bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulating Sphingosine-1-Phosphate receptors to improve chemotherapy delivery to Ewing sarcoma
Authors: Marmonti Enrica , Savage Hannah , Zhang Aiqian , Alvarez Claudia , Morrell Miriam , Schadler Keri 
Published: October 2019

ABSTRACTTumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper-permeability promotes chemotherapy delivery primarily to a tumor’s periphery. Here we identify a method for enhancing chemotherapy delivery and efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein-coupled Sphinosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper-permeability can be reversed. In this study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE-013 caused more organized, mature, and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved chemotherapy delivery to the tumor and anti-tumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.NOVELTY AND IMPACTThis study demonstrates that Sphingosine-1-Phosphate (S1P) receptors are potential novel targets for tumor vasculature remodeling and adjuvant therapy for the treatment of Ewing Sarcoma. Unlike receptor tyrosine kinases that have already been extensively evaluated for use as vascular normalizing agents in oncology, S1P receptors are G protein-coupled receptors, which have not been well studied in tumor endothelium. Pharmacologic activators and inhibitors of S1P receptors are currently in clinical trials for treatment of auto-immune and cardiovascular diseases, indicating potential for clinical translation of this work.
New genome assemblies reveal patterns of domestication and adaptation acrossBrettanomyces(Dekkera) species
Authors: Roach Michael J. , Borneman Anthony R. 
Published: October 2019

AbstractBackgroundYeast of the genusBrettanomycesare of significant interest, both for their capacity to spoil, as well as their potential to positively contribute to different industrial fermentations. However, considerable variance exists in the depth of research and knowledgebase of the five currently known species ofBrettanomyces. For instance,Brettanomyces bruxellensishas been heavily studied and many resources are available for this species, whereasBrettanomyces nanusis rarely studied and lacks a publicly available genome assembly altogether. The purpose of this study is to fill this knowledge gap and explore the genomic adaptations that have shaped the evolution of this genus.ResultsStrains for each of the five widely accepted species ofBrettanomyces(Brettanomyces anomalus,B. bruxellensis,Brettanomyces custersianus,Brettanomyces naardenensis, andB. nanus) were sequenced using a combination of long- and short-read sequencing technologies. Highly contiguous assemblies were produced for each species. Sweeping and extensive structural variation between the species’ genomes were observed and gene expansions in fermentation-relevant genes (particularly inB. bruxellensisandB. nanus) were identified. Numerous horizontal gene transfer (HGT) events in allBrettanomycesspecies’, including an HGT event that is probably responsible for allowingB. bruxellensisandB. anomalusto utilize sucrose were also observed.ConclusionsGenomic adaptations and some evidence of domestication that have taken place inBrettanomycesare outlined. These new genome assemblies form a valuable resource for future research inBrettanomyces.
A HypomorphicCystathionine ß-SynthaseGene Contributes to Cavefish Eye Loss by Disrupting Optic Vasculature
Authors: Ma Li , Gore Aniket V. , Castranova Daniel , Shi Janet , Ng Mandy , Tomins Kelly A. , van der Weele Corine M. , Weinstein Brant M. , Jeffery William R. 
Published: October 2019

AbstractVestigial structures are key indicators of evolutionary descent but the mechanisms underlying their development are poorly understood. This study examines vestigial eye formation in the teleostAstyanax mexicanus, which consists of a sighted surface-dwelling morph and different populations of blind cave morphs. Cavefish embryos initially develop optic primordia but vestigial eyes are formed during larval development. Multiple genetic factors are involved in cavefish eye loss but none of the mutated genes have been identified. Here we identifycystathionine ß-synthase(cbsa), which encodes the key enzyme of the transsulfuration pathway, as a mutated gene responsible for eye degeneration in multiple cavefish populations. The inactivation ofcbsaaffects eye development by inducing accumulation of the transsulfuration intermediate homocysteine and defects in optic vasculature, including aneurysms and eye hemorrhages, leading to oxygen deficiency. Our findings suggest that localized modifications in the circulatory system and hypoxia had important roles in the evolution of vestigial eyes in blind cavefish.
Identification of Fis1 interactors inToxoplasma gondiireveals a novel protein required for peripheral distribution of the mitochondrion
Authors: Jacobs Kylie , Charvat Robert , Arrizabalaga Gustavo 
Published: October 2019

