bluuebunny/crossref_metadata_2025 huggingface dataset:
Role Of The C-C Motif Chemokine Ligand 5 (CCL5) And Its Receptor, C-C Motif Chemokine Receptor 5 (CCR5) In The Genesis Of Aldosterone-induced Hypertension, Vascular Dysfunction, And End-organ Damage
Authors: Costa Rafael M. , Cerqueira Débora M. , Bruder-Nascimento Ariane , Alves Juliano V. , Awata Wanessa A.C. , Singh Shubhnita , Kufner Alexander , Cifuentes-Pagano Eugenia , Pagano Patrick J. , Ho Jacqueline , Bruder-Nascimento Thiago
Published: September 2023

Background

Aldosterone, a mineralocorticoid steroid hormone, has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of C-C Motif Chemokine Ligand 5 (CCL5) and its receptor, C-C Motif Chemokine Receptor 5 (CCR5), are well known in infectious diseases, but their roles in the genesis of aldosterone-induced vascular injury and hypertension are unknown.

Methods

We analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5+/+) and CCR5 knockout (CCR5−/−) mice treated with aldosterone (600 µg/kg/day for 14 days) while receiving 1% saline to drink.

Results

Here, we show that CCR5 plays a central role in aldosterone-induced vascular injury, hypertension, and renal damage. Long-term infusion of aldosterone in CCR5+/+mice resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression. Aldosterone treatment also triggered vascular injury, characterized by endothelial dysfunction and inflammation, hypertension, and renal damage. Mice lacking CCR5 were protected from aldosterone-induced vascular damage, hypertension, and renal injury. Mechanistically, we demonstrated that CCL5 increased NADPH oxidase 1 (Nox1) expression, reactive oxygen species (ROS) formation, NFκB activation, and inflammation and reduced nitric oxide production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aortae incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking Nox1, NFκB, or with Maraviroc treatment.

Conclusions

Our data demonstrate that CCL5/CCR5, through activation of NFkB and Nox1, is critically involved in aldosterone-induced vascular and renal damage and hypertension. Our data place CCL5 and CCR5 as potential targets for therapeutic interventions in conditions with aldosterone excess.
In silicosingle-cell metabolism analysis unravels a new transition stage of CD8 T cells 4 days post-infection
Authors: Christophe Arpin , Picard Franck , Gandrillon Olivier
Published: September 2023

CD8 T cell proper differentiation during antiviral responses relies on metabolic adaptations. Herein, we investigated global metabolic activity in single CD8 T cells along anin vivoresponse by estimating metabolic fluxes from single-cell RNA-sequencing data. The approach was validated by the observation of metabolic variations known from experimental studies on global cell populations, while adding temporally detailed information and unravelling yet undescribed sections of CD8 T cell metabolism that are affected by cellular differentiation. Furthermore, inter-cellular variability in gene expression level, highlighted by single cell data, and heterogeneity of metabolic activity 4 days post-infection, revealed a new transition stage accompanied by a metabolic switch in activated cells differentiating into full-blown effectors.
TIM-4 Identifies Effector B Cells Expressing a RORγt-Driven Proinflammatory Cytokine Module That Promotes Immune Responsiveness
Authors: Ding Qing , Wu Yufan , Triglia Elena Torlai , Gommerman Jennifer L. , Subramanian Ayshwarya , Kuchroo Vijay K. , Rothstein David M.
Published: September 2023

B cells can express pro-inflammatory cytokines that promote a wide variety of immune responses. Here we show that B cells expressing the phosphatidylserine receptor TIM-4, preferentially express IL-17A, as well as IL-22, IL-6, IL-1β, and GM-CSF - a collection of cytokines reminiscent of pathogenic Th17 cells. Expression of this proinflammatory module requires IL-23R signaling and selective expression of RORγt and IL-17A by TIM-4+B cells. TIM-4+B cell-derived-IL-17A not only enhances the severity of experimental autoimmune encephalomyelitis (EAE) and promotes allograft rejection, but also acts in an autocrine manner to prevent their conversion into IL-10-expressing B cells with regulatory function. Thus, IL-17A acts as an inflammatory mediator and also enforces the proinflammatory activity of TIM-4+B cells. Thus, TIM-4 serves as a broad marker for RORγt+effector B cells (Beff) and allows further study of the signals regulating Beff differentiation and effector molecule expression.
Genomic comparison of the temperate coralAstrangia poculatawith tropical corals yields insights into winter quiescence, innate immunity, and sexual reproduction
Authors: Stankiewicz Kathryn H. , Guiglielmoni Nadège , Kitchen Sheila A. , Flot Jean-François , Barott Katie L. , Davies Sarah W. , Finnerty John R. , Grace Sean P. , Kaufman Leslie S. , Putnam Hollie M. , Rotjan Randi D. , Sharp Koty H. , Baums Iliana B.
Published: September 2023

