bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recycling old drugs: cardiac glycosides as therapeutics to target barrier inflammation of the vasculature, meninges and choroid plexus
Authors: Jansson Deidre , Dieriks Victor Birger , Rustenhoven Justin , Smyth Leon C.D. , Scotter Emma , Aalderink Miranda , Feng Sheryl , Johnson Rebecca , Schweder Patrick , Mee Edward , Heppner Peter , Turner Clinton , Curtis Maurice , Faull Richard , Dragunow Mike 
Published: April 2020

AbstractNeuroinflammation is a key component of virtually all neurodegenerative diseases; preceding neuronal loss and associating directly with cognitive impairment. Neuroinflammatory signals can originate and be amplified at barrier tissues such as brain vasculature, surrounding meninges and the choroid plexus. We designed a high-throughput screening system to target inflammation in cells of the blood-brain barrier (primary human pericytes and endothelia) and microglia enabling us to target human disease-specific inflammatory modifiers. Screening an FDA-approved drug library we identified digoxin and lanatoside C, members of the cardiac glycoside family as inflammatory modulating drugs that work in blood-brain barrier cells. A novelex vivoassay of leptomeningeal and choroid plexus explants further confirmed that these drugs maintain their function in 3D cultures of brain border tissues. While current therapeutic strategies for the treatment of neurodegenerative diseases are missing the mark in terms of targets, efficacy and translatability, our innovative approach usingin vitroandex vivohuman barrier cells and tissues to target neuroinflammatory pathways is a step forward in drug development and testing, and brings us closer to translatable treatments for human neurodegenerative disease.One Sentence SummaryWe have identified cardiac glycosides as powerful regulators of neuroinflammatory pathways in brain-barrier tissues such as vasculature, meninges and choroid plexus.
Epstein-Barr virus nuclear antigen 2 (EBNA2) extensively rewires the human chromatin landscape at autoimmune risk loci
Authors: Hong Ted , Parameswaran Sreeja , Donmez Omer , Miller Daniel , Forney Carmy , Lape Michael , Ribeiro Mariana Saint Just , Liang Jun , Edsall Lee E. , Magnusen Albert , Miller William , Chepelev Iouri , Harley John B. , Zhao Bo , Kottyan Leah C. , Weirauch Matthew T. 
Published: April 2020

AbstractThe interplay between environmental and genetic factors plays a key role in the development of many autoimmune diseases. In particular, the Epstein-Barr virus (EBV) is an established contributor to multiple sclerosis, lupus, and other disorders. Previously, we demonstrated that the EBV nuclear antigen 2 (EBNA2) transactivating protein occupies up to half of the risk loci for a set of seven autoimmune disorders. To further examine the mechanistic roles played by EBNA2 at these loci on a genome-wide scale, we globally examined gene expression, chromatin accessibility, chromatin looping, and EBNA2 binding, in a B cell line that was 1) uninfected, 2) infected with a strain of EBV lacking EBNA2, or 3) infected with a strain that expresses EBNA2. We identified >400 EBNA2-dependent differentially expressed human genes and >5,000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed >2,000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP-seq data revealed >1,700 regions where EBNA2 altered chromatin looping interactions. Importantly, autoimmune genetic risk loci were highly enriched at the sites of these EBNA2-dependent chromatin-altering events. We present examples of autoimmune risk genotype-dependent EBNA2 events, nominating genetic risk mechanisms for autoimmune risk loci such asZMIZ1. Taken together, our results reveal important interactions between host genetic variation and EBNA2-driven disease mechanisms. Further, our study highlights a critical role for EBNA2 in rewiring human gene regulatory programs through rearrangement of the chromatin landscape and nominates these interactions as components of genetic mechanisms that influence the risk of multiple autoimmune diseases.
Primate phylogenomics uncovers multiple rapid radiations and ancient interspecific introgression
Authors: Vanderpool Dan , Minh Bui Quang , Lanfear Robert , Hughes Daniel , Murali Shwetha , Harris R. Alan , Raveendran Muthuswamy , Muzny Donna M. , Gibbs Richard A. , Worley Kim C. , Rogers Jeffrey , Hahn Matthew W. 
Published: April 2020

