Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence

Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53‑positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male‑specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male‑specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53‑specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male‑specific genetic association of the human p53 locus (TP53) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.     

dbDiarrhea: The database of pathogen proteins and vaccine antigens from diarrheal pathogens

Diarrhea occurs world-wide and is most commonly caused by gastrointestinal infections which kill around 2.2 million people globally each year, mostly children in developing countries. We describe here dbDiarrhea, which is currently the most comprehensive catalog of proteins implicated in the pathogenesis of diarrhea caused by major bacterial, viral and parasitic species. The current release of the database houses 820 proteins gleaned through an extensive and critical survey of research articles from PubMed. The major contributors to this compendium of proteins are Escherichia coli and Salmonella enterica. These proteins are classified into different categories such as Type III secretion system effectors, Type III secretion system components, and Pathogen proteins. There is another complementary module called ‘Host proteins’. dbDiarrhea also serves as a repository of the research articles describing (1) trials of subunit and whole organism vaccines (2) high-throughput screening of Type III secretion system inhibitors and (3) diagnostic assays, for various diarrheal pathogens. The database is web accessible through an intuitive user interface that allows querying proteins and research articles for different organism, keywords and accession number. Besides providing the search facility through browsing, the database supports sequence similarity search with the BLAST tool. With the rapidly burgeoning global burden of the diarrhea, we anticipate that this database would serve as a source of useful information for furthering research on diarrhea. The database can be freely accessed at http://www.juit.ac.in/attachments/dbdiarrhea/diarrhea_home.html.     

Soft phonation index — a sensitive parameter?

Objective  The diagnosis of voice disorders is based on perceptual and acoustic paradigms. Modern acoustic analysis systems are relatively inexpensive and user friendly. One aspect of laryngeal function that is of great interest is the extent of vocal fold closure. Soft phonation index (SPI) is the parameter in Multi Dimensional Voice Program, which reflects the approximation of vocal folds. High values of SPI are stated to correlate with incomplete vocal fold adduction and are a better indicator of breathiness than EGG. This study aims to determine the sensitivity of this acoustic parameter of SPI, as a reflective indicator of incomplete vocal fold adduction in male patients diagnosed with unilateral vocal nodules. Methodology  60 participants were included in the study; 30 with normal vocal fold functioning in the control group and 30 with unilateral vocal nodules in the experimental group. The phonation sample of vowel /a/ was recorded into CSL 4150 of Kay Elemetrics, in a sound treated room. The readings of SPI on the MDVP analysis was extracted and subjected to statistical analysis using independent samples ‘t-test’ using SPSS Version 11. Results  The results of the study reveal that there was a statistically significant difference between the means of the SPI values between the control and the experimental groups. Discussion  It can be understood that SPI is a sensitive parameter to detect abnormalities in vocal fold approximation in the considered population of individuals with vocal nodules. This is in coherence with a study done on patients with vocal fold palsy and cordectomy, wherein SPI was found to be a good indicator of breathiness. The SPI mean obtained for participants in the control group was higher than the Western normative mean specified in MDVP, which highlights the importance of establishing normative values for Indian population. Conclusion  It can be concluded that SPI was sensitive to detect changes affecting vocal fold closure in unilateral vocal nodules. But this conclusion has to be generalized with caution keeping in mind that only one population with vocal pathology was studied. The factors of vocal fold physiology and mechanical properties of vocal tract, which may contribute to individual variations in SPI values, have to be considered for further research.     

Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design,synthesis, and X-ray cocrystal structure

A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.     

Evaluation of a novel shape-based computational filter for lead evolution: application to thrombin inhibitors

A novel shape-feature-based computational method is described and used to rapidly filter compound libraries. The computational model, built using three-dimensional conformations of active and inactive molecules, consists of a collection of whole molecule shapes and chemical feature positions that are ranked according to their correlation with activity. A small ensemble of these shapes and features is used to filter virtual compound libraries. The method is applied to two thrombin data sets and is shown to be efficient in identifying novel scaffolds with enhanced hit rates.     

Randomized study of the dopamine receptor agonist piribedil in the treatment of mild cognitive impairment

OBJECTIVE: Age-related decrease in dopamine D(2) receptors is associated with cognitive decline in healthy elderly individuals. This study was an investigation of whether the dopamine receptor agonist piribedil improves global cognitive function in patients with mild cognitive impairment. METHOD: In a 90-day randomized double-blind study, treatment with piribedil was compared to placebo in 60 patients with clinically diagnosed mild cognitive impairment and a Mini-Mental State Examination (MMSE) score of 21 to 25. The primary outcome was change in MMSE score. RESULTS: Of the 30 patients randomly assigned to each treatment group, 19 (63.3%) of those taking piribedil and eight (26.7%) of those treated with placebo had increases in MMSE scores, to 26 or more. The response rate and the mean increase in MMSE scores were significantly greater with piribedil. CONCLUSIONS: Patients with mild cognitive impairment had improvement in global cognitive function when treated with the dopamine receptor agonist piribedil. The results support the role of age-related dopamine decline in cognitive impairment of the elderly.