A novel extension of half-logistic distribution with statistical inference, estimation and applications.

In the present study, we develop and investigate the odd Frechet Half-Logistic (OFHL) distribution that was developed by incorporating the half-logistic and odd Frechet-G family. The OFHL model has very adaptable probability functions: decreasing, increasing, bathtub and inverted U shapes are shown for the hazard rate functions, illustrating the model's capacity for flexibility. A comprehensive account of the mathematical and statistical properties of the proposed model is presented. In estimation viewpoint, six distinct estimation methodologies are used to estimate the unknown parameters of the OFHL model. Furthermore, an extensive Monte Carlo simulation analysis is used to evaluate the effectiveness of these estimators. Finally, two applications to real data are used to demonstrate the versatility of the suggested method, and the comparison is made with the half-logistic and some of its well-known extensions. The actual implementation shows that the suggested model performs better than competing models.

Multiple antigen peptide containing B and T cell epitopes of F1 antigen of Yersinia pestis showed enhanced Th1 immune response in murine model.

Yersinia pestis is a facultative bacterium that can survive and proliferate inside host macrophages and cause bubonic, pneumonic and systemic infection. Apart from humoral response, cell-mediated protection plays a major role in combating the disease. Fraction 1 capsular antigen (F1-Ag) of Y. pestis has long been exploited as a vaccine candidate. In this study, F1-multiple antigenic peptide (F1-MAP or MAP)-specific cell-mediated and cytokine responses were studied in murine model. MAP consisting of three B and one T cell epitopes of F1-antigen with one palmitoyl residue was synthesized using Fmoc chemistry. Mice were immunized with different formulations of MAP in poly DL-lactide-co-glycolide (PLGA) microspheres. F1-MAP with CpG oligodeoxynucleotide (CpG-ODN) as an adjuvant showed enhanced in vitro T cell proliferation and Th1 (IL-2, IFN-γ and TNF-α) and Th17 (IL-17A) cytokine secretion. Similar formulation also showed significantly higher numbers of cytokine (IL-2, IFN-γ)-secreting cells. Moreover, F1-MAP with CpG formulation showed significantly high (P < 0.001) percentage of CD4(+) IFN-γ(+) cells as compared to CD8(+) IFN-γ(+) cells, and also more (CD4- IFN-γ)(+) cells secrete perforin and granzyme as compared to (CD8- IFN-γ)(+) showing Th1 response. Thus, the study highlights the importance of Th1 cytokine and existence of CD4(+) and CD8(+) immune response. This study proposes a new perspective for the development of vaccination strategies for Y. pestis that trigger T cell immune response.

Methylation profile of promoter region of p16 gene in colorectal cancer patients of Kashmir valley.

Colorectal cancer (CRC) commonly known as bowel cancer is the third most common cause of cancer-related deaths in the western world and has been reported to show geographical variation in its incidence. Cancer development and progression is a complex process dictated by changes in expression and regulation of various genes which include tumor suppressor genes, DNA repair genes, translation regulatory genes and others. The aim of this case control study was to analyze the promoter hypermethylation at CpG islands of p16 gene in CRC patients among the Kashmiri population and co- relate it with expression pattern of p16. Genomic DNA was isolated from surgically resected tumor and adjacent normal samples and was modified using bisulphite modification kit. Methylation-specific polymerase chain reaction (PCR) was setup for the analysis of the promoter hypermethylation of p16 gene. The epigenetic analysis revealed that unlike other high risk regions, Kashmiri population has a different promoter hypermethylation profile of p16 gene as 66 percent of the cases showed p16 promoter hypermethylation in comparison to 20 percent of the normal cases which also showed promoter hypermethylation of p16 gene. The association of promoter hypermethylation with colorectal cancer was found to be significant (P=0.0006). Occurrence of p16 promoter hypermethylation was found to be unequally distributed in males and females with more frequency in males than in females but the difference was not statistically significant(P =0.7635). Similarly, frequency of p16 promoter hypermethylation was found to be certainly higher in Stage III/IV (83.33 percent) compared to Stage I/II (56.25 percent) but the difference was not statistically significant (P =0.0673). Also, the degree of p16 promoter hypermethylation increased with the increasing severity of the lesion but the difference was not again statistically significant (P =0.6145). Promoter hypermethylation correlated with the decrease in expression of the p16 gene in CRC patients leading to the diseased phenotype. These results suggest that p16 aberrant promoter hypermethylation in Kashmiri population contributes to the process of carcinogenesis in CRC and may be developed into a valuable tool for CRC diagnosis at early stages.

