bluuebunny/crossref_metadata_2025_split huggingface dataset:
Obesity-associated lipidomic remodeling of the adrenal gland indicates an important role of the FADS2-arachidonic acid axis in adrenocortical hormone production
Authors: Witt Anke , Mirtschink Peter , Palladini Alessandra , Mateska Ivona , Abdelmegeed Heba , Grzybek Michal , Wielockx Ben , Peitzsch Mirko , Coskun Ünal , Chavakis Triantafyllos , Alexaki Vasileia Ismini 
Published: September 2020

AbstractObjectiveAdrenocortical hormone levels increase in obesity, potentially contributing to development of obesity-associated pathologies. Here we explored whether lipidomic remodeling of the adrenal gland could mediate altered adrenocortical steroidogenesis during obesity.MethodsLipidomic analysis was performed in adrenal glands using shotgun mass spectrometry (MS), and steroid profiling of sera by liquid chromatography tandem mass spectrometry (LC-MS/MS) from lean and obese mice. Gene expression analysis was performed in adrenal glands and adrenocortical cell populations. The role of Fatty Acid Desaturase 2 (FADS2) and arachidonic acid on steroid hormone production was studied in primary adrenal gland cell cultures.ResultsAdrenal glands of obese mice displayed a distinct lipidomic profile, encompassing longer and more unsaturated storage lipids and phospholipids compared to adrenal glands of lean mice. Arachidonoyl acyl chains were abundant in the adrenal gland phospholipidome and increased upon obesity. This was accompanied by increasedFads2expression, the rate-limiting enzyme of arachidonic acid synthesis, and enhanced plasma adrenocortical hormone levels. Inhibition of FADS2 in primary adrenal gland cell cultures abolished steroidogenesis, which was restored by arachidonic acid supplementation.ConclusionsOur data suggest that the FADS2 – arachidonic acid axis regulates adrenocortical hormone synthesis, while alterations in the content of arachidonoyl chains in the adrenal gland phopsholipidome could account for disturbed adrenocortical hormone production.HighlightsThe adrenal gland lipidome is remodeled in obesity.Arachidonoyl groups are abundant in the adrenal gland phospholipidome and increase in obesity.FADS2 is highly expressed in the adrenal gland and its expression is further increased in obesity.FADS2 inhibition blunts adrenocortical steroidogenesis in primary adrenal gland cell cultures, while arachidonic acid supplementation restores it.
Evolutionarily conserved chaperone-mediated proteasomal degradation of a disease-linked aspartoacylase variant
Authors: Gersing Sarah K. , Wang Yong , Grønbæk-Thygesen Martin , Kampmeyer Caroline , Clausen Lene , Andréasson Claes , Stein Amelie , Lindorff-Larsen Kresten , Hartmann-Petersen Rasmus 
Published: September 2020

AbstractCanavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we examine the stability and degradation pathway of ASPA C152W. When we expressed ASPA C152W inSaccharomyces cerevisiae, we found a decreased steady state compared to wild-type ASPA as a result of increased proteasomal degradation. However, molecular dynamics simulations of ASPA C152W did not substantially deviate from wild-type ASPA, indicating that the native state is structurally preserved. Instead, we suggest that the C152W substitution prevents ASPA from reaching its stable native conformation, presumably by impacting onde novofolding. Systematic mapping of the protein quality control components acting on misfolded and aggregation-prone species of C152W, revealed that the degradation is highly dependent on the molecular chaperone Hsp70, its co-chaperone Hsp110 as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. In human cells, ASPA C152W displayed increased proteasomal turnover that was similarly dependent on Hsp70 and Hsp110. We propose that Hsp110 is a potential therapeutic target for misfolding ASPA variants that trigger Canavan disease due to excessive degradation.
Joint actions of diverse transcription factor families establish neuron-type identities and promote enhancer selectivity
Authors: Jimeno-Martín Angela , Sousa Erick , Brocal-Ruiz Rebeca , Daroqui Noemi , Maicas Miren , Flames Nuria 
Published: September 2020