AbstractOur understanding of the evolutionary history of primates is undergoing continual revision due to ongoing genome sequencing efforts. Bolstered by growing fossil evidence, these data have led to increased acceptance of once controversial hypotheses regarding phylogenetic relationships, hybridization and introgression, and the biogeographical history of primate groups. Among these findings is a pattern of recent introgression between species within all major primate groups examined to date, though little is known about introgression deeper in time. To address this and other phylogenetic questions, here we present new reference genome assemblies for three Old World Monkey species:Colobus angolensis ssp. palliatus(the black and white colobus),Macaca nemestrina(southern pig-tailed macaque), andMandrillus leucophaeus(the drill). We combine these data with 23 additional primate genomes to estimate both the species tree and individual gene trees using thousands of loci. While our species tree is largely consistent with previous phylogenetic hypotheses, the gene trees reveal high levels of genealogical discordance associated with multiple primate radiations. We use strongly asymmetric patterns of gene tree discordance around specific branches to identify multiple instances of introgression between ancestral primate lineages. In addition, we exploit recent fossil evidence to perform fossil-calibrated molecular dating analyses across the tree. Taken together, our genome-wide data help to resolve multiple contentious sets of relationships among primates, while also providing insight into the biological processes and technical artifacts that led to the disagreements in the first place.
Girls gone wild: Social isolation induces hyperactivity and exploration in aged female mice
Authors: Sullens D. Gregory , Gilley Kayla , Jensen Kendall , Sekeres Melanie J. 
Published: April 2020

ABSTRACTThe likelihood of experiencing social isolation increases later in life, particularly for females. It remains unknown how late-life social isolation impacts cognition and affective behavior in aged mice. We assessed the impact of late-life social isolation in 18-month old female mice. One month of single-housing did not lead to robust depressive-like symptomology, altered social interaction behavior, or sensitivity to context fear acquisition or memory. Rather, isolation increased hyperactivity and exploration, and reduced anxiety-like behavior in the open field and elevated plus maze, findings that have been similarly observed in young female and male mice following early-life isolation. These findings suggest that hyperactivity is a robust behavior following social isolation across the lifespan.
Tuning Hsp104 specificity to selectively detoxify α-synuclein
Authors: Mack Korrie L. , Kim Hanna , Jackrel Meredith E. , Lin JiaBei , DeNizio Jamie E. , Yan Xiaohui , Chuang Edward , Tariq Amber , Cupo Ryan R. , Castellano Laura M. , Caldwell Kim A. , Caldwell Guy A. , Shorter James 
Published: April 2020

SummaryHsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, α-synuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms, involving α-synuclein disaggregation or detoxification of α-synuclein conformers without disaggregation. Importantly, both types of α-synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in aC. elegansmodel of Parkinson’s disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.
Chikungunya virus infection impairs the function of osteogenic cells
Authors: Roy Enakshi , Shi Wen , Duan Bin , Reid St Patrick 
Published: April 2020

AbstractChikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus, spread by theAedesspecies (sp.) mosquitoes. Chikungunya virus (CHIKV) causes a condition characterized by high fever, headache, rash, and joint pain. Recent investigations reveal presence of bone lesions and erosive arthritis in the joints of CHIKV infected patients, indicating an association of bone pathology with CHIKV infection. However, the molecular mechanism underlying CHIKV-induced bone pathology remains poorly defined. Bone marrow derived mesenchymal stem cells (BMSCs) contribute to bone homeostasis by differentiating into osteogenic cells which later mature to form the bone. Disruption of osteogenic differentiation and function of BMSCs lead to bone pathologies. Studies show that virus infections can alter the properties and function of BMSCs. However, to date, pathogenesis of CHIKV infection in this context has not been studied. In the current study, we investigated the susceptibility of BMSCs and osteogenic cells to CHIKV and studied the effect of infection on these cells. To our knowledge, for the first time we report that CHIKV can productively infect BMSCs and osteogenic cells. We also observed a decreased gene expression of the major regulator of osteogenic differentiation, RUNX2 in CHIKV infected osteogenic cells. Furthermore, impaired functional properties of osteogenic cells i.e. decreased production and activity of alkaline phosphatase (ALP) and matrix mineralization were observed in the presence of CHIKV infection. Thus, we conclude that CHIKV likely impairs osteogenic differentiation of BMSCs indicating a possible role of BMSCs in altering bone homeostasis during CHIKV infection.ImportancePresently, no vaccines or treatment options are available for CHIKV infection. Joint pain is one of the major concerns. Although studies have shown an association between bone pathology and infection, the molecular pathogenesis in context of bone pathology is poorly defined. Here, we demonstrate for the first time that BMSCs and BMSC-derived osteogenic cells are susceptible to CHIKV infection and infection likely alters function of the osteogenic cells. This study highlights altered osteogenic differentiation as a possible mechanism for causing the bone pathology observed in CHIKV pathogenesis.
Spt5 phosphorylation and the Rtf1 Plus3 domain promote Rtf1 function through distinct mechanisms
Authors: Chen Jennifer J. , Mbogning Jean , Hancock Mark A. , Majdpour Dorsa , Madhok Manan , Nassour Hassan , Dallagnol Juliana C. , Pagé Viviane , Chatenet David , Tanny Jason C. 
Published: April 2020

