bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding The Myelin g ratio From First Principles, Its Derivation, Uses And Artifacts
Authors: Gow Alexander
Published: September 2024

In light of the increasing importance for measuring myelingratios - the ratio of axon-to-fiber (axon + myelin) diameters in myelin internodes - to understand normal physiology, disease states, repair mechanisms and myelin plasticity, there is urgent need to minimize processing and statistical artifacts in current methodologies. Unfortunately, many contemporary studies fall prey to a variety of artifacts, which reduce study outcome robustness and slow development of novel therapeutics. Underlying causes stem from a lack of understanding of the myelingratio, which has persisted more than a century. An extended exploratory data analysis from first principles (the axon-fiber diameter relation) is presented herein and has major consequences for interpreting publishedgratio studies. Indeed, a model of the myelin internode naturally emerges because of (1) the strong positive correlation between axon and fiber diameters and (2) the demonstration that the relation between these variables is one of direct proportionality. From this model, a robust framework for data analysis, interpretation and understanding allows specific predictions about myelin internode structure under normal physiological conditions. Further, the model establishes that a regression fit togratio plots has zero slope, and it identifies the underlying causes of several data processing artifacts that can be mitigated by plottinggratios against fiber diameter (not axon diameter). Hypothesis testing can then be used for extending the model and evaluating myelin internodal properties under pathophysiological conditions (accompanying article). For without a statistical model as anchor, hypothesis testing is aimless like a rudderless ship on the ocean.
Knowledge of Childhood and Adolescent Cancer Among Primary Caregivers: An Observational and Prospective Study
Authors: Meza Soto Gladys Areli , Lopez Gonzalez Maribel , Montoya Hernandez Maria Azucena , Zarate Amador Josseline DC , Galan Solano Marian Del Rocio , Estrada Alvarez Jose Alberto
Published: September 2024

Background: Childhood and adolescent cancer represents a significant public health issue, being the leading cause of disease-related mortality in this age group. Previous studies in Greece, Turkey, and Mexico have shown that parents and caregivers lack adequate knowledge about this topic. Despite WHO efforts to create new strategies, late diagnosis persists in Mexico. Early identification of initial signs and symptoms by parents and caregivers is crucial for seeking timely medical care. Objective: To evaluate the knowledge of childhood and adolescent cancer among primary caregivers in primary care settings. Methods: An observational, descriptive, cross-sectional, and prospective study was conducted at Family Medicine Unit No. 69 in Coatzacoalcos, Veracruz, from April 2023 to January 2024. The "Survey for parents and caregivers about knowledge of cancer in children" by Dr. Ana Cecilia Vazquez was administered with prior informed consent. Qualitative and quantitative variables were analyzed using percentages and measures of central tendency, respectively. Bivariate analysis was performed using the Chi-square test with SPSS software. Results: A total of 374 caregivers were evaluated, with an age range of 17 to 78 years (X̅=35.5, σ= ± 11.8). The majority were female (60.2%), married (48.7%), maternal caregivers (54%), with professional education (38%), and employed (62.3%). 77.8% of the caregivers had inadequate knowledge, while 22.2% had adequate knowledge about childhood and adolescent cancer. There was a statistically significant association (p<0.05) between knowledge and sociodemographic variables such as maternal role, age, education level, marital status, and number of children. Conclusion: The alternate hypothesis that primary caregivers possess adequate knowledge of childhood and adolescent cancer is rejected. It is essential to develop educational strategies to increase knowledge about childhood cancer to improve early detection. This includes using educational materials and audiovisual media such as the PAHO video "The rhythm that gives us life" and distributing brochures and questionnaires targeted at caregivers. Keywords: cancer, child, childhood, adolescent, adolescence.
Hepatic GCGR is required for the superior weight loss effects of a structurally related analogue of the dual GCGR/GLP1R agonist survodutide
Authors: Long Fen , Klug Manuel , Challa Tenagne D. , Efthymiou Vissarion , Wolfrum Christian , Horvath Carla
Published: September 2024

The dual glucagon/glucagon-like peptide 1 receptor (GCGR/GLP1R) agonists have superior efficacy in promoting weight loss and metabolic improvements in obesity and metabolic dysfunction-associated steatohepatitis (MASH) than current available mono-agonists. However, the mechanisms underlying these benefits are not fully understood. While the effects on appetite regulation and glucose control through GLP1R agonism are well established, the role of GCGR agonism in promoting weight loss and metabolic changes is less defined. Using a dual GCGR/GLP1R agonist BI 456908 and a selective GLP1R agonist semaglutide, we could show that the dual agonist achieved superior weight loss efficacy by engaging hepatic GCGR without adversely affecting glucose control. Furthermore, we could demonstrate that hepatic GCGR is critical for facilitating plasma and liver lipid clearance stimulated by the dual agonist. Overall, these findings highlight the crucial metabolic contributions of hepatic GCGR to the efficacy of combined GCGR/GL1R activation.
Merkel cell carcinoma-derived macrophage migration inhibitory factor (MIF) may promote persistence of Chronic Lymphocytic Leukemia
Authors: Alencar Gabriel F. , Rodriguez Haroldo J. , Pulliam Thomas H. , Remington Allison J. , Gilmour Macy W. , Alam Rian , Jabbour Austin J. , Mullen Logan J. , DeBuysscher Blair L. , Nghiem Paul , Taylor Justin J.
Published: September 2024

