Identifiability of a Coalescent-based Population Tree Model

Identifiability of evolutionary tree models has been a recent topic of discussion and some models have been shown to be non-identifiable. A coalescent-based rooted population tree model, originally proposed by Nielsen et al. 1998 [2], has been used by many authors in the last few years and is a simple tool to accurately model the changes in allele frequencies in the tree. However, the identifiability of this model has never been proven. Here we prove this model to be identifiable by showing that the model parameters can be expressed as functions of the probability distributions of subsamples. This a step toward proving the consistency of the maximum likelihood estimator of the population tree based on this model.Comment: 11 pages, 1 figur

Dorsal penile nerve block for robot-assisted radical prostatectomy catheter related pain: a randomized, double-blind, placebo-controlled trial

Purpose: Following Robotic-Assisted Radical Prostatectomy (RARP) patients routinely have penile pain and urethral discomfort secondary to an indwelling urethral catheter. Our objective was to assess the effect of dorsal penile nerve block with bupivacaine on urethral catheter-related pain after RARP. Methods: From 2012–2013, 140 patients with organ-confined prostate cancer were enrolled in an IRB approved double-blinded, randomized control trial comparing a dorsal penile nerve block of bupivacaine versus placebo after RARP performed by a single-surgeon. Patients were asked to complete questionnaires using the Wong-Bakers FACES Pain Rating scale while hospitalized and for 9 days post-operatively, until the catheter was removed. The primary end-points were: catheter-related discomfort, abdominal (incisional) pain, and bladder spasm-related discomfort. Secondary end-points included narcotic and other analgesic usage. Results: 120 patients were randomized to placebo vs. bupivacaine dorsal penile nerve bock. The two arms (n = 56 bupivacaine and n = 60 placebo) did not differ in preoperative, perioperative, or pathological results. There was no difference in narcotic utilization between the two cohorts. Abdominal pain was slightly lower in the bupivacaine arm at 6 hours compared to the placebo arm, but there was no difference in abdominal pain at other time points, and there were no differences in reported catheter-related discomfort or bladder spasm-associated discomfort at any of the measured time points. Conclusions: The data does not support the routine use of a dorsal penile nerve block with bupivacaine following RARP

A Rare HBV Subgenotype D4 with Unique Genomic Signatures Identified in North-Eastern India –An Emerging Clinical Challenge?

BACKGROUND/AIMS: HBV has been classified into ten genotypes (A-J) and multiple subgenotypes, some of which strongly influence disease outcome and their distribution also correlate with human migration. HBV infection is highly prevalent in India and its diverse population provides an excellent opportunity to study the distinctiveness of HBV, its evolution and disease biology in variegated ethnic groups. The North-East India, having international frontiers on three sides, is one of the most ethnically and linguistically diverse region of the country. Given the paucity of information on molecular epidemiology of HBV in this region, the study aimed to carry out an in-depth genetic characterization of HBV prevailing in North-East state of Tripura. METHODS: From sera of chronically HBV infected patients biochemical/serological tests, HBV DNA quantification, PCR-amplification, sequencing of PreS/S or full-length HBV genomes were done. HBV genotype/subgenotype determination and sequence variability were assessed by MEGA5-software. The evolutionary divergence times of different HBV subgenotypes were estimated by DNAMLK/PHYLIP program while jpHMM method was used to detect any recombination event in HBV genomes. RESULTS: HBV genotypes D (89.5%), C (6.6%) and A (3.9%) were detected among chronic carriers. While all HBV/A and HBV/C isolates belonged to subgenotype-A1 and C1 respectively, five subgenotypes of HBV/D (D1-D5) were identified including the first detection of rare D4. These non-recombinant Indian D4 (IndD4) formed a distinct phylogenetic clade, had 2.7% nucleotide divergence and recent evolutionary radiation than other global D4. Ten unique amino acids and 9 novel nucleotide substitutions were identified as IndD4 signatures. All IndD4 carried T120 and R129 in ORF-S that may cause immune/vaccine/diagnostic escape and N128 in ORF-P, implicated as compensatory Lamivudine resistance mutation. CONCLUSIONS: IndD4 has potential to undermine vaccination programs or anti-viral therapy and its introduction to North-East India is believed to be linked with the settlement of ancient Tibeto-Burman migrants from East-Asia

