bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas
Authors: Mazuelas Helena , Magallón-Lorenz Míriam , Uriarte-Arrázola Itziar , Negro Alejandro , Rosas Inma , Blanco Ignacio , Castellanos Elisabeth , Lázaro Conxi , Gel Bernat , Carrió Meritxell , Serra Eduard 
Published: December 2022

AbstractCutaneous neurofibromas (cNFs) are benign Schwann cell (SC) tumors arising from subepidermal glia. Neurofibromatosis Type 1 (NF1) individuals may develop thousands of cNFs, greatly affecting their quality of life. cNF growth is governed by the proliferation ofNF1(-/-) SCs, highly influenced by the interaction with aNF1(+/-) microenvironment, consisting of fibroblasts (FBs), immune cells, etc. To decompose crosstalk between SCs and the microenvironment we used single cultures and co-cultures of cNF-derived SCs and FBs and identified an expression signature specific to SC-FB interaction. This signature was enriched in genes involved in immune cell migration, that were functionally validated by secretion analysis of SC-FB co-cultures, suggesting a role of SC-FB crosstalk in immune cell recruitment. The signature also captured components of different developmental signaling pathways, among them, the cAMP elevator G protein-coupled receptor 68 (GPR68). Activation of Gpr68 by Ogerin reduced the viability and proliferation of cNF-derived SCs and SC-FB co-cultures. Moreover, Ogerin in combination with the MEKi Selumetinib induced loss of viability, SC differentiation, and death. These results were corroborated using an iPSC-derived 3D neurofibromasphere model. The unbalancing of the Ras and cAMP pathways by combining a MEKi and a cAMP elevator arises as a potential treatment for cNFs.
PhyloAcc-GT: A Bayesian method for inferring patterns of substitution rate shifts and associations with binary traits under gene tree discordance
Authors: Yan Han , Hu Zhirui , Thomas Gregg , Edwards Scott V. , Sackton Timothy B. , Liu Jun S. 
Published: December 2022

AbstractAn important goal of evolutionary genomics is to identify genomic regions whose substitution rates differ among lineages. For example, genomic regions experiencing accelerated molecular evolution in some lineages may provide insight into links between genotype to phenotype. Several comparative genomics methods have been developed to identify genomic accelerations between species, including a Bayesian method called PhyloAcc, which models shifts in substitution rate in multiple target lineages on a phylogeny. However, few methods consider the possibility of discordance between the trees of individual loci and the species tree due to incomplete lineage sorting, which might cause false positives. Here we present PhyloAcc-GT, which extends PhyloAcc by modeling gene tree heterogeneity to detect rate shifts across genomic regions. Given a species tree, we adopt the multispecies coalescent model as the prior distribution of gene trees, use Markov chain Monte Carlo (MCMC) for inference, and design novel MCMC moves to sample gene trees efficiently. Through extensive simulations, we show that PhyloAcc-GT outperforms PhyloAcc and other methods in identifying target-lineage-specific accelerations and detecting complex patterns of rate shifts, and is robust to specification of population size parameters. We apply PhyloAcc-GT to two examples of convergent evolution: flightlessness in ratites and marine mammal adaptations. PhyloAcc-GT is usually more conservative than PhyloAcc in calling convergent rate shifts because it identifies more accelerations on ancestral than on terminal branches. In summary, PhyloAcc-GT is a useful tool to identify shifts in substitution rate associated with specific target lineages while accounting for incomplete lineage sorting.
Reliability of resting-state functional connectivity in the human spinal cord: assessing the impact of distinct noise sources
Authors: Kaptan Merve , Horn Ulrike , Vannesjo S. Johanna , Mildner Toralf , Weiskopf Nikolaus , Finsterbusch Jürgen , Brooks Jonathan C.W. , Eippert Falk 
Published: December 2022