While concurrent diagnoses of Merkel cell carcinoma (MCC) and other cancers, like Chronic lymphocytic leukemia (CLL), are rare, patients with MCC have a 30-fold higher incidence of CLL. While these increases have been attributed to the ability of CLL to suppress immune responses allowing for the emergence of MCC, here we found evidence that MCC could support the persistence of CLL. Using single cell sequencing approaches and computational analyses of MCC and CLL from a patient where both cancers were present in the same lymph node, we found that production of macrophage migration inhibitory factor (MIF) by MCC could promote the persistence of CLL through stimulation of CD74 and CXCR4. These results may explain why blood cell counts rapidly normalized after treatment for MCC and were maintained at normal levels despite the absence of treatment for CLL.

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Beyond immunity: a transcriptomic landscape of Plasmodium’s modulation of mosquito metabolic pathways
Authors: García-Longoria L , Berthomieu A , Hellgren O , Rivero A
Published: September 2024

The focus of mosquito-Plasmodiuminteractions has predominantly been centered on mosquito immunity, revealing key mechanisms by which mosquitoes attempt to combatPlasmodiuminfection. However, recent evidence suggests that beyond immunity, a multitude of mosquito physiological and metabolic pathways play crucial roles in determining whether the parasite completes its development within the mosquito. We review which of these metabolic pathways are potentially modulated byPlasmodium, revealing a fragmented and occasionally contradictory state of knowledge. We then present a comprehensive transcriptomic analysis ofPlasmodium-infected and uninfected mosquitoes, examining gene expression of crucial genes across different stages of the parasite’s development. These genes range from key enzymes and proteins involved in gut structure and function, to genes involved in egg production and resorption, salivary gland invasion and mosquito behaviour. For this purpose, we use a non-model system consisting of the avian malaria parasitePlasmodium relictum, an invasive parasite threatening bird biodiversity across the world, and its natural vector, the mosquitoCulex pipiens. Our results reveal how at each stage of its development within the mosquito,Plasmodiummodulates a myriad of mosquito metabolic pathways, in ways that potentially favour its survival and the completion of its life cycle. We discuss whether this constitutes sufficient evidence of parasite-driven manipulation or whether the changes are simply the mosquito’s response to the infection, which the parasite may serendipitously exploit to enhance its fitness. Our study extends the comparative transcriptomic analyses of malaria-infected mosquitoes beyond human and rodent parasites, and provides insights into the degree of conservation of metabolic pathways and into the selective pressures exerted byPlasmodiumparasites on their vectors.
Respiration shapes response speed and accuracy with a systematic time lag
Authors: Harting Cosima , Hehemann Lena , Stetza Lisa , Kayser Christoph
Published: September 2024

Sensory-cognitive functions are intertwined with physiological processes such as the heart beat or respiration. For example, we tend to align our respiratory cycle to expected events or actions. This happens during sports but also in computer-based tasks and systematically structures respiratory phase around relevant events. However, studies also show that trial-by-trial variations in respiratory phase shape brain activity and the speed or accuracy of individual responses. We show that both phenomena, the alignment of respiration to expected events and the explanatory power of the respiratory phase on behaviour co-exist. In fact, both the average respiratory phase of an individual relative to the experimental trials and trial-to-trial variations in respiratory phase hold significant predictive power on behavioural performance, in particular for reaction times. This co-modulation of respiration and behaviour emerges regardless of whether an individual generally breathes faster or slower and is strongest for the respiratory phase about two seconds prior to participant's responses. The persistence of these effects across 12 datasets with 277 participants performing sensory-cognitive tasks confirm the robustness of these results, and suggest a profound and time-lagged influence of structured respiration on sensory-motor responses.
Probing other's Presence: Probabilistic Inference Across Brain Scales Reveals Enhanced Excitatory Synaptic Efficacy
Authors: Esmaeili Amirhossein , Demolliens Marie , Viersen Marjolein , Ziaeemehr Abolfazl , Isbaine Faical , Huguet Pascal , Zaal Frank , Jirsa Viktor , Boussaoud Driss , Hashemi Meysam
Published: September 2024

The presence of conspecifics is a fundamental and arguably invariant prerequisite of social cognition across numerous animal species. While the influence of social presence on behavior has been among the focal points of investigation in social psychology for over a century, its underlying neural mechanisms remain largely unexplored. Here, we attempt to bridge this gap by investigating how the presence of conspecifics changes synaptic efficacy from measurements across spatiotemporal brain scales, and how such changes could lead to modulations of task performance in monkeys and humans. In monkeys performing an association learning task, social presence increased excitatory synaptic efficacy in attention-oriented regions dorsolateral prefrontal cortex and anterior cingulate cortex. In humans performing a visuomotor task, the presence of conspecifics facilitated performance in one of the subject groups, and this facilitation was linked to enhanced excitatory synaptic efficacy within the dorsal and ventral attention networks. We propose that presence-induced improvements in task performance arise from attentional modulation mediated by changes in excitatory synaptic efficacy across three spatiotemporal brain scales, namely, micro-scale (single neurons), meso-scale (cortical columns) and macro-scale (whole-brain). Our findings from Bayesian learning converge to establish a novel, multi-scale framework for understanding the neural underpinnings of social presence effects. This probabilistic framework offers a fresh perspective on social presence research, and lays the groundwork for future investigations into the complex interplay between social presence, neural dynamics, and behavior.
A unified model of hippocampal spatial and object cells involving bidirectionally coupled Lateral and Medial Entorhinal Cortical layers
Authors: Patil Bharat K. , Aziz Azra , Saka Manoj Kumar , Deshmukh Sachin S. , Chakravarthy V. Srinivasa
Published: September 2024

