MicroRNA and messenger RNA profiling reveals new biomarkers and mechanisms for RDX induced neurotoxicity

Background RDX is a well-known pollutant to induce neurotoxicity. MicroRNAs (miRNA) and messenger RNA (mRNA) profiles are useful tools for toxicogenomics studies. It is worthy to integrate MiRNA and mRNA expression data to understand RDX-induced neurotoxicity. Results Rats were treated with or without RDX for 48 h. Both miRNA and mRNA profiles were conducted using brain tissues. Nine miRNAs were significantly regulated by RDX. Of these, 6 and 3 miRNAs were up- and down-regulated respectively. The putative target genes of RDX-regulated miRNAs were highly nervous system function genes and pathways enriched. Fifteen differentially genes altered by RDX from mRNA profiles were the putative targets of regulated miRNAs. The induction of miR-71, miR-27ab, miR-98, and miR-135a expression by RDX, could reduce the expression of the genes POLE4, C5ORF13, SULF1 and ROCK2, and eventually induce neurotoxicity. Over-expression of miR-27ab, or reduction of the expression of unknown miRNAs by RDX, could up-regulate HMGCR expression and contribute to neurotoxicity. RDX regulated immune and inflammation response miRNAs and genes could contribute to RDX- induced neurotoxicity and other toxicities as well as animal defending reaction response to RDX exposure. Conclusions Our results demonstrate that integrating miRNA and mRNA profiles is valuable to indentify novel biomarkers and molecular mechanisms for RDX-induced neurological disorder and neurotoxicity.published_or_final_versio

Genes Underlying Positive Influence Of Prenatal Environmental Enrichment And Negative Influence Of Prenatal Earthquake Simulation And Corrective Influence Of Chinese Herbalmedicine On Rat Offspring: Irf7 And Ninj2

Background: Prenatal environmental enrichment (EE) has been proven to positively affect but prenatal stress negatively influence the physiological and psychological processes in animals, whose trans-generational genetic mechanism remains unclearly defined. We aimed to investigate and find out key genes underlying the positive-negative effects derived from prenatal interventions.Materials and Methods: Pregnant rats were randomized into EE group (EEG), earthquake simulation group (ESG), herbal group (HG) received herbal supplements in feed after earthquake simulation, and control group (CG).Results: Light Box Defecation Test (LBDT) showed EEG offspring presented less fecal pellets than CG offspring, ESG’s more than CG’s, and HG’s less than ESG (p’s<0.05). Open-field Test (OFT) score of EEG was higher than CG offspring, of ESG’s was lower than CG’s, and HG’s higher than ESG’s. Irf7 and Ninj were screened, which were up-regulated in EEG, down-regulated in ESG (FC<0.5), and were neutralized in HG. Prenatal EE could positively promote the nervous system development, prenatal earthquake simulation could retard the nervous system development and Chinese herbal remedy (JKSQW) which could correct the retardation.Conclusion: The negative-positive prenatal effect could contribute to altered gene expression of Irf7 and Ninj2 which also could play a key role in the improving function of JKSQWfor the kidneys.Keywords: Prenatal stress; Earthquake simulation; Light Box Defecation Test; Open-field Test; Irf7; Ninj

The physiological responses of cacao to the environment and the implications for climate change resilience. A review

Cacao (Theobroma cacao L.) is a tropical perennial crop which is of great economic importance to the confectionary industry and to the economies of many countries of the humid tropics where it is grown. Some recent studies have suggested climate change could severely impact cacao production in West Africa. It is essential to incorporate our understanding of the physiology and genetic variation within cacao germplasm when discussing the implications of climate change on cacao productivity and developing strategies for climate resilience in cacao production. Here we review the current research on the physiological responses of cacao to various climate factors. Our main findings are 1) water limitation causes significant yield reduction in cacao but genotypic variation in sensitivity is evident, 2) in the field cacao experiences higher temperatures than is often reported in the literature, 3) the complexity of the cacao/ shade tree interaction can lead to contradictory results, 4) elevated CO2 may alleviate some negative effects of climate change 5) implementation of mitigation strategies can help reduce environmental stress, 6) significant gaps in the research need addressing to accelerate the development of climate resilience. Harnessing the significant genetic variation apparent within cacao germplasm is essential to develop modern varieties capable of high yields in non-optimal conditions. Mitigation strategies will also be essential but to use shading to best effect shade tree selection is crucial to avoid resource competition. Cacao is often described as being sensitive to climate change but genetic variation, adaptive responses, appropriate mitigation strategies and interactive climate effects should all be considered when predicting the future of cacao production. Incorporating these physiological responses to various environmental conditions and developing a deeper understanding of the processes underlying these responses will help to accelerate the development of a more resource use efficient tree ensuring sustainable production into the future

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review.

