bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANTITUMOR SULFATED POLYSACCHARIDES FROM BROWN ALGAEDictyota caribaea
Authors: Brígido Assef Alexia Nathália , da Costa Bianca Barros , Moreira Thamyris Almeida , do Carmo Luana David , de Fátima Goebel de Souza Tamiris , Nunes Alencar Nylane Maria , Negreiros Nunes Ana Paula , Cinelli Leonardo Paes , Wilke Diego Veras 
Published: April 2020

AbstractSulfated polysaccharides (SP) are a complex group of bioactive molecules able to inhibit tumor growth. SP increase the effectiveness of chemotherapy and reduce some side effects. Brown algae produce SP with several biological activities including antitumor. This work aimed to investigate the antitumor effect of SP from the brown algaeDictyota caribaea(Dc-SP). Dc-SP were extracted with proteolytic enzyme and supernatant was precipitated with increasing concentrations of ethanol. Antiproliferative activity of Dc-SP was tested by the MTT assay against colon cancer (HCT 116) and metastatic melanoma (B16-F10) cell lines. The antitumor effect was evaluated on Swiss mice transplanted with sarcoma 180 tumor and treated i.p. during 7 days with saline or Dc-SP (25 and 50 mg/kg/animal). Dc-SP did not exhibit cytotoxicityin vitro, however the Dc-SP-treated mice depicted up to 50% tumor growth inhibition. Dc-SP treatment induced spleen weight increasing along with intense white pulp disorganization. Furthermore Dc-SP did not depict hepatic toxicity, nephrotoxicity nor leukopenia and did induce increase of platelets count. Altogether, these results represent a promising antitumor host dependent effect induced by Dc-SP.
The origin and evolution of a distinct mechanism of transcription initiation in yeasts
Authors: Lu Zhaolian , Lin Zhenguo 
Published: April 2020

ABSTRACTThe molecular process of transcription by RNA Polymerase II is highly conserved among eukaryotes (“classic model”). Intriguingly, a distinct way of locating transcription start sites (TSSs) was found in a budding yeastSaccharomyces cerevisiae(“scanning model”). The origin of the “scanning model” and its underlying genetic mechanisms remain unsolved. Herein, we applied genomic approaches to address these questions. We first identified TSSs at a single-nucleotide resolution for 12 yeast species using the nAnT-iCAGE technique, which significantly improved the annotations of these genomes by providing accurate 5’boundaries of protein-coding genes. We then infer the initiation mechanism of a species based on its TSS maps and genome sequences. We found that the “scanning model” had originated after the split ofYarrowia lipolyticaand the rest of budding yeasts. An adenine-rich region immediately upstream of TSS had appeared during the evolution of the “scanning model” species, which might facilitate TSS selection in these species. Both initiation mechanisms share a strong preference for pyrimidine-purine dinucleotides surrounding the TSS. Our results suggested that the purine is required for accurately recruiting the first nucleotide, increasing the chance of being capped during mRNA maturation, which is critical for efficient translation initiation. Based on our findings, we proposed a model of TSS selection for the “scanning model” species. Besides, our study also demonstrated that the intrinsic sequence feature primarily determines the distribution of initiation activities within a core promoter (core promoter shape).
Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells
Authors: Muñoz-Rojas Andrés R. , Kelsey Ilana , Pappalardo Jenna , Miller-Jensen Kathryn 
Published: April 2020