Popularly referred to as the GPS of the brain, the hippocampus has a variety of neurons that encode spatial properties of the environment. These spatial cells of the hippocampus may be broadly placed under two categories – those that encode spatial locations (e.g. place cells, grid cells etc) and those that encode spatial objects (eg. Object-sensitive cells. Object-trace cells etc). There are computational models that explain emergence of specific types of spatial cells, but it is challenging to construct integrative models that can demonstrate the emergence of the complete range of spatial cells both space and object type. We present a simple, unified computational model that explains the emergence of a wide variety of object- and spatially-sensitive neurons in the hippocampus. The model is essentially a deep neural network that combines visual and path integration information. The visual information is received by a part of the model that is analogous to Lateral Entorhinal Cortex (LEC) and path integration information is received by a layer analogous to Medial Entorhinal Cortex (MEC). In order to arrive at a consistent estimate of position, LEC and MEC in the model are connected laterally using a Graph Neural Network. The model is trained to predict position, orientation and reward of a simulated agent. The agent explores a box-like environment with colored walls and objects on the floor and is rewarded based on its encounters with objects. The model demonstrates the emergence of the following 7 types of spatial and object cells - place, grid, border, object, object-sensitive, object-vector and, object-trace cells. The model findings compare favorably with a large body of experimental literature on hippocampal spatial cells.
Overcoming the limitations of motion sensor models by considering dendritic computations
Authors: Luna Raúl , Serrano-Pedraza Ignacio , Bertalmío Marcelo
Published: September 2024

The estimation of motion is a fundamental process for any sighted animal. Computational models for motion sensors have a long and successful history but they still suffer from fundamental shortcomings, as they disagree with physiological evidence and each model is dedicated to a specific type of motion, which is controversial from a biological standpoint. In this work we propose a new approach for modeling motion sensors that considers dendritic computations, a key aspect for predicting single-neuron responses that had previously been absent from motion models. We show how, by taking into account the dynamic and input-dependent nature of dendritic nonlinearities, our motion sensor model is able to overcome the fundamental limitations of standard approaches.
START domains generate paralog-specific regulons from a single network architecture
Authors: Holub Ashton S , Choudury Sarah G , Andrianova Ekaterina P. Y , Dresden Courtney E , Urquidi Camacho Ricardo , Jouline Igor , Husbands Aman Y
Published: September 2024

Functional divergence of transcription factors (TFs) has driven cellular and organismal complexity throughout evolution, but its mechanistic drivers remain poorly understood. Here we test for new mechanisms using CORONA (CNA) and PHABULOSA (PHB), two functionally diverged paralogs in the CLASS III HOMEODOMAIN LEUCINE ZIPPER (HD-ZIPIII) family of TFs. We show that virtually all genes bound by PHB (~99%) are also bound by CNA, ruling out occupation of distinct sets of genes as a mechanism of functional divergence. Further, genes bound and regulated by both paralogs are almost always regulated in the same direction, ruling out opposite regulation of shared targets as a mechanistic driver. Functional divergence of CNA and PHB instead results from differential usage of shared binding sites, with hundreds of uniquely regulated genes emerging from a commonly bound genetic network. Regulation of a given gene by CNA or PHB is thus a function of whether a bound site is considered 'responsive' versus 'non-responsive' by each paralog. Discrimination between responsive and non-responsive sites is controlled, at least in part, by their lipid binding START domain. This suggests a model in which HD-ZIPIII TFs use information integrated by their START domain to generate paralog-specific transcriptional outcomes from a shared network architecture. Taken together, our study identifies a new mechanism of HD-ZIPIII TF paralog divergence and proposes the ubiquitously distributed START evolutionary module as a driver of functional divergence.
iSeqsSearch: Incremental Protein Search for iBlast/iMMSeqs2/iDiamond
Authors: Yoo Hyunwoo , Refahi Mohammad S , Polikar Robi , Sokhansanj Bahrad A , Brown James R , Rosen Gail L
Published: September 2024