ABSTRACTToxoplasma gondii’s singular mitochondrion is very dynamic and undergoes morphological changes throughout the parasite’s life cycle. During parasite division, the mitochondrion elongates, enters the daughter cells just prior to cytokinesis and undergoes fission. Extensive morphological changes also occur as the parasite transitions from the intracellular to the extracellular environment. We show that treatment with the ionophore monensin causes reversible constriction of the mitochondrial outer membrane, and that this effect depends on the function of the fission related protein Fis1. We also observed that mislocalization of the endogenous Fis1 causes a dominant negative effect that affects the morphology of the mitochondrion. As this suggests Fis1 interacts with proteins critical for maintenance of mitochondrial structure, we performed various protein interaction trap screens. In this manner we identified a novel outer mitochondrial membrane protein, LMF1, which is essential for positioning of the mitochondrion in intracellular parasites. Normally, while inside a host cell, the parasite mitochondrion is maintained in a lasso shape that stretches around the parasite periphery where it has regions of coupling with the parasite pellicle, suggesting the presence of membrane contact sites. In intracellular parasites lacking LMF1 the mitochondrion is retracted away from the pellicle and instead is collapsed, as only normally seen in extracellular parasites. We show that this phenotype is associated with defects in parasite fitness and mitochondrial segregation. Thus, LMF1 is necessary for mitochondrial association with the parasite pellicle during intracellular growth and proper mitochondrial morphology is a prerequisite for mitochondrial division.IMPORTANCEToxoplasma gondiiis an opportunistic pathogen that can cause devastating tissue damage in the immunocompromised and the congenitally infected. Current therapies are not effective against all life stages of the parasite and many cause toxic effects. The single mitochondrion of this parasite is a validated drug target and it changes its shape throughout its life cycle. When the parasite is inside of a cell, the mitochondrion adopts a lasso shape that lies in close proximity to the pellicle. The functional significance of this morphology is not understood nor are the proteins involved currently known. We have identified a protein that is required for proper mitochondrial positioning at the periphery and that likely plays a role in tethering this organelle. Loss of this protein results in dramatic changes to the mitochondrial morphology and significant parasite division and propagation defects. Our results give important insight into the molecular mechanisms regulating mitochondrial morphology.
Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome
Authors: Tsumoto Kunichika , Ashihara Takashi , Naito Narumi , Shimamoto Takao , Amano Akira , Kurata Yasutaka , Kurachi Yoshihisa 
Published: October 2019

ABSTRACTOne phenotypic feature of Brugada syndrome (BrS) is slowed conduction due to the reduction (loss-of-function) of Na+ channels. In contrast, recent clinical observations in BrS patients highlighted the poor correlation between the phenotype (typical ECG change or lethal arrhythmia) and the genotype (SCN5A mutation). Inspired by our previous theoretical study which showed that reduced Na+ channels in the lateral membrane (LM) of ventricular myocytes caused the slowing of conduction under myocardial ischemia, we hypothesized that a loss-of-function of Na+ channels caused by the decreases in Na+ channel expression within myocytes leads to phase-2 reentry (P2R), the major triggering mechanism of lethal arrhythmias in BrS. We constructed an in silico human ventricular myocardial strand and ring models, and investigated the relationship between the subcellular Na+ channel distribution and P2R. Reducing Na+ channel expression in the LM of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients. Furthermore, we showed that both the reduction in Na+ channels on the LM of each myocyte and tissue-level heterogeneity of Na+ channel expression were essential for P2R as well as P2R-mediated reentrant excitation. Our data suggest that the alteration in subcellular Na+ channel distribution together with a tissue-level heterogeneity of Na+ channels can cause arrhythmogenesis in BrS.
Cell type specific genetic regulation of gene expression across human tissues
Authors: Kim-Hellmuth Sarah , Aguet François , Oliva Meritxell , Muñoz-Aguirre Manuel , Wucher Valentin , Kasela Silva , Castel Stephane E. , Hamel Andrew R. , Viñuela Ana , Roberts Amy L. , Mangul Serghei , Wen Xiaoquan , Wang Gao , Barbeira Alvaro N. , Garrido-Martín Diego , Nadel Brian , Zou Yuxin , Bonazzola Rodrigo , Quan Jie , Brown Andrew , Martinez-Perez Angel , Soria José Manuel ,   GTEx Consortium, Getz Gad , Dermitzakis Emmanouil T. , Small Kerrin S. , Stephens Matthew , Xi Hualin S. , Im Hae Kyung , Guigó Roderic , Segrè Ayellet V. , Stranger Barbara E. , Ardlie Kristin G. , Lappalainen Tuuli 
Published: October 2019