AbstractRtf1 is a conserved RNA polymerase II (RNAPII) elongation factor that promotes co-transcriptional histone modification, RNAPII transcript elongation, and mRNA processing. Rtf1 function requires phosphorylation of Spt5, an essential RNAPII processivity factor. Spt5 is phosphorylated within its C-terminal domain (CTD) by cyclin-dependent kinase 9 (Cdk9), catalytic component of positive transcription elongation factor b (P-TEFb). Rtf1 recognizes phosphorylated Spt5 (pSpt5) through its Plus3 domain. Since Spt5 is a unique target of Cdk9, and Rtf1 is the only known pSpt5-binding factor, the Plus3/pSpt5 interaction is thought to be a key Cdk9-dependent event regulating RNAPII elongation. Here we dissect Rtf1 regulation by pSpt5 in the fission yeastSchizosaccharomyces pombe. We demonstrate that the Plus3 domain of Rtf1 (Prf1 inS. pombe) and pSpt5 are functionally distinct, and that they act in parallel to promote Prf1 function. This alternate Plus3 domain function involves an interface that overlaps with the pSpt5 binding site and that can interact with single-stranded nucleic acid or with the Polymerase Associated Factor (PAF) Complexin vitro. We further show that the C-terminal region of Prf1, which also interacts with PAF, has a similar parallel function with pSpt5. Our results elucidate unexpected complexity underlying Cdk9-dependent pathways that regulate transcription elongation.
Comprehensive database of secondary metabolites from cyanobacteria
Authors: Jones Martin R. , Pinto Ernani , Torres Mariana A. , Dörr Fabiane , Mazur-Marzec Hanna , Szubert Karolina , Tartaglione Luciana , Dell’Aversano Carmela , Miles Christopher O. , Beach Daniel G. , McCarron Pearse , Sivonen Kaarina , Fewer David P. , Jokela Jouni , Janssen Elisabeth M.-L. 
Published: April 2020

AbstractCyanobacteria form harmful mass blooms in freshwater and marine environments around the world. A range of secondary metabolites has been identified from cultures of cyanobacteria and biomass collected from cyanobacterial bloom events. A comprehensive database is necessary to correctly identify cyanobacterial metabolites and advance research on their abundance, persistence and toxicity in natural environments. We consolidated open access databases and manually curated missing information from the literature published between 1970 and March 2020. The result is the database CyanoMetDB, which includes more than 2000 entries based on more than 750 literature references. This effort has more than doubled the total number of entries with complete literature metadata and structural composition (SMILES codes) compared to publicly available databases to this date. Over the past decade, more than one hundred additional secondary metabolites have been identified yearly. We organized all entries into structural classes and conducted substructure searches of the provided SMILES codes. This approach demonstrated, for example, that 65% of the compounds carry at least one peptide bond, 57% are cyclic compounds, and 30% carry at least one halogen atom. Structural searches by SMILES code can be further specified to identify structural motifs that are relevant for analytical approaches, research on biosynthetic pathways, bioactivity-guided analysis, or to facilitate predictive science and modeling efforts on cyanobacterial metabolites. This database facilitates rapid identification of cyanobacterial metabolites from toxic blooms, research on the biosynthesis of cyanobacterial natural products, and the identification of novel natural products from cyanobacteria.
Stability of the vaginal microbiota during pregnancy and its importance for early infant colonization
Authors: Mortensen Martin S. , Rasmussen Morten A. , Stokholm Jakob , Brejnrod Asker D. , Balle Christina , Thorsen Jonathan , Krogfelt Karen A. , Bisgaard Hans , Sørensen Søren J. 
Published: April 2020

