Pathological glial tau accumulations in neurodegenerative disease: review and case report

Abnormal deposits of tau protein accumulate in glia in many neurodegenerative diseases. This suggests that in some instances the disease process may target glial tau, with neuronal degeneration a secondary consequence of this process. In this report, we summarize the pattern of glial tau pathology in various neurodegenerative disorders and add original findings from a case of sporadic frontotemporal dementia that exhibits astrocytic tau pathology. The neurodegenerative diseases span the spectrum of relative neuronal and glial tau involvement, from disorders affecting only neuronal tau to those in which abnormal tau deposits are found only in glia. From this, we conclude that glial tau can be a primary target of the disease process, and that this can lead to neuronal degeneration.     

Effects of diurnal temperature variation on microbial community and petroleum hydrocarbon biodegradation in contaminated soils from a sub‐Arctic site

Contaminated soils are subject to diurnal and seasonal temperature variations during on‐site ex‐situ bioremediation processes. We assessed how diurnal temperature variations similar to that in summer at the site from which petroleum hydrocarbon‐contaminated soil was collected affect the soil microbial community and the extent of biodegradation of petroleum hydrocarbons compared with constant temperature regimes. Microbial community analyses for 16S rRNA and alkB genes by pyrosequencing indicated that the microbial community for soils incubated under diurnal temperature variation from 5°C to 15°C (VART5‐15) evolved similarly to that for soils incubated at constant temperature of 15°C (CST15). In contrast, under a constant temperature of 5°C (CST5), the community evolved significantly different. The extent of biodegradation of C10–C16 hydrocarbons in the VART5‐15 systems was 48%, comparable with the 41% biodegradation in CST15 systems, but significantly higher than CST5 systems at 11%. The enrichment of Gammaproteobacteria was observed in the alkB gene‐harbouring communities in VART5‐15 and CST15 but not in CST5 systems. However, the Actinobacteria was abundant at all temperature regimes. The results suggest that changes in microbial community composition as a result of diurnal temperature variations can significantly influence petroleum hydrocarbon bioremediation performance in cold regions.     

Exploring the structure of opioid receptors with homology modeling based on single and multiple templates and subsequent docking: A comparative study

Opioid receptors are the principal targets for opioids, which have been used as analgesics for centuries. Opioid receptors belong to the rhodopsin family of G-protein coupled receptors (GPCRs). In the absence of crystal structures of opioid receptors, 3D homology models have been reported with bovine rhodopsin as a template, though the sequence homology is low. Recently, it has been reported that use of multiple templates results in a better model for a target having low sequence identity with a single template. With the objective of carrying out a comparative study on the structural quality of the 3D models based on single and multiple templates, the homology models for opioid receptors (mu, delta and kappa) were generated using bovine rhodopsin as single template and the recently deposited crystal structures of squid rhodopsin, turkey β-1 and human β-2 adrenoreceptors along with bovine rhodopsin as multiple templates. In this paper we report the results of comparison between the refined 3D models based on multiple sequence alignment (MSA) and models built with bovine rhodopsin as template, using validation programs PROCHECK, PROSA, Verify 3D, Molprobity and docking studies. The results indicate that homology models of mu and kappa with multiple templates are better than those built with only bovine rhodopsin as template, whereas, in many aspects, the homology model of delta opioid receptor with single template is better with respect to the model based on multiple templates. Three nonselective ligands were docked to both the models of mu, delta and kappa opioid receptors using GOLD 3.1. The results of docking complied well with the pharamacophore, reported for nonspecific opioid ligands. The comparison of docking results for models with multiple templates and those with single template have been discussed in detail. Three selective ligands for each receptor were also docked. As the crystallographic structures are not yet known, this comparison will help in choosing better homology models of opioid receptors for studying ligand receptor interactions to design new potent opioid antagonists.     

Association of Common Polymorphisms in TNFA,NFkB1 and NFKBIA with Risk and Prognosis of Esophageal Squamous Cell Carcinoma

Background

Tumour necrosis factor-alpha (TNF-α) and nuclear factor of kappa light chain gene enhancer in activated B cells (NF-κB) play critical role in carcinogenesis processes like tumour initiation, proliferation, migration and invasion. Single nucleotide polymorphisms in TNF-α, NF-κB and its inhibitor IκB genes were shown to be associated with susceptibility and prognosis of several cancers; however, their role in esophageal squamous cell carcinoma (ESCC) is not well recognised. Therefore, in present study, we aimed to investigate association of common polymorphisms in TNFA, NFkB1 and NFKBIA with risk and prognosis of ESCC in northern Indian population.

Methods

We genotyped 290 ESCC patients (including 162 followed up cases) and 311 mean age, gender and ethnicity matched controls for TNFA -308G>A, NFkB1 -94ATTG ins/del and NFKBIA (-826C>T and 3’UTRA>G) polymorphisms using PCR alone or followed by RFLP and TaqMan assay.

