bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate Cancer
Authors: Sheahan Anjali V. , Morel Katherine L. , Burkhart Deborah L. , Baca Sylvan C. , Labbé David P. , Roehle Kevin , Heckler Max , Calagua Carla , Ye Huihui , Galbo Phillip , Panja Sukanya , Mitrofanova Antonina , Hamid Anis A. , Kibel Adam S. , Choudhury Atish D. , Pomerantz Mark M. , Freedman Matthew L. , Sweeney Christopher J. , Dougan Stephanie K. , Sowalsky Adam G. , Loda Massimo , Olson Brian M. , Ellis Leigh 
Published: August 2019

AbstractProstate cancers are considered immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor therapy (CPI). Recently, enrichment of interferon (IFN) response genes predicts a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models derepresses expression of double-strand RNA (dsRNA), associated with upregulation of genes involved in antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response, including PD-L1. Similarly, application of a novel EZH2 derived gene signature to human prostate sample analysis indicated an inverse correlation between tumor EZH2 activity/expression with T-cell inflamed and IFN gene signatures and PD-L1 expression. EZH2 inhibition combined with PD-1 CPI significantly enhances antitumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI.
Vitamins D3 and D2 have marked but different global effects on gene expression in a rat oligodendrocyte precursor cell line
Authors: Mengozzi Manuela , Hesketh Andrew , Bucca Giselda , Ghezzi Pietro , Smith Colin P. 
Published: August 2019

AbstractVitamin D deficiency increases the risk of developing multiple sclerosis (MS) but there is uncertainty about what dose and form of vitamin D could improve the clinical course of MS. The mechanisms underlying the effects of vitamin D in MS are not clear. Vitamin D3 increases the rate of differentiation of primary oligodendrocyte precursor cells (OPCs), suggesting that it might help remyelination in addition to modulating the immune response. Here we analyzed the transcriptome of differentiating rat CG4 OPCs treated with vitamin D2 or with D3 at 24 h and 72 h following onset of differentiation. Differentiation alone changed the expression of about 10% of the genes at 72 h compared to 24 h. Vitamin D2 and D3 exerted different effects on gene expression, with D3 influencing 1,272 genes and D2 574 at 24 h. The expression of the vast majority of these genes was either not changed in differentiating cells not exposed to vitamin D or followed the same trajectory as the latter. D3-repressed genes were enriched for gene ontology categories including transcription factors and the Notch pathway, while D3-induced genes were enriched for the Ras pathway. These findings should help to identify mechanisms mediating D3 action in MS.
Multivoxel codes for representing and integrating acoustic features in human cortex
Authors: Sohoglu Ediz , Kumar Sukhbinder , Chait Maria , Griffiths Timothy D. 
Published: August 2019

AbstractUsing fMRI and multivariate pattern analysis, we determined whether acoustic features are represented by independent or integrated neural codes in human cortex. Male and female listeners heard band-pass noise varying simultaneously in spectral (frequency) and temporal (amplitude-modulation [AM] rate) features. In the superior temporal plane, changes in multivoxel activity due to frequency were largely invariant with respect to AM rate (and vice versa), consistent with an independent representation. In contrast, in posterior parietal cortex, neural representation was exclusively integrated and tuned to specific conjunctions of frequency and AM features. Direct between-region comparisons show that whereas independent coding of frequency and AM weakened with increasing levels of the hierarchy, integrated coding strengthened at the transition between non-core and parietal cortex. Our findings support the notion that primary auditory cortex can represent component acoustic features in an independent fashion and suggest a role for parietal cortex in feature integration and the structuring of acoustic input.Significance statementA major goal for neuroscience is discovering the sensory features to which the brain is tuned and how those features are integrated into cohesive perception. We used whole-brain human fMRI and a statistical modeling approach to quantify the extent to which sound features are represented separately or in an integrated fashion in cortical activity patterns. We show that frequency and AM rate, two acoustic features that are fundamental to characterizing biological important sounds such as speech, are represented separately in primary auditory cortex but in an integrated fashion in parietal cortex. These findings suggest that representations in primary auditory cortex can be simpler than previously thought and also implicate a role for parietal cortex in integrating features for coherent perception.
Glucagon-like peptide-1 receptor agonist, exendin-4, reduces reinstatement of heroin seeking behavior in rats
Authors: Douton Joaquin E. , Augusto Corinne , Stultzfus Brooke A , Carkaci-Salli Nurgul , Vrana Kent E. , Grigson Patricia S. 
Published: August 2019