AbstractThe Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci (cis-QTLs) for the majority of genes across a wide range of human tissues. However, the interpretation of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. Here, we map interactions between computational estimates of cell type abundance and genotype to identify cell type interaction QTLs for seven cell types and show that cell type interaction eQTLs provide finer resolution to tissue specificity than bulk tissuecis-eQTLs. Analyses of genetic associations to 87 complex traits show a contribution from cell type interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.One Sentence SummaryEstimated cell type abundances from bulk RNA-seq across tissues reveal the cellular specificity of quantitative trait loci.
Selective Translation Complex Profiling Reveals Staged Initiation and Co-translational Assembly of Initiation Factor Complexes
Authors: Wagner Susan , Herrmannová Anna , Hronová Vladislava , Sen Neelam , Hannan Ross D. , Hinnebusch Alan G. , Shirokikh Nikolay E. , Preiss Thomas , Valášek Leoš Shivaya 
Published: October 2019

SUMMARYTranslational control targeting mainly the initiation phase is central to the regulation of gene expression. Understanding all of its aspects requires substantial technological advancements. Here we modified yeast Translational Complex Profile sequencing (TCP-seq), related to ribosome profiling, and adopted it for mammalian cells. Human TCP-seq, capable of capturing footprints of 40S subunits (40Ses) in addition to 80S ribosomes (80Ses), revealed that mammalian and yeast 40Ses distribute similarly across 5’UTRs indicating considerable evolutionary conservation. We further developed a variation called Selective TCP-seq (Sel-TCP-seq) enabling selection for 40Ses and 80Ses associated with an immuno-targeted factor in yeast and human. Sel-TCP-seq demonstrated that eIF2 and eIF3 travel along 5’UTRs with scanning 40Ses to successively dissociate upon start codon recognition. Manifesting the Sel-TCP-seq versatility for gene expression studies, we also identified four initiating 48S conformational intermediates, provided novel insights into ATF4 and GCN4 mRNA translational control, and demonstrated co-translational assembly of initiation factor complexes.
Unconventional kinetochore kinases KKT10/19 promote the metaphase to anaphase transition in Trypanosoma brucei
Authors: Ishii Midori , Akiyoshi Bungo 
Published: October 2019

