bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tibetan terrestrial and aquatic ecosystems collapsed with cryosphere loss inferred from sedimentary ancient metagenomics
Authors: Liu Sisi , Stoof-Leichsenring Kathleen R. , Harms Lars , Schulte Luise , Mischke Steffen , Kruse Stefan , Zhang Chengjun , Herzschuh Ulrike 
Published: November 2023

AbstractGlacier and permafrost shrinkage and land-use intensification threaten diverse mountain wildlife and affect nature conservation strategy. Our understanding of alpine ecological dynamics is, however, insufficient because time series portraying ecosystem complexity adequately are missing. Here, we present an ancient metagenomic record tracing 317 terrestrial and aquatic taxa, including mammals, fish, plants, and microorganisms retrieved from a lake sediment core from the southeastern Tibetan Plateau covering the last 18,000 years. We infer that steppe-meadow turned into woodland at 14 ka (cal BP) controlled by warming-induced cryosphere loss, further driving a change of herbivore dominance from wild yak to deer. Network analyses reveal that root hemiparasitic and cushion plants are keystone taxa, likely altering the terrestrial ecosystem via facilitation. These findings refute the hypothesis of top-down control by large herbivores in the alpine ecosystem. We also find that glacier mass loss significantly contributes to considerable turnover in the aquatic community at 14 ka, transitioning from glacier-related (blue-green) algae to abundant non-glacier-preferring picocyanobacteria, macrophytes, fish, and fish-eating otters. Human impact contributes little to shaping the alpine ecosystems. By applying network analysis, we provide the first sedaDNA-based assessment of the stress-gradient hypothesis. As cryosphere loss is ongoing due to climate warming, prioritizing the protection of habitats with rich nurse plants that aid neighbors in adapting to stressful conditions is likely to be a more beneficial conservation measure than livestock reduction in the Tibetan Plateau.Significance statementMerging ancient metagenomics and network analysis gives new insights into conserving the Tibetan alpine ecosystem under ongoing warming and human perturbations. We investigated the assembly of the Yak steppe-meadow ecosystem and an alpine lake system in response to cryosphere changes over the past ∼18,000 years on the Tibetan Plateau. Large herbivores cannot be a cost-effective natural climate solution to stabilize the Tibetan alpine ecosystem because they are not keystone taxa at the ecosystem scale. Furthermore, there is no support that land use considerably shapes the alpine communities and ecosystems. Protection policy should thus prioritize focus on alpine areas with intense land use and rich in root hemiparasitic and cushion plants because these taxa act as facilitators in the ecosystem.
Msc1 is a nuclear envelope protein that reinforces DNA repair in late mitosis
Authors: Medina-Suárez Sara , Ayra-Plasencia Jessel , Pérez-Martínez Lara , Butter Falk , Machín Félix 
Published: November 2023

SummaryPrecise double-strand break (DSB) repair is paramount for genome stability. Homologous recombination (HR) repairs DSBs when cyclin-dependent kinase (CDK) activity is high, which correlates with the availability of the sister chromatid as a template. However, anaphase and telophase are paradoxical scenarios since high CDK favors HR despite sister chromatids being no longer aligned. To identify factors specifically involved in DSB repair in late mitosis, we have undertaken comparative proteomics inSaccharomyces cerevisiaeand found that Msc1, a poorly characterized nuclear envelope protein, is significantly enriched upon both random and guided DSBs. We further show that Δmsc1is more sensitive to DSBs in late mitosis, and has a delayed repair of DBSs, as indicated by increased Rad53 hyperphosphorylation, fewer Rad52 repair factories, and slower HR completion. We discuss how Msc1 may favor the formation of Rad52 factories and the timely completion of HR before cytokinesis.
CPSign - Conformal Prediction for Cheminformatics Modeling
Authors: McShane Staffan Arvidsson , Norinder Ulf , Alvarsson Jonathan , Ahlberg Ernst , Carlsson Lars , Spjuth Ola 
Published: November 2023

