An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-β signalling

Transforming growth factor (TGF)-β induces various cellular responses principally through Smad-dependent transcriptional regulation. Activated Smad complexes cooperate with transcription factors in regulating a group of target genes. The target genes controlled by the same Smad-cofactor complexes are denoted a synexpression group. We found that an Id-like helix-loop-helix protein, human homologue of Maid (HHM), is a synexpression group-restricted regulator of TGF-β signalling. HHM suppressed TGF-β-induced growth inhibition and cell migration but not epithelial–mesenchymal transition. In addition, HHM inhibited TGF-β-induced expression of plasminogen activator inhibitor-type 1 (PAI-1), PDGF-B, and p21WAF, but not Snail. We identified a basic-helix-loop-helix protein, Olig1, as one of the Smad-binding transcription factors affected by HHM. Olig1 interacted with Smad2/3 in response to TGF-β stimulation, and was involved in transcriptional activation of PAI-1 and PDGF-B. HHM, but not Id proteins, inhibited TGF-β signalling-dependent association of Olig1 with Smad2/3 through physical interaction with Olig1. HHM thus appears to regulate a subset of TGF-β target genes including the Olig1-Smad synexpression group. HHM is the first example of a cellular response-selective regulator of TGF-β signalling with clearly determined mechanisms

In Vivo Methods to Study Uptake of Nanoparticles into the Brain

Several in vivo techniques have been developed to study and measure the uptake of CNS compounds into the brain. With these techniques, various parameters can be determined after drug administration, including the blood-to-brain influx constant (Kin), the permeability-surface area (PS) product, and the brain uptake index (BUI). These techniques have been mostly used for drugs that are expected to enter the brain via transmembrane diffusion or by carrier-mediated transcytosis. Drugs that have limitations in entering the brain via such pathways have been encapsulated in nanoparticles (based on lipids or synthetic polymers) to enhance brain uptake. Nanoparticles are different from CNS compounds in size, composition and uptake mechanisms. This has led to different methods and approaches to study brain uptake in vivo. Here we discuss the techniques generally used to measure nanoparticle uptake in addition to the techniques used for CNS compounds. Techniques include visualization methods, behavioral tests, and quantitative methods

Mycobacterium vaccae as Adjuvant Therapy to Anti-Tuberculosis Chemotherapy in Never-Treated Tuberculosis Patients: A Meta-Analysis

OBJECTIVE: To evaluate the effectiveness and safety of heat-killed M. vaccae added to chemotherapy of never-treated tuberculosis (TB) patients. METHODS: The databases of Medline, Embase, Biosis, Cochrane Central Register of Controlled Trials, SCI, CBM, VIP and CNKI were searched. Randomized controlled trials (RCT) and Controlled clinical trials (CCT) comparing M. vaccae with or without a placebo-control injection as adjuvant therapy in the chemotherapy of never-treated TB patients were included. Two reviewers independently performed data extraction and quality assessment. Data were analyzed using RevMan 5.0 software by The Cochrane Collaboration. RESULTS: Fifty four studies were included. At the end of the follow-up period, Pooled RR (Risk Ratio) and its 95% CI of sputum smear conversion rate were 1.07 (1.04, 1.10) in TB patients without complications, 1.17 (0.92, 1.49) in TB patients with diabetes mellitus, 1.02 (0.94, 1.10) in TB patients with hepatitis B, and 1.46 (0.21, 10.06) in TB patients with pneumosilicosis. In elderly TB patients the RR was 1.22 (1.13, 1.32). Analysis of each time point during the follow-up period showed that M. vaccae could help to improve the removal of acid-fast bacilli from the sputum, and promote improvement of radiological focal lesions and cavity closure. Compared with the control group, the differences in levels of immunological indicators of Th1 such as IL-2 and TNF-α were not statistical significant (P = 0.65 and 0.31 respectively), and neither was that of IL-6 produced by Th2 (P = 0.52). An effect of M. vaccae of prevention of liver damage was found in TB patients with hepatitis B (RR 0.20 and 95% CI (0.12, 0.33). No systemic adverse events were reported. CONCLUSION: Added to chemotherapy, M. vaccae is helpful in the treatment of never-treated TB patients in terms of improving both sputum conversion and X-ray appearances

A Policy-Driven Large Scale Ecological Restoration: Quantifying Ecosystem Services Changes in the Loess Plateau of China

As one of the key tools for regulating human-ecosystem relations, environmental conservation policies can promote ecological rehabilitation across a variety of spatiotemporal scales. However, quantifying the ecological effects of such policies at the regional level is difficult. A case study was conducted at the regional level in the ecologically vulnerable region of the Loess Plateau, China, through the use of several methods including the Universal Soil Loss Equation (USLE), hydrological modeling and multivariate analysis. An assessment of the changes over the period of 2000–2008 in four key ecosystem services was undertaken to determine the effects of the Chinese government's ecological rehabilitation initiatives implemented in 1999. These ecosystem services included water regulation, soil conservation, carbon sequestration and grain production. Significant conversions of farmland to woodland and grassland were found to have resulted in enhanced soil conservation and carbon sequestration, but decreased regional water yield under a warming and drying climate trend. The total grain production increased in spite of a significant decline in farmland acreage. These trends have been attributed to the strong socioeconomic incentives embedded in the ecological rehabilitation policy. Although some positive policy results have been achieved over the last decade, large uncertainty remains regarding long-term policy effects on the sustainability of ecological rehabilitation performance and ecosystem service enhancement. To reduce such uncertainty, this study calls for an adaptive management approach to regional ecological rehabilitation policy to be adopted, with a focus on the dynamic interactions between people and their environments in a changing world

Brain Derived Neurotrophic Factor (BDNF) Expression Is Regulated by MicroRNAs miR-26a and miR-26b Allele-Specific Binding

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3′UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3′UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3′UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptide's localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3′UTR functional variants altering miRNAs-BDNF binding

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Application of acoustic emission, anisotropy of acoustic velocity and palaeomagnetie technology to determine in-situ stress in tight sands

In-situ stress is an important basic parameter for well path optimization, hydraulic fracturing design, sand control and safe drilling mud window design. Tradition in-situ stress determination methods include lab and field tests. laboratory in-situ stress experiments became more and more sophisticated by incorporating methods known from disciplines like seismology, acoustic emission and non-destructive testing. However, most of lab in-situ stress experiments such as differential strain analysis, and acoustic emission et al., only can only judge in-situ stress magnitude or orientation. Moreover, it’s expensive and time-consuming for core samples preparation, processing and conduct in-situ stress experiments. Therefore, improve experimental accuracy and speed with low cost is highly desirable. In this paper, the combination of acoustic emission, anisotropy of acoustic velocity and palaeomagnetie technology to determine in-situ stress magnitude and orientation is proposed. Anisotropy of acoustic velocity method is applied to determine the direction of the maximum principle stress with respect to the master orientation line. The geographic orientation of cores is calibrated by using viscous remanent magnetization component. Then, the geographic orientations of the maximum and minor principal in-situ stresses are determined, which can guide the direction of drilled cores in following acoustic emission experiments. The in-situ stress measurement using Kaiser effect in maximum and minimum principal in-situ stress direction under confining pressures with the same depth was performed, which can simulate the original in-situ stress condition of rock samples and decrease the number of drilled cores. Eight in-situ stress test points at different depth in tight sands of Changqing oilfield, Ordos Basin, China are examined to validate the accuracy of this approach. The results demonstrate that the calculated results based on the experiments are in good accordance with mini-frac measurements, which provide a good tool for drilling and hydraulic fracturing stimulation design. © 2017 by Korean Society for Rock Mechanics