ABSTRACTTo systematically investigate the complexity of neuron-specification regulatory networks we performed an RNA interference (RNAi) screen against all 875 transcription factors (TFs) encoded inCaenorhabditis elegansgenome and searched for defects in nine different neuron types of the monoaminergic (MA) superclass and two cholinergic motoneurons.We identified 91 TF candidates to be required for correct generation of these neuron types of which 28 were confirmed by mutant analysis. We found that correct reporter expression in each individual neuron type requires at least nine different TFs. Individual neuron types do not usually share TFs involved in their specification but share a common pattern of TFs belonging to the five most common TF families: Homeodomain (HD), basic Helix Loop Helix (bHLH), Zinc Finger (ZF), Basic Leucine Zipper Domain (bZIP) and Nuclear Hormone Receptors (NHR). HD TF members are over-represented, supporting a key role for this family in the establishment of neuronal identities. These five TF families area also prevalent when considering mutant alleles with previously reported neuronal phenotypes inC. elegans,Drosophilaor mouse. In addition, we studied terminal differentiation complexity focusing on the dopaminergic terminal regulatory program. We found two HD TFs (UNC-62 and VAB-3) that work together with known dopaminergic terminal selectors (AST-1, CEH-43, CEH-20). Combined TF binding sites for these five TFs constitute a cis-regulatory signature enriched in the regulatory regions of dopaminergic effector genes. Our results provide new insights on neuron-type regulatory programs inC. elegansthat could help better understand neuron specification and evolution of neuron types.
Nanoscopy on the Chea(i)p
Authors: Diederich Benedict , Helle Øystein , Then Patrick , Carravilla Pablo , Schink Kay Oliver , Hornung Franziska , Deinhardt-Emmer Stefanie , Eggeling Christian , Ahluwalia Balpreet Singh , Heintzmann Rainer 
Published: September 2020

AbstractSuper-resolution microscopy allows for stunning images with a resolution well beyond the optical diffraction limit, but the imaging techniques are demanding in terms of instrumentation and software. Using scientific-grade cameras, solid-state lasers and top-shelf microscopy objective lenses drives the price and complexity of the system, limiting its use to well-funded institutions. However, by harnessing recent developments in CMOS image sensor technology and low-cost illumination strategies, super-resolution microscopy can be made available to the mass-markets for a fraction of the price. Here, we present a 3D printed, self-contained super-resolution microscope with a price tag below 1000 $ including the objective and a cellphone. The system relies on a cellphone to both acquire and process images as well as control the hardware, and a photonic-chip enabled illumination. The system exhibits 100nmoptical resolution using single-molecule localization microscopy and can provide live super-resolution imaging using light intensity fluctuation methods. Furthermore, due to its compactness, we demonstrate its potential use inside bench-top incubators and high biological safety level environments imaging SARS-CoV-2 viroids. By the development of low-cost instrumentation and by sharing the designs and manuals, the stage for democratizing super-resolution imaging is set.
Inferring Patterns of Hybridization and Polyploidy in the Plant GenusPenstemon(Plantaginaceae)
Authors: Blischak Paul D. , Thompson Coleen E. , Waight Emiko M. , Kubatko Laura S. , Wolfe Andrea D. 
Published: September 2020