AbstractConformal prediction has seen many applications in pharmaceutical science, being able to calibrate outputs of machine learning models and producing valid prediction intervals. We here present the open source software CPSign that is a complete implementation of conformal prediction for cheminformatics modeling. CPSign implements inductive and transductive conformal prediction for classification and regression, and probabilistic prediction with the Venn-ABERS methodology. The main chemical representation is signatures but other types of descriptors are also supported. The main modeling methodology is support vector machines (SVMs), but additional modeling methods are supported via an extension mechanism, e.g. DeepLearning4j models. We also describe features for visualizing results from conformal models including calibration and efficiency plots, as well as features to publish predictive models as REST services. We compare CPSign against other common cheminformatics modeling approaches including random forest, and a directed message-passing neural network. The results show that CPSign produces robust predictive performance with comparative predictive efficiency, with superior runtime and lower hardware requirements compared to neural network based models. CPSign has been used in several studies and is in production-use in multiple organizations. The ability to work directly with chemical input files, perform descriptor calculation and modeling with SVM in the conformal prediction framework, with a single software package having a low footprint and fast execution time makes CPSign a convenient and yet flexible package for training, deploying, and predicting on chemical data.
A novel clinical metaproteomics workflow enables bioinformatic analysis of host-microbe dynamics in disease
Authors: Do Katherine , Mehta Subina , Wagner Reid , Bhuming Dechen , Rajczewski Andrew T. , Skubitz Amy P.N. , Johnson James E. , Griffin Timothy J. , Jagtap Pratik D. 
Published: November 2023

ABSTRACTClinical metaproteomics has the potential to offer insights into the host-microbiome interactions underlying diseases. However, the field faces challenges in characterizing microbial proteins found in clinical samples, which are usually present at low abundance relative to the host proteins. As a solution, we have developed an integrated workflow coupling mass spectrometry-based analysis with customized bioinformatic identification, quantification and prioritization of microbial and host proteins, enabling targeted assay development to investigate host-microbe dynamics in disease. The bioinformatics tools are implemented in the Galaxy ecosystem, offering the development and dissemination of complex bioinformatic workflows. The modular workflow integrates MetaNovo (to generate a reduced protein database), SearchGUI/PeptideShaker and MaxQuant (to generate peptide-spectral matches (PSMs) and quantification), PepQuery2 (to verify the quality of PSMs), and Unipept and MSstatsTMT (for taxonomy and functional annotation). We have utilized this workflow in diverse clinical samples, from the characterization of nasopharyngeal swab samples to bronchoalveolar lavage fluid. Here, we demonstrate its effectiveness via analysis of residual fluid from cervical swabs. The complete workflow, including training data and documentation, is available via the Galaxy Training Network, empowering non-expert researchers to utilize these powerful tools in their clinical studies.
Development and validation of a reliable DNA copy-number-based machine learning algorithm (CopyClust) for breast cancer integrative cluster classification
Authors: Young Cameron C. , Eason Katherine , Garcia Raquel Manzano , Moulange Richard , Mukherjee Sach , Chin Suet-Feung , Caldas Carlos , Rueda Oscar M. 
Published: November 2023

AbstractThe Integrative Clusters (IntClusts) provide a framework for the classification of breast cancer tumors into 10 distinct genomic subtypes based on DNA copy number and gene expression. Current classifiers achieve only low accuracy without gene expression data, warranting the development of new approaches to copy-number-only-based IntClust classification. A novel XGBoost-driven classification algorithm,CopyClust, was trained using genomic features from METABRIC and validated on TCGA achieving a nine-percentage point or greater improvement in overall IntClust subtype classification accuracy.
Symbiosis modulates gene expression of symbionts, but not hosts, under thermal challenge
Authors: Aichelman Hannah E , Huzar Alexa K , Wuitchik Daniel M , Atherton Kathryn F , Wright Rachel M , Dixon Groves , Schlatter E , Haftel Nicole , Davies Sarah W 
Published: November 2023