AbstractEarly life microbiota has been linked to the development of chronic inflammatory diseases. It has been hypothesized that maternal vaginal microbiota is an important initial seeding source and therefore can have lifelong effects on disease risk. To understand maternal vaginal microbiota’s role in seeding the child’s microbiota and the extent of delivery mode-dependent transmission, we studied 700 mother-child dyads from the COPSAC2010 cohort.The maternal vaginal microbiota was evaluated in the third trimester and compared with the children’s fecal and airway microbiota.The vaginal samples displayed known stable community state types and only 1:6 changed over time. Only one OTU was significantly transferred to children’s fecal compartment, but an inflated number had positive transfer odds. A few taxonomic families showed early transfer enrichment to vaginally-born children, indicating vertical transfer, while half of the observed transfer effects were delivery mode independent enrichment with attenuating strength over time, indicating a common reservoir.
Reanalysis of Genome Sequences of tomato accessions and its wild relatives: Development of tomato genomic variation (TGV) database integrating SNPs and INDELs polymorphisms
Authors: Gupta Prateek , Dholaniya Pankaj Singh , Devulapalli Sameera , Tawari Nilesh Ramesh , Sreelakshmi Yellamaraju , Sharma Rameshwar 
Published: April 2020

AbstractMotivationFacilitated by technological advances and expeditious decrease in the sequencing costs, whole-genome sequencing (WGS) is increasingly implemented to uncover variations in cultivars/accessions of many crop plants. In tomato (Solanum lycopersicum), the availability of the genome sequence, followed by the resequencing of tomato cultivars and its wild relatives, has provided a prodigious resource for the improvement of traits. A high-quality genome resequencing of 84 tomato accessions and wild relatives generated a dataset that can be used as a resource to identify agronomically important alleles across the genome. Converting this dataset into a searchable database, including information about the influence of SNPs on protein function, provides valuable information about the genetic variations. The database will assist in searching for functional variants of a gene for introgression into tomato cultivars.ResultsA recent release of better-quality tomato genome reference assembly SL3.0, and new annotation ITAG3.2 of SL3.0, dropped 3,857 genes, added 4,900 novel genes, and updated 20,766 genes. Using the above version, we remapped the data from the tomato lines resequenced under the “100 Tomato Genome ReSequencing Project” on new tomato genome assembly SL3.0 and made an online searchable Tomato Genomic Variations (TGV) database. The TGV contains information about SNPs and InDels and expands it by functional annotation of variants with new ITAG3.2 using SIFT4G software. This database with search function assists in inferring the influence of SNPs on the function of a target gene. This database can be used for selecting SNPs, which can be potentially deployed for improving tomato traits.Availability and ImplementationTGV is freely available athttp://psd.uohyd.ac.in/tgv.Contactrameshwar.sharma@gmail.com
Stability of extemporaneously compounded amiloride nasal spray
Authors: Yellepeddi Venkata , Sayre Casey , Burrows Anna , Watt Kevin , Davies Simon , Strauss John , Battaglia Marco 
Published: April 2020

