bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nitric Oxide Regulates theRalstonia solanacearumType 3 Secretion System
Authors: Hendrich Connor G. , Truchon Alicia N. , Dalsing Beth L. , Allen Caitilyn 
Published: October 2020

AbstractRalstonia solancearumcauses bacterial wilt disease on diverse plant hosts.R. solanacearumcells enter a host from soil or infested water through the roots, then multiply and spread in the water-transporting xylem vessels. Despite the low nutrient content of xylem sap,R. solanacearumgrows very well inside the host, using denitrification to respire in this hypoxic environment.R. solanacearumgrowthin plantaalso depends on the successful deployment of protein effectors into host cells via a Type III Secretion System (T3SS). The T3SS is absolutely required forR. solanacearumvirulence, but it is metabolically costly and can trigger host defenses. Thus, the pathogen’s success depends on optimized regulation of the T3SS. We found that a byproduct of denitrification, the toxic free-radical nitric oxide (NO), positively regulates theR. solanacearumT3SS bothin vitroandin planta. Using chemical treatments andR. solanacearummutants with altered NO levels, we show that the expression of a key T3SS regulator is induced by NO in culture. Analyzing the transcriptome ofR. solanacearumresponding to varying levels of NO both in culture andin plantarevealed that the T3SS and effectors were broadly upregulated with increasing levels of NO. This regulation was specific to the T3SS and was not shared by other stressors. Our results suggest thatR. solanacearumexperiences an NO-rich environment in the plant host and may use this NO as a signal to activate T3SS during infection.
Associations between childhood family emotional health, fronto-limbic grey matter volume, and saliva 5mC in young adulthood
Authors: Pfeiffer JR , Bustamante Angela C. , Kim Grace S. , Armstrong Don , Knodt Annchen R. , Koenen Karestan C. , Hariri Ahmad R. , Uddin Monica 
Published: October 2020

AbstractBackgroundPoor family emotional health (FEH) during childhood is prevalent and impactful, and likely confers similar neurodevelopmental risks as other adverse social environments. Pointed FEH study efforts are underdeveloped, and the mechanisms by which poor FEH are biologically embedded are unclear. The current exploratory study examined whether variability in DNA methylation (DNAm) and fronto-limbic grey matter volume may represent pathways through which FEH may become biologically embedded.ResultsSelf-reported childhood FEH was nominally associated with right hemisphere hippocampus (b=10.4, p=0.005), left hemisphere amygdala (b=5.3, p=0.009), and right hemisphere amygdala (b=5.8, p=0.016) volumes. Childhood FEH was also nominally associated with 49 DNAm MEs (prange=3×10−6to 0.047). After limiting analyses to probes correlated between saliva and brain, saliva-derived DNAm MEs partially mediated the association between FEH and right hippocampal volume (Burlywood ME indirect effect b=-111, p=0.014), and fully mediated the FEH and right amygdala volume relationship (Pink4 ME indirect effect b=-48, p=0.026). Modules were enriched with probes falling in genes with immune, CNS, and metabolic functions.ConclusionsFindings extend work highlighting neurodevelopmental variability associated with adverse social environment exposure during childhood by specifically implicating poor FEH, while informing a mechanism of biological embedding. FEH-associated epigenetic signatures could function as proxies of altered fronto-limbic grey matter volume associated with poor childhood FEH and inform further investigation into primarily affected tissues such as endocrine, immune, and CNS cell types.
Self-similar synchronization of calcium and membrane potential transitions during AP cycles predict HR across species
Authors: Sirenko Syevda Tagirova , Tsutsui Kenta , Tarasov Kirill , Yang Dongmei , Wirth Ashley N , Maltsev Victor A. , Ziman Bruce D. , Yaniv Yael , Lakatta Edward G. 
Published: October 2020