An endoscopic and histopathological assessment and correlation of endoscopic score with clinical activity index (CIBDAI) in the diagnosis of canine idiopathic inflammatory bowel disease.

Background: Inflammatory bowel disease (IBD) in dogs is often characterized by a relapsing and remitting clinical course. Determination of inflammatory activity is important for assessing the disease extent, severity, and tailoring appropriate treatment. Aims: The study was conducted to record the macroscopic and microscopic changes associated with IBD to assess the usefulness of endoscopy in the diagnosis of the disease and to correlate the clinical activity index (CIBDAI) with endoscopic score. Methods: Thirty-three dogs with idiopathic IBD were selected after thorough examination and exclusion. Gastroduodenoscopy and colonoscopy were performed to document the gross macroscopic intestinal lesions. Histopathology of endoscopic aided biopsy samples was used to confirm the disease. Results: Mucosal erythema and increased friability were the most predominant endoscopic findings in the stomach, duodenum, and colon of IBD dogs. Lymphoplasmacytic infiltration was predominant in the mucosal samples on histopathology and diffuse form of IBD is more common in canines. Gastroduodenoscopy and colonoscopy in combination with endoscopically guided biopsy and histopathology are of value in the assessment and diagnosis of IBD. There was no correlation between the clinical inflammatory bowel disease activity index (CIBDAI) with the endoscopic score. Conclusion: A diffuse form of IBD and colitis is more common in dogs in comparison to human IBD where the disease manifests in two distinct forms. Colonoscopy with ileal biopsy could act as a gold standard in the confirmation of diffuse IBD in dogs. CIBDAI can be used as a reliable measure of clinical signs of inflammation and histopathology can be used as a definitive diagnosis of intestinal inflammation.

Comparative evaluation of straight and curved extension dialysis catheters for continuous renal replacement therapy in dogs with acute kidney injury.

Background: A patent dual-lumen dialysis catheter is one of the basic requirements for efficient extracorporeal (EC) therapy. Aims: The objective of this study was to measure the resistance to blood flow offered by straight and curved-extension dual-lumen dialysis catheters used for continuous renal replacement therapy (CRRT). Methods: Twenty dogs suffering from acute kidney injury (AKI) were subjected to CRRT. The dogs were allocated randomly to Group-I (curved extension catheter, n=12) or Group II (straight extension catheter, n=8), based on the type of dual-lumen catheter used in CRRT. The catheter outflow and inflow pressures were recorded at blood pump speeds of 50 ml/min and 99-100 ml/min. Data were tested for normality, and differences in mean inflow and outflow catheter resistances were evaluated for statistical significance using independent samples t-tests. Results: Straight extension catheters offered lower inflow resistance than curved extension catheters at both 50 ml/min (41.50 ± 5.84 mm Hg vs. 63.75 ± 6.88 mm Hg, P=0.03) and 99-100 ml/min (63.00 ± 8.11 mm Hg vs. 86.92 ± 7.02 mm Hg, P=0.04) blood flow rates. Straight extension catheters also offered lower outflow resistance than curved catheters at 99-100 ml/min blood flow rate (-94.12 ± 7.91 mm Hg vs. -128.25 ± 7.56 mm Hg, P=0.01; the negative signs only indicate the direction of blood flow). Conclusion: These findings suggest that straight-extension dual-lumen dialysis catheters perform better than the curved model in extracorporeal renal replacement therapy by considering their lower resistance to blood flow.

Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis.

In normal colon, claudin-7 is one of the highly expressed claudin proteins and its knockdown in mice results in altered epithelial cell homeostasis and neonatal death. Notably, dysregulation of the epithelial homeostasis potentiates oncogenic transformation and growth. However, the role of claudin-7 in the regulation of colon tumorigenesis remains poorly understood. Using a large colorectal cancer (CRC) patient database and mouse models of colon cancer, we found claudin-7 expression to be significantly downregulated in cancer samples. Most notably, forced claudin-7 expression in poorly differentiated and highly metastatic SW620 colon cancer cells induced epithelial characteristics and inhibited their growth in soft agar and tumor growth in vivo. By contrast, knockdown of claudin-7 in HT-29 or DLD-1 cells induced epithelial-to-mesenchymal transition (EMT), colony formation, xenograft-tumor growth in athymic mice and invasion. Importantly, a claudin-7 signature gene profile generated by overlapping the DEGs (differentially expressed genes in a high-throughput transcriptome analysis using claudin-7-manipulated cells) with human claudin-7 signature genes identified high-risk CRC patients. Furthermore, Rab25, a colon cancer suppressor and regulator of the polarized cell trafficking constituted one of the highly upregulated DEGs in claudin-7 overexpressing cells. Notably, silencing of Rab25 expression counteracted the effects of claudin-7 expression and not only increased proliferation and cell invasion but also increased the expression of p-Src and mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 that were suppressed upon claudin-7 overexpression. Of interest, CRC cell lines, which exhibited decreased claudin-7 expression, also exhibited promoter DNA hypermethylation, a modification associated with transcriptional silencing. Taken together, our data demonstrate a previously undescribed role of claudin-7 as a colon cancer suppressor and suggest that loss of claudin-7 potentiates EMT to promote colon cancer, in a manner dependent on Rab25.