Facultatively symbiotic corals provide important experimental models to explore the establishment, maintenance, and breakdown of the mutualism between corals and members of the algal family Symbiodiniaceae. The temperate coralAstrangia poculatais one such model as it is not only facultatively symbiotic, but also occurs across a broad temperature and latitudinal gradient. Here, we report thede novochromosome-scale assembly and annotation of theA. poculatagenome. Though widespread segmental/tandem duplications of genomic regions were detected, we did not find strong evidence of a whole genome duplication (WGD) event. Comparison of the gene arrangement betweenA. poculataand the tropical coralAcropora milleporarevealed 56.38% of the orthologous genes were conserved in syntenic blocks despite ∼415 million years of divergence. Gene families related to sperm hyperactivation and innate immunity, including lectins, were found to contain more genes inA. milleporarelative toA. poculata. Sperm hyperactivation inA. milleporais expected given the extreme requirements of gamete competition during mass spawning events in tropical corals, while lectins are important in the establishment of coral-algal symbiosis. By contrast, gene families involved in sleep promotion, feeding suppression, and circadian sleep/wake cycle processes were expanded inA. poculata. These expanded gene families may play a role inA. poculata’s ability to enter a dormancy-like state (“winter quiescence”) to survive freezing temperatures at the northern edges of the species’ range.
Predicting Long and Short Duration Beta Bursts from Subthalamic Nucleus Local Field Potential Activity in Parkinson’s Disease
Authors: Abdi-Sargezeh Bahman , Shirani Sepehr , Sharma Abhinav , Starr Philip A. , Little Simon , Oswal Ashwini
Published: September 2023

Neural activities within the beta frequency range (13-30 Hz) are not stationary, but occur in transient packets known as beta bursts. Parkinson’s disease (PD) is characterized by the occurrence of beta bursts of increased duration and amplitude within the cortico-basal ganglia network. The pathophysiological importance of beta bursts is exemplified by the fact that they serve as a clinically useful feedback signal in beta amplitude triggered adaptive Deep Brain Stimulation (aDBS). Prolonged duration beta bursts are closely associated with motor impairments in PD, whilst bursts of shorter duration may have a physiological role. Consequently, we aimed to develop a deep learning-based pipeline capable of predicting long (>150ms) and short (<150ms) duration beta bursts from subthalamic nucleus local field potential (LFP) recordings. Our approach achieved promising accuracy values of 87% and 85.2% in two patients implanted with a DBS device that was capable of long-term wireless LFP sensing. Our findings highlight the feasibility of prolonged beta burst prediction and could inform the development of a new type of intelligent DBS approach with the capability of delivering stimulation only during the occurrence of prolonged bursts.
Massive detection of cryptic recessive genetic defects in cattle mining millions of life histories
Authors: Besnard Florian , Guintard Ana , Grohs Cécile , Guzylack-Piriou Laurence , Cano Margarita , Escouflaire Clémentine , Hozé Chris , Leclerc Hélène , Buronfosse Thierry , Dutheil Lucie , Jourdain Jeanlin , Barbat Anne , Fritz Sébastien , Deloche Marie-Christine , Remot Aude , Gaussères Blandine , Clément Adèle , Bouchier Marion , Contat Elise , Relun Anne , Plassard Vincent , Rivière Julie , Péchoux Christine , Vilotte Marthe , Eche Camille , Kuchly Claire , Charles Mathieu , Boulling Arnaud , Viard Guillaume , Minéry Stéphanie , Barbey Sarah , Birbes Clément , Danchin-Burge Coralie , Launay Frédéric , Mattalia Sophie , Allais-Bonnet Aurélie , Ravary Bérangère , Millemann Yves , Guatteo Raphaël , Klopp Christophe , Gaspin Christine , Iampietro Carole , Donnadieu Cécile , Milan Denis , Arcangioli Marie-Anne , Boussaha Mekki , Foucras Gilles , Boichard Didier , Capitan Aurélien
Published: September 2023

We present a data-mining framework designed to detect recessive defects in livestock that have been previously missed due to a lack of specific signs, incomplete penetrance, or incomplete linkage disequilibrium. This approach leverages the massive data generated by genomic selection. Its basic principle is to compare the observed and expected numbers of homozygotes for sliding haplotypes in animals with different life histories. Within three cattle breeds, we report 33 new loci responsible for increased risk of juvenile mortality and present a series of validations based on large-scale genotyping, clinical examination, and functional studies for candidate variants affecting theNOA1,RFC5,andITGB7genes. In particular, we describe disorders associated withNOA1andRFC5mutations for the first time in vertebrates. The discovery of these many new defects will help to characterize the genetic basis of inbreeding depression, while their management will improve animal welfare and reduce losses to the industry.
A Genetically Encoded Actuator Selectively Boosts L-type Calcium Channels in Diverse Physiological Settings
Authors: del Rivero Morfin Pedro J. , Chavez Diego Scala , Jayaraman Srinidhi , Yang Lin , Kochiss Audrey L. , Colecraft Henry M. , Liu X. Shawn , Marx Steven O. , Rajadhyaksha Anjali M. , Ben-Johny Manu
Published: September 2023

L-type Ca2+channels (CaV1.2/1.3) convey influx of calcium ions (Ca2+) that orchestrate a bevy of biological responses including muscle contraction and gene transcription. Deficits in CaV1 function play a vital role in cardiac and neurodevelopmental disorders. Yet conventional pharmacological approaches to upregulate CaV1 are limited, as excessive Ca2+influx leads to cytotoxicity. Here, we develop a genetically encoded enhancer of CaV1.2/1.3 channels (GeeC) to manipulate Ca2+entry in distinct physiological settings. Specifically, we functionalized a nanobody that targets the CaVmacromolecular complex by attaching a minimal effector domain from a CaVenhancer—leucine rich repeat containing protein 10 (Lrrc10). In cardiomyocytes, GeeC evoked a 3-fold increase in L-type current amplitude. In neurons, GeeC augmented excitation-transcription (E-T) coupling. In all, GeeC represents a powerful strategy to boost CaV1.2/1.3 function in distinct physiological settings and, in so doing, lays the groundwork to illuminate new insights on neuronal and cardiac physiology and disease.
Immunohistochemical and ultrastructural characterization of the inner ear epithelial cells of splitnose rockfish (Sebastes diploproa)
Authors: Kwan Garfield T. , Andrade Leonardo R. , Prime Kaelan J. , Tresguerres Martin
Published: September 2023