AbstractReticulate evolutionary events are hallmarks of plant phylogeny, and are increasingly recognized as common occurrences in other branches of the Tree of Life. However, inferring the evolutionary history of admixed lineages presents a difficult challenge for systematists due to genealogical discordance caused by both incomplete lineage sorting (ILS) and hybridization. Methods that accommodate both of these processes are continuing to be developed, but they often do not scale well to larger numbers of species. An additional complicating factor for many plant species is the occurrence of whole genome duplication (WGD), which can have various outcomes on the genealogical history of haplotypes sampled from the genome. In this study, we sought to investigate patterns of hybridization and WGD in two subsections from the genusPenstemon(Plantaginaceae; subsect.HumilesandProceri), a speciose group of angiosperms that has rapidly radiated across North America. Species in subsect.HumilesandProcerioccur primarily in the Pacific Northwest of the United States, occupying habitats such as mesic, subalpine meadows, as well as more well-drained substrates at varying elevations. Ploidy levels in the subsections range from diploid to hexaploid, and it is hypothesized that most of the polyploids are hybrids (i.e., allopolyploids). To estimate phylogeny in these groups, we first developed a method for estimating quartet concordance factors (QCFs) from multiple sequences sampled per lineage, allowing us to model all haplotypes from a polyploid. QCFs represent the proportion of gene trees that support a particular species quartet relationship, and are used for species network estimation in the program SNaQ (Solís-Lemus & Ané. 2016.PLoS Genet.12:e1005896). Using phased haplotypes for nuclear amplicons, we inferred species trees and networks for 38 taxa fromP. subsect.HumilesandProceri. Our phylogenetic analyses recovered two clades comprising a mix of taxa from both subsections, indicating that the current taxonomy for these groups is inconsistent with our estimates of phylogeny. In addition, there was little support for hypotheses regarding the formation of putative allopolyploid lineages. Overall, we found evidence for the effects of both ILS and admixture on the evolutionary history of these species, but were able to evaluate our taxonomic hypotheses despite high levels of gene tree discordance. Our method for estimating QCFs from multiple haplotypes also allowed us to include species of varying ploidy levels in our analyses, which we anticipate will help to facilitate estimation of species networks in other plant groups as well.
A telomere to telomere assembly ofOscheius tipulaeand the evolution of rhabditid nematode chromosomes
Authors: Gonzalez de la Rosa Pablo Manuel , Thomson Marian , Trivedi Urmi , Tracey Alan , Tandonnet Sophie , Blaxter Mark 
Published: September 2020

ABSTRACTEukaryotic chromosomes have phylogenetic persistence. In many taxa, the number of chromosomes is related to the number of centromeres. However, in some groups, such as rhabditid nematodes, centromeric function is distributed across multiple sites on each chromosome. These holocentric chromosomes might,a priori, be expected to be permissive of large-scale chromosomal rearrangement, as chromosomal fragments could still partition correctly and fusions would not generate lethal conflict between multiple centromeres. Here, we explore the phylogenetic stability of nematode chromosomes using a new telomere-to-telomere assembly of the rhabditine nematodeOscheius tipulaegenerated from nanopore long reads. The 60 MbO. tipulaegenome is resolved into six chromosomal molecules. We find evidence of specific chromatin diminution at all telomeres. Comparing this chromosomalO. tipulaeassembly with chromosomal assemblies of diverse rhabditid nematodes we identify seven ancestral chromosomal elements (Nigon elements), and present a model for the evolution of nematode chromosomes through rearrangement and fusion of these elements. We identify frequent fusion events involving NigonX, the element associated with the rhabditid X chromosome, and thus sex-chromosome associated gene sets differ markedly between species. Despite the karyotypic stability, gene order within chromosomes defined by Nigon elements is not conserved. Our model for nematode chromosome evolution provides a platform for investigation of the tensions between local genome rearrangement and karyotypic evolution in generating extant genome architectures.
Capture of mouse and human stem cells with features of formative pluripotency
Authors: Kinoshita Masaki , Barber Michael , Mansfield William , Cui Yingzhi , Spindlow Daniel , Stirparo Giuliano Giuseppe , Dietmann Sabine , Nichols Jennifer , Smith Austin 
Published: September 2020