AbstractThe kinetochore is a macromolecular protein complex that drives chromosome segregation in eukaryotes. Unlike most eukaryotes that have canonical kinetochore proteins, evolutionarily divergent kinetoplastids such as Trypanosoma brucei have unconventional kinetochore proteins. T. brucei also lacks a canonical spindle checkpoint system and it therefore remains unknown how mitotic progression is regulated in this organism. Here we characterized two paralogous kinetochore proteins with a CLK-like kinase domain, KKT10 and KKT19, which localize at kinetochores in metaphase but disappear at the onset of anaphase. We found that these proteins are functionally redundant. Double knockdown of KKT10/19 led to a significant delay in the metaphase to anaphase transition. A kinase-dead mutant of KKT10 failed to rescue the KKT10/19 depletion phenotype, suggesting that its kinase activity is essential. We also found that phosphorylation of two kinetochore proteins KKT4 and KKT7 depends on KKT10/19 in vivo. Finally, we showed that the N-terminal part of KKT7 directly interacts with KKT10 and that kinetochore localization of KKT10 depends not only on KKT7 but also on the KKT8 complex. Our results reveal that kinetochore localization of KKT10/19 is tightly controlled to regulate the metaphase to anaphase transition in T. brucei.SummaryTrypanosoma brucei has unique kinetochore proteins and lacks a canonical spindle checkpoint system. How mitotic progression is regulated in this organism remains unclear. Here we show that two redundant protein kinases KKT10/19 promote the metaphase to anaphase transition.
A single-cell transcriptome atlas of the adult muscle precursors uncovers early events in fiber-type divergence inDrosophila
Authors: Zappia Maria Paula , de Castro Lucia , Ariss Majd M. , Islam Abul B.M.M.K. , Frolov Maxim V 
Published: October 2019

SummaryInDrosophila, the wing disc-associated adult muscle precursors (AMPs) give rise to the fibrillar indirect flight muscles (IFM) and the tubular direct flight muscles (DFM). To understand early transcriptional events underlying this muscle diversification, we performed single cell RNA-sequencing experiments and built a cell atlas of AMPs associated with third instar larval wing disc. Our analysis identified distinct transcriptional signatures for IFM and DFM precursors that underlie the molecular basis of their divergence. The atlas further revealed various states of differentiation of AMPs, thus illustrating previously unappreciated spatial and temporal heterogeneity among them. We identified and validated novel markers for both IFM and DFM precursors at various states of differentiation by immunofluorescence and genetic tracing experiments. Finally, we performed a systematic genetic screen using a panel of markers from the reference cell atlas as an entry point and found a novel gene,Ama, which is functionally important in muscle development. Thus, our work provides a framework of leveraging scRNA-seq for gene discovery and therefore, this strategy can be applied to other scRNA-seq datasets.
Channel nuclear pore protein 54 directs sexual differentiation and neuronal wiring required for female reproductive behaviors inDrosophila
Authors: Nallasivan Mohanakarthik P. , Haussmann Irmgard U. , Civetta Alberto , Soller Matthias 
Published: October 2019

AbstractThe post-mating response induced by male-derived sex-peptide inDrosophilafemales is a well-established model to elucidate how complex innate behaviors are hard-wired into the brain. Here, we found that the channel nuclear pore proteinNup54gene is essential for the sex-peptide response as viable mutant alleles do not lay eggs and reduce receptivity upon sex-peptide exposure. Nup54 directs correct wiring of few adult brain neurons that expresspickpocketand are required for egg laying, but channel Nups also mediate sexual differentiation and male X-chromosome dosage compensation. Consistent with links of Nups to speciation, the Nup54 promoter is a hot spot for rapid evolution and promoter variants alter expression in transgenes. These results implicate altered expression of Nup54 to the onset of speciation processes leading to changes in neuronal wiring and sexual differentiation as a response to sexual conflict arising from male-derived SP to direct the female post-mating response.
Polyglutamine-related aggregates serve as a potent antigen source for cross presentation by dendritic cells
Authors: Tabachnick-Cherny Shira , Berko Dikla , Pinto Sivan , Curato Caterina , Wolf Yochai , Porat Ziv , Karmona Rotem , Tirosh Boaz , Jung Steffen , Navon Ami 
Published: October 2019

