediction across all experiments, distorting the measured performance. The source code and our dataset splits are available athttps://github.com/tfiedlerdev/pretraining-aware-hotprot.
Expression and characterization of the complete cyanophage genome PP in the heterologous hostSynechococcus elongatusPCC 7942
Authors: Li Guorui , Feng Jia , Zhu Xiaofei , Chai Yujie , Sun Tao , Jiang Jianlan 
Published: July 2024

AbstractCyanophages are considered a promising biological management option for treating cyanobacterial blooms. Broadening the host range of cyanophages and/or shortening the lysis cycle by designing and synthesizing artificial cyanophages are potential strategies to enhance their effectiveness and efficiency. However, the rescue of artificial cyanophage genomes remains unexplored. In this study, we achieved the integration of a full-length cyanophage genome, PP, which originally infectsPlectonema boryanumFACHB-240, into the model cyanobacteriumSynechococcus elongatusPCC 7942. Since the integration of these large fragments (∼42 kb) into cyanobacteria depended on conjugation viaEscherichia coli, the toxic open reading frames (ORFs) of PP toE. coliwere first identified, leading to the identification of toxic ORF6, ORF11, and ORF22. The original PP genome was then rearranged, and the three toxic ORFs were controlled using a tandem induction switch. The full length of the PP genome was integrated into the genome ofS. elongatusPCC 7942 via two rounds of homologous recombination.Interestingly, compared to the control strain, the integration of the PP genome decreased photosynthesis and carbon fixation inS. elongatusPCC 7942, exhibiting cyanophage-like behavior. Transcriptomic analysis revealed that 32 of the 41 ORFs of the PP genome were transcribed inS. elongatusPCC 7942, significantly altering the energy metabolism and carbon fixation pathways. These influences were further demonstrated using metabolomics. This study provides a comprehensive approach for the artificial design and integration of cyanophage genomes in cyanobacteria, laying the foundation for their real rescue in the future.
Seumetry: a versatile and comprehensive R toolkit to accelerate high-dimensional flow and mass cytometry data analysis
Authors: Borggrewe Malte , Flosbach Markus ,   Hamburg Intestinal Tissue Study Group, Bonn Stefan , Bunders Madeleine J. 
Published: July 2024

AbstractRecent progress in flow and mass cytometry technologies enables the simultaneous measurement of over 50 parameters for an individual cell. The resulting increase in data volume and complexity present challenges, as conventional analysis methods based on manual gating are time-consuming and fail to capture unknown or minor cell populations. Advances in single-cell RNA sequencing (scRNAseq) technologies have prompted the development of sophisticated computational analysis tools specifically designed to process and analyze high-dimensional biological data, some of which could significantly improve certain aspects of cytometry data analysis. Building on these advances, we here present Seumetry, a framework that combines flow and mass cytometry data-specific analysis methods with the capabilities of Seurat, a powerful tool for the analysis of scRNAseq data. Seumetry offers advanced quality control, data visualizations, and differential population abundance and protein expression analysis. We tested Seumetry on an in-house generated complex dataset of immune cells from different layers of human intestines, demonstrating that Seumetry accurately identifies distinct immune cell populations. Furthermore, using a publicly available mass cytometry dataset, Seumetry recapitulates previously published results, further validating its use for high-dimensional flow and mass cytometry data. In summary, Seumetry provides a new scalable framework for the comprehensive analysis of high-dimensional cytometry data with seamless integration into commonly used scRNAseq analysis tools, enabling in-depth analysis methods to facilitate biological interpretations.
A chemical-genetic system to rapidly inhibit the PP2A-B56 phosphatase
Authors: Allan LA , Corno A , Valverde JM , Toth R , Ly T , Saurin AT 
Published: July 2024

AbstractSerine-threonine phosphatases have been challenging to study because of the lack of specific inhibitors. Their catalytic domains are druggable, but these are shared or very similar between individual phosphatase complexes, precluding their specific inhibition. Instead, phosphatase complexes achieve specificity by interacting with short-linear motifs (SLiMs) in substrates or their binding partners. We develop here a chemical-genetic system to rapidly inhibit these interactions within the PP2A-B56 family. Drug-inducible recruitment of ectopic SLiMs (“directSLiMs”) is used to rapidly block the SLiM-binding pocket on the B56 regulatory subunit, thereby displacing endogenous interactors and inhibiting PP2A-B56 activity within seconds. We use this system to characterise PP2A-B56 substrates during mitosis and to identify a novel role for PP2A-B56 in maintaining kinetochore-microtubule attachments at metaphase. The directSLiMs approach can be used to inhibit any other phosphatase, enzyme or protein that uses a critical SLiM-binding interface, providing a powerful strategy to inhibit and characterise proteins once considered .“undruggable”.
Whole-Body Networks: A Holistic Approach for Studying Aging
Authors: Stylianou Orestis , Meixner Johannes M. , Schlick Tilman , Krüger Colin M. 
Published: July 2024