Background: The advancement of sequencing technology has led to a rapid increase in the amount of DNA and protein sequence data; consequently, the size of genomic and proteomic databases is constantly growing. As a result, database searches need to be continually updated to account for the new data being added. Continually re-searching the entire existing dataset, however, wastes resources. Incremental database search can address this problem. Methods: One recently introduced incremental search method is iBlast, which wraps the BLAST sequence search method with an algorithm to reuse previously processed data and thereby increase search efficiency. The iBlast wrapper, however, must be generalized to support more performant DNA/protein sequence search methods that have been developed, namely MMseqs2 and Diamond. Moreover, the previously published iBlast wrapper has to be revised to be more robust and usable by the general community. Results: iMMseqs2 and iDiamond, which apply the incremental approach, obtain results nearly identical to those achieved using only MMseqs2 and Diamond. Notably, when comparing ranking comparison methods such as the Pearson correlation, we observe a high concordance of over 0.9, indicating similar results. Moreover, in some cases, our incremental approach applying iBlast merge function and using m8 formats including the new m8e format provides more hits compared to the conventional MMseqs2 and Diamond. Conclusion: The incremental approach using iMMseqs2 and iDiamond demonstrates efficiency in terms of reusing previously processed data while maintaining high accuracy and concordance in search results. This method can reduce resource waste in continually growing genomic and proteomic database searches. The sample codes are made available at GitHub: https://github.com/EESI/Incremental-Protein-Search.
TAAR2-9 Knockout Mice Exhibit Reduced Wakefulness and Disrupted REM Sleep
Authors: Park Sunmee , Heu Jasmine , Scheldrup Gavin , Tisdale Ryan , Sun Yu , Haire Meghan , Ma Shun-Chieh , Hoener Marius C. , Kilduff Thomas S.
Published: September 2024

Trace amine-associated receptor 1 (TAAR1) has gained attention for its roles in modulating neural systems, sleep/wake control, and as a therapeutic target for neuropsychiatric disorders. Although TAARs 2-9 were initially identified as non-canonical olfactory receptors, recent studies have identified extra-nasal receptor distribution of multiple TAARs. To evaluate whether TAARs 2-9 have a role in arousal state regulation, we investigated sleep/wake control in male TAAR2-9 knockout (KO) mice. After determination of baseline sleep/wake patterns, the homeostatic response to sleep deprivation and response to TAAR1 agonists were compared between KO and C57BL/6J mice. Although the EEG of TAAR2-9 KO mice had lower power in the delta and theta bands and higher power in the gamma range, sleep/wake states were readily identified. KO mice had more NREM sleep during the dark phase and more REM sleep during the light phase. Sleep/wake was fragmented in KO mice with shorter Wake and REM bouts during the dark phase and more REM bouts during the light phase. KO mice exhibited more REM sleep during a sleep latency test but the homeostatic response to sleep loss did not differ between the strains. A high dose of the TAAR1 agonist RO5256390 increased Wake and reduced NREM sleep in KO mice whereas RO5256390 and the partial TAAR1 agonist RO5263397 suppressed REM sleep. The number of tyrosine hydroxylase-immunoreactive neurons in the ventral tegmental area was significantly elevated in KO mice. These dopaminergic and sleep/wake alterations in TAAR2-9 KO mice highlight the need for further elucidation of the functions of TAAR2-9.
A benchmarking study of copy number variation inference methods using single-cell RNA-sequencing data
Authors: Chen Xin , Fang Li Tai , Chen Zhong , Chen Wanqiu , Zhu Bin , Wu Hongjin , Moos Malcolm , Farmer Andrew , Zeng Feng , Song Lijuan , Zhang Xiaowen , Xiong Wei , Gong Shusheng , Jones Wendell , Mason Christopher E , Wu Shixiu , Xiao Chunlin , Wang Charles
Published: September 2024

Single-cell RNA-sequencing (scRNA-seq) has emerged as a powerful tool for cancer research, enabling in-depth characterization of tumor heterogeneity at the single-cell level. Recently, scRNA-seq copy number variation (scCNV) inference methods have been developed, expanding the application of scRNA-seq to study genetic heterogeneity in cancer using transcriptomic data. However, the fidelity of these methods has not been investigated systematically. In this study, we benchmarked five commonly used scCNV inference methods, HoneyBADGER, CopyKAT, CaSpER, inferCNV, and sciCNV. We evaluated their performance across four different scRNA-seq platforms derived data from a multicenter study. We further evaluated the scCNV performance using scRNA-seq datasets derived from mixed samples consisting of five human lung adenocarcinoma cell lines and generated a clinical scRNA-seq dataset from a human small cell lung cancer patient to validate our findings. Our evaluation criteria included sensitivity and specificity of CNV detection, and subclone identification from mixed cancer samples. We found that the sensitivity and specificity of the five scCNV inference methods varied, depending on the selection of reference data, sequencing depths, and read lengths. Overall, CopyKAT and CaSpER exhibited superior performance to other methods, while inferCNV, sciCNV, and CopyKAT outperformed other methods in subclone identification accuracy. Remarkably, inferCNV achieved high accuracy in subclone identification when using data from a “single scRNA-seq protocol”, however, when applying these methods to a dataset derived from multiple scRNA-seq platforms from the mixed samples, we found that batch effects significantly affected the performance of subclone identification for most methods, except for HoneyBADGER. Our benchmarking study revealed the strengths and weaknesses of each of the five scCNV inference methods and provided guidance for selecting the optimal CNV inference method using scRNA-seq data.
A double hit affecting the IKZF1-IKZF2 tandem in immune cells of schizophrenic patients regulate specific symptoms
Authors: Ballasch Ivan , Lopez-Molina Laura , Galan-Ganga Marcos , Sancho-Balsells Anna , Rodriguez-Navarro Irene , Borras-Pernas Sara , Rabadan Maria-Angeles , Chen Wanqi , Pasto-Pellicer Carlota , Flotta Francesca , Fernandez-Irigoyen Joaquin , Santamaria Enrique , Aguilar Ruth , Dobano Carlota , Egri Natalia , Hernandez Carla , Alfonso Miqueu , Juan Manel , Alberch Jordi , del Toro Daniel , Arranz Belen , Canals Josep-Maria , Giralt Albert
Published: September 2024

Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive-negative-cognitive) of schizophrenic-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from human patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenic-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia.
A new Polerovirus species in plants from the Asparagaceae family defined by its RNA-silencing repressor protein P0
Authors: Dekker Rob J , de Leeuw Wim C , van Olst Marina , Ensink Wim A , van Leeuwen Selina , Breit Timo M , Jonker Martijs J
Published: September 2024

To contribute to the discovery of the global virome, we explored plants from an urban botanic garden in the Netherlands for new and variant plant viruses. Analyzing RNA from 25 plants from theAsparagaceaefamily with both RNA-seq, as well as smallRNA-seq revealed in six plants the presence of a variant Polerovirus from theSolemoviridaefamily that shows an overall RNA-sequence identity of 93% to the known Ornithogalum Virus 5 (OV-5). Amino acid sequence comparison of the complex set of proteins produced by the new virus revealed that all but Protein-0, showed high similarity (> 91%) with those of the OV-5 virus. The similarity between the new P0 protein and the OV-5 P0 protein, however, was for all variants less than 83%, well below the ICTV species protein-based demarcation criterium. Hence, we named the new virus Asparagaceae Polerovirus 1 (AspPolV-1).
Unveiling multi-scale architectural features in single-cell Hi-C data using scCAFE
Authors: Wang Fuzhou , Lin Jiecong , Alinejad-Rokny Hamid , Ma Wenjing , Meng Lingkuan , Huang Lei , Yu Jixiang , Chen Nanjun , Wang Yuchen , Yao Zhongyu , Xie Weidun , Li Xiangtao , Wong Ka-Chun
Published: September 2024

Single-cell Hi-C (scHi-C) has provided unprecedented insights into the heterogeneity of 3D genome organization. However, its sparse and noisy nature poses challenges for computational analyses, such as chromatin architectural feature identification. Here, we introduce scCAFE, a deep learning model for the multi-scale detection of architectural features at the single-cell level. scCAFE provides a unified framework for annotating chromatin loops, TAD-like domains (TLDs), and compartments across individual cells. Our model outperforms previous scHi-C loop calling methods and delivers accurate predictions of TLDs and compartments that are biologically consistent with previous studies. The resulting single-cell annotations also offer a measure to characterize the heterogeneity of different levels of architectural features across cell types. We leverage this heterogeneity and identify a series of marker loop anchors, which demonstrate the potential of the 3D genome data to annotate cell identities without the aid of simultaneously sequenced omics data. Overall, scCAFE not only serves as a useful tool for analyzing single-cell genomic architecture, but also paves the way for precise cell-type annotations solely based on 3D genome features.
Colora: A Snakemake Workflow for Complete Chromosome-scaleDe NovoGenome Assembly
Authors: Obinu Lia , Booth Timothy , De Weerd Heleen , Trivedi Urmi , Porceddu Andrea
Published: September 2024

Background

De novoassembly creates reference genomes that underpin many modern biodiversity and conservation studies. Large numbers of new genomes are being assembled by labs around the world. To avoid duplication of efforts and variable data quality, we desire a best-practice assembly process, implemented as an automated portable workflow.

Results

Here we present Colora, a Snakemake workflow that produces chromosome-scalede novoprimary or phased genome assemblies complete with organelles using PacBio HiFi, Hi-C, and optionally ONT reads as input. The source code of Colora is available on GitHub:https://github.com/LiaOb21/colora. Colora is also available at the Snakemake Workflow Catalog (https://snakemake.github.io/snakemake-workflow-catalog/?usage=LiaOb21%2Fcolora).

Conclusion

Colora is a user-friendly, versatile, and reproducible pipeline that is ready to use by researchers looking for an automated way to obtain high-qualityde novogenome assemblies.
Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults
Authors: Gong Qiuyu , Sharma Mehul , Kuan Emma L. , Glass Marla C. , Chander Aishwarya , Singh Mansi , Graybuck Lucas T. , Thomson Zachary J. , LaFrance Christian M. , Zaim Samir Rachid , Peng Tao , Okada Lauren Y. , Genge Palak C , Henderson Katherine E. , Dornisch Elisabeth M. , Layton Erik D. , Wittig Peter J. , Heubeck Alexander T. , Mukuka Nelson M. , Reading Julian , Roll Charles R. , Hernandez Veronica , Parthasarathy Vaishnavi , Stuckey Tyanna J. , Musgrove Blessing , Swanson Elliott , Lord Cara , Weiss Morgan D.A. , Phalen Cole G. , Mettey Regina R. , Lee Kevin J. , Johanneson John B. , Kawelo Erin K. , Garber Jessica , Krishnan Upaasana , Smithmyer Megan , Wherry E. John , Vella Laura , Henrickson Sarah E. , Kopp Mackenzie S. , Savage Adam K. , Becker Lynne A. , Meijer Paul , Coffey Ernest M. , Goronzy Jorg J. , Speake Cate , Bumol Thomas F. , Goldrath Ananda W. , Torgerson Troy R. , Li Xiao-jun , Skene Peter J. , Buckner Jane H. , Gustafson Claire E.
Published: September 2024

