Increased Brain White Matter Axial Diffusivity Associated with Fatigue,Pain and Hyperalgesia in Gulf War Illness

Background

Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction.

Methods

Gulf War veterans (n = 31) and sedentary veteran and civilian controls (n = 20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs.

Results

Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis.

Conclusion

The right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness.     

Characterization of excretory/secretory endopeptidase and metallo-aminopeptidases from Taenia crassiceps metacestodes

Cysticercosis is caused by Taenia spp. metacestodes, which must survive in the host tissues to complete their life cycle. Their survival depends on their control of host immune responses. Because many parasites use proteases to modulate host responses, we examined culture media from Taenia crassiceps metacestodes for protease activity using peptide substrates. We identified prominent aminopeptidase activity at neutral pH, which was inhibited by chelating agents and partially inhibited by the aminopeptidase inhibitor, bestatin. Endopeptidase substrates were optimally cleaved at slightly acidic pH and endopeptidase activity was inhibited by cysteine protease inhibitors. Gel filtration FPLC and subsequent visualization by silver staining revealed a metallo-aminopeptidase of molecular weight 21 kDa and cysteine proteases of Mr 70 and 64 kDA. Recombinant IL-2 was digested when incubated with parasite culture supernatants, but not with control media. IL-2 degradation was completely inhibited by 1,10 phenanthroline and partially inhibited by bestatin, suggesting that a metallo-aminopeptidase was responsible. Incubation of human IgG with culture supernatants resulted in complete degradation of IgG, which was blocked by cysteine protease inhibitors. These observations demonstrate that Taenia spp. metacestodes secrete a number of proteolytic enzymes, which may target molecules from the host immune system and assist in evasion of the host immune response.     

Regulation by mitochondrial superoxide and NADPH oxidase of cellular formation of nitrated cyclic GMP: potential implications for ROS signalling

8-Nitro-cGMP (8-nitroguanosine 3',5'-cyclic monophosphate) is a nitrated derivative of cGMP, which can function as a unique electrophilic second messenger involved in regulation of an antioxidant adaptive response in cells. In the present study, we investigated chemical and biochemical regulatory mechanisms involved in 8-nitro-cGMP formation, with particular focus on the roles of ROS (reactive oxygen species). Chemical analyses demonstrated that peroxynitrite-dependent oxidation and myeloperoxidase-dependent oxidation of nitrite in the presence of H2O2 were two major pathways for guanine nucleotide nitration. Among the guanine nucleotides examined, GTP was the most sensitive to peroxynitrite-mediated nitration. Immunocytochemical and tandem mass spectrometric analyses revealed that formation of 8-nitro-cGMP in rat C6 glioma cells stimulated with lipopolysaccharide plus pro-inflammatory cytokines depended on production of both superoxide and H2O2. Using the mitochondria-targeted chemical probe MitoSOX Red, we found that mitochondria-derived superoxide can act as a direct determinant of 8-nitro-cGMP formation. Furthermore, we demonstrated that Nox2 (NADPH oxidase 2)-generated H2O2 regulated mitochondria-derived superoxide production, which suggests the importance of cross-talk between Nox2-dependent H2O2 production and mitochondrial superoxide production. The results of the present study suggest that 8-nitro-cGMP can serve as a unique second messenger that may be implicated in regulating ROS signalling in the presence of NO.     

Evolutionary Dynamics of Tat in HIV-1 Subtypes B and C

Evolutionary characteristics of HIV-1 have mostly studied focusing its structural genes, Gag, Pol and Env. However, regarding the process of HIV-1''s evolution, few studies emphasize on genetic changes in regulatory proteins. Here we investigate the evolutionary dynamics of HIV-1, targeting one of its important regulatory proteins, Tat. We performed a phylogenetic analysis and employed a Bayesian coalescent-based approach using the BEAST package to investigate the evolutionary changes in Tat over time in the process of HIV-1 evolution. HIV-1 sequences of subtypes B and C from different parts of the world were obtained from the Los Alamos database. The mean estimated nucleotide substitution rates for Tat in HIV-1 subtypes B and C were 1.53x10^-3 (95% highest probability density- HPD Interval: 1.09 x10^-3 to 2.08x10^-3) and 2.14x10^-3 (95% HPD Interval: 1.35 x10^-3 to 2.91x10^-3) per site per year, respectively, which is relatively low compared to structural proteins. The median times of the most recent common ancestors (tMRCA) were estimated to be around 1933 (95% HPD, 1907–1952) and 1956 (95% HPD, 1934–1970) for subtypes B and C, respectively. Our analysis shows that subtype C appeared in the global population two decades after the introduction of subtype B. A Gaussian Markov random field (GMRF) skyride coalescent analysis demonstrates that the early expansion rate of subtype B was quite high, rapidly progressing during the 1960s and 1970s to the early 1990s, after which the rate increased up to the 2010s. In contrast, HIV-1 subtype C exhibited a relatively slow occurrence rate until the late 1980s when there was a sharp increase up to the end of 1990s; thereafter, the rate of occurrence gradually slowed. Our study highlights the importance of examining the internal/regulatory genes of HIV-1 to understand its complete evolutionary dynamics. The study results will therefore contribute to better understanding of HIV-1 evolution.     

Mercury alters the bacterial community structure and diversity in soil even at concentrations lower than the guideline values

This study evaluated the effect of inorganic mercury (Hg) on bacterial community and diversity in different soils. Three soils—neutral, alkaline and acidic—were spiked with six different concentrations of Hg ranging from 0 to 200 mg kg⁻¹ and aged for 90 days. At the end of the ageing period, 18 samples from three different soils were investigated for bacterial community structure and soil physicochemical properties. Illumina MiSeq-based 16s ribosomal RNA (rRNA) amplicon sequencing revealed the alteration in the bacterial community between un-spiked control soils and Hg-spiked soils. Among the bacterial groups, Actinobacteria (22.65%) were the most abundant phyla in all samples followed by Proteobacteria (21.95%), Bacteroidetes (4.15%), Firmicutes (2.9%) and Acidobacteria (2.04%). However, the largest group showing increased abundance with higher Hg doses was the unclassified group (45.86%), followed by Proteobacteria. Mercury had a considerable negative impact on key soil functional bacteria such as ammonium oxidizers and nitrifiers. Canonical correspondence analysis (CCA) indicated that among the measured soil properties, Hg had a major influence on bacterial community structure. Furthermore, nonlinear regression analysis confirmed that Hg significantly decreased soil bacterial alpha diversity in lower organic carbon containing neutral and alkaline soils, whereas in acidic soil with higher organic carbon there was no significant correlation. EC₂₀ values obtained by a nonlinear regression analysis indicated that Hg significantly decreased soil bacterial diversity in concentrations lower than several guideline values.

     

Bioremediation of mercury: not properly exploited in contaminated soils!

Applied Microbiology and Biotechnology - Contamination of land and water caused by heavy metal mercury (Hg) poses a serious threat to biota worldwide. The seriousness of toxicity of this neurotoxin...