AbstractMacrophages are innate immune cells that contribute to fighting infections, tissue repair, and maintaining tissue homeostasis. To enable such functional diversity, macrophages resolve potentially conflicting cues in the microenvironment via mechanisms that remain unclear. Here, we used single-cell RNA sequencing to explore how individual macrophages respond when co-stimulated with the inflammatory stimuli, LPS+IFN-γ, and the resolving cytokine, IL-4. We found that co-stimulated macrophages displayed a distinct global transcriptional program. However, variable negative cross-regulation between some LPS+IFN-γ- and IL-4-specific genes resulted in significant cell-to-cell heterogeneity in transcription. Interestingly, negative cross-regulation led to mutually exclusive expression of the T-cell-polarizing cytokinesIl6andIl12bversus the IL-4-associated factorsArg1andChil3in single co-stimulated macrophages, and single-cell secretion measurements showed that these specialized functions were maintained for at least 48 hours. Overall, our study suggests that increasing functional diversity in the population is one strategy macrophages use to respond to conflicting environmental cues.
Targeting the Src pathway enhances the efficacy of selective FGFR inhibitors in cancers with FGFR3 alterations
Authors: Lima Nadia Carvalho , Atkinson Eliza , Bunney Tom D , Katan Matilda , Huang Paul H. 
Published: April 2020

AbstractSelective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our preclinical data provides evidence that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in cancer patients with FGFR3 molecular alterations.
Using asymmetry to your advantage: learning to acquire and accept external assistance during prolonged split-belt walking
Authors: Sánchez Natalia , Simha Surabhi N. , Donelan J. Maxwell , Finley James M. 
Published: April 2020

AbstractPeople often adapt their coordination patterns during walking to reduce energy cost by using sources of external assistance in the environment. Adaptation to walking on a split-belt treadmill, where one belt moves faster than the other, provides an opportunity for people to acquire positive work from the treadmill to reduce metabolic cost by modifying where they step on the faster belt. Though we know what people should do to acquire this assistance, this strategy is not observed during typical adaptation studies. Here, by extending the duration of adaptation, we show that people continuously optimize energetic cost by adjusting foot placement to acquire positive work from the treadmill and reduce the work performed by the legs. These results demonstrate that learning to acquire and take advantage of assistance to reduce energetic cost is central in shaping adaptive locomotion, but this process occurs over timescales longer than those used in typical studies.
The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer
Authors: Gibbs Zane A. , Reza Luis C. , Cheng Chun-Chun , Westcott Jill M. , McGlynn Kathleen , Whitehurst Angelique W. 
Published: April 2020

ABSTRACTCancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. Here we report that ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), associates with SMAD3 to modulate transcription of transforming growth factor β (TGFβ)-dependent genes and thereby promote growth and survival. In addition, we identify the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that also support tumor cell viability. Importantly, we find that TRIM27 alone is necessary for ZNF165 transcriptional activity and is required for orthotopic tumor growthin vivo. Our findings indicate that aberrant expression of a testis-specific transcription factor is sufficient to co-opt somatic transcriptional machinery to drive a pro-tumorigenic gene expression program.
TagSeq for gene expression in non-model plants: a pilot study at the Santa Rita Experimental Range NEON core site
Authors: Marx Hannah E. , Scheidt Stephen , Barker Michael S. , Dlugosch Katrina M. 
Published: April 2020

ABSTRACTPremise of the studyTagSeq is a cost-effective approach for gene expression studies requiring a large number of samples. To date, TagSeq studies in plants have been limited to those with a high quality reference genome. We tested the suitability of reference transcriptomes for TagSeq in non-model plants, as part of a study of natural gene expression variation at the Santa Rita Experimental Range NEON core site.MethodsTissue for TagSeq was sampled from multiple individuals of four species [Bouteloua aristidoidesandEragrostis lehmanniana(Poaceae);Tidestromia lanuginosa(Amaranthaceae), andParkinsonia florida(Fabaceae)] at two locations on three dates (56 samples total). One sample per species was used to create a reference transcriptome via standard RNA-seq. TagSeq performance was assessed by recovery of reference loci, specificity of tag alignments, and variation among samples.ResultsA high fraction of tags aligned to each reference and mapped uniquely. Expression patterns were quantifiable for tens of thousands of loci, which revealed consistent spatial differentiation in expression for all species.DiscussionTagSeq usingde novoreference transcriptomes was an effective approach to quantifying gene expression in this study. Tags were highly locus specific and generated biologically informative profiles for four non-model plant species.
JN403, an alpha-7-nicotine-acetylcholine-receptor agonist, reduces alpha-synuclein induced inflammatory parameters ofin vitromicroglia but fails to attenuate the reduction of TH positive nigral neurons in a focal alpha-synuclein overexpression mouse model of Parkinson’s disease
Authors: Lee Bolam , Noelker Carmen , Feuerbach Dominik , Timmermann Lars , Chiu W.-H , Oertel Wolfgang H. 
Published: April 2020