The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination. The resulting resource includes scRNA-seq datasets of >16 million PBMCs, interrogating 71 immune cell subsets from our new Immune Health Atlas. This study allows unique insights into the composition and transcriptional state of immune cells at homeostasis, with vaccine perturbation, and across age. We find that T cells specifically accumulate age-related transcriptional changes more than other immune cells, independent from inflammation and chronic perturbation. Moreover, impaired memory B cell responses to vaccination are linked to a Th2-like state shift in older adults’ memory CD4 T cells, revealing possible mechanisms of immune dysregulation during healthy human aging. This extensive resource is provided with a suite of exploration tools athttps://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/to enhance data accessibility and further the understanding of immune health across age.
m6AConquer: a Data Resource for Unified Quantification and Integration of m6A Detection Techniques
Authors: Zhao Xichen , Ye Haokai , Li Tenglong , Rigden Daniel J , Wei Zhen
Published: September 2024

N6-methyladenosine (m6A) is the most prevalent RNA modification in mammalian cells and the most extensively studied epitranscriptomic mark. More than 10 m6A detection techniques have been proposed to measure m6A stoichiometry at either the site or peak level. However, these detection techniques are processed through heterogeneous pipelines, using different computational filters and reference features, leading to difficulties in fully harnessing data integration and analysis across orthogonal m6A detection techniques. Our m6AConquer (Consistent Quantification of External m6A RNA Modification Data) tackles this challenge by establishing a consistent multi-omics data-sharing standard, summarizing quantitative m6A data from 10 detection techniques using a unified reference feature set. Furthermore, we standardize site calling and m6A count matrix normalization procedures across platforms through a computational framework that accounts for over-dispersion in m6A levels. Available m6A detection techniques can be categorized into four types: antibody-assisted, chemical-assisted, enzyme-assisted, and direct-RNA sequencing. We leverage this categorization to develop a reproducibility-based integration framework that enables the reliable detection of high-confidence m6A sites confirmed across orthogonal techniques. Empirical evaluations report that both the site-calling and the integration framework outperform common alternatives, enhancing biological relevance. We apply interpretable machine learning models on our integrated high-confidence sites, and the results consistently identify proximity to intron-exon junctions as the driving predictor of m6A site coordinates across different techniques, demonstrating the high quality of the data curated in m6AConquer. m6AConquer webserver is freely accessible under: http://rnamd.org/m6aconquer.
Sex-dependent effects of a high-fat diet on the hypothalamic response in mouse
Authors: Dreux Virginie , Lefebvre Candice , Breemeersch Charles-Edward , Salaun Colin , Bole-Feysot Christine , Guerin Charlene , Dechelotte Pierre , Goichon Alexis , Coeffier Moise , Langlois Ludovic David
Published: September 2024

Sex differences in rodent models of diet-induced obesity are still poorly documented, particularly regarding how central mechanisms vary between sexes in response to an obesogenic diet. Here, we wanted to determine whether obesity phenotype and hypothalamic response differed between male and female C57Bl/6J mice when exposed to a high-fat diet (HFD). Mice were exposed either a free 60% HFD or standard diet first for both a long- (14 weeks) and shorter-periods of time (3, 7, 14 and 28 days). Analysis of the expression profile of key neuronal, glial and inflammatory hypothalamic markers was performed using RT-qPCR. In addition, astrocytic and microglial morphology was examined in the arcuate nucleus. Monitoring of body weight and composition revealed that body weight and fat mass gain appeared earlier and was more pronounced in male mice. After 14 weeks of HFD exposure, normalized increase of body weight reached similar levels between male and female mice. Overall, both sexes under HFD displayed a decrease of orexigenic neuropeptides expression and an increase in POMC gene expression was observed only in female mice. In addition, changes in the expression of hypothalamic inflammatory markers were relatively modest. We also reported that the glial cell markers expression and morphology were affected by HFD in a sex- and time dependent manner, suggesting a more pronounced glial cell activation in female mice. Taken together, these data show that male and female mice responded differently to HFD exposure, both on short- and long-term and suggest that a strong inflammatory hypothalamic profile is not systematically present in DIO models. Nevertheless, in addition to these present data, the underlying mechanisms should be deciphered in further investigations.
TopBP1 biomolecular condensates: a new therapeutic target in advanced-stage colorectal cancer.
Authors: Morano Laura , Vie Nadia , Aissanou Adam , Egger Tom , Aze Antoine , Fiachetti Solene , Seitz Herve , Milazzo Louis-Antoine , GARAMBOIS Veronique , Bonnefoy-Berard Nathalie , Gongora Celine , Constantinou Angelos , Basbous Jihane
Published: September 2024