AbstractBackgroundTranslation of knowledge of sinoatrial nodal “SAN” automaticity gleaned from animal studies to human dysrhythmias, e.g. “Sick Sinus” Syndrome (SSS) requiring electronic pacemaker insertion has been sub-optimal, largely because heart rate (HR) varies widely across species.ObjectivesTo discover regulatory universal mechanisms of normal automaticity in SAN pacemaker cells that are self-similar across species.MethodSub-cellular Ca2+releases, whole cell AP-induced Ca2+transients and APs were recorded in isolated mouse, guinea-pig, rabbit and human SAN cells. Parametric Ca2+and Vm Kinetic Transitions (PCVKT) during phases of AP cycles from their ignition to recovery were quantified.ResultsAlthough both action potential cycle lengths (APCL) and PCVKT during AP cycles differed across species by ten-fold, trans-species scaling of PCVKT during AP cycles and scaling, of PCVKT to APCL in cellsin vitro, EKG RR intervalsin vivo, and BM were self-similar (obeyed power laws) across species. Thus, APCLin vitro, HRin vivo, and BM ofanyspecies can be predicted by PCVKT during AP cycles in SAN cells measured in any single speciesin vitro.ConclusionsIn designing optimal HR to match widely different BM and energy requirements from mice to humans, nature did not “reinvent pacemaker cell wheels”, but differentially scaled kinetics of gears that regulate the rates at which the “wheels spin”. This discovery will facilitate the development of novel pharmalogic therapies and biologic pacemakers featuring a normal, wide-range rate regulation in animal models and the translation of these to humans to target recalcitrant human SSS.Condensed AbstractStudies in animal models are an important facet of cardiac arrhythmia research. Because HR differs by over ten-fold between some animals and humans, translation of knowledge about regulatory mechanisms of SAN normal automaticity gleaned from studies in animal models to target human SSS has been sub-optimal. Our findings demonstrating that trans-species self-similarity of sub-cellular and cellular mechanisms that couple Ca2+to Vm during AP cycles can predict heart ratein vivofrom mice to humans will inform on the design of novel studies in animal models and facilitate translation of this knowledge to target human disease.
Fatty acid binding protein 5 forms higher order assemblies with FLAP or COX-2 in LPS-stimulated macrophages
Authors: Elder Shelby E. , Bauer Nicholas C. , Soberman Roy J. , Schmider Angela B. 
Published: October 2020

AbstractImmune cells must integrate multiple extracellular signals to produce an appropriate inflammatory response, including production of a dynamic mix of eicosanoids and related bioactive lipids. Synthesis of these lipids is initiated on the membrane surface of the nuclear envelope and endoplasmic reticulum. One critical question is how the precursor arachidonic acid (AA) is distributed between the initial biosynthetic enzymes of the arachidonate 5-lipoxygenase (5-LO) and prostaglandin-endoperoxidase synthase-1/2 (COX-1/2) related pathways. To understand these balancing mechanisms, we hypothesized that fatty acid binding proteins mediate this process. We employed a multi-modal imaging approach by combining direct stochastic optical reconstruction microscopy (dSTORM) with computational analyses and fluorescence lifetime imaging microscopy (FLIM) to delineate the relationships of fatty acid binding proteins 3, 4, and 5 (FABP3–5) with 5-LO activating protein (FLAP), COX-1, and COX-2 in the presence of a stimulus (lipopolysaccharide, LPS) that triggers the synthesis of prostaglandin E2(PGE2). LPS triggers a redistribution of FABP5 to higher order assemblies of COX-2 or FLAP. This was evidenced by a decrease in lifetime determined by FLIM. Colocalization between FABP3 and FLAP decreased, but no other changes in distribution were observed for FABP3 and FABP4. In contrast, assemblies of FABP5 with COX-1 were smaller and showed an increase in lifetime. The data indicate that FABP5 is a member of higher order assemblies of eicosanoid biosynthetic enzymes and that FABP5 may play a key role in regulating the organization of these structures. FABP5 is positioned to distribute AA to both the 5-LO and COX-2 pathways.
Melanocytes determine angiogenesis gene expression across human tissues
Authors: Freilikhman Shirly , Halasi Marianna , Eran Alal , Adini Irit 
Published: October 2020