Results

TNFA -308GA genotype was associated with increased risk of ESCC specifically in females and in patients with regional lymph node involvement, while, NFKBIA -826CT+TT genotype conferred decreased risk of ESCC in females. Haplotypes of NFKBIA -826C>T and 3’UTRA>G polymorphisms, C_-826G₃’_UTR and T_-826A₃’_UTR, were associated with reduced risk of ESCC. No independent role of NFkB1 -94ATTG ins/del polymorphism in susceptibility of ESCC was found. Multi-dimensionality reduction analysis showed three factor model TNFA-308, NFKBIA-826, NFKBIA 3’UTR as better predictor for risk of ESCC. Furthermore, combined risk genotype analysis of all studied polymorphisms showed increased risk of ESCC in patients with 1-3 risk genotype compared to ‘0’ risk genotype. Survival analysis did not show any significant prognostic effect of studied polymorphisms. However, in stepwise multivariate analysis, metastasis was found to be independent prognostic predictor of ESCC patients.

Conclusion

TNFA-308 and NFKBIA (-826C>T and 3’UTRA>G) polymorphisms may play role in susceptibility but not in prognosis of ESCC patients in northern Indian population.     

Quantitation of Helicobacter pylori ureC gene and its comparison with different diagnostic techniques and gastric histopathology

Numerous diagnostic assays for Helicobacter pylori detection are available. However, these techniques have their own advantages as well as limitations. Here we tried to develop a real-time quantitative (Q) PCR assay to measure ureC copy number to detect H. pylori, based on the fact that there is only one copy of the ureC gene per bacterium. We enrolled 120 adult patients [non-ulcer dyspepsia (NUD) 60, peptic ulcer disease (PUD) 20, gastric cancer (GC) 40] undergoing upper gastrointestinal endoscopies. During each endoscopic examination, antral biopsies from normal region of the antrum were obtained and subjected to the following tests: RUT, culture, histopathology, H. pylori-specific ureC PCR and ureC Q-PCR. Calculation of H. pylori copy number was based on the standard curve generated using 10-fold dilutions of DNA extracted from the H. pylori control strain varying from 10⁵ to 10¹ copies. The prevalence of H. pylori infection in our study population was 54% with no significant difference among disease and control population. The sensitivity of Q-PCR was found to be 100% which was highest among all diagnostic tests. The established Q-PCR is around 10 times more sensitive than the conventional PCR method. The copy number of H. pylori DNA was significantly increased when overall gastritis, H. pylori density, chronic inflammation and intestinal metaplasia were present. In summary, we developed a rapid and sensitive Q-PCR method for detecting H. pylori. This technique offers a significant improvement over other available methods for detecting H. pylori in clinical and research samples.     

Cyclooxygenase-2 deficiency attenuates adipose tissue differentiation and inflammation in mice

Obesity is associated with a variety of disorders and is a significant health problem in developed countries. One factor controlling the level of adiposity is the differentiation of cells into adipocytes. Adipocyte differentiation requires expression of peroxisome proliferator-activated receptor γ (PPARγ), which is activated by ligands to regulate expression of genes involved in adipocyte differentiation. Although 15-deoxy-Δ(12,14)-prostaglandin (PG) J(2) (15d-PGJ(2)) has long been known to be a potent activator of PPARγ, the importance of its synthesis in adipose tissue in vivo is not clear. The current study utilized mice deficient in cyclooxygenase-2 (COX-2) to examine the role of COX-2-derived PGs as in vivo modulators of adiposity. As compared with strain- and age-matched wild-type controls, the genetic deficiency of COX-2 resulted in a significant reduction in total body weight and percent body fat. Although there were no significant differences in food consumption between groups, COX-2-deficient mice showed increased metabolic activity. Epididymal adipose tissue from wild-type mice produced a significantly greater level of 15d-PGJ(2), as compared with adipose tissue isolated from mice deficient in COX-2. Furthermore, production of the precursor required for 15d-PGJ(2) formation, PGD(2), was also significantly reduced in COX-2-deficient adipose tissue. The expression of markers for differentiated adipocytes was significantly reduced in adipose tissue from COX-2-deficient mice, whereas preadipocyte marker expression was increased. Macrophage-dependent inflammation was also significantly reduced in adipose tissue of COX-2-deficient mice. These findings suggest that reduced adiposity in COX-2-deficient mice results from attenuated PPARγ ligand production and adipocyte differentiation.     

Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma

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Packed bed dynamics during microbial treatment of wastewater: modelling and simulation

A mathematical model consisting of mass balance equations and accounting for bioreaction and mass transfer is presented to describe both unsteady and steady-state degradation of phenol in a biofilter. The model has been validated for the steady-state situation with literature work. The model has been able to predict the dynamics of the biofiltration process with variations in system and operating conditions as inlet substrate concentration, liquid phase mass transfer coefficients, particle size, Henry's constant, inlet velocity, growth and half saturation constants and bed void fraction. The results show that inlet substrate concentration, inlet velocity, growth and half saturation constants and liquid phase mass transfer coefficients significantly control the operational dynamics. It is also shown that inhibition effects can be neglected for low concentrations (<0.5 kg m(-3)) of phenol. Thus, the model can be used as a design tool for a biofilter.