In cancer cells, ATR signaling is crucial to tolerate the intrinsically high damage levels that normally block replication fork progression. Assembly of TopBP1, a multifunctional scaffolding protein, into condensates is required to amplify ATR kinase activity to the levels needed to coordinate the DNA damage response and manage DNA replication stress. Many ATR inhibitors are tested for cancer treatment in clinical trials, but their overall effectiveness is often compromised by the emergence of resistance and toxicities. In this proof-of-concept study, we propose to disrupt the ATR pathway by targeting TopBP1 condensation. First, we screened a molecule-based library using a previously developed optogenetic approach and identified several TopBP1 condensation inhibitors. Amongst them, AZD2858 disrupted TopBP1 assembly induced by the clinically relevant topoisomerase I inhibitor SN-38, thereby inhibiting the ATR/Chk1 signaling pathway. We found that AZD2858 exerted its effects by disrupting TopBP1 self-interaction and binding to ATR in mammalian cells, and by increasing its chromatin recruitment in cell-free Xenopus laevis egg extracts. Moreover, AZD2858 prevented S-phase checkpoint induction by SN-38, leading to increased DNA damage and apoptosis in a colorectal cancer cell line. Lastly, AZD2858 showed synergistic effect in combination with the FOLFIRI chemotherapy regimen in a spheroid model of colorectal cancer.
A Statistically-Robust Model Of The Axomyelin Unit Under Normal Physiologic Conditions With Application To Disease States
Authors: Gow Alexander , Dupree Jeffrey L , Feinstein Douglas L , Boullerne Anne
Published: September 2024

Despite tremendous progress in characterizing the myriad cellular structures in the nervous system, a full appreciation of the interdependent and intricate interactions between these structures is as yet unfulfilled. Indeed, few more so than the interaction between the myelin internode and its ensheathed axon. More than a half-century after the ultrastructural characterization of this axomyelin unit, we lack a reliable understanding of the physiological properties, the significance and consequence of pathobiological processes, and the means to gauge success or failure of interventions designed to mitigate disease. Herein, we highlight shortcomings in the most common statistical procedures used to characterize the axomyelin unit, with particular emphasis on the underlying principles of simple linear regression. These shortcomings lead to insensitive detection and/or ambiguous interpretation of normal physiology, disease mechanisms and remedial methodologies. To address these problems, we syndicate insights from early seminal myelin studies and use a statistical model of the axomyelin unit that is established in the accompanying article. Herein, we develop and demonstrate a statistically-robust analysis pipeline with which to examine and interpret axomyelin physiology and pathobiology in two disease states, experimental autoimmune encephalomyelitis and therumpshakermouse model of leukodystrophy. On a cautionary note, our pipeline is a relatively simple and streamlined approach that is not necessarily a panacea for allgratio analyses. Rather, it approximates a minimum effort needed to elucidate departures from normal physiology and to determine if more comprehensive studies may lead to deeper insights.
A new framework for SubtiWiki, the database for the model organism Bacillus subtilis
Authors: Elfmann Christoph , Dumann Vincenz , van den Berg Tim , Stulke Jorg
Published: September 2024

Bacillus subtilis is a Gram-positive model bacterium and one of the most-studied and best understood organisms. The complex information resulting from its investigation is compiled in the database SubtiWiki (https://subtiwiki.uni-goettingen.de/v5) in an integrated and intuitive manner. To enhance the utility of SubtiWiki, we have added novel features such as a viewer to interrogate conserved genomic organization, a widget that shows mutant fitness data for all non-essential genes, and a widget showing protein structures, structure predictions and complex structures. Moreover, we have integrated metabolites as new entities. The new framework also includes a documented API, enabling programmatic access to data for computational tasks. Here we present the recent developments of SubtiWiki and the current state of the data for this organism.
Solanum pan-genomics and pan-genetics reveal paralogs as contingencies in crop engineering
Authors: Benoit Matthias , Jenike Katharine M , Satterlee James W , Ramakrishnan Srividya , Gentile Iacopo , Hendelman Anat , Passalacqua Michael J , Suresh Hamsini , Shohat Hagai , Robitaille Gina M , Fitzgerald Blaine , Alonge Michael M , Wang Xingang , Santos Ryan , He Jia , Ou Shujun , Golan Hezi , Green Yumi , Swartwood Kerry , Sierra Gina P , Orejuela Andres , Fornaguera Federico , Goodwin Sara , McCombie William Richard , Kizito Elizabeth Balyejusa , Gagnon Edeline , Knapp Sandra , Sarkinen Tiina , Frary Amy , Gillis Jesse , Van Eck Joyce , Schatz Michael C , Lippman Zachary B
Published: September 2024