AbstractSeveral angiogenesis-dependent diseases, including age-related macular degeneration and infantile hemangioma, display differential prevalence among Black, as compared to White individuals. Although socioeconomic status and genetic architecture have been suggested as explaining these differences, we have recently shown that pigment productionper semight be involved. For example, we have shown that the extracellular protein fibromodulin is a pro-angiogenic factor highly secreted by melanocytes in White but not Black individuals. Still, additional pigment-dependent angiogenic factors and their molecular mechanisms remain to be identified. Understanding the contribution of pigmentation to angiogenesis in health and disease is essential for precision medicine of angiogenesis-dependent diseases with racial disparity. Toward that goal, we compared the transcriptomes of Black and White individuals in three tissues with angiogenic activity, namely artery, whole blood, and skin. We identified several differentially expressed angiogenesis pathways, including artery morphogenesis, regulation of endothelial cell chemotaxis, and cellular response to vascular endothelial growth factor stimulus. We then demonstrated that the expression of key genes in these pathways is directly modulated by the degree of pigmentation. We further identified the precise pigment production pathway controlling the expression of these genes, namely melanocortin 1 receptor (MC1R) signaling. These results demonstrate pigment-mediated regulation of angiogenesis-related pathways and their driver genes across human tissues.
Disparate Bone Anabolic Cues Activate Bone Formation by Regulating the Rapid Lysosomal Degradation of Sclerostin Protein
Authors: Gould Nicole R. , Williams Katrina M. , Joca Humberto C. , Torre Olivia M. , Lyons James S. , Leser Jenna M. , Srikanth Manasa P. , Hughes Marcus , Khairallah Ramzi J. , Feldman Ricardo A. , Ward Christopher W. , Stains Joseph P. 
Published: October 2020

AbstractThe down regulation of sclerostin mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation that occurs hours after stimulation. Here, we describe, for the first time, the rapid post-translational degradation of sclerostin protein by the lysosome following mechanical load or PTH. We present a unifying model, integrating both new and established mechanically- and hormonally-activated effectors into the regulated degradation of sclerostin by lysosomes. Using anin vivomechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using Gaucher disease iPSCs. These results inform a paradigm shift in how bone anabolic cues post-translationally regulate sclerostin and expands our understanding of how osteocytes regulate this fundamentally important protein to regulate bone formation.
Ten complete mitochondrial genomes of Gymnocharacini (Stethaprioninae, Characiformes): evolutionary relationships and a repetitive element in the Control Region (D-loop)
Authors: Pasa Rubens , Menegídio Fabiano Bezerra , Rodrigues-Oliveira Igor Henrique , da Silva Iuri Batista , de Campos Matheus Lewi Cruz Bonaccorsi , Rocha-Reis Dinaíza Abadia , Heslop-Harrison John Seymour (Pat) , Schwarzacher Trude , Kavalco Karine Frehner 
Published: October 2020

AbstractWe are presenting the complete mitogenomes of eight fish species/cytotypes from Neotropical region belonging to theAstyanaxandPsalidodongenus:A. aeneus, A. altiparanae, P. fasciatus(from two locations - Upper Paraná and São Francisco river basins),A. lacustris, P. rivularis(two cytotypes) andP. rioparanaibano. We perform the whole-genome sequencing for six of these species in a Novaseq 6000 - by Illumina, meanwhile two genomes were assembled from raw data available in databases. Plus, we reassembled and annotated the mitochondrial genomes forA. mexicanusandP. paranae, both already described and with raw data available online. All the genomes presented the same organization, with 13 protein-coding genes, 22 tRNA genes and two rRNA genes. Aiming to contribute to the understanding of the several cryptic species complexes and phylogeny of the genus, we perform Bayesian analysis using the 13 protein-coding genes from these species, plusDeuterodon gitonand using aBryconspecies as outgroup.
Chromatin accessibility profiles of castration-resistant prostate cancers reveal novel subtypes and therapeutic vulnerabilities
Authors: Tang Fanying , Wang Shangqian , Wong Chen Khuan , Lee Cindy J. , Cohen Sandra , Park Jane , Hill Corinne E. , Eng Kenneth , Bareja Rohan , Han Teng , Liu Eric Minwei , Palladino Ann , Di Wei , Gao Dong , Abida Wassim , Beg Shaham , Puca Loredana , Berger Michael F. , Gopalan Anuradha , Dow Lukas E. , Mosquera Juan Miguel , Beltran Himisha , Sternberg Cora N. , Chi Ping , Scher Howard I. , Sboner Andrea , Chen Yu , Khurana Ekta 
Published: October 2020