The inner ear of teleost fish regulates the ionic and acid-base chemistry and secretes the protein matrix of the endolymph to facilitate otolith biomineralization, which are used to maintain vestibular and auditory functions. The otolith is biomineralized in a concentric ring pattern corresponding to seasonal growth, and this CaCO3polycrystal has become a vital aging and life-history tool for fishery managers, ecologists, and conservation biologists. Moreover, biomineralization patterns are sensitive to environmental variability including climate change, thereby threatening the accuracy and relevance of otolith-reliant toolkits. However, the cellular biology of the inner ear is poorly characterized, which is a hurdle for a mechanistic understanding of the underlying processes. This study provides a systematic characterization of the cell types in the inner ear of splitnose rockfish (Sebastes diploproa). Scanning electron microscopy revealed the apical morphologies of the six inner ear cell types. Additionally, immunostaining and confocal microscopy characterized the expression and subcellular localization of the proteins Na+/K+-ATPase, carbonic anhydrase, V-type H+-ATPase, Na+-K+-2Cl--Co-Transporter, Otolith Matrix Protein 1, and Otolin-1 in six inner ear cell types bordering the endolymph. This fundamental cytological characterization of the rockfish inner ear epithelium illustrates the intricate physiological processes involved in otolith biomineralization, and highlights how greater mechanistic understanding is necessary to predict their multi-stressor responses to future climate change.
Gene expression changes inDrosophila melanogasterfemales associated with the rescue of thebag of marbles(bam) hypomorph fertility defect byWolbachia pipientis
Authors: Kagemann Catherine H. , Colocho Gabriela M. , Aquadro Charles F.
Published: September 2023

Wolbachia pipientisare maternally transmitted endosymbiotic bacteria commonly found in arthropods and nematodes. These bacteria manipulate reproduction of the host to increase their transmission using mechanisms, such as cytoplasmic incompatibility, that favor infected female offspring. Interestingly,W. pipientisinfection partially rescues female fertility in flies containing hypomorph mutations ofbag of marbles(bam) inD. melanogaster, which functions in germline stem cell (GSC) maintenance and differentiation. Here we evaluated the effect ofW. pipientisvariant infection on host gene expression using RNA-seq. RNA-seq analysis using theW. pipientisinfected relative to uninfectedbamhypomorph genotype had differential expression for many ofbam’sgenetic and physical interactors. The highest magnitude of differential expression ofbam’sinteractors and other GSC genes involved in cystoblast differentiation occurred prior to peak fertility rescue. Our analysis showed that ubiquitination and histone lysine methylation could be important mechanisms involved in thebamhypomorph fertility rescue byW. pipientis.
Picoeukaryotic photosynthetic potential is functionally redundant but taxonomically structured at global scale
Authors: Schickele Alexandre , Debeljak Pavla , Ayata Sakina-Dorothée , Bittner Lucie , Pelletier Eric , Guidi Lionel , Irisson Jean-Olivier
Published: September 2023

Primary production, performed by RUBISCO, and often associated with carbon concentration mechanisms, is of major importance in the oceans. Thanks to growing metagenomic resources (e.g., eukaryotic Metagenome-Assembled-Genomes; MAGs), we provide the first reproducible machine-learning-based framework to derive the potential biogeography of a given function, through the multi-output regression of the standardized number of reads of the associated genes on environmental climatologies. We use it to study the genomic potential of C4-photosynthesis of picoeukaryotes, a diverse and abundant group of marine unicellular photosynthetic organisms. We show that the genomic potential supporting C4-enzymes and RUBISCO exhibit strong functional redundancy and an important affinity towards tropical oligotrophic waters. This redundancy is then structured taxonomically by the dominance of Mamiellophyceae and Prymnesiophyceae in mid and high latitudes. Finally, unlike the genomic potential related to most C4-enzymes, the one of RUBISCO showed a clear pattern affinity for temperate waters.
Exploring an EM-algorithm for banded regression in computational neuroscience
Authors: Fuglsang Søren A. , Madsen Kristoffer H. , Puonti Oula , Siebner Hartwig R. , Hjortkjær Jens
Published: September 2023

Regression is a principal tool for relating brain responses to stimuli or tasks in computational neuroscience. This often involves fitting linear models with predictors that can be divided into groups, such as distinct stimulus feature subsets in encoding models or features of different neural response channels in decoding models. When fitting such models, it can be relevant to impose differential shrinkage of the different groups of regression weights. Here, we explore a framework that allow for straightforward definition and estimation of such models. We present an expectation-maximization algorithm for tuning hyperparameters that control shrinkage of groups of weights. We highlight properties, limitations, and potential use-cases of the model using simulated data. Next, we explore the model in the context of a BOLD fMRI encoding analysis and an EEG decoding analysis. Finally, we discuss cases where the model can be useful and scenarios where regularization procedures complicate model interpretation.
Structural Flexibility and Disassembly Kinetics of Single Ferritins Using Optical Nanotweezers
Authors: Yousefi Arman , Zheng Ze , Zargarbashi Saaman , Assadipapari Mahya , Hickman Graham J. , Parmenter Christopher D. J. , Bueno-Alejo Carlos J. , Sanderson Gabriel , Craske Dominic , Xu Lei , Rahmani Mohsen , Ying Cuifeng
Published: September 2023