Selenium-dependent glutathione peroxidase modules encoded by RNA viruses.

Glutathione peroxidase (GPx) is the prototypical eukaryotic selenoprotein, with the rare amino acid selenocysteine (Sec) at the enzyme active site, encoded by the UGA codon in RNA. A DNA virus, Molluscum contagiosum, has now been shown to encode a functional selenium-dependent GPx enzyme. Using modifications of conventional sequence database searching techniques to locate potential viral GPx modules, combined with structurally guided comparative sequence analysis, we provide compelling evidence that Se-dependent GPx modules are encoded in a number of RNA viruses, including potentially serious human pathogens like HIV-1 and hepatitis C virus, coxsackievirus B3, HIV-2, and measles virus. Analysis of the sequences of multiple viral isolates reveals conservation of the putative GPx-related features, at least within viral subtypes or genotypes, supporting the hypothesis that these are functional GPx modules.

Molecular modeling and in vitro activity of an HIV-1-encoded glutathione peroxidase.

Based on theoretical evidence, it has been proposed that HIV-1 may encode several selenoprotein modules, one of which (overlapping the env gp41-coding region) has highly significant sequence similarity to the mammalian selenoprotein glutathione peroxidase (GPx; EC ). The similarity score of the putative HIV-1 viral GPx homolog relative to an aligned set of known GPx is 6.3 SD higher than expected for random sequences of similar composition. Based on that alignment, a molecular model of the HIV-1 GPx was constructed by homology modeling from the bovine GPx crystal structure. Despite extensive truncation relative to the cellular GPx gene, the structural core and the geometry of the catalytic triad of selenocysteine, glutamine, and tryptophan are well conserved in the viral GPx. All of the insertions and deletions predicted by the alignment proved to be structurally feasible. The model is energetically favorable, with a computed molecular mechanics strain energy close to that of the bovine GPx structure, when normalized on a per-residue basis. However, considering the remote homology, this model is intended only to provide a working hypothesis allowing for a similar active site and structural core. To validate the theoretical predictions, we cloned the hypothetical HIV-1 gene and found it to encode functional GPx activity when expressed as a selenoprotein in mammalian cells. In transfected canine kidney cells, the increase in GPx activity ranged from 21% to 43% relative to controls (average 30%, n = 9, P < 0.0001), whereas, in transfected MCF7 cells, which have low endogenous GPx activity, a near 100% increase was observed (average 99%, n = 3, P < 0.05).

Nutrition, HIV, and drug abuse: the molecular basis of a unique role for selenium.

HIV-infected injection drug users (IDUs) often suffer from serious nutritional deficiencies. This is a concern because plasma levels of micronutrients such as vitamin B12, zinc, and selenium have been correlated with mortality risk in HIV-positive populations. Injection drug use also increases lipid peroxidation and other indicators of oxidative stress, which, combined with antioxidant deficiencies, can stimulate HIV-1 replication through activation of NF-kappaB transcription factors, while weakening immune defenses. As detailed herein, these prooxidant stimuli can also increase the pathogenic effects of HIV-1 by another mechanism, involving viral selenoproteins. Overlapping the envelope coding region, HIV-1 encodes a truncated glutathione peroxidase (GPx) gene (see #6 in reference list). Sequence analysis and molecular modeling show that this viral GPx (vGPx) module has highly significant structural similarity to known mammalian GPx, with conservation of the catalytic triad of selenocysteine (Sec), glutamine, and tryptophan. In addition to other functions, HIV-1 vGPx may serve as a negative regulator of proviral transcription, by acting as an NF-kappaB inhibitor (a known property of cellular GPx). Another potential selenoprotein coding function of HIV-1 is associated with the 3' end of the nef gene, which terminates in a conserved UGA (potential Sec) codon in the context of a sequence (Cys-Sec) identical to the C-terminal redox center of thioredoxin reductase, another cellular regulator of NF-kappaB. Thus, in combination with known cellular mechanisms involving Se, viral selenoproteins may represent a unique mechanism by which HIV-1 monitors and exploits an essential micronutrient to optimize its replication relative to the host.