AbstractAlpha-7-nicotine-acetylcholine-receptor (α7-nAChRs) agonists modulate the cholinergic antiinflammatory pathway to attenuate proinflammatory signals and reduce dopaminergic neuronal cell loss in toxin-induced experimental murine models of Parkinson’s disease (PD). The protein α-synuclein (αSyn) is considered to represent the major pathogenic component in the etiology and progression of sporadic PD. However, no research has been performed to evaluate the effect of α7-nAChR agonists in human αSyn mediated models of PD. We, therefore, investigated the effect of the compound JN403, an α7-nAChR specific agonist, in αSyn treatedin vitromicroglia culture and in a human αSyn overexpressionin vivomouse model. In primary mouse microglia cells, αSyn fragment 61-140 treatment increased the release of nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-6, and decreased cell viability. In contrast, 100 nM or 1 μM of JN403 co-incubation significantly reduced the level of NO and TNF-α release in the microglial cells. For in-vivo testing of JN403, a recombinant adeno-associated viral vector (rAAV)-mediated unilateral intranigral overexpression of human wild-type-αSyn (WT-αSyn) or of the control protein luciferase (luc) was induced via stereotactic delivery in C57/BL6N mice. Targeted WT-αSyn overexpression reduced 20% of the number of tyrosine hydroxylase (TH) positive (+) nigral neurons after 10 weeks. Subcutaneous daily treatment of 30 mg/kg JN403 over 9 weeks starting at postoperative week 1 did not alter the decrease of TH+ neuronal numbers, and microglial density in WT-αSyn overexpression mouse model. The reduced density of TH+ striatal terminals in the WT-αSyn groups was also not recovered by the JN403 treatment. In summary, JN403, an α7-nAChR specific agonist shows a beneficial effect on ameliorating proinflammatory signals in αSyn exposed microglia cells. However, no significant in-vivo treatment effect was found in an intranigral WT-αSyn overexpression mouse model of PD.
Interpretable machine learning framework reveals novel gut microbiome features in predicting type 2 diabetes
Authors: Gou Wanglong , Ling Chu-wen , He Yan , Jiang Zengliang , Fu Yuanqing , Xu Fengzhe , Miao Zelei , Sun Ting-yu , Lin Jie-sheng , Zhu Hui-lian , Zhou Hongwei , Chen Yu-ming , Zheng Ju-Sheng 
Published: April 2020

AbstractGut microbiome targets for type 2 diabetes (T2D) prevention among human cohorts have been controversial. Using an interpretable machine learning-based analytic framework, we identified robust human gut microbiome features, with their optimal threshold, in predicting T2D. Based on the results, we constructed a microbiome risk score (MRS), which was consistently associated with T2D across 3 independent Chinese cohorts involving 9111 participants (926 T2D cases). The MRS could also predict future glucose increment, and was correlated with a variety of gut microbiota-derived blood metabolites. Faecal microbiota transplantation from humans to germ-free mice demonstrated a causal role of the identified combination of microbes in the T2D development. We further identified adiposity and dietary factors which could prospectively modulate the MRS, and found that body fat distribution may be the key factor modulating the gut microbiome-T2D relationship. Taken together, we proposed a new analytical framework for the investigation of microbiome-disease relationship. The identified microbiota may serve as potential drug targets for T2D in future.
Pyridoxal Kinase Inhibition by Artemisinins Downregulates Inhibitory Neurotransmission
Authors: Kasaragod Vikram Babu , Pacios-Michelena Anabel , Schaefer Natascha , Zheng Fang , Bader Nicole , Alzheimer Christian , Villmann Carmen , Schindelin Hermann 
Published: April 2020