AbstractAging is a multiorgan disease, yet the traditional approach is to study each organ in isolation. Such organ-specific studies allowed us to gather invaluable information regarding the pathomechanisms that contribute to senescence. But we believe that a big-picture exploration of the whole-body network (WBN) during aging could be complementary. In this study, we analyzed the functional magnetic resonance imaging (fMRI), breathing rate and heart rate time series of a young and an elderly group during eyes-open resting-state. By exploring the time-lagged coupling between the different organs we constructed WBNs. First, we showed that our analytical pipeline could identify regional differences in the networks of both populations, allowing us to proceed with the remaining of the analysis. By comparing the WBNs of young and elderly, a complex relationship emerged where some connections were stronger and some weaker in the elderly. Finally, the interconnectivity and segregation of the WBNs negatively correlated with the short-term memory of the young participants. This study:i) validated our methods,ii) identified differences between the two groups andiii) showed correlation with behavioral metrics. We are at the edge of a paradigm shift on how aging-related research is conducted and we believe that our methodology should be implemented in more complex mental and/or physical tasks to better demonstrate the alterations of WBNs as we age.
Personality development in wild house mice: Evidence for a nutrition-dependent sensitive period early in life
Authors: Walasek Nicole , Jovicic Milan , Guenther Anja 
Published: July 2024

AbstractChanging environmental conditions pose serious challenges to organisms, for example, by disrupting access to food. Across species and traits, animals use phenotypic plasticity to rapidly adjust to such changes. Previous work has demonstrated that wild house mice are able to adjust stress coping to changing food quality within just three generations. However, we do not know when during ontogeny changing conditions induce phenotypic adjustments. We tested experimentally when during ontogeny (as fetus, newborn, weanling, or late adolescent) a food switch between standard and high-quality food shapes personality development (stress coping and stress perception) in cage-housed, wild house mice (Mus musculus domesticus). Personality traits were assessed in the Open Field and the Elevated Plus Maze at different time points during ontogeny (weaning, early adolescence, late adolescence, and adulthood). We observed three key findings. First, as mice grow older they tend to use more passive stress-coping strategies, indicating higher risk aversion. This relationship holds irrespective of food quality. However, mice fed with high-quality food show, on average, more active stress coping compared to mice receiving standard-quality food. Second, the fetal life stage might be a sensitive period for stress coping in response to experiencing decreases in nutritional quality. Third, experiencing an increase in nutritional quality may slow the age-related switch towards a passive stress-coping strategy. Our findings contrast previous work observing passive stress coping in mice living in semi-natural enclosures fed with high-quality food. We propose that the social environment of mice living in cages vs mice living in small groups may explain these differences. Our results highlight the need for experiments across the breadth of development comparing captive and semi-free-living animals. Ultimately, such studies will help us understand the complex relationships between development, nutrition, the (social) environment, and personality.
SLC45A4encodes a mitochondrial putrescine transporter that promotes GABAde novosynthesis
Authors: Colson Cecilia , Wang Yujue , Atherton James , Su Xiaoyang 
Published: July 2024

ABSTRACTSolute carriers (SLC) are membrane proteins that facilitate the transportation of ions and metabolites across either the plasma membrane or the membrane of intracellular organelles. With more than 450 human genes annotated as SLCs, many of them are still orphan transporters without known biochemical functions. We developed a metabolomic-transcriptomic association analysis, and we found that the expression of SLC45A4 has a strong positive correlation with the cellular level of γ-aminobutyric acid (GABA). Using mass spectrometry and the stable isotope tracing approach, we demonstrated that SLC45A4 promotes GABAde novosynthesis through the Arginine/Ornithine/Putrescine (AOP) pathway. SLC45A4 functions as a putrescine transporter localized to the mitochondrial membrane to facilitate GABA production. Taken together, our results revealed a new biochemical mechanism where SLC45A4 controls GABA production.
Δ133p53α and Δ160p53α isoforms of the tumor suppressor protein p53 exert dominant-negative effect primarily by co-aggregation
Authors: Zhao Liuqun , Punga Tanel , Sanyal Suparna 
Published: July 2024