Ferritin, a spherical protein shell assembled from 24 subunits, functions as an efficient iron storage and release system through its channels. Understanding how various chemicals affect the structural behaviour of ferritin is crucial for unravelling the origins of iron-related diseases in living organisms including humans. In particular, the influence of chemicals on ferritin’s dynamics and iron release is barely explored at the single-protein level. Here, by employing optical nanotweezers using double nanohole (DNH) structures, we examined the effect of ascorbic acid (reducing reagent) and pH on ferritin’s conformational dynamics. The dynamics of ferritin increased as the concentration of ascorbic acid approached saturation. At pH 2.0 ferritin exhibited significant structural fluctuations and eventually underwent a stepwise disassembly into fragments. This work, for the first time, tracked the disassembly pathway and kinetics of single ferritins in solution. We identified four critical fragments during its disassembly pathway, which are 22-mer, 12-mer, tetramer, and dimer subunits. Moreover, we presented the first single-molecule evidence of the cooperative disassembly of ferritin. Interrogating ferritin’s structural change in response to different chemicals holds importance for understanding their roles in iron metabolism, hence facilitating further development of medical treatments for the associated diseases.
Functional diversity ofNLRP3gain-of-function mutants associated with CAPS autoinflammation
Authors: Cosson Camille , Riou Romane , Patoli Danish , Niu Tingting , Rey Amaury , Groslambert Marine , Chatre Elodie , Allatif Omran , Henry Thomas , Venet Fabienne , Milhavet Florian , Boursier Guilaine , Belot Alexandre , Jamilloux Yvan , Merlin Etienne , Duquesne Agnès , Grateau Gilles , Savey Léa , Jacques Maria Alexandre Thibault , Pagnier Anne , Poutrel Solène , Lambotte Olivier , Mallebranche Coralie , Rieux-Laucat Frédéric , Bader-Meunier Brigitte , Amoura Zahir , Melki Isabelle , Touitou Isabelle , Geyer Matthias , Georgin-Lavialle Sophie , Py Bénédicte F.
Published: September 2023

NLRP3-associated autoinflammatory disease (NLRP3-AID or CAPS) is an heterogenous group of monogenic autoinflammations associated withNLRP3gain-of-function mutations. The poor functional characterization of mostNLRP3variants is a barrier to diagnosis although patients can be efficiently treated with anti-IL-1 approaches. In addition, while NLRP3 inflammasome is controlled by coordinated priming and activation signals, gain-of-functions ofNLRP3variants have been only investigated in response to priming. Here, we functionally characterize 34NLRP3variantsin vitroby determining their activity in response to induction, priming and/or activation signals, and their sensitivity to inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on their profile of signals required for their activation, that correlate partly with the symptoms severities. We identify a new group ofNLRP3mutants responding to the activation signal without priming, with patients often misdiagnosed. Our results identify key NLRP3 residues controlling the inflammasome activity and sensitivity to inhibitors. The comparison of four inhibitors on the 34 variants identifies inhibitory mechanisms with broader efficiency for future drug design. Altogether, our results provide new insights on NLRP3 activation and an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and anti-inflammatory disease drug development.

eTOC Summary

Functional characterization of 34 CAPS-associatedNLRP3variants identifies polymorphisms versus gain-of-function pathogenic mutants, and highlights diversities in the signals controlling their activation and in their sensitivity to inhibitors. This study provides tools for CAPS diagnosis and anti-inflammation drug development and insights on NLRP3 control mechanisms.
The evolution of environmentally mediated social interactions and posthumous spite under isolation by distance
Authors: Mullon Charles , Peña Jorge , Lehmann Laurent
Published: September 2023

Many social interactions happen indirectly via modifications of the environment, e.g. through the secretion of functional compounds or the depletion of renewable resources. Here, we derive the selection gradient on a quantitative trait affecting dynamical environmental variables that feed back on reproduction and survival in a finite patch-structured population subject to isolation by distance. Our analysis shows that the selection gradient depends on how a focal individual influences the fitness of all future individuals in the population through modifications of the environmental variables they experience, weighted by the neutral relatedness between recipients and the focal. The evolutionarily relevant trait-driven environmental modifications are formalized as the extended phenotypic effects of an individual, quantifying how a trait change in an individual in the present affects the environmental variables in all patches at all future times. When the trait affects reproduction and survival through a payoff function, the selection gradient can be expressed in terms of extended phenotypic effects weighted by scaled-relatedness. We show how to compute extended phenotypic effects, relatedness, and scaled-relatedness using Fourier analysis, which allow us to investigate a broad class of environmentally mediated social interactions in a tractable way. We use our approach to study the evolution of a trait controlling the costly production of some lasting commons (e.g. a common-pool resource or a toxic compound) that can diffuse in space and persist in time. We show that indiscriminate posthumous spite readily evolves in this scenario. More generally whether selection favours environmentally mediated altruism or spite is determined by the spatial correlation between an individual’s lineage and the commons originating from its patch. The sign of this correlation depends on interactions between dispersal patterns and the commons’ renewal dynamics. More broadly, we suggest that selection can favour a wide range of social behaviours when these have carry-over effects in space and time.
Leishmaniinae: evolutionary inferences based on protein expression profiles (PhyloQuant) congruent with phylogenetic relationships amongLeishmania, Endotrypanum, Porcisia, Zelonia, Crithidia,andLeptomonas
Authors: Mule Simon Ngao , Alemán Evaristo Villalba , Fernandes Livia Rosa , Saad Joyce S. , de Oliveira Gilberto Santos , Martins Deivid , Angeli Claudia Blanes , Brandt-Almeida Deborah , Cortez Mauro , Larsen Martin Røssel , Shaw Jeffrey J. , Teixeira Marta M. G. , Palmisano Giuseppe
Published: September 2023