ABSTRACTThe anti-malarial artemisinins have also been implicated in the regulation of various other cellular pathways. Despite their widespread application, the cellular specificities and molecular mechanisms of target recognition by artemisinins remain poorly characterized. We recently demonstrated how these drugs modulate inhibitory postsynaptic signaling by direct binding to the scaffolding protein gephyrin. Here, we report the crystal structure of the central metabolic enzyme pyridoxal kinase (PDXK), which catalyzes the production of the active form of vitamin-B6 (also known as pyridoxal 5’-phosphate, PLP), in complex with artesunate at 2.4-Å resolution. Partially overlapping binding of artemisinins with the substrate pyridoxal inhibits PLP biosynthesis as demonstrated by kinetic measurements. Electrophysiological recordings from hippocampal slices and activity measurements of glutamic acid decarboxylase (GAD), a PLP-dependent enzyme synthesizing the neurotransmitter γ-aminobutyric acid (GABA), define how artemisinins interfere presynaptically with GABAergic signaling. Our data provide a comprehensive picture of artemisinin-induced effects on inhibitory signaling in the brain.
Differential regulation of the immune system in a brain-liver-fats organ network during short term fasting
Authors: Huang Susie S.Y. , Makhlouf Melanie , AbouMoussa Eman H. , Ruiz Tejada Segura Mayra L. , Mathew Lisa S. , Wang Kun , Leung Man C. , Chaussabel Damien , Logan Darren W. , Scialdone Antonio , Garand Mathieu , Saraiva Luis R. 
Published: April 2020

ABSTRACTDifferent fasting regimens are known to promote health, mitigate chronic immunological disorders, and improve age-related pathophysiological parameters in animals and humans. Indeed, several clinical trials are currently ongoing using fasting as a potential therapy for a wide range of conditions. Fasting alters metabolism by acting as a reset for energy homeostasis. However, the molecular mechanisms underlying the beneficial effects of short-term fasting (STF) are still not well understood, particularly at the systems or multi-organ level. Here, we investigated the dynamic gene expression patterns associated with six periods of STF in nine different mouse organs. We cataloged the transcriptional dynamics within and between organs during STF and discovered differential temporal effects of STF among organs. Using gene ontology enrichment analysis, we identified an organ network sharing 37 common biological pathways perturbed by STF. This network incorporates the brain, liver, interscapular brown adipose tissue, and posterior-subcutaneous white adipose tissue, hence we named it the brain-liver-fats organ network. Using Reactome pathways analysis, we identified the immune system, dominated by T cell regulation processes, as a central and prominent target of systemic modulations during STF in this organ network. The changes we identified in specific immune components point to the priming of adaptive immunity and parallel the fine-tuning of innate immune signaling. Our study provides a comprehensive multi-organ transcriptomic profiling of mice subjected to multiple periods of STF, and adds new insights into the molecular modulators involved in the systemic immuno-transcriptomic changes that occur during short-term energy loss.
Thermal adaptation rather than demographic history drives genetic structure inferred by copy number variants in a marine fish
Authors: Cayuela Hugo , Dorant Yann , Mérot Claire , Laporte Martin , Normandeau Eric , Gagnon-Harvey Stéphane , Sirois Pascal , Bernatchez Louis 
Published: April 2020