AbstractProtective MHC-I dependent immune responses require an overlap between repertoires of proteins directly presented on target cells and cross-presented by professional antigen presenting cells (APC), specifically dendritic cells (DCs). How stable proteins that rely on DRiPs for direct presentation are captured for cell-to-cell transfer remains enigmatic. Here we address this issue using a combination ofin vitroandin vivoapproaches involving stable and unstable versions of ovalbumin model antigens displaying DRiP-dependent and -independent antigen presentation, respectively. Apoptosis, but not necrosis of donor cells was found associated with robust p62-dependent global protein aggregate formation and captured stable proteins permissive for DC cross-presentation. Potency of aggregates to serve as antigen source was directly demonstrated using polyglutamine-equipped model substrates. Collectively, our data implicate global protein aggregation in apoptotic cells as a mechanism that ensures the overlap between MHC-I epitopes presented directly or cross-presented by APC and demonstrate the unusual ability of DC to process stable protein aggregates.SummaryProtective T cell immunity relies on the overlap of the antigen repertoire expressed by cells and the repertoire presented by dendritic cells that are required to trigger naïve T cells. We suggest a mechanism that contributes to ensure this antigenic overlap. Our findings demonstrate that upon apoptosis stable proteins are aggregated in p62-dependent pathway and that dendritic cells are capable to efficiently process these aggregates to retrieve antigens for T cell stimulation.
Transcriptional analysis of wheat seedlings inoculated with Fusarium culmorum under continual exposure to disease defence inductors
Authors: Antalová Zuzana , Bleša Dominik , Martinek Petr , Matušinsky Pavel 
Published: October 2019

AbstractA facultative parasite of cereals, Fusarium culmorum is a soil-, air- and seed-borne fungus causing foot and root rot, fusarium seedling blight, and especially Fusarium head blight, a spike disease leading to decreased yield and mycotoxin contamination of grain. In the present study, we tested changes in expression of wheat genes (B2H2, ICS, PAL, and PR2) involved in defence against diseases. We first compared expression of the analysed genes in seedlings of non-inoculated and artificially inoculated wheat (variety Bohemia). The second part of the experiment compared expression of these genes in seedlings grown under various treatment conditions. These treatments were chosen to determine the effects of prochloraz, sodium bicarbonate, ergosterol, aescin and potassium iodide on expression of the analysed defence genes. In addition to the inoculated and non-inoculated cultivar Bohemia, we examined two other varieties of wheat with contrasting resistance to Fusarium sp. infection. These were the blue aleurone layer variety Scorpion that is susceptible to Fusarium sp. infection and variety V2-49-17 with yellow endosperm and partial resistance to Fusarium sp. infection. In this manner, we were able to compare potential effects of inductors upon defence gene expression among three varieties with different susceptibility to infection but also between inoculated and non-inoculated seedlings of a single variety. The lowest infection levels were detected in the sodium bicarbonate treatment. Sodium bicarbonate had not only negative influence on Fusarium growth but also positively affected expression of plant defence genes. Expression of the four marker genes shown to be important in plant defence was significantly affected by the treatments. The greatest upregulation in comparison to the water control was identified under all treatments for the B2H2 gene. Only expression of PAL under the ergosterol and prochloraz treatments were not statistically significant.
Manganese-enhanced MRI (MEMRI) in breast and prostate cancers: exploring the potential role of calcium receptors
Authors: Baio Gabriella , Fabbi Marina , Cilli Michele , Rosa Francesca , Boccardo Simona , Valdora Francesca , Salvi Sandra , Basso Luca , Emionite Laura , Gianolio Eliana , Aime Silvio , Neumaier Carlo Emanuele 
Published: October 2019

ABSTRACTProceduresTo assess the relationship between Manganese Enhanced Magnetic Resonance Imaging (MEMRI) and the expression of calcium receptors in human prostate and breast cancer animal models.MethodsNOD/SCID mice were inoculated with MDA-MB-231 breast cancer cells and prostate PC3 cancer cells to develop orthotopic or pseudometastatic cancer animal models. Mice were studied on a clinical 3T scanner by using a prototype birdcage coil before and after intravenous injection of MnCl2. Assessment of receptor’s status was carried out after the MR images acquisition by immunohistochemistry on excised tumours.ResultsManganese contrast enhancement in breast or prostate cancer animal models well correlated with CaSR expression (p<0.01), whereas TRPV6 expression levels appeared not relevant to the Mn uptake.ConclusionMEMRI appears an efficient tool to characterize human breast and prostate cancer animal models in the presence of different expression level of CaSR.