Evolutionary relationships among parasites of the subfamily Leishmaniinae, which comprises pathogen agents of leishmaniasis, were inferred based on differential protein expression profiles from mass spectrometry-based quantitative data using the PhyloQuant method. Evolutionary distances following identification and quantification of protein and peptide abundances using Proteome Discoverer (PD) and MaxQuant (MQ) softwares were estimated for 11 species from 6 Leishmaniinae genera. Results clustered all dixenous species of the genusLeishmania, subgeneraL. (Leishmania), L. (Viannia)andL. (Mundinia),sister to the dixenous species of generaEndotrypanumandPorcisia.Positioned basal to the assemblage formed by all these parasites were the species of generaZelonia,CrithidiaandLeptomonas, so far described as monoxenous of insects although eventually reported from humans. Inferences based on protein expression profiles were congruent with currently established phylogeny using DNA sequences. Our results reinforce PhyloQuant as a valuable approach to infer evolutionary relationships consistent with genera, subgenera, and species-specific biological characteristics, able to resolve within Leishmaniinae, which is comprised of very tightly related trypanosomatids that are just beginning to be phylogenetically unravelled. In additional to evolutionary history, mapping of species-specific protein expression is paramount to understand differences in infection processes, disease presentations, tissue tropisms, potential to jump from insects to vertebrates including humans, and potential targets for species-specific diagnostic and drug development.
Pangenome graph layout by Path-Guided Stochastic Gradient Descent
Authors: Heumos Simon , Guarracino Andrea , Schmelzle Jan-Niklas M. , Li Jiajie , Zhang Zhiru , Hagmann Jörg , Nahnsen Sven , Prins Pjotr , Garrison Erik
Published: September 2023

Motivation

The increasing availability of complete genomes demands for models to study genomic variability within entire populations. Pangenome graphs capture the full genomic similarity and diversity between multiple genomes. In order to understand them, we need to see them. For visualization, we need a human readable graph layout: A graph embedding in low (e.g. two) dimensional depictions. Due to a pangenome graph’s potential excessive size, this is a significant challenge.

Results

In response, we introduce a novel graph layout algorithm: the Path-Guided Stochastic Gradient Descent (PG-SGD). PG-SGD uses the genomes, represented in the pangenome graph as paths, as an embedded positional system to sample genomic distances between pairs of nodes. This avoids the quadratic cost seen in previous versions of graph drawing by Stochastic Gradient Descent (SGD). We show that our implementation efficiently computes the low dimensional layouts of gigabase-scale pangenome graphs, unveiling their biological features.

Availability

We integrated PG-SGD inODGIwhich is released as free software under the MIT open source license. Source code is available athttps://github.com/pangenome/odgi.

Contact

egarris5@uthsc.edu
Phylociraptor – A unified computational framework for reproducible phylogenomic inference
Authors: Resl Philipp , Hahn Christoph
Published: September 2023

Multi-stage phylogenomic analyses require complex computational environments. A unified framework for software- and parameter space exploration, data organisation and -deposition is currently lacking. We present phylociraptor (https://github.com/reslp/phylociraptor), a pipeline facilitating fast, reliable, portable (containerized), and reproducible phylogenomics. We demonstrate phylociraptor’s utility and uncover topological discrepancies associated with software and parameter choices in large-scale datasets (31-101 species, 241-2894 genes) addressing enigmatic questions in fungal and vertebrate evolution.
Apoptosis-coupled senescence causes cancer cell senotherapy
Authors: Youn Byung-Soo
Published: September 2023