AbstractIncreasing evidence shows that structural variants represent an overlooked aspect of genetic variation with consequential evolutionary roles. Among those, copy number variants (CNVs), including duplicated genomic region and transposable elements (TEs) may contribute to local adaptation and/or reproductive isolation among divergent populations. Those mechanisms suppose that CNVs could be important drivers of population genetic structure, whose study is generally restricted to the use of SNPs. Taking advantage of recent developments allowing CNV analysis from RAD-seq data, we investigated how variation in fitness-related traits, local thermal conditions and demographic history are associated with CNVs, and how subsequent copy number variation drives population genetic structure in a marine fish, the capelin (Mallotus villosus). We collected 1536 DNA samples from 35 sampling sites in the north Atlantic Ocean and identified 6620 CNVs. We found associations between CNVs and the gonadosomatic index, suggesting that duplicated regions could affect female fitness by modulating oocyte production. We also detected 105 CNV candidates associated with water temperature, among which 20% corresponded to genomic regions located within the sequence of protein-coding genes, suggesting local adaptation to cold water by means of gene amplification. We also identified 175 CNVs associated with the divergence of three parapatric glacial lineages, of which 24% were located within protein-coding genes, which might contribute to genetic incompatibilities and ultimately, reproductive isolation. Lastly, our analyses unveiled a hierarchical, complex CNV population structure determined by temperature and local geography, that was very different from that inferred based on SNPs in a previous study. Our findings underscore the complementarity of those two types of markers in population genomics studies.
Breast cancer-associated skeletal muscle mitochondrial dysfunction and lipid accumulation is reversed by PPARG
Authors: Wilson Hannah E. , Stanton David A. , Pistilli Emidio E. 
Published: April 2020

ABSTRACTThe peroxisome-proliferator activated receptors (PPARs) have been previously implicated in the pathophysiology of skeletal muscle dysfunction in women with breast cancer (BC) and in animal models of BC. Here, we sought to describe the metabolic alterations induced in skeletal muscle by BC-derived factors in anin vitroconditioned media (CM) system and hypothesized that BC cells secrete a factor that represses PPAR-gamma (PPARG) expression and its transcriptional activity, leading to downregulation of PPARG target genes involved in mitochondrial function and other metabolic pathways. We found that BC-derived factors repress PPAR-mediated transcriptional activity without altering protein expression of PPARG. Further, we show that BC-derived factors induce significant alterations in skeletal muscle mitochondrial function and lipid metabolism, which are rescued with exogenous expression of PPARG. The PPARG agonist drug rosiglitazone was able to rescue BC-induced lipid accumulation, but did not rescue effects of BC-derived factors on PPAR-mediated transcription or mitochondrial function. These data suggest that BC-derived factors induce deficits in lipid metabolism and mitochondrial function via different mechanisms that are both related to PPARG signaling, with mitochondrial dysfunction likely being altered via repression of PPAR-mediated transcription, and lipid accumulation being altered via transcription-independent functions of PPARG.
Genome-wide local ancestries discriminate homoploid hybrid speciation from secondary introgression in the red wolf (Canidae:Canis rufus)
Authors: Chafin Tyler K. , Douglas Marlis R. , Douglas Michael E. 
Published: April 2020

AbstractHybridization is well recognized as a driver of speciation, yet it often remains difficult to parse phylogenomically in that post-speciation gene flow frequently supersedes an ancestral signal. Here we examined how interactions between recombination and gene flow shaped the phylogenomic landscape of red wolf to create non-random retention of introgressed ancestry. Our re-analyses of genomic data recapitulate fossil evidence by demonstrating red wolf was indeed extant and isolated prior to more recent admixture with other North American canids. Its more ancient divergence, now sequestered within low-recombinant regions on the X-chromosome (i.e., chromosomal ‘refugia’), is effectively masked by multiple, successive waves of secondary introgression that now dominate its autosomal ancestry. These interpretations are congruent with more theoretical explanations that describe the manner by which introgression can be localized within the genome through recombination and selection. They also tacitly support the large-X effect, i.e., the manner by which loci that contribute to reproductive isolation can be enriched on the X-chromosome. By contrast, similar, high recombinant regions were also found as enriched within very shallow gene trees, thus reflecting post-speciation gene flow and a compression of divergence estimates to 1/20thof that found in recombination ‘cold spots’. Our results effectively reconcile conflicting hypotheses regarding the impact of hybridization on evolution of North American canids and support an emerging framework within which the analysis of a phylogenomic landscape structured by recombination can be used to successfully address the macroevolutionary implications of hybridization.