SUMMARYPluripotent cells emerge via a naïve founder population in the blastocyst, acquire capacity for germline and soma formation, and then undergo lineage priming. Mouse embryonic stem (ES) cells and epiblast stem cells (EpiSCs) represent the initial naïve and final primed phases of pluripotency, respectively. Here we investigate the intermediate formative stage. Using minimal exposure to specification cues, we expand stem cells from formative mouse epiblast. Unlike ES cells or EpiSCs, formative stem (FS) cells respond directly to germ cell induction. They colonise chimaeras including the germline. Transcriptome analyses show retained pre-gastrulation epiblast identity. Gain of signal responsiveness and chromatin accessibility relative to ES cells reflect lineage capacitation. FS cells show distinct transcription factor dependencies from EpiSCs, relying critically on Otx2. Finally, FS cell culture conditions applied to human naïve cells or embryos support expansion of similar stem cells, consistent with a conserved attractor state on the trajectory of mammalian pluripotency.
The lysosomal TRPML1 channel promotes breast cancer survival by supporting mitochondrial function and cellular metabolism
Authors: Almasi Shekoufeh , Kennedy Barry E. , Yoast Ryan E. , Emrich Scott M. , Trebak Mohamed , Hiani Yassine El 
Published: September 2020

AbstractTriple-negative breast cancer (TNBC) is an aggressive subtype representing approximately 10%-20% of breast cancers and lacking effective therapies. TRPML1, which is a lysosomal Ca2+ release channel upregulated in TNBC, promotes TNBC tumor growth. Here we show a novel crosstalk between lysosomes and mitochondria mediated by TRPML1 in TNBC. TRPML1 is required for the maintenance of mitochondrial function and reactive oxygen species (ROS) homeostasis. TRPML1 knockdown inhibits TNBC mitochondrial respiration, glycolysis and ATP production, leading to reduced proliferation, promotion of cell cycle arrest and apoptosis with enhanced global and mitochondrial ROS. Further, TRPML1 downregulation enhances the cytotoxic effect of Doxorubicin in TNBC cells. Our data reveal a hitherto unknown link between lysosomal TRPML1 channels and mitochondrial metabolism and suggest that TRPML1 inhibition in combination with established chemotherapies could be an effective strategy against TNBC tumors.
Two cortical representations of voice control are differentially involved in speech fluency
Authors: Neef Nicole E. , Primaßin Annika , von Gudenberg Alexander Wolff , Dechent Peter , Riedel Heiner Christian , Paulus Walter , Sommer Martin 
Published: September 2020

AbstractRecent studies have identified two distinct cortical representations of voice control in humans, the ventral and the dorsal laryngeal motor cortex. Strikingly, while persistent developmental stuttering has been linked to a white matter deficit in the ventral laryngeal motor cortex, intensive fluency shaping intervention modulated the functional connectivity of the dorsal laryngeal motor cortical network. Currently, it is unknown whether the underlying structural network organization of these two laryngeal representations is distinct or differently shaped by stuttering intervention. Using probabilistic diffusion tractography in 22 individuals who stutter and participated in a fluency shaping intervention, in 18 individuals who stutter and did not participate in the intervention, and in 28 control participants, we here compare structural networks of the dorsal laryngeal motor cortex and the ventral laryngeal motor cortex and test intervention-related white matter changes. We show (i) that all participants have weaker ventral laryngeal motor cortex connections compared to the dorsal laryngeal motor cortex network, regardless of speech fluency, (ii) connections of the ventral laryngeal motor cortex were stronger in fluent speakers, (iii) the connectivity profile of the ventral laryngeal motor cortex predicted stuttering severity, (iv) but the ventral laryngeal motor cortex network is resistant to a fluency shaping intervention. Our findings substantiate a weaker structural organization of the ventral laryngeal motor cortical network in developmental stuttering and imply that assisted recovery supports neural compensation rather than normalization. Moreover, the resulting dissociation provides evidence for functionally segregated roles of the ventral laryngeal motor cortical and dorsal laryngeal motor cortical networks.
Investigation Gene body methylation is under selection inArabidopsis thaliana
Authors: Muyle Aline , Ross-Ibarra Jeffrey , Seymour Danelle K. , Gaut Brandon S. 
Published: September 2020