AbstractIncreasing ocean temperatures are causing dysbiosis between coral hosts and their symbionts. Previous work suggests that coral host gene expression responds more strongly to environmental stress compared to their intracellular symbionts; however, the causes and consequences of this phenomenon remain untested. We hypothesized that symbionts are less responsive because hosts modulate symbiont environments to buffer stress. To test this hypothesis, we leveraged the facultative symbiosis between the scleractinian coralOculina arbusculaand its symbiontBreviolum psygmophilumto characterize gene expression responses of both symbiotic partnersinandex hospiteunder thermal challenges. To characterize host andin hospitesymbiont responses, symbiotic and aposymbioticO. arbusculawere exposed to three treatments: 1) control (18°C), 2) heat (32°C), and 3) cold (6°C). This experiment was replicated withB. psygmophilumcultured fromO. arbusculato characterizeex hospitesymbiont responses. Both thermal challenges elicited classic environmental stress responses (ESRs) inO. arbuscularegardless of symbiotic state, with hosts responding more strongly to cold challenge. Hosts also exhibited stronger responses thanin hospitesymbionts.Inandex hospite B. psygmophilumboth downregulated genes associated with photosynthesis under thermal challenge; however,ex hospitesymbionts exhibited greater gene expression plasticity and differential expression of genes associated with ESRs. Taken together, these findings suggest thatO. arbusculahosts may buffer environments ofB. psygmophilumsymbionts; however, we outline the future work needed to confirm this hypothesis.
ANDES: a novel best-match approach for enhancing gene set analysis in embedding spaces
Authors: Li Lechuan , Dannenfelser Ruth , Cruz Charlie , Yao Vicky 
Published: November 2023

AbstractEmbedding methods have emerged as a valuable class of approaches for distilling essential information from complex high-dimensional data into more accessible lower-dimensional spaces. Applications of embedding methods to biological data have demonstrated that gene embeddings can effectively capture physical, structural, and functional relationships between genes. However, this utility has been primarily realized by using gene embeddings for downstream machine learning tasks. Much less has been done to examine the embeddings directly, especially analyses of gene sets in embedding spaces. Here, we propose ANDES, a novel best-match approach that can be used with existing gene embeddings to compare gene sets while reconciling gene set diversity. This intuitive method has important downstream implications for improving the utility of embedding spaces for various tasks. Specifically, we show how ANDES, when applied to different gene embeddings encoding protein-protein interactions, can be used as a novel overrepresentation-based and rank-based gene set enrichment analysis method that achieves state-of-the-art performance. Additionally, ANDES can use multi-organism joint gene embeddings to facilitate functional knowledge transfer across organisms, allowing for phenotype mapping across model systems. Our flexible, straightforward best-match methodology can be extended to other embedding spaces with diverse community structures between set elements.
Multi-Step Control of Homologous Recombination by Mec1/ATR Ensures Robust Suppression of Gross Chromosomal Rearrangements
Authors: Xie Bokun , Sanford Ethan James , Hung Shih-Hsun , Wagner Mateusz Maciej , Heyer Wolf-Dietrich , Smolka Marcus B. 
Published: November 2023

AbstractThe Mec1/ATR kinase is crucial for genome stability, yet the mechanism by which it prevents gross chromosomal rearrangements (GCRs) remains unknown. Here we find that in cells with deficient Mec1 signaling, GCRs accumulate due to the deregulation of multiple steps in homologous recombination (HR). Mec1 primarily suppresses GCRs through its role in activating the canonical checkpoint kinase Rad53, which ensures the proper control of DNA end resection. Upon loss of Rad53 signaling and resection control, Mec1 becomes hyperactivated and triggers a salvage pathway in which the Sgs1 helicase is recruited to sites of DNA lesions via the 911-Dpb11 scaffolds to favor heteroduplex rejection and limit HR-driven GCR accumulation. Fusing an ssDNA recognition domain to Sgs1 bypasses the requirement of Mec1 signaling for GCR suppression and nearly eliminates D-loop formation, thus preventing non-allelic recombination events. We propose that Mec1 regulates multiple steps of HR to prevent GCRs while ensuring balanced HR usage when needed for promoting tolerance to replication stress.
Prokrustean Graph: A substring index for rapid k-mer size analysis
Authors: Park Adam , Koslicki David 
Published: November 2023