Although new generations of anti-cancer modalities have been accumulated involving immuno-oncology cancers remain prevailing. This implies the current understanding of cancer cell biology is far from satisfactory. Curation of cancers is extremely rare. We hypothesized what could be the easiest Achilles’ Hill of cancer cells such that simple administration can jab cancer cells to be knocked out. Of conspicuous differences between cancer cells and normal cells, for example, metabolism, hypoxia, anaerobic glycolysis, uncontrolled cell proliferation, etc. exist. What could be the easiest and the most reliable anti-cancer modalities? We discovered one was cancer cell senescence (CCS) because cancer cells are the most presenescent (old) cells. We utilized a synthetic polyphenol designated as ONG41008. ONG41008 was able to induce massive senescence of pathologic myofibroblasts (pMFBs) and a vast majority of representative human cancer cells as well as a line of primary NSCLCs. All these cells turned out to be senescence-associated beta-galactosidase (SAbGAL) positive to different degrees, which does not mean real senescence is occurring in these cells. ONG41008 did not harm normal cells and elicited massive senescence in pMFBs without apoptosis. However, ONG41008 caused massive senescence as well as apoptosis in cancer cells. In other words, ONG41008 was capable of sensing intracellular molecular environments between normal cells, cancer cells, and pMFBs. This molecular recognition capability prompted us to explore how ONG4008 behaved on A549 (a human lung adenocarcinoma), PANC1(malignant human ductal adenocarcinoma), and mdr+PC3 (multidrug-resistant human prostate cancer). TP53, p21, and p16 were induced and/or nuclear relocated, suggesting that ONG41008 was recognized by these cells. ONG41008 drove A549 and PANC1 at G2/M phase arrest during 48 hrs, resulting in massive mitotic collapse. All cells died. Moreover, the cisplatin-resistant mdr+PC3 was also eliminated by ONG41008. An array of common components of apoptosis were activated, and especially, induction of Mcl1 was especially notable. These senolytics features were reported to oncogene-induced-senescence (OIS), in which the expression of over two activated oncogenes in the embryonic fibroblasts caused massive senescence and cell death as well. And the signature expression of Mcl1, an anti-apoptotic protein (a long form), was notable but two kinds of short forms are pro-apoptotic proteins. OIS was conductedin vitrocell culture models and whether or not the presence of OIS counterpartin vivoremains to be delineated.

Taken together, we discovered a synthetic polyphenol referred to as ONG41008 was both senogenic and senolytic and its senescent impacts may make the cell cycles of the ONG41008-treated cancer cells immensely arrested at the G2/M phase, leading to mitotic slippage and cell death. This interesting observation may be able to create an idealistic anti-cancer modality, specifically killing cancer cells, but normal cells remain unharmed.
Global assessment of effective population sizes: consistent taxonomic differences in meeting the 50/500 rule
Authors: Clarke Shannon H. , Lawrence Elizabeth R. , Matte Jean-Michel , Gallagher Brian K. , Salisbury Sarah J. , Michaelides Sozos N. , Koumrouyan Ramela , Ruzzante Daniel E. , Grant James W.A. , Fraser Dylan J.
Published: September 2023

Effective population size (Ne) is a particularly useful metric for conservation as it affects genetic drift, inbreeding and adaptive potential within populations. Current guidelines recommend a minimumNeof 50 and 500 to avoid short-term inbreeding and to preserve long-term adaptive potential, respectively. However, the extent to which wild populations reach these thresholds globally has not been investigated, nor has the relationship betweenNeand human activities. Through a quantitative review, we generated a dataset with 4145 georeferencedNeestimates from 3576 unique populations, extracted from 712 articles. These data show that certain taxonomic groups are less likely to meet 50/500 thresholds and are disproportionately impacted by human activities; plant, mammal, and amphibian populations had a ≤52% probability of reachingN̂e= 50 and a <5% probability of reachingN̂e= 500. Populations listed as being of conservation concern according to the IUCN Red List had a lowerN̂ethan unlisted populations, and this relationship held true across all taxonomic groups.N̂ewas reduced in areas with a greater Global Human Footprint, especially for amphibians and mammals, however relationships varied between taxa. We also highlight several considerations for future works estimatingN̂e, including the role that gene flow and subpopulation structure plays in the estimation ofN̂ein wild populations, and the need for finer-scale taxonomic analyses. Our findings provide guidance for more specific thresholds based onNeand help prioritize assessment of populations from taxa most at risk of failing to meet conservation thresholds.
Marangoni-like tissue flows enhance symmetry breaking of embryonic organoids
Authors: Gsell Simon , Tlili Sham , Merkel Matthias , Lenne Pierre-François
Published: September 2023

During early development of multi-cellular animals, cells self-organize to set up the body axes, such as the primary head-to-tail axis, based on which the later body plan is defined. Several signaling pathways are known to control body axis formation. Here, we show, however, that also tissue mechanics plays an important role during this process. We focus on the emergence of a primary axis in initially spherical aggregates of mouse embryonic stem cells, which mirrors events in the early mouse embryo. These aggregates break rotational symmetry to establish an axial organization with domains of different expression profiles, e.g. of the transcription factor T/Bra and the adhesion molecule E-cadherin. Combining quantitative microscopy and physical modeling, we identify large-scale tissue flows with a recirculation component and demonstrate that they significantly contribute to symmetry breaking. We show that the recirculating flows are explained by a difference in tissue surface tension across domains, akin to Marangoni flows, which we further confirm by aggregate fusion experiments. Our work highlights that body axis formation is not only driven by biochemical processes, but that it can also be amplified by tissue flows. We expect that this type of amplification may operate in many other organoid andin-vivosystems.
Integrative pan-cancer analysis reveals a common architecture of dysregulated transcriptional networks characterized by loss of enhancer methylation
Authors: Ankill Jørgen , Zhao Zhi , Tekpli Xavier , Kure Elin H. , Kristensen Vessela N. , Mathelier Anthony , Fleischer Thomas
Published: September 2023

