Structural Modeling and DNA Binding Autoinhibition Analysis of Ergp55, a Critical Transcription Factor in Prostate Cancer

BACKGROUND: The Ergp55 protein belongs to Ets family of transcription factor. The Ets proteins are highly conserved in their DNA binding domain and involved in various development processes and regulation of cancer metabolism. To study the structure and DNA binding autoinhibition mechanism of Ergp55 protein, we have produced full length and smaller polypeptides of Ergp55 protein in E. coli and characterized using various biophysical techniques. RESULTS: The Ergp55 polypeptides contain large amount of α-helix and random coil structures as measured by circular dichorism spectroscopy. The full length Ergp55 forms a flexible and elongated molecule as revealed by molecular modeling, dynamics simulation and structural prediction algorithms. The binding analyses of Ergp55 polypeptides with target DNA sequences of E74 and cfos promoters indicate that longer fragments of Ergp55 (beyond the Ets domain) showed the evidence of auto-inhibition. This study also revealed the parts of Ergp55 protein that mediate auto-inhibition. SIGNIFICANCE: The current study will aid in designing the compounds that stabilize the inhibited form of Ergp55 and inhibit its binding to promoter DNA. It will contribute in the development of drugs targeting Ergp55 for the prostate cancer treatment

Bitter Taste Receptors Influence Glucose Homeostasis

TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease

Bioaccumulation and Toxicity of Organic Chemicals in Terrestrial Invertebrates

Terrestrial invertebrates are key components in ecosystems, with crucial roles in soil structure, functioning, and ecosystem services. The present chapter covers how terrestrial invertebrates are impacted by organic chemicals, focusing on up-to-date information regarding bioavailability, exposure routes and general concepts on bioaccumulation, toxicity, and existing models. Terrestrial invertebrates are exposed to organic chemicals through different routes, which are dependent on both the organismal traits and nature of exposure, including chemical properties and media characteristics. Bioaccumulation and toxicity data for several groups of organic chemicals are presented and discussed, attempting to cover plant protection products (herbicides, insecticides, fungicides, and molluscicides), veterinary and human pharmaceuticals, polycyclic aromatic compounds, polychlorinated biphenyls, flame retardants, and personal care products. Chemical mixtures are also discussed bearing in mind that chemicals appear simultaneously in the environment. The biomagnification of organic chemicals is considered in light of the consumption of terrestrial invertebrates as novel feed and food sources. This chapter highlights how science has contributed with data from the last 5 years, providing evidence on bioavailability, bioaccumulation, and toxicity derived from exposure to organic chemicals, including insights into the main challenges and shortcomings to extrapolate results to real exposure scenarios

Exercise therapy in Type 2 diabetes

Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity

Measuring routine childhood vaccination coverage in 204 countries and territories, 1980-2019: a systematic analysis for the Global Burden of Disease Study 2020, Release 1

Background: Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. // Methods: For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dose-specific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territories from 1980 to 2019, adjusting for biases in country-reported data and reflecting reported stockouts and supply disruptions. We analysed global and regional trends in coverage and numbers of zero-dose children (defined as those who never received a diphtheria-tetanus-pertussis [DTP] vaccine dose), progress towards GVAP targets, and the relationship between vaccine coverage and sociodemographic development. // Findings: By 2019, global coverage of third-dose DTP (DTP3; 81·6% [95% uncertainty interval 80·4–82·7]) more than doubled from levels estimated in 1980 (39·9% [37·5–42·1]), as did global coverage of the first-dose measles-containing vaccine (MCV1; from 38·5% [35·4–41·3] in 1980 to 83·6% [82·3–84·8] in 2019). Third-dose polio vaccine (Pol3) coverage also increased, from 42·6% (41·4–44·1) in 1980 to 79·8% (78·4–81·1) in 2019, and global coverage of newer vaccines increased rapidly between 2000 and 2019. The global number of zero-dose children fell by nearly 75% between 1980 and 2019, from 56·8 million (52·6–60·9) to 14·5 million (13·4–15·9). However, over the past decade, global vaccine coverage broadly plateaued; 94 countries and territories recorded decreasing DTP3 coverage since 2010. Only 11 countries and territories were estimated to have reached the national GVAP target of at least 90% coverage for all assessed vaccines in 2019. // Interpretation: After achieving large gains in childhood vaccine coverage worldwide, in much of the world this progress was stalled or reversed from 2010 to 2019. These findings underscore the importance of revisiting routine immunisation strategies and programmatic approaches, recentring service delivery around equity and underserved populations. Strengthening vaccine data and monitoring systems is crucial to these pursuits, now and through to 2030, to ensure that all children have access to, and can benefit from, lifesaving vaccines

Compression behavior of VC0:85 up to 53 GPa

Samples of VC0:85 sandwiched between aluminum disks were compressed in a diamond anvil cell and X-ray diffraction patterns recorded at high pressures up to 53 GPa using synchrotron radiation. The presence of aluminum in the cell rendered the sample pressure nearly hydrostatic and also served as the pressure standard. No phase transformation was observed up to the highest pressure. The measured unit cell volume versus pressure data gave 258 xB1; 11 GPa and 4.5 xB1; 0.6 for the bulk modulus and the pressure derivative, respectively