AbstractIn castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR)-dependence due to lineage plasticity, which has become more prevalent, leads to clinically highly aggressive tumors with few therapeutic options and is mechanistically poorly defined. To identify the master transcription factors (TFs) of CRPC in a subtype-specific manner, we derived and collected 29 metastatic human prostate cancer organoids and cell lines, and generated ATAC-seq, RNA-seq and DNA sequencing data. We identified four subtypes and their master TFs using novel computational algorithms: AR-dependent; Wnt-dependent, driven by TCF; neuroendocrine, driven by ASCL1 and NEUROD1 and stem cell-like (SCL), driven by the AP-1 family. The transcriptomic signatures of these four subtypes enabled the classification of 370 patients. We find that AP-1 co-operates with the inhibitable YAP/TAZ/TEAD pathway in the SCL subtype, the second most common group of CRPC tumors after AR-dependent. Together, this molecular classification reveals new drug targets and can potentially guide therapeutic decisions.
A toolbox for imaging RIPK1, RIPK3 and MLKL in mouse and human cells
Authors: Samson André L. , Fitzgibbon Cheree , Patel Komal M. , Hildebrand Joanne M. , Whitehead Lachlan W. , Rimes Joel S. , Jacobsen Annette V. , Horne Christopher R. , Gavin Xavier J. , Young Samuel N. , Rogers Kelly L. , Hawkins Edwin D. , Murphy James M. 
Published: October 2020

ABSTRACTNecroptosis is a lytic, inflammatory cell death pathway that is dysregulated in many human pathologies. The pathway is executed by a core machinery comprising the RIPK1 and RIPK3 kinases, which assemble into necrosomes in the cytoplasm, and the terminal effector pseudokinase, MLKL. RIPK3-mediated phosphorylation of MLKL induces oligomerization and translocation to the plasma membrane where MLKL accumulates as hotspots and perturbs the lipid bilayer to cause death. The precise choreography of events in the pathway, where they occur within cells, and pathway differences between species, are of immense interest. However, they have been poorly characterized due to a dearth of validated antibodies for microscopy studies. Here, we describe a toolbox of antibodies for immunofluorescent detection of the core necroptosis effectors, RIPK1, RIPK3 and MLKL, and their phosphorylated forms, in human and mouse cells. By comparing reactivity with endogenous proteins in wild-type cells and knockout controls in basal and necroptosis-inducing conditions, we characterise the specificity of frequently-used commercial and recently-developed antibodies for detection of necroptosis signaling events. Importantly, our findings demonstrate that not all frequently-used antibodies are suitable for monitoring necroptosis by immunofluorescence microscopy, and methanol-is preferable to paraformaldehyde-fixation for robust detection of specific RIPK1, RIPK3 and MLKL signals.
LACCASE is Necessary for Root Development inSalvia miltiorrhiza
Authors: Zhou Zheng , Li Qing , Wang Yun , Xiao Liang , Bu Qitao , Hao Kai , Guo Meili , Chen Wansheng , Zhang Lei 
Published: October 2020

AbstractLaccases are multicopper-containing glycoproteins related to monolignol oxidation and polymerization. These properties indicate that laccases are involved in the formation of important medicinal phenolic acid compounds inSalvia miltiorrhizasuch as salvianolic acid B (SAB), which is used for cardiovascular disease treatment. To date, 29 laccases have been found inS. miltiorrhiza, some of which influence the synthesis of phenolic acids. Because of the functional redundancy of laccase genes, their roles inS. miltiorrhizaare poorly understood. In this study, the CRISPR/Cas9 system was first used for dual gene locus targeting inS. miltiorrhizato knock out multiple laccase family genes. The development of the roots was retarded, and root microstructure was abnormal in laccase mutant lines. Additionally, the accumulation of phenolic acid compounds as well as lignin was dramatically reduced. This study suggests that SmLACs are necessary for root development and phenolic acid compound metabolism inS. miltiorrhiza.
Development and analytical validation of a finite element model of fluid transport through osteochondral tissue
Authors: Hislop Brady D. , Heveran Chelsea M. , June Ronald K. 
Published: October 2020