AbstractAnxiety disorders (AD) are the most common mental illnesses affecting an estimated 40 million adults in the United States. Amiloride, a diuretic agent, has shown efficacy in treating AD in preclinical models by inhibiting the acid-sensing ion channels (ASIC). By delivering amiloride via nasal route, rapid onset of action can be achieved due to direct “nose-to-brain” access. Therefore, this study reports the formulation, physical, chemical, and microbiological stability of an extemporaneously prepared amiloride 2 mg/mL nasal spray. The amiloride nasal spray was prepared by adding 100 mg of amiloride hydrochloride to 50 mL of sterile water for injection in a sterile reagent bottle. A stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated. Forced-degradation studies were performed to confirm the ability of the HPLC method to identify the degradation products from amiloride distinctively. The physical stability of the amiloride nasal spray was assessed by pH, clarity, and viscosity assessments. For chemical stability studies, samples of nasal sprays stored at room temperature were collected at time-points 0, 3 hr., 24 hr., and 7 days and were assayed in triplicate using the stability-indicating HPLC method. Microbiological stability of the nasal spray solution was evaluated for up to 7 days based on the sterility test outlined in United States Pharmacopoeia (USP) chapter 71. The stability-indicting HPLC method identified the degradation products of amiloride without interference from amiloride. All tested solutions retained over 90% of the initial amiloride concentration for the 7-day study period. There were no changes in color, pH, and viscosity in any sample. The nasal spray solutions were sterile for up to 7 days in all samples tested. An extemporaneously prepared nasal spray solution of amiloride hydrochloride (2 mg/mL) was physically, chemically, and microbiologically stable for 7 days when stored at room temperature.
Gastrointestial absorption of pimozide is enhanced by inhibition of P-glycoprotein
Authors: Morishita Hiroki , Okawa Kozue , Ishii Misaki , Mizoi Kenta , Arakawa Hiroshi , Yano Kentaro , Ogihara Takuo 
Published: April 2020

AbstractFollowing the death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy, a role of drug-drug interaction was suggested. Here, we investigated P-glycoprotein (P-gp)-mediated interaction among the three drugs using in vitro methods. Sertraline or aripiprazole significantly increased the permeability of pimozide in Caco-2 cell monolayers. ATPase assay indicated that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentrations. The values of the kinetic parameters of carrier-mediated efflux, calculated from the concentration dependence of pimozide efflux from LLC-GA5-COL150 cells expressing human P-gp, were as follows: maximum transport rate (Jmax) = 84.9 ± 8.9 pmol/min/mg protein, half-saturation concentration (Kt) = 10.6 ± 4.7 μM, first-order rate constant (kd) = 0.67 ± 0.14 pmol/min/mg protein. Further, the efflux ratio of pimozide in LLC-GA5-COL150 cells was significantly decreased in the presence of sertraline or aripiprazole. These results indicate that pimozide is a substrate of P-gp, and its efflux is inhibited by sertraline and aripiprazole. Thus, P-gp inhibition by sertraline and/or aripiprazole may alter the gastrointestinal permeability of co-administered pimozide, resulting in an increased blood concentration of pimozide, which may increase the likelihood of pimozide’s known life-threatening side effect of QT prolongation.
Keep Garfagnina alive. An integrated study on patterns of homozygosity, genomic inbreeding, admixture and breed traceability of the Italian Garfagnina goat breed
Authors: Dadousis Christos , Cecchi Francesca , Ablondi Michela , Fabbri Maria Chiara , Stella Alessandra , Bozzi Riccardo 
Published: April 2020

AbstractThe objective of this study was to investigate the genomic background of the Garfagnina (GRF) goat breed that faces the risk of extinction. In total, 48 goats genotyped with the Illumina CaprineSNP50 BeadChip were analyzed together with 214 goats belonging to 9 Italian breeds (~25 goats/breed) from the AdaptMap project [Argentata (ARG), Bionda dell’Adamello (BIO), Ciociara Grigia (CCG), Di Teramo (DIT), Garganica (GAR), Girgentana (GGT), Orobica (ORO), Valdostana (VAL) and Valpassiria (VSS)]. We estimated i) runs of homozygosity (ROH), ii) admixture ancestries and iii) traceability success via discriminant analysis on principal components (DAPC) based on cross-validation. For GRF, an excess of frequent ROH (more than 45% in the GRF samples analyzed) was detected on CHR 12 at, roughly 50.25-50.94Mbp (ARS1 assembly), spanned between the CENPJ (centromere protein) and IL17D (interleukin 17D) genes. The same area was also present in DIT, while the broader region (~49.25-51.94Mbp) was shared among the ARG, CCG, and GGT. Admixture analysis depicted the uniqueness of the GRF breed, with a small part of common ancestry shared with BIO, VSS, ARG and CCG breeds. The DAPC model resulted in a 100% assignment success. We hope this work will contribute to the efforts of preventing the GRF from extinction and to add value to all the socio-agro-economic factors related with the farming of the GRF breed.