BACKGROUND: The management of articular cartilage defects presents many clinical challenges due to its avascular, aneural and alymphatic nature. Bone marrow stimulation techniques, such as microfracture, are the most frequently used method in clinical practice however the resulting mixed fibrocartilage tissue which is inferior to native hyaline cartilage. Other methods have shown promise but are far from perfect. There is an unmet need and growing interest in regenerative medicine and tissue engineering to improve the outcome for patients requiring cartilage repair. Many published reviews on cartilage repair only list human clinical trials, underestimating the wealth of basic sciences and animal studies that are precursors to future research. We therefore set out to perform a systematic review of the literature to assess the translation of stem cell therapy to explore what research had been carried out at each of the stages of translation from bench-top (in vitro), animal (pre-clinical) and human studies (clinical) and assemble an evidence-based cascade for the responsible introduction of stem cell therapy for cartilage defects. This review was conducted in accordance to PRISMA guidelines using CINHAL, MEDLINE, EMBASE, Scopus and Web of Knowledge databases from 1st January 1900 to 30th June 2015. In total, there were 2880 studies identified of which 252 studies were included for analysis (100 articles for in vitro studies, 111 studies for animal studies; and 31 studies for human studies). There was a huge variance in cell source in pre-clinical studies both of terms of animal used, location of harvest (fat, marrow, blood or synovium) and allogeneicity. The use of scaffolds, growth factors, number of cell passages and number of cells used was hugely heterogeneous. SHORT CONCLUSIONS: This review offers a comprehensive assessment of the evidence behind the translation of basic science to the clinical practice of cartilage repair. It has revealed a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence. Drivers for progress in this space are largely driven by patient demand, surgeon inquisition and a regulatory framework that is learning at the same pace as new developments take place

T-Analyst: a program for efficient analysis of protein conformational changes by torsion angles

T-Analyst is a user-friendly computer program for analyzing trajectories from molecular modeling. Instead of using Cartesian coordinates for protein conformational analysis, T-Analyst is based on internal bond-angle-torsion coordinates in which internal torsion angle movements, such as side-chain rotations, can be easily detected. The program computes entropy and automatically detects and corrects angle periodicity to produce accurate rotameric states of dihedrals. It also clusters multiple conformations and detects dihedral rotations that contribute hinge-like motions. Correlated motions between selected dihedrals can also be observed from the correlation map. T-Analyst focuses on showing changes in protein flexibility between different states and selecting representative protein conformations for molecular docking studies. The program is provided with instructions and full source code in Perl

MiR-133a in Human Circulating Monocytes: A Potential Biomarker Associated with Postmenopausal Osteoporosis

Background: Osteoporosis mainly occurs in postmenopausal women, which is characterized by low bone mineral density (BMD) due to unbalanced bone resorption by osteoclasts and formation by osteoblasts. Circulating monocytes play important roles in osteoclastogenesis by acting as osteoclast precursors and secreting osteoclastogenic factors, such as IL-1, IL-6 and TNF-a. MicroRNAs (miRNAs) have been implicated as important biomarkers in various diseases. The present study aimed to find significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis. Methodology/Principal Findings: We used ABI TaqManH miRNA array followed by qRT-PCR validation in circulating monocytes to identify miRNA biomarkers in 10 high and 10 low BMD postmenopausal Caucasian women. MiR-133a was upregulated (P = 0.007) in the low compared with the high BMD groups in the array analyses, which was also validated by qRT-PCR (P = 0.044). We performed bioinformatic target gene analysis and found three potential osteoclast-related target genes, CXCL11, CXCR3 and SLC39A1. In addition, we performed Pearson correlation analyses between the expression levels of miR-133a and the three potential target genes in the 20 postmenopausal women. We did find negative correlations between miR-133a and all the three genes though not significant. Conclusions/Significance: This is the first in vivo miRNA expression analysis in human circulating monocytes to identif

M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis

BACKGROUND: The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. METHODS: M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. RESULTS: M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity. CONCLUSIONS: This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy

Global transcriptional response to mammalian temperature provides new insight into Francisella tularensis pathogenesis

<p>Abstract</p> <p>Background</p> <p>After infecting a mammalian host, the facultative intracellular bacterium, <it>Francisella tularensis</it>, encounters an elevated environmental temperature. We hypothesized that this temperature change may regulate genes essential for infection.</p> <p>Results</p> <p>Microarray analysis of <it>F. tularensis </it>LVS shifted from 26°C (environmental) to 37°C (mammalian) showed ~11% of this bacterium's genes were differentially-regulated. Importantly, 40% of the protein-coding genes that were induced at 37°C have been previously implicated in virulence or intracellular growth of <it>Francisella </it>in other studies, associating the bacterial response to this temperature shift with pathogenesis. Forty-four percent of the genes induced at 37°C encode proteins of unknown function, suggesting novel <it>Francisella </it>virulence traits are regulated by mammalian temperature. To explore this possibility, we generated two mutants of loci induced at 37°C [FTL_1581 and FTL_1664 (<it>deoB</it>)]. The FTL_1581 mutant was attenuated in a chicken embryo infection model, which was likely attributable to a defect in survival within macrophages. FTL_1581 encodes a novel hypothetical protein that we suggest naming <it>t</it>emperature-<it>i</it>nduced, <it>v</it>irulence-associated locus <it>A</it>, <it>tivA</it>. Interestingly, the <it>deoB </it>mutant showed diminished entry into mammalian cells compared to wild-type LVS, including primary human macrophages and dendritic cells, the macrophage-like RAW 264.7 line, and non-phagocytic HEK-293 cells. This is the first study identifying a <it>Francisella </it>gene that contributes to uptake into both phagocytic and non-phagocytic host cells.</p> <p>Conclusion</p> <p>Our results provide new insight into mechanisms of <it>Francisella </it>virulence regulation and pathogenesis. <it>F. tularensis </it>LVS undergoes considerable gene expression changes in response to mammalian body temperature. This temperature shift is important for the regulation of genes that are critical for the pathogenesis of <it>Francisella</it>. Importantly, the compilation of temperature-regulated genes also defines a rich collection of novel candidate virulence determinants, including <it>tivA </it>(FTL_1581). An analysis of <it>tivA </it>and <it>deoB </it>(FTL_1664) revealed that these genes contribute to intracellular survival and entry into mammalian cells, respectively.</p