AbstractDespite the widespread adoption ofk-mer-based methods in bioinformatics, understanding the influence ofk-mer sizes remains a persistent challenge. Selecting an optimalk-mer size or employing multiplek-mer sizes is often arbitrary, application-specific, and fraught with computational complexities. Typically, the influence ofk-mer size is obscured by the outputs of complex bioinformatics tasks, such as genome analysis, comparison, assembly, alignment, and error correction. However, it is frequently overlooked that every method is built above a well-definedk-mer-based object like Jaccard Similarity, de Bruijn graphs,k-mer spectra, and Bray-Curtis Dissimilarity. Despite these objects offering a clearer perspective on the role ofk-mer sizes, the dynamics ofk-mer-based objects with respect tok-mer sizes remain surprisingly elusive.This paper introduces a computational framework that generalizes the transition ofk-mer-based objects acrossk-mer sizes, utilizing a novel substring index, the Prokrustean graph. The primary contribution of this framework is to compute quantities associated withk-mer-based objects for allk-mer sizes, where the computational complexity depends solely on the number of maximal repeats and is independent of the range ofk-mer sizes. For example, counting vertices of compacted de Bruijn graphs fork= 1, …, 100 can be accomplished in mere seconds with our substring index constructed on a gigabase-sized read set.Additionally, we derive a space-efficient algorithm to extract the Prokrustean graph from the Burrows-Wheeler Transform. It becomes evident that modern substring indices, mostly based on longest common prefixes of suffix arrays, inherently face difficulties at exploring varyingk-mer sizes due to their limitations at grouping co-occurring substrings.We have implemented four applications that utilize quantities critical in modern pangenomics and metagenomics. The code for these applications and the construction algorithm is available athttps://github.com/KoslickiLab/prokrustean.
Metagenomic Immunoglobulin Sequencing (MIG-Seq) Exposes Patterns of IgA Antibody Binding in the Healthy Human Gut Microbiome
Authors: Olm Matthew R. , Spencer Sean P. , Silva Evelyn Lemus , Sonnenburg Justin L. 
Published: November 2023

AbstractIgA, the most highly produced human antibody, is continually secreted into the gut to shape the intestinal microbiota. Methodological limitations have critically hindered defining which microbial strains are targeted by IgA and why. Here, we develop a new technique, Metagenomic Immunoglobulin Sequencing (MIG-Seq), and use it to determine IgA coating levels for thousands of gut microbiome strains in healthy humans. We find that microbes associated with both health and disease have higher levels of coating, and that microbial genes are highly predictive of IgA binding levels, with mucus degradation genes especially correlated with high binding. We find a significant reduction in replication rates among microbes bound by IgA, and demonstrate that IgA binding is more correlated with host immune status than traditional microbial abundance measures. This study introduces a powerful technique for assessing strain-level IgA binding in human stool, paving the way for deeper understanding of IgA-based host microbe interactions.
Sex-dependent effects of angiotensin type 2 receptor expressing medial prefrontal cortex (mPFC) interneurons in fear extinction learning
Authors: Smith Hannah C. , Yu Zhe , Iyer Laxmi , Marvar Paul J. 
Published: November 2023

ABSTRACTBackgroundThe renin-angiotensin system (RAS) has been identified as a potential therapeutic target for PTSD, though its mechanisms are not well understood. Brain angiotensin type 2 receptors (AT2Rs) are a subtype of angiotensin II receptors located in stress and anxiety-related regions, including the medial prefrontal cortex (mPFC), but their function and mechanism in the mPFC remain unexplored. We therefore used a combination of imaging, cre/lox, and behavioral methods to investigate mPFC-AT2R-expressing neuron involvement in fear learning.MethodsTo characterize mPFC-AT2R-expressing neurons in the mPFC, AT2R-Cre/td-Tomato male and female mice were used for immunohistochemistry (IHC). mPFC brain sections were stained with glutamatergic or interneuron markers, and density of AT2R+cells and colocalization with each marker was quantified. To assess fear-related behaviors in AT2R-flox mice, we selectively deleted AT2R from mPFC neurons using an AAV-Cre virus. Mice then underwent Pavlovian auditory fear conditioning, approach/avoidance, and locomotion testing.ResultsIHC results revealed that AT2R is densely expressed in the mPFC. Furthermore, AT2R is primarily expressed in somatostatin interneurons in females but not males. Following fear conditioning, mPFC-AT2R deletion impaired extinction in female but not male mice. Locomotion was unaltered by mPFC-AT2R deletion in males or females, while AT2R-deleted females had increased exploratory behavior.ConclusionThese results lend support for mPFC-AT2R+ neurons as a novel subgroup of somatostatin interneurons that influence fear extinction in a sex-dependent manner. This furthers underscores the role of mPFC in top-down regulation and a unique role for peptidergic (ie., angiotensin) mPFC regulation of fear and sex differences.
Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission
Authors: Christophers Briana , Leahy Shannon N. , Soffar David B. , von Saucken Victoria E. , Broadie Kendal , Baylies Mary K. 
Published: November 2023

AbstractCofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shownDrosophilacofilin (DmCFL) knockdown causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy (NM) caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics byDmCFLknockdown would impact other aspects of muscle development, and, thus, conducted an RNA sequencing analysis which unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL deficiency causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However,DmCFLknockdown results in mislocalization of glutamate receptors containing the GluRIIA subunit in more deteriorated muscles and neurotransmission strength is strongly impaired. These findings expand our understanding of cofilin’s roles in muscle to include NMJ structural development and suggest that NMJ defects may contribute to NM pathophysiology.Summary statementCofilin regulates muscle postsynaptic actin organization, structural maintenance, glutamate receptor composition, and neuromuscular junction function in aDrosophilanemaline myopathy disease model.
Versatile toolkit for highly-efficient and scarless overexpression of circular RNAs
Authors: Stringer Brett W. , Gabryelska Marta , Marri Shashikanth , Clark Letitia , Lin He , Gantley Laura , Liu Ryan , Wilusz Jeremy E. , Conn Vanessa M. , Conn Simon J. 
Published: November 2023

ABSTRACTCircular RNAs (circRNAs) are a class of single-stranded, covalently closed RNA that contain a unique back-splice junction (bsj) sequence created by the ligation of their 5’ and 3’ ends via spliceosome-catalyzed back-splicing. A key step in illuminating the cellular roles of specific circRNAs is via increasing their expression. This is frequently done by transfecting cells with plasmid DNA containing cloned exons from which the circRNA is transcribed, flanked by sequences that promote back-splicing. We observed that commonly used plasmids lead to the production of circRNAs with molecular scars at the circRNA bsj. Stepwise redesign of the cloning vector corrected this problem, ensuringbona fidecircRNAs are produced with their natural bsj at high efficiency. The fidelity of circRNAs produced from this new construct was validated by RNA sequencing and also functionally validated. To increase the utility of this modified resource for expressing circRNA, we developed an expanded set of vectors incorporating this design that (i) enables selection with a variety of antibiotics and fluorescent proteins, (ii) employs a range of promoters varying in promoter strength and (iii) generated a complementary set of lentiviral plasmids for difficult-to-transfect cells. These resources provide a novel and versatile toolkit for high-efficiency and scarless overexpression of circular RNAs that fulfill a critical need for the investigation of circRNA function.
Solving the time-dependent protein distributions for autoregulated bursty gene expression using spectral decomposition
Authors: Wu Bingjie , Holehouse James , Grima Ramon , Jia Chen 
Published: November 2023

AbstractIn this study, we obtain an exact time-dependent solution of the chemical master equation (CME) of an extension of the two-state telegraph model describing bursty or non-bursty protein expression in the presence of positive or negative autoregulation. Using the method of spectral decomposition, we show that the eigenfunctions of the generating function solution of the CME are Heun functions, while the eigenvalues can be determined by solving a continued fraction equation. Our solution generalizes and corrects a previous time-dependent solution for the CME of a gene circuit describing non-bursty protein expression in the presence of negative autoregulation [“Exact time-dependent solutions for a self-regulating gene.” Phys. Rev. E 83: 062902 (2011)]. In particular, we clarify that the eigenvalues are generally not real as previously claimed. We also investigate the relationship between different types of dynamic behavior and the type of feedback, the protein burst size, and the gene switching rate.