AbstractBackgroundStudies have shown that ‘satiety’ agents such as exendin-4 (a glucagon-like peptide-1 analog) reduce responding for addictive drugs (e.g., cocaine, nicotine, alcohol). In this study we tested the effect of exendin-4 on cue-induced and drug-induced reinstatement of heroin seeking behavior in rats.MethodsThis study consisted of three phases: In Phase 1, 55 male Sprague-Dawley rats had 15 daily pairings of saccharin with heroin self-administration. In Phase 2, rats experienced a 16-day home cage abstinence period and daily treatment with vehicle or exendin-4. On day 17, an extinction/reinstatement test was performed to assess drug seeking. In Phase 3, rats experienced 9 days of extinction followed by a reinstatement only test. Finally, expression of mRNA for various receptors in the nucleus accumbens shell (NAcS) was measured using RTqPCR.ResultsIn Phase 1, rats that avoided intake of the heroin-paired saccharin cue exhibited shorter latency to obtain the first infusion. In Phase 2, treatment with exendin-4 decreased cue-induced, but not drug-induced heroin seeking. In Phase 3, saccharin avoiders previously treated with exendin-4 increased acceptance of saccharin, and 1-hour pretreatment with Exendin-4 abolished drug-induced heroin seeking. Finally, exendin-4 treatment increased expression of mRNA for the Orexin 1 receptor (OX1) in the NAcS, but did not affect expression of dopamine D2 receptors, GLP-1 receptors, or leptin receptors in this same structure.ConclusionExendin-4 reduced cue- and drug-induced heroin seeking and increased acceptance of the drug-associated saccharin cue. These changes in behavior were accompanied by an increase in the expression of the OX1 receptor in the NAcS.
Non-Homology-Based Prediction of Gene Functions
Authors: Dai Xiuru , Xu Zheng , Liang Zhikai , Tu Xiaoyu , Zhong Silin , Schnable James C. , Li Pinghua 
Published: August 2019

AbstractAdvances in genome sequencing and annotation have eased the difficulty of identifying new gene sequences. Predicting the functions of these newly identified genes remains challenging. Genes descended from a common ancestral sequence are likely to have common functions. As a result homology is widely used for gene function prediction. This means functional annotation errors also propagate from one species to another. Several approaches based on machine learning classification algorithms were evaluated for their ability to accurately predict gene function from non-homology gene features. Among the eight supervised classification algorithms evaluated, random forest-based prediction consistently provided the most accurate gene function prediction. Non-homology-based functional annotation provides complementary strengths to homology-based annotation, with higher average performance in Biological Process GO terms, the domain where homology-based functional annotation performs the worst, and weaker performance in Molecular Function GO terms, the domain where the accuracy of homology-based functional annotation is highest. Non-homology-based functional annotation based on machine learning may ultimately prove useful both as a method to assign predicted functions to orphan genes which lack functionally characterized homologs, and to identify and correct functional annotation errors which were propagated through homology-based functional annotations.
U1 snRNP regulates cancer cell migration and invasion
Authors: Oh Jung-Min , Venters Christopher C. , Di Chao , Pinto Anna Maria , Wan Lili , Younis Ihab , Cai Zhiqiang , Arai Chie , So Byung Ran , Dreyfuss Gideon 
Published: August 2019

AbstractStimulated cells and cancer cells have widespread shortening of mRNA 3’-utranslated regions (3’UTRs) and switches to shorter mRNA isoforms due to usage of more proximal polyadenylation signals (PASs) in the last exon and in introns. U1 snRNA (U1), vertebrates’ most abundant non-coding (spliceosomal) small nuclear RNA, silences proximal PASs and its inhibition with antisense morpholino oligonucleotides (U1 AMO) triggers widespread mRNA shortening. Here we show that U1 AMO also modulates cancer cells’ phenotype, dose-dependently increasing migration and invasion in vitro by up to 500%, whereas U1 over-expression has the opposite effect. In addition to 3’UTR length, numerous transcriptome changes that could contribute to this phenotype are observed, including alternative splicing, and mRNA expression levels of proto-oncogenes and tumor suppressors. These findings reveal an unexpected link between U1 regulation and oncogenic and activated cell states, and suggest U1 as a potential target for their modulation.
Structure-function analysis reveals a DNA polymerization-independent role for mitochondrial DNA polymerase IC in African trypanosomes
Authors: Miller Jonathan C , Delzell Stephanie B , Concepción-Acevedo Jeniffer , Boucher Michael J , Klingbeil Michele M 
Published: August 2019