AbstractThe investigation of spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord, where it has stimulated interest from a clinical perspective. A number of resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated robust functional connectivity between the time series of BOLD fluctuations in bilateral dorsal horns and between those in bilateral ventral horns, in line with the functional neuroanatomy of the spinal cord. A necessary step prior to extension to clinical studies is assessing the reliability of such resting-state signals, which we aimed to do here in a group of 45 healthy young adults at the clinically prevalent field strength of 3T. When investigating connectivity in the entire cervical spinal cord, we observed fair to good reliability for dorsal-dorsal and ventral-ventral connectivity, whereas reliability was poor for within- and between-hemicord dorsal-ventral connectivity. Considering how prone spinal cord fMRI is to noise, we extensively investigated the impact of distinct noise sources and made two crucial observations: removal of physiological noise led to a reduction in functional connectivity strength and reliability – due to the removal of stable and participant-specific noise patterns – whereas removal of thermal noise considerably increased the detectability of functional connectivity without a clear influence on reliability. Finally, we also assessed connectivity within spinal cord segments and observed that while the pattern of connectivity was similar to that of whole cervical cord, reliability at the level of single segments was consistently poor. Taken together, our results demonstrate the presence of reliable resting-state functional connectivity in the human spinal cord even after thoroughly accounting for physiological and thermal noise, but at the same time urge caution if focal changes in connectivity (e.g. due to segmental lesions) are to be studied, especially in a longitudinal manner.
Broader functions of TIR domains in Arabidopsis immunity
Authors: Jacob Pierre , Hige Junko , Song Lijiang , Bayless Adam , Russ Dor , Bonardi Vera , El-Kasmi Farid , Wünsch Lisa , Yang Yu , Fitzpatrick Connor R. , McKinney Brock J. , Nishimura Marc T. , Grant Murray R. , Dangl Jeffery L. 
Published: December 2022

AbstractTIR domains are NAD-degrading enzymes that function during immune signaling in prokaryotes, plants, and animals. In plants, most TIR domains are incorporated into intracellular immune receptors. In Arabidopsis, TIR-derived small molecules bind and activate EDS1 heterodimers, which in turn activate RNLs, a class of cation channel-forming immune receptors. RNL activation drives cytoplasmic Ca2+influx, transcriptional reprogramming, pathogen resistance and host cell death. We screened for mutants that suppress an RNL activation mimic allele and identified a TIR-containing immune receptor, SADR1. Despite functioning downstream of an auto-activated RNL, SADR1 is not required for defense signaling triggered by other tested TIR-containing immune receptors. SADR1 is required for defense signaling initiated by some trans-membrane pattern recognition receptors and contributes to the unbridled spread of cell death inlesion simulating disease 1. Together with RNLs, SADR1 regulates defense gene expression at infection site borders, likely in a non-autonomous manner. RNL mutants that cannot sustain this pattern of gene expression are unable to prevent disease spread beyond localized infection sites, suggesting that this pattern corresponds to a pathogen containment mechanism. SADR1 potentiates RNL-driven immune signaling partially through the activation of EDS1, but also partially independently of EDS1. We studied EDS1-independent TIR function using nicotinamide, an NADase inhibitor. We observed decreased defense induction from trans-membrane pattern recognition receptors and decreased calcium influx, pathogen growth restriction and host cell death following intracellular immune receptor activation. We demonstrate that TIR domains can potentiate calcium influx and defense and are thus broadly required for Arabidopsis immunity.
Extracellular vesicle-associated cholesterol dictates the regenerative functions of macrophages in the brain
Authors: Vanherle Sam , Guns Jeroen , Loix Melanie , Mingneau Fleur , Dierckx Tess , Vangansewinkel Tim , Wolfs Esther , Lins Paula Pincela , Bronckaers Annelies , Lambrichts Ivo , Dehairs Jonas , Swinnen Johannes V. , Verberk Sanne G.S. , Haidar Mansour , Hendriks Jerome J.A. , Bogie Jeroen F.J. 
Published: December 2022

AbstractMacrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Here, we demonstrate that extracellular vesicles (EVs) secreted by repair-associated macrophages (RAMs) enhance remyelinationex vivoandin vivoby promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated cholesterol levels and that cholestserol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV-associated cholesterol was found to promote OPC differentiation through direct membrane fusion. Collectively, our findings highlight that EVs are essential for cholesterol trafficking in the brain and that changes in cholesterol abundance dictate the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders.
Differential and overlapping effects between exogenous and endogenous attention shape perceptual facilitation during visual processing
Authors: Landry Mathieu , Da Silva Castanheira Jason , Jerbi Karim 
Published: December 2022