AbstractFluid transport between cartilage and bone is critical to joint health. The objective of this study was to develop and analytically validate a finite element model of osteochondral tissue capable of modeling cartilage-bone fluid transport. A biphasic viscoelastic model using an ellipsoidal fiber distribution was created with three distinct layers of cartilage (superficial zone, middle zone, and deep zone) along with a layer of subchondral bone. For stress-relaxation in unconfined compression, our results for compressive stress, radial stress, effective fluid pressure, and elastic recoil were compared with established biphasic analytical solutions. Our model also shows the development of fluid pressure gradients at the cartilage-bone interface during loading. Fluid pressure gradients developed at the cartilage-bone interface with consistently higher pressures in cartilage following initial loading to 10% strain, followed by convergence towards equal pressures in cartilage and bone during the 400s relaxation period. These results provide additional evidence that fluid is transported between cartilage and bone during loading and improves upon estimates of the magnitude of this effect through incorporating a realistic distribution and estimate of the collagen ultrastructure. Understanding fluid transport between cartilage and bone may be key to new insights about the mechanical and biological environment of both tissues in health and disease.
Somatic CAG expansion in Huntington’s disease is dependent on the MLH3 endonuclease domain, which can be excluded viaMLH3splice redirection to suppress expansion
Authors: Roy Jennie C. L. , Vitalo Antonia , Andrew Marissa A. , Mota-Silva Eduarda , Kovalenko Marina , Burch Zoe , Nhu Anh M. , Cohen Paula E. , Grabczyk Ed , Wheeler Vanessa C. , Pinto Ricardo Mouro 
Published: October 2020

AbstractSomatic expansion of the CAG repeat tract that causes Huntington’s disease (HD) is thought to contribute to the rate of disease pathogenesis. Therefore, factors influencing repeat expansion are potential therapeutic targets. Genes in the DNA mismatch repair pathway are critical drivers of somatic expansion in HD mouse models. Here, we have tested, using genetic and pharmacological approaches, the role of the endonuclease domain of the mismatch repair protein MLH3 in somatic CAG expansion in HD mice and patient cells. A point mutation in the MLH3 endonuclease domain completely eliminated CAG expansion in the brain and peripheral tissues of a HD knock-in mouse model (HttQ111). To test whether the MLH3 endonuclease could be manipulated pharmacologically, we delivered splice switching oligonucleotides in mice to redirectMlh3splicing to exclude the endonuclease domain. Splice redirection to an isoform lacking the endonuclease domain was associated with reduced CAG expansion. Finally, CAG expansion in HD patient-derived primary fibroblasts was also significantly reduced by redirectingMLH3splicing to the endogenous endonuclease domain-lacking isoform. These data indicate the potential of targeting the MLH3 endonuclease domain to slow somatic CAG repeat expansion in HD, a therapeutic strategy that may be applicable across multiple repeat expansion disorders.
Large-Scale Labeling and Assessment of Sex Bias in Publicly Available Expression Data
Authors: Flynn Emily , Chang Annie , Altman Russ B. 
Published: October 2020

ABSTRACTWomen are at more than 1.5-fold higher risk for clinically relevant adverse drug events. While this higher prevalence is partially due to gender-related effects, biological sex differences likely also impact drug response. Publicly available gene expression databases provide a unique opportunity for examining drug response at a cellular level. However, missingness and heterogeneity of metadata prevent large-scale identification of drug exposure studies and limit assessments of sex bias. To address this, we trained organism-specific models to infer sample sex from gene expression data, and used entity normalization to map metadata cell line and drug mentions to existing ontologies. Using this method, we infer sex labels for 450,371 human and 245,107 mouse microarray and RNA-seq samples from refine.bio. Overall, we find slight female bias (52.1%) in human samples and (62.5%) male bias in mouse samples; this corresponds to a majority of single sex studies, split between female-only and male-only (33.3% vs 18.4% in human and 31.0% vs 30.4% in mouse respectively). In drug studies, we find limited evidence for sex-sampling bias overall; however, specific categories of drugs, including human cancer and mouse nervous system drugs, are enriched in female-only and male-only studies respectively. Our expression-based sex labels allow us to further examine the complexity of cell line sex and assess the frequency of metadata sex label misannotations (2-5%). We make our inferred and normalized labels, along with flags for misannotated samples, publicly available to catalyze the routine use of sex as a study variable in future analyses.