Aberrant DNA methylation contributes to gene expression deregulation in cancer. However, these alterations’ precise regulatory role and clinical implications are still not fully understood. In this study, we performed expression-methylation Quantitative Trait Loci (emQTL) analysis to identify deregulated cancer-driving transcriptional networks linked to CpG demethylation pan-cancer. By analyzing 33 cancer types from The Cancer Genome Atlas, we identified and confirmed significant correlations between CpG methylation and gene expression (emQTL) incisandtrans, both across and within cancer types. Bipartite network analysis of the emQTL revealed groups of CpGs and genes related to important biological processes involved in carcinogenesis; specifically, we identified three types of emQTL networks associated with alterations linked to the regulation of proliferation, metabolism, and hormone-signaling. These bipartite communities were characterized by loss of enhancer methylation in transcription factor binding regions (TFBRs) located in enhancers. The underlying CpGs were topologically linked to upregulated genes through chromatin loops. Loss of enhancer methylation and target genes were exemplified in pancreatic cancer. Penalized Cox regression analysis showed a significant prognostic impact of the pan-cancer emQTL. Taken together, our integrative pan-cancer analysis reveals a common architecture of aberrant DNA demethylation that illustrates a convergence of pathological regulatory mechanisms across cancer types.
RGS2 is an innate immune checkpoint for TLR4 and Gαq-mediated IFNγ generation and lung injury
Authors: Joshi Jagdish Chandra , Joshi Bhagwati , Zhang Cuiping , Banerjee Somenath , Vellingiri Vigneshwaran , Raghunathrao Vijay Avin Balaji , Zhang Lianghui , Amin Ruhul , Song Yuanlin , Mehta Dolly
Published: September 2023

IFNγ, a type II interferon secreted by immune cells, augments tissue responses to injury following pathogenic infections leading to lethal acute lung injury (ALI). Alveolar macrophages (AM) abundantly express Toll-like receptor-4 and represent the primary cell type of the innate immune system in the lungs. A fundamental question remains whether AM generation of IFNg leads to uncontrolled innate response and perpetuated lung injury. LPS induced a sustained increase in IFNg levels and unresolvable inflammatory lung injury in the mice lacking RGS2 but not in RGS2 null chimeric mice receiving WT bone marrow or receiving the RGS2 gene in AM. Thus, indicating RGS2 serves as a gatekeeper of IFNg levels in AM and thereby lung’s innate immune response. RGS2 functioned by forming a complex with TLR4 shielding Gaq from inducing IFNg generation and AM inflammatory signaling. Thus, inhibition of Gaq blocked IFNg generation and subverted AM transcriptome from being inflammatory to reparative type in RGS2 null mice, resolving lung injury.

Highlights

RGS2 levels are inversely correlated with IFNγ in ARDS patient’s AM.

RGS2 in alveolar macrophages regulate the inflammatory lung injury.

During pathogenic insult RGS2 functioned by forming a complex with TLR4 shielding Gαq from inducing IFNγ generation and AM inflammatory signaling.

eToc Blurb

Authors demonstrate an essential role of RGS2 in macrophages in airspace to promoting anti-inflammatory function of alveolar macrophages in lung injury. The authors provided new insight into the dynamic control of innate immune response by Gαq and RGS2 axis to prevent ALI.
Neutron Scattering Analysis ofCryptococcus neoformansPolysaccharide Reveals Solution Rigidity and Repeating Fractal-like Structural Patterns
Authors: Wang Ziwei , Teixeira Susana C. M. , Strother Camilla , Bowen Anthony , Casadevall Arturo , Cordero Radamés JB
Published: September 2023

ABSTRACT

Cryptococcus neoformansis a fungal pathogen that can cause life-threatening brain infections in immunocompromised individuals. Unlike other fungal pathogens, it possesses a protective polysaccharide capsule that is crucial for its virulence. During infections,Cryptococcuscells release copious amounts of extracellular polysaccharides (exo-PS) that interfere with host immune responses. Both exo-PS and capsular-PS play pivotal roles inCryptococcusinfections and serve as essential targets for disease diagnosis and vaccine development strategies. However, understanding their structure is complicated by their polydispersity, complexity, sensitivity to sample isolation and processing, and scarcity of methods capable of isolating and analyzing them while preserving their native structure. In this study, we employ small-angle neutron scattering (SANS) and ultra-small angle neutron scattering (USANS) for the first time to investigate both fungal cell suspensions and extracellular polysaccharides in solution. Our data suggests that exo- PS in solution exhibits collapsed chain-like behavior and demonstrates mass fractal properties that indicate a relatively condensed pore structure in aqueous environments. This observation is also supported by scanning electron microscopy (SEM). The local structure of the polysaccharide is characterized as a rigid rod, with a length-scale corresponding to 3 to 4 repeating units. This research not only unveils insights into exo-PS and capsular-PS structures but also demonstrates the potential of USANS for studying changes in cell dimensions and the promise of contrast variation in future neutron scattering studies.
Sensitivity analysis identifies the factors driving the enzymatic saccharification of lignocellulose
Authors: De Partho Sakha , Theilmann Jasmin , Raguin Adélaïde
Published: September 2023