ABSTRACTThe mitochondrial DNA ofTrypanosoma bruceiand related parasites is a catenated network containing thousands of minicircles and tens of maxicircles called kinetoplast DNA (kDNA). Replication of the single nucleoid requires at least three DNA polymerases (POLIB, POLIC, and POLID) each having discrete localization near the kDNA during S phase. POLIB and POLID have roles in minicircle replication while the specific role of POLIC in kDNA maintenance is less clear. Here, we use an RNAi-complementation system to dissect the functions of the distinct POLIC domains: the conserved family A DNA polymerase domain (POLA) and the uncharacterized N-terminal region (UCR). While RNAi complementation with wild-type POLIC restored kDNA content and cell cycle localization, active site point mutations in the POLA domain impaired minicircle replication similarly to POLIB and POLID depletions. Complementation with the POLA domain alone abolished POLIC foci formation and partially rescued the RNAi phenotype. Furthermore, we provide evidence of a crucial role for the UCR in cell cycle localization and segregation of kDNA daughter networks. This is the first report of a DNA polymerase that impacts DNA segregation.Summary statementMitochondrial DNA segregation in African trypanosomes is supported by a dual-functioning DNA polymerase.
Principles for engineering microbial composition and ecosystem functioning
Authors: Albright Michaeline B.N. , Sevanto Sanna , Gallegos-Graves La Verne , Dunbar John 
Published: August 2019

AbstractMicrobial probiotics are designed to improve functions in diverse ecosystems, yet probiotics often fail to have the desired beneficial effects. The introduction of probiotics to an environment with a preexisting microbiome is analogous to an invasion event, but is rarely considered in this light. Here, we tested the relative importance of propagule pressure (inoculation dose and frequency) compared to biotic interactions (composition of introduced and resident communities) in driving microbial composition and functional outcomes following microbial community invasions in experimental microcosms. Ecosystem functioning was assessed through measurements of CO2production and DOC (dissolved organic carbon) accumulation, an activity and an environmental modification metric, respectively. Further, to test the dependence of propagule pressures versus biotic interactions was dependent on environmental context, experiments were performed on two different substrates, R2A agar and plant litter. In both environments, we found that biotic interactions were more important than propagule pressure in driving microbial composition. Moreover, bacteria were more successful invaders than fungi. While successful invasion is a first step, ultimately the success of microbial invasions in microbiome engineering applications is measured by the impact on ecosystem functioning. As with shaping the microbiome composition, biotic interactions were key to functional outcomes, but the magnitude of the functional impact varied by environment. Identifying general principles that determine the community composition and functioning following microbial invasions is key to efficient community engineering.SignificanceWith increasing frequency humans are introducing new microbes into pre-existing microbiomes to alter functioning. Examples include, modification of microflora in human guts for better health, and soil for food security and/or climate management. Probiotic applications are often approached as trial-and-error endeavors and have mixed outcomes. We propose that increased success in microbiome engineering may be achieved by better understanding of microbial invasions. We conducted a microbial community invasion experiment, to test the relative importance of propagule pressure and biotic interactions in driving microbial community composition and ecosystem functioning in microcosms. We found that biotic interactions were more important than propagule pressure in determining the impact of microbial invasions. Furthermore, the principles for community engineering vary among organismal groups (bacteria versus fungi).
STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation
Authors: Conway Megan E. , McDaniel Joy M. , Graham James M. , Guillen Katrin P. , Oliver Patsy G. , Parker Stephanie L. , Yue Peibin , Turkson James , Buchsbaum Donald J. , Welm Bryan E. , Myers Richard M. , Varley Katherine E. 
Published: August 2019

AbstractBreast cancers can be divided into subtypes with different prognoses and treatment responses based on global gene expression differences. Luminal breast cancer gene expression and proliferation are driven by the transcription factors Estrogen Receptor α (ER), FOXA1 and GATA3. Targeting ER is the most effective therapy for treating luminal breast cancer because ER is the master regulator of the luminal gene expression program. In contrast, it is unclear which transcription factors are responsible for driving the gene expression signature that defines basal-like triple negative breast cancer, and there are no targeted therapies approved to treat this aggressive subtype of the disease. This study utilized integrated analysis of DNA methylation, chromatin accessibility, transcription factor binding, and gene expression in large collections of breast cancer cell lines and patient tumors to identify transcription factors responsible for the basal-like gene expression program. The results of this study indicate that glucocorticoid receptor (GR) and signal transducer and activator of transcription 3 (STAT3) bind to the same genomic regulatory regions that are specifically open and unmethylated in basal-like breast cancer. These transcription factors cooperate to regulate expression of hundreds of genes in the basal-like gene expression signature and these downstream genes are associated with poor prognosis in patients. Furthermore, combination treatment with small molecule drugs that inhibit both transcription factors leads to synergistic decreases in cell proliferation in cell lines and patient-derived organoid models. This study demonstrates that GR and STAT3 cooperate to regulate the basal-like breast cancer gene expression program and provides the basis for improved therapy for basal-like triple negative breast cancer through rational combination of STAT3 and GR inhibitors.
Endosomal explosion induced by hypertonicity
Authors: Wang Shupeng , Wu Song 
Published: August 2019