Pan-genomics and genome editing technologies are revolutionizing the breeding of globally cultivated crops. A transformative opportunity lies in the reciprocal exchange of genotype-to-phenotype knowledge of agricultural traits between these major crops and hundreds of locally cultivated indigenous crops, thereby enhancing the diversity and resilience of our food system. However, species-specific genetic variants and their interactions with desired natural or engineered mutations pose barriers to achieving predictable phenotypic effects, even between closely related crops or genotypes. Here, by establishing a pan-genome of the crop-rich genus Solanum and integrating functional genomics and genetics, we show that gene duplication and subsequent paralog diversification are a major obstacle to genotype-phenotype predictability. Despite broad conservation of gene macrosynteny among chromosome-scale references for 22 species, including 13 indigenous crops, hundreds of global and lineage-specific gene duplications exhibited dynamic evolutionary trajectories in paralog sequence, expression, and function, including among members of key domestication gene families. Extending our pan-genome with 10 cultivars of African eggplant and leveraging quantitative genetics and genome editing, we uncovered an intricate history of paralog emergence and evolution within this indigenous crop. The loss of an ancient redundant paralog of the classical regulator of stem cell proliferation and fruit organ number, CLAVATA3 (CLV3), was compensated by a lineage-specific tandem duplication. Subsequent pseudogenization of the derived copy followed by a cultivar-specific structural variant resulted in a single fused functional copy of CLV3 that modifies locule number alongside a newly identified gene controlling the same trait. Our findings demonstrate that paralog diversifications over short evolutionary periods are critical yet underexplored contingencies in trait evolvability and independent crop domestication histories. Unraveling these contingencies is crucial for translating genotype-to-phenotype relationships across related species.
spaDesign: A Statistical Framework to Improve the Design of Sequencing-based Spatial Transcriptomics Experiments
Authors: Xie Juan , Jeon Hyeongseon , Chang Won , Jeon Yeseul , Li Zihai , Ma Qin , Chung Dongjun
Published: September 2024

Rigorous experimental design is essential for obtaining biologically meaningful findings and high-throughput spatial transcriptomics studies are not an exception. While some efforts have been made to improve the design of these studies, it is still significantly understudied yet how to optimize key experimental factors of these experiments. In the case of sequencing-based spatial transcriptomics studies, determining the minimum sequencing depth is an important experimental factor to decide. To address this critical limitation, here we propose spaDesign, a statistical framework to improve the design of sequencing-based spatial transcriptomics experiments. spaDesign is a statistically rigorously designed framework that employs Poisson-Gaussian process and Fisher-Gaussian kernel mixture. It can easily simulate a range of spatial transcriptomics data with various sequencing depths, effect sizes, and spatial patterns, which allows rigorous estimation of needed total sequencing depths to detect spatial domains based on spatial transcriptomics experiments. We demonstrated the utility and power of spaDesign using 10X Visium data of the human brain and the chicken heart.
Rapid production of modified cattle and sheep from spermatid-like stem cells
Authors: Yang Lei , Di Anqi , Song Lishuang , Liu Xuefei , Wu Di , Wang Song , Hao Zhenting , Bu Lige , Bai Chunling , Su Guanghua , Wei Zhuying , Zhang Li , Liu Zhonghua , Gao Shaorong , Li Guangpeng
Published: September 2024

Haploid androgenetic stem cells (haSCs) are revolutionary resources for studying animal traits and greatly impact livestock breeding, but livestock haSCs have yet to be obtained. Here, we report the derivation of cattle and sheep haSCs using a novel FACE medium, and these cells harbor formative pluripotency features. Notably, knockout cattle and sheep can be efficiently obtained upon injection of the protaminized haSCs with targeted gene mutations into oocytes.
Brownian motion data augmentation: a method to push neural network performance on nanopore sensors
Authors: Kipen Javier , Jaldén Joakim
Published: September 2024

Nanopores are highly sensitive sensors that have achieved commercial success in DNA/RNA sequencing, with potential applications in protein sequencing and biomarker identification. Solid-state nanopores, in particular, face challenges such as instability and low signal-to-noise ratios (SNRs), which lead scientists to adopt data-driven methods for nanopore signal analysis, although data acquisition remains restrictive. In this paper, we augment training samples by simulating virtual Brownian motion based on dynamic models in the literature. We apply this method to a publicly available dataset of a classification task containing nanopore reads of DNA with encoded barcodes. A neural network named QuipuNet was previously published for this dataset, and we demonstrate that our augmentation method produces a noticeable increase in QuipuNets accuracy. Furthermore, we introduce a novel neural network named YupanaNet, which achieves greater accuracy (95.8%) than QuipuNet (94.6%) on the same dataset. YupanaNet benefits from both the enhanced generalization provided by Brownian motion data augmentation and the incorporation of novel architectures, including skip connections and a self-attention mechanism.
Cholinergic feedback for context-specific modulation of sensory representations
Authors: Yu Bin , Yue Yuxuan , Ren Chi , Yun Rui , Lim Byungkook , Komiyama Takaki
Published: September 2024

The brain’s ability to prioritize behaviorally relevant sensory information is crucial for adaptive behavior, yet the underlying mechanisms remain unclear. Here, we investigated the role of basal forebrain cholinergic neurons in modulating olfactory bulb (OB) circuits in mice.

Calcium imaging of cholinergic feedback axons in OB revealed that their activity is strongly correlated with orofacial movements, with little responses to passively experienced odor stimuli. However, when mice engaged in an odor discrimination task, OB cholinergic axons rapidly shifted their response patterns from movement-correlated activity to odor-aligned responses.

Notably, these odor responses during olfactory task engagement were absent in cholinergic axons projecting to the dorsal cortex. The level of odor responses correlated with task performance. Inactivation of OB-projecting cholinergic neurons during task engagement impaired performance and reduced odor responses in OB granule cells. Thus, the cholinergic system dynamically modulates sensory processing in a modality-specific and context-dependent manner, providing a mechanism for a flexible and adaptive sensory prioritization.