Abstractp53 is a tumor suppressor protein with multiple isoforms with shared or specific functions. However, two of its isoforms, Δ133p53α and Δ160p53α, with large N-terminal deletions, can cause cancer. These isoforms exert a dominant-negative effect on full-length p53 (FLp53), although the precise molecular mechanisms are unknown. Here, we investigate the mechanisms of action of Δ133p53α and Δ160p53α isoforms using chromatin immunoprecipitation, luciferase expression, subcellular fractionation, immunofluorescence assays, and apoptotic caspase activity assay. Our study elucidates that these DNA-binding deficient p53 isoforms form hetero-tetrameric complexes with FLp53 and disrupt FLp53’s DNA binding and transcriptional activities when present in a higher proportion than FLp53 in the tetramer. However, these structurally unstable isoforms promote vigorous protein aggregation involving FLp53, disrupting its structure and sequestering it in the cytoplasmic and nuclear aggregates, thereby limiting its availability to function as a transcription activator protein. Thus, co-aggregation of Δ133p53α and Δ160p53α with FLp53, rather than hetero-tetramerization, is likely the primary factor contributing to their dominant-negative effect. Modulating the stability and aggregation of p53 isoforms could be a novel strategy for cancer therapy.
Parental-effect gene-drive elements under partial selfing, or why doCaenorhabditisgenomes have hyperdivergent regions?
Authors: Rockman Matthew V. 
Published: July 2024

ABSTRACTSelf-fertileCaenorhabditisnematodes carry a surprising number ofMedeaelements, alleles that act in heterozygous mothers and cause death or developmental delay in offspring that don’t inherit them. At some loci, both alleles in a cross operate as independentMedeas, affecting all the homozygous progeny of a selfing heterozygote. The genomic coincidence ofMedeaelements and ancient, deeply coalescing haplotypes, which pepper the otherwise homogeneous genomes of these animals, raises questions about how these apparent gene-drive elements persist for long periods of time. Here I investigate how mating system affects the evolution ofMedeas, and their paternal-effect counterparts,peels. Despite an intuition that antagonistic alleles should induce balancing selection by killing homozygotes, models show that, under partial selfing, antagonistic elements experience positive frequency dependence: the common allele drives the rare one extinct, even if the rare one is more penetrant. Analytical results for the threshold frequency required for one allele to invade a population show that a very weakly penetrant allele, one whose effects would escape laboratory detection, could nevertheless prevent a much more penetrant allele from invading under high rates of selfing. Ubiquitous weak antagonisticMedeasandpeelscould then act as localized barriers to gene flow between populations, generating genomic islands of deep coalescence. Analysis of gene expression data, however, suggest that this cannot be the whole story. A complementary explanation is that ordinary ecological balancing selection generates ancient haplotypes on whichMedeascan evolve, while high homozygosity in these selfers minimizes the role of gene drive in their evolution.
A nuclear RNA degradation code for eukaryotic transcriptome surveillance
Authors: Soles Lindsey V. , Liu Liang , Zou Xudong , Yoon Yoseop , Li Shuangyu , Tian Lusong , Valdez Marielle Cárdenas , Yu Angela , Yin Hong , Li Wei , Ding Fangyuan , Seelig Georg , Li Lei , Shi Yongsheng 
Published: July 2024

SUMMARYThe RNA exosome plays critical roles in eukaryotic RNA degradation, but it remains unclear how the exosome specifically recognizes its targets. The PAXT connection is an adaptor that recruits the exosome to polyadenylated RNAs in the nucleus, especially transcripts polyadenylated at intronic poly(A) sites. Here we show that PAXT-mediated RNA degradation is induced by the combination of a 5′ splice site and a poly(A) junction, but not by either sequence alone. These sequences are bound by U1 snRNP and cleavage/polyadenylation factors, which in turn cooperatively recruit PAXT. As the 5′ splice site-poly(A) junction combination is typically not found on correctly processed full-length RNAs, we propose that it functions as a “nuclear RNA degradation code” (NRDC). Importantly, disease-associated single nucleotide polymorphisms that create novel 5′ splice sites in 3′ untranslated regions can induce aberrant mRNA degradation via the NRDC mechanism. Together our study identified the first NRDC, revealed its recognition mechanism, and characterized its role in human diseases.