AbstractTransferring DNA into cells to regulate cell function is a novel research field in recent decades.
Chitosan is a gene vector with the properties of low-cost and safe, but high efficient delivery has remained challenging. We developed a strategy termed EEIH for endosomal explosion induced by hypertonicity, in which short-time exposure to hypertonic solutions triggers endosomes destabilization like explosions. EEIH can force chitosan/DNA polyplexes to break through the endosomal barriers to approach the nucleus, which results in boosting the transfection efficiency of chitosan in several cell lines. We demonstrate that EEIH is a significant and practical strategy in chitosan transfection system without sophisticated modification of chitosan.
Rapid Sensorimotor Reinforcement in the Olfactory Striatum
Authors: Millman Daniel J. , Murthy Venkatesh N. 
Published: August 2019

AbstractRodents can successfully learn multiple, novel stimulus-response associations after only a few repetitions when the contingencies predict reward. The circuits modified during such reinforcement learning to support decision making are not known, but the olfactory tubercle (OT) and posterior piriform cortex (pPC) are candidates for decoding reward category from olfactory sensory input and relaying this information to cognitive and motor areas. Here, we show that an explicit representation for reward category emerges in the OT within minutes of learning a novel odor-reward association, whereas the pPC lacks an explicit representation even after weeks of overtraining. The explicit reward category representation in OT is visible in the first sniff (50-100ms) of an odor on each trial, and precedes the motor action. Together, these results suggest that coding of stimulus information required for reward prediction does not occur within olfactory cortex, but rather in circuits involving the olfactory striatum.
Tradeoffs in optimal control capture patterns of human sensorimotor control and adaptation
Authors: Cluff Tyler , Crevecoeur Frederic , Scott Stephen H. 
Published: August 2019

AbstractModern control theory highlights strategies that consider a range of factors, such as errors caused by environmental disturbances or inaccurate estimates of body or environmental dynamics. Here we reveal similar diversity in how humans naturally adapt and control their arm movements. We divided participants into groups based on how well they adapted to interaction loads during a single session of reaching movements. This classification revealed differences in how participants controlled their movements and responded to mechanical perturbations. Interestingly, variation in behaviour across good and partial adapters resembled simulations from stochastic and robust optimal feedback control, respectively, where the latter minimizes the effect of disturbances, including those introduced by inaccurate internal models of movement dynamics. In a second experiment, we varied the interaction loads over short time periods making it difficult to adapt. Under these conditions, participants who otherwise adapted well altered their behaviour and more closely resembled those using a robust control strategy. Taken together, the results suggest the diversity of how humans control and adapt their arm movements may reflect the accuracy of (or confidence in) their internal models. Our findings may open novel perspectives for interpreting motor behaviour in uncertain environments, or when neurologic dysfunction compromises motor adaptation.
Characterization of neurogenic niches in the telencephalon of juvenile and adult sharks
Authors: Docampo-Seara A , Pereira-Guldrís S , Sánchez-Farías N , Mazan S , Rodríguez MA , Candal E 
Published: August 2019

AbstractNeurogenesis is a multistep process by which progenitor cells become terminally differentiated neurons. Adult neurogenesis has gathered increasing interest with the aim of developing new cell-based treatments for neurodegenerative diseases in humans. Active sites of adult neurogenesis exist from fish to mammals, although in the adult mammalian brain the number and extension of neurogenic areas is considerably reduced in comparison to non-mammalian vertebrates, and they become mostly reduced to the telencephalon. Much of our understanding in this field is based in studies on mammals and zebrafish, a modern bony fish. The use of the cartilaginous fish Scyliorhinus canicula (representative of basal gnathostomes) as a model expands the comparative framework to a species that shows highly neurogenic activity in the adult brain. In this work, we studied the proliferation pattern in the telencephalon of juvenile and adult specimens of S. canicula by using antibodies against the proliferation marker PCNA. We have characterized proliferating niches by using stem cell markers (Sox2), glial markers (GFAP, BLBP and GS), intermediate progenitor cell markers (Dlx2 and Tbr2) and markers for migrating neuroblasts (DCX). Based in the expression pattern of these markers, we demonstrate the existence of different cell subtypes within the PCNA immunoreactive zones including non-glial stem cells, glial progenitors, intermediate progenitor-like cells and migratory neuroblasts, which were widely distributed in the ventricular zone of the pallium, suggesting that the main progenitor types that constitute the neurogenic niche in mammals are already present in cartilaginous fishes.