IL1B Induced Smad 7 Negatively Regulates Gastrin Expression

BACKGROUND: Helicobacter pylori elicited IL1B is one of the various modulators responsible for perturbation of acid secretion in gut. We have earlier reported that IL1B activated NFkB downregulates gastrin, a major modulator of acid secretion. However, we hypothesized that regulation of gastrin by IL1B would depend on the cell's ability to integrate inputs from multiple signaling pathways to generate appropriate biological response. PRINCIPAL FINDING: In this study, we report that IL1B induces Smad 7 expression by about 4.5 fold in gastric carcinoma cell line, AGS. Smad 7 resulted in transcriptional repression of gastrin promoter by about 6.5 fold when co-transfected with Smad 7 expression vector and gastrin-promoter luciferase in AGS cells. IL1B inhibited phosphorylation of Smad 3 and subsequently interfered with nuclear translocation of the positive Smad complex, thus occluding it off the gastrin promoter. IL1B promoter polymorphisms (-511T/-31C IL1B) are known to be associated with H. pylori associated gastro-duodenal ulcer. We observed that IL1B expressed from -31T promoter driven IL1B cDNA elicited 3.5 fold more Smad 7 than that expressed from the IL1B-31C variant in AGS cells. This differential activation of Smad 7 by IL1B promoter variants translated into differential downregulation of gastrin expression. We further analyzed Smad 7, NFkB, IL1B and gastrin expression in antral gut biopsy samples of patients with H. pylori associated duodenal ulcer and normal individuals. We observed that individuals with duodenal ulcer had significantly lower levels of IL1B, Smad 7, NFkB and corresponding higher level of gastrin expression. CONCLUSION: Pro-inflammatory cytokine IL1B repress gastrin expression by activating Smad 7 and subsequent inhibition of nuclear localization of Smad 3/4 complex. Polymorphic promoter variants of IL1B gene can modulate the IL1B expression which resulted in differential activation Smad 7 and consequent repression of gastrin expression, respectively. Analysis of H. pylori infected duodenal ulcer patient's gut biopsy samples also supported this observation

NF-kappaB Mediated Transcriptional Repression of Acid Modifying Hormone Gastrin

Helicobacter pylori is a major pathogen associated with the development of gastroduodenal diseases. It has been reported that H. pylori induced pro-inflammatory cytokine IL1B is one of the various modulators of acid secretion in the gut. Earlier we reported that IL1B-activated NFkB down-regulates gastrin, the major hormonal regulator of acid secretion. In this study, the probable pathway by which IL1B induces NFkB and affects gastrin expression has been elucidated. IL1B-treated AGS cells showed nine-fold activation of MyD88 followed by phosphorylation of TAK1 within 15 min of IL1B treatment. Furthermore, it was observed that activated TAK1 significantly up-regulates the NFkB subunits p50 and p65. Ectopic expression of NFkB p65 in AGS cells resulted in about nine-fold transcriptional repression of gastrin both in the presence and absence of IL1B. The S536A mutant of NFkB p65 is significantly less effective in repressing gastrin. These observations show that a functional NFkB p65 is important for IL1B-mediated repression of gastrin. ChIP assays revealed the presence of HDAC1 and NFkB p65 along with NCoR on the gastrin promoter. Thus, the study provides mechanistic insight into the IL1B-mediated gastrin repression via NFk

Approximate Likelihood Estimation of Divergence Time Range Using a Coalescent-based Model

We present an estimation of divergence time-range based on a coalescent model. This model sum the probability of coalescent trees, taking into account the effect of incomplete lineage sorting. Maximum likelihood estimate based on this model has been computed previously; however, a formula for divergence time-range estimate or confidence interval has never been presented for this model as the expression of the likelihood makes this estimation difficult to compute. Our formula for the divergence time-range estimate can be readily coded into a program. We did not use a simulation or resampling-based approach and therefore our method is fast and less computationally intensive. We demonstrate that our method is much faster and as accurate a simulation-based approach