AbstractIn plants, mammals and insects, some genes are methylated in the CG dinucleotide context, a phenomenon called gene body methylation. It has been controversial whether this phenomenon has any functional role. Here, we took advantage of the availability of 876 leaf methylomes inArabidopsis thalianato characterize the population frequency of methylation at the gene level and estimated the site-frequency spectrum of allelic states (epialleles). Using a population genetics model specifically designed for epigenetic data, we found that genes with ancestral gene body methylation are under significant selection to remain methylated. Conversely, all genes taken together were inferred to be under selection to be unmethylated. The estimated selection coefficients were small, similar to the magnitude of selection acting on codon usage. We also estimated thatA. thalianais losing gene body methylation three-fold more rapidly than gaining it, which could be due to a recent reduction in the efficacy of selection after a switch to selfing. Finally, we investigated the potential function of gene body methylation through its link with gene expression level. Across genes with polymorphic methylation states, the expression of gene body methylated alleles was consistently and significantly higher than unmethylated alleles. Although it is difficult to disentangle genetic from epigenetic effects, our work suggests that gbM has a small but measurable effect on fitness, perhaps due to its association to a phenotype like gene expression.
Genetic manipulation of insulin/insulin-like growth factor signaling pathway activity has sex-biased effects onDrosophilabody size
Authors: Millington Jason W. , Brownrigg George P. , Basner-Collins Paige J. , Sun Ziwei , Rideout Elizabeth J. 
Published: September 2020

ABSTRACTInDrosophila, female body size is approximately 30% larger than male body size due to an increased rate of larval growth. While the mechanisms that control this sex difference in body size remain incompletely understood, recent studies suggest that the insulin/insulin-like growth factor signaling pathway (IIS) plays a role in the sex-specific regulation of growth during development. In larvae, IIS activity differs between the sexes, and there is evidence of sex-specific regulation of IIS ligands. Yet, we lack knowledge of how changes to IIS activity impact growth in each sex, as the majority of studies on IIS and body size use single- or mixed-sex groups of larvae and/or adult flies. The goal of our current study was to clarify the requirement for IIS activity in each sex during the larval growth period. To achieve this goal we used established genetic approaches to enhance, or inhibit, IIS activity, and quantified body size in male and female larvae. Overall, genotypes that inhibited IIS activity caused a female-biased decrease in body size, whereas genotypes that augmented IIS activity caused a male-specific increase in body size. This data extends our current understanding of larval growth by showing that most changes to IIS pathway activity have sex-biased effects on body size, and highlights the importance of analyzing data by sex in larval growth studies.
Airway Basal Cells show a dedifferentiated KRT17highPhenotype and promote Fibrosis in Idiopathic Pulmonary Fibrosis
Authors: Jaeger Benedikt , Schupp Jonas Christian , Plappert Linda , Terwolbeck Oliver , Kayser Gian , Engelhard Peggy , Adams Taylor Sterling , Zweigerdt Robert , Kempf Henning , Lienenklaus Stefan , Garrels Wiebke , Nazarenko Irina , Jonigk Danny , Wygrecka Malgorzata , Klatt Denise , Schambach Axel , Kaminski Naftali , Prasse Antje 
Published: September 2020

ABSTRACTIdiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. In this study we focus on the profibrotic properties of airway basal cells (ABC) obtained from patients with IPF (IPF-ABC). Single cell RNA sequencing of bronchial brushes revealed extensive reprogramming of IPF-ABC towards a KRT17highPTENlowdedifferentiated cell type. In the 3D organoid model, compared to ABC obtained from healthy volunteers, IPF-ABC give rise to more bronchospheres,de novobronchial structures resembling lung developmental processes, induce fibroblast proliferation and extracellular matrix deposition in co-culture. Intratracheal application of IPF-ABC into minimally injured lungs of Rag2-/-or NRG mice causes severe fibrosis, remodeling of the alveolar compartment, and formation of honeycomb cyst-like structures. Connectivity MAP analysis of scRNA seq of bronchial brushings suggested that gene expression changes in IPF-ABC can be reversed by SRC inhibition. After demonstrating enhanced SRC expression and activity in these cells, and in IPF lungs, we tested the effects of saracatinib, a potent SRC inhibitor previously studied in humans. We demonstrated that saracatinib modifiedin-vitroandin-vivothe profibrotic changes observed in our 3D culture system and novel mouse xenograft model.