AbstractVisuospatial attention is not a monolithic process and can be divided into different functional systems. In this framework, exogenous attention reflects the involuntary orienting of attention resources following a salient event, whereas endogenous attention corresponds to voluntary orienting based on the goals and intentions of individuals. Previous work shows that these attention processes map onto distinct functional systems, yet evidence suggests that they are not fully independent. In the current work, we investigated the differential and overlapping effects of exogenous and endogenous attention on visual processing. We combined spatial cueing of visuospatial attention, electroencephalography (EEG), and multivariate pattern analysis (MVPA) to examine where and when the effects of exogenous and endogenous attention were maximally different and maximally similar. Critically, MVPA provided new insights by examining whether classifiers trained to decode the cueing effect for one attention process (e.g., exogenous attention) can successfully decode the cueing effect for the other attention process (e.g., endogenous attention). These analyses uncovered differential and overlapping effects between exogenous and endogenous attention. Next, we combined principal component analyses, single-trial event-related potentials, and mediation analysis to determine whether these effects facilitate perception, as indexed by the behavioral spatial cueing effects of exogenous and endogenous attention. This approach revealed that three EEG components shape the cueing effects of exogenous and endogenous attention at various times after target onset. Altogether, our study provides a comprehensive account about how overlapping and differential processes of endogenous and exogenous relate to perceptual facilitation in the context of visuospatial attention.Significance StatementTop-down and bottom-up attention represent separate functional systems in the brain. Previous research suggests, however, that they are not fully independent, and can interfere with each other. In the present study, the authors use machine learning techniques and recordings of brain activity to investigate differences and similarities between top-down and bottom-up attention during the visual processing of stimuli. This approach allowed them to explore how top-down and bottom-up attention processes facilitate perception. Their results show that top-down and bottom-up attention operate differently as early as 100ms after the onset of a target. In contrast, they operate similarly 200ms after the target onset. Most importantly, these effects are directly related to the participants’ perceptual behavior. In sum, our study shows that top-down and bottom-up attention support the perception of stimuli through overlapping and distinct spatio-temporal brain patterns.
MYSM1 co-activates ERα action via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer
Authors: Luan Ruina , Sun Ge , Zhou Baosheng , Wang Manlin , Bai Yu , Wang Chunyu , Wang Shengli , Zeng Kai , Feng Jianwei , He Mingcong , Lin Lin , Wei Yuntao , Zhang Qiang , Zhao Yue 
Published: December 2022

AbstractEndocrine resistance is a crucial challenge in estrogen receptor alpha (ERα)-positive breast cancer (BCa) therapy. Aberrant alteration in modulation of E2/ERα signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Thus, identification the efficient ERα cofactor remains necessary for finding a potential therapeutic target for endocrine resistance. Herein, we have demonstrated that Myb like, SWIRM and MPN domains 1 (MYSM1) as a histone deubiquitinase is a novel ERα co-activator with establishedDrosophilaexperimental model. Our results showed that MYSM1 participated in up-regulation of ERα action via histone and non-histone deubiquitination. We provided the evidence to show that MYSM1 was involved in maintenance of ERα stability via ERα deubiquitination. Furthermore, silencing MYSM1 induced enhancement of histone H2A ubiquitination as well as reduction of histone H3K4me3 and H3Ac levels atcisregulatory elements on promoter of ERα-regulated gene. In addition, MYSM1 depletion attenuated cell proliferation/growth in BCa-derived cell lines and xenograft models. Knockdown of MYSM1 increased the sensitivity of antiestrogen agents in BCa cells. MYSM1 was highly expressed in clinical BCa samples, especially in aromatase inhibitor (AI) non-responsive tissues. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ERα action and provide a potential therapeutic target for endocrine resistance in BCa.
Prokaryote communities associated with different types of tissue formed and substrates inhabited bySerpula lacrymans
Authors: Embacher Julia , Zeilinger Susanne , Kirchmair Martin , Neuhauser Sigrid 
Published: December 2022

AbstractThe basidiomyceteSerpula lacrymansis responsible for timber destruction in houses. Basidiomycetes are known to harbor a diverse but poorly understood microbial community of bacteria, archaea, yeasts, and filamentous fungi in their fruiting bodies. In this study, we used amplicon-sequencing to analyze the abundance and composition of prokaryotic communities associated with fruiting bodies ofS. lacrymansand compared them to communities of surrounding material to access the ‘background’ community structure. Our findings indicate that bacterial genera cluster depended on sample type, and that the main driver for microbial diversity is specimen, followed by sample origin. The most abundant bacterial phylum identified in the fruiting bodies was Pseudomonadota, followed by Actinomycetota and Bacteroidota. The prokaryote community of the mycelium was dominated by Actinomycetota, Halobacterota, and Pseudomonadota. Actinomycetota was the most abundant phylum in both environment samples (infested timber and underground scree), followed by Bacillota in wood and Pseudomonadota in underground scree.Nocardioides, Pseudomonas, Pseudonochardia, StreptomycesandRubrobacterspp. were among others found to comprise the core microbiome ofS. lacrymansbasidiocarps. This research contributes to the understanding of the holobiontS. lacrymansand gives hints to potential bacterial phyla important for its development and life style.Highlights-The prokaryote communities associated withS. lacrymansmycelia and fruiting bodies as well as wood and non-woody substrate form distinct clusters.-Across all samples 30% of OTU’s were shared (core microbiome) while the number of unique OTUs was small.-Fruiting bodies (n= 8) ofS. lacrymansshared a core set of 365 OTU’s, dominated by Actinobacteriodota (44%), Pseudomonadota (28%), and Acidobacteriodota (9%).-Tissue/sample type is the main factor influencing diversity, followed by sample origin.
Modulation of lysosomal Cl-mediates migration and apoptosis through the TRPML1 as a lysosomal Cl-sensor
Authors: Lee Dongun , Shin Dong Min , Hong Jeong Hee 
Published: December 2022