Corn stover is the most abundant form of crop residue that can serve as a source of lignocellulosic biomass in biorefinery approaches, for instance for the production of bioethanol. In such biorefinery processes, the constituent polysaccharide biopolymers are typically broken down into simple monomeric sugars by enzymatic saccharification, for further downstream fermentation into bioethanol. However, the recalcitrance of this material to enzymatic saccharification invokes the need for innovative pre-treatment methods to increase sugar conversion yield. Here, we focus on experimental glucose conversion time-courses for corn stover lignocellulose that has been pre-treated with different acid-catalysed processes and intensities. We identify the key parameters that determine enzymatic saccharification dynamics by performing a Sobol's sensitivity analysis on the comparison between the simulation results from our complex stochastic biophysical model, and the experimental data that we accurately reproduce. We find that the parameters relating to cellulose crystallinity and those associated with the cellobiohydrolase activity are predominantly driving the enzymatic saccharification dynamics. We confirm our computational results using mathematical calculations for a purely cellulosic substrate. On the one hand, having identified that only five parameters drastically influence the saccharification dynamics allows us to reduce the dimensionality of the parameter space (from nineteen to five parameters), which we expect will significantly speed up our fitting algorithm for comparison of experimental and simulated saccharification time-courses. On the other hand, these parameters directly highlight key targets for experimental endeavours in the optimisation of pre-treatment and saccharification conditions. Finally, this systematic and two-fold theoretical study, based on both mathematical and computational approaches, provides experimentalists with key insights that will support them in rationalising their complex experimental results.
New observations of fluorescent organisms in the Banda Sea and in the Red Sea
Authors: Poding Lars Henrik , Jaegers Peter , Huhn Mareike , Herlitze Stefan , Senen Budiono , Limmon Gino Valentino
Published: September 2023

Fluorescence is a widespread phenomenon found in animals, bacteria, fungi, and plants. In marine environments fluorescence has been proposed to play a role in physiological and behavioral responses. Many fluorescent proteins and other molecules have been described in jellyfish, corals, and fish. Here we describe fluorescence in marine species, which we observed and photographed during night dives in the Banda Sea, Indonesia, and in the Red Sea, Egypt. Among various phyla we found fluorescence in sponges, molluscs, tunicates, and fish. Our study extends the knowledge on how many different organisms fluoresce in marine environments. We describe the occurrence of fluorescence in 27 species, in which fluorescence has not been described yet in peer-reviewed literature. It especially extends the knowledge beyond Scleractinia, the so far best described taxon regarding diversity in fluorescent proteins.
Annotated Compendium of 102 Breast Cancer Gene-Expression Datasets
Authors: Nwosu Ifeanyichukwu O. , Tabler Daniel D. , Chipman Greg , Piccolo Stephen R.
Published: September 2023

Transcriptomic data from breast-cancer patients are widely available in public repositories. However, before a researcher can perform statistical inferences or make biological interpretations from such data, they must find relevant datasets, download the data, and perform quality checks. In many cases, it is also useful to normalize and standardize the data for consistency and to use updated genome annotations. Additionally, researchers need to parse and interpret metadata: clinical and demographic characteristics of patients. Each of these steps requires computational and/or biomedical expertise, thus imposing a barrier to reuse for many researchers. We have identified and curated 102 publicly available, breast-cancer datasets representing 17,151 patients. We created a reproducible, computational pipeline to download the data, perform quality checks, renormalize the raw gene-expression measurements (when available), assign gene identifiers from multiple databases, and annotate the metadata against the National Cancer Institute Thesaurus, thus making it easier to infer semantic meaning and compare insights across datasets. We have made the curated data and pipeline freely available for other researchers to use. Having these resources in one place promises to accelerate breast-cancer research, enabling researchers to address diverse types of questions, using data from a variety of patient populations and study contexts.
Genome-wide association mapping of bruchid resistance loci in soybean
Authors: Mukuze Clever , Msiska Ulemu M. , Badji Afang , Obua Tonny , Kweyu Sharon V. , Nghituwamhata Selma N. , Rono Evalyne C. , Maphosa Mcebisi , Kasule Faizo , Tukamuhabwa Phinehas
Published: September 2023

Soybean is a globally important industrial, food, and cash crop. Despite its importance in present and future economies, its production is severely hampered by bruchids (Callosobruchus chinensis), a destructive storage insect pest, causing considerable yield losses. Therefore, the identification of genomic regions and candidate genes associated with bruchid resistance in soybean is crucial as it helps breeders develop new soybean varieties with improved resistance and quality. In this study, 6 multi-locus methods of the mrMLM model for genome-wide association study were used to dissect the genetic architecture of bruchid resistance using 5 traits: percentage adult bruchid emergence (PBE), percentage weight loss (PWL), growth index (GI), median development period (MDP), and Dobie susceptibility index (DSI) on 100 diverse soybean genotypes, genotyped with 14,469 single-nucleotide polymorphism (SNP) markers. Using the best linear unbiased predictors (BLUPs), 13 quantitative trait nucleotides (QTNs) were identified by the mrMLM model, 3 of which, rs16_14976250, rs1_22916615, and rs16_14975721, were associated with more than 1 bruchid resistance trait. As a result, the identified QTNs linked with resistance traits can be employed in marker-assisted breeding for the accurate and rapid screening of soybean genotypes for resistance to bruchids. Moreover, a gene search on the Phytozome soybean reference genome identified 27 potential candidate genes located within a window of 478.45 kb upstream and downstream of the most reliable QTNs. These candidate genes exhibit molecular and biological functionalities associated with various soybean resistance mechanisms and, therefore, could be incorporated into the farmers’ preferred soybean varieties that are susceptible to bruchids.