AbstractLysosomes are responsible for protein degradation and clearance in cellular recycling centers. It has been known that the lysosomal chloride level is enriched and involved in intrinsic lysosomal function. However, the mechanism by which chloride levels can be sensed and the chloride-mediated lysosomal function is unknown. In this study, we verified that reduced chloride levels acutely induced lysosomal calcium release through TRPML1 and lysosomal repositioning toward juxtanuclear region. Functionally, low chloride-induced lysosomal calcium release attenuated cellular migration. In addition, spontaneous exposure to low chloride levels dysregulated lysosomal biogenesis and subsequently induced the delayed migration and promoted apoptosis. Two chloride-sensing GXXXP motifs in the TRPML1 were identified. Mutations in the GXXXP motif of TRPML1 did not affect chloride levels and no changes in migratory ability. In this study, we demonstrated that the depleted chloride approach induces reformation of the lysosomal calcium pool, and subsequent dysregulated cancer progression will assist in improving therapeutic strategies for lysosomal accumulation-associated diseases or cancer cell apoptosis.
Membrane association is required for Stmn2-mediated axon protection
Authors: Thornburg-Suresh Emma J.C. , Richardson Jerianne E. , Summers Daniel W. 
Published: December 2022

ABSTRACTAxon integrity is essential for functional connectivity in the nervous system. The degeneration of stressed or damaged axons is a common and sometimes initiating event in neurodegenerative disorders. Cellular factors that preserve axon integrity have an important influence on the fate of a damaged axon. Stathmin-2 (Stmn2) is an axon maintenance factor that is depleted in Amyotrophic Lateral Sclerosis and replenishment of Stmn2 can restore neurite outgrowth in diseased neurons. Stathmins have a well-documented role in microtubule dynamics during neurodevelopment, yet mechanisms responsible for Stmn2-mediated axon maintenance in injured neurons are not known. We demonstrate that membrane association of Stmn2 is critical for its axon-protective activity. Axonal enrichment of Stmn2 is driven by palmitoylation as well as tubulin interaction. We discover that another Stathmin, Stmn3, co-migrates with Stmn2-containing vesicles and undergoes regulated degradation through DLK-JNK signaling. The Stmn2 membrane targeting domain is both necessary and sufficient for localization to a specific vesicle population and confers sensitivity to DLK-dependent degradation. Our findings reveal a broader role for DLK in tuning the local abundance of palmitoylated Stathmins in axon segments. Moreover, palmitoylation is a critical component of Stathmin-mediated axon protection and defining the Stmn2-containing vesicle population will provide important clues toward mechanisms of axon maintenance.
Expanded Multiplexing on Sensor-Constrained Microfluidic Partitioning Systems
Authors: Kota Pavan K. , Vu Hoang-Anh , LeJeune Daniel , Han Margaret , Syed Saamiya , Baraniuk Richard G. , Drezek Rebekah A. 
Published: December 2022

AbstractMicrofluidics can split samples into thousands or millions of partitions such as droplets or nanowells. Partitions capture analytes according to a Poisson distribution, and in diagnostics, the analyte concentration is commonly calculated with a closed-form solution via maximum likelihood estimation (MLE). Here, we present a generalization of MLE with microfluidics, an extension of our previously developed Sparse Poisson Recovery (SPoRe) algorithm, and anin vitrodemonstration with droplet digital PCR (ddPCR) of the new capabilities that SPoRe enables. Many applications such as infection diagnostics require sensitive detection and broad-range multiplexing. Digital PCR coupled with conventional target-specific sensors yields the former but is constrained in multiplexing by the number of available measurement channels (e.g., fluorescence). In our demonstration, we circumvent these limitations by broadly amplifying bacteria with 16S ddPCR and assigning barcodes to nine pathogen genera using only five nonspecific probes. Moreover, we measure only two probes at a time in multiple groups of droplets given our two-channel ddPCR system. Although individual droplets are ambiguous in their bacterial content, our results show that the concentrations of bacteria in the sample can be uniquely recovered given the pooled distribution of partition measurements from all groups. We ultimately achieve stable quantification down to approximately 200 total copies of the 16S gene per sample, enabling a suite of clinical applications given a robust upstream microbial DNA extraction procedure. We develop new theory that generalizes the application of this framework to a broad class of realistic sensors and applications, and we prove scaling rules for system design to achieve further expanded multiplexing. This flexibility means that the core principles and capabilities demonstrated here can generalize to most biosensing applications with microfluidic partitioning.