Military personnel with chronic symptoms following blast traumatic brain injury have differential expression of neuronal recovery and epidermal growth factor receptor genes

Objective: Approximately one-quarter of military personnel who deployed to combat stations sustained one or more blast-related, closed-head injuries. Blast injuries result from the detonation of an explosive device. The mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI), and place military personnel at high risk for chronic symptoms of post-concussive disorder (PCD), post-traumatic stress disorder (PTSD), and depression are not elucidated. Methods: To investigate the mechanisms of persistent blast-related symptoms, we examined expression profiles of transcripts across the genome to determine the role of gene activity in chronic symptoms following blast-TBI. Active duty military personnel with (1) a medical record of a blast-TBI that occurred during deployment (n = 19) were compared to control participants without TBI (n = 17). Controls were matched to cases on demographic factors including age, gender, and race, and also in diagnoses of sleep disturbance, and symptoms of PTSD and depression. Due to the high number of PCD symptoms in the TBI+ group, we did not match on this variable. Using expression profiles of transcripts in microarray platform in peripheral samples of whole blood, significantly differentially expressed gene lists were generated. Statistical threshold is based on criteria of 1.5 magnitude fold-change (up or down) and p-values with multiple test correction (false discovery rate \u3c0.05). Results: There were 34 transcripts in 29 genes that were differentially regulated in blast-TBI participants compared to controls. Up-regulated genes included epithelial cell transforming sequence and zinc finger proteins, which are necessary for astrocyte differentiation following injury. Tensin-1, which has been implicated in neuronal recovery in pre-clinical TBI models, was down-regulated in blast-TBI participants. Protein ubiquitination genes, such as epidermal growth factor receptor, were also down-regulated and identified as the central regulators in the gene network determined by interaction pathway analysis. Conclusion: In this study, we identified a gene-expression pathway of delayed neuronal recovery in military personnel a blast-TBI and chronic symptoms. Future work is needed to determine if therapeutic agents that regulate these pathways may provide novel treatments for chronic blast-TBI-related symptoms

Mechanism of methanol oxidation by quinoprotein methanol dehydrogenase

At neutral pH, oxidation of CH3OH → CH2O by an o-quinone requires general-base catalysis and the reaction is endothermic. The active-site –CO2− groups of Glu-171 and Asp-297 (Glu-171–CO2− and Asp-297–CO2−) have been considered as the required general base catalysts in the bacterial o-quinoprotein methanol dehydrogenase (MDH) reaction. Based on quantum mechanics/molecular mechanics (QM/MM) calculations, the free energy for MeOH reduction of o-PQQ when MeOH is hydrogen bonded to Glu-171–CO2− and the crystal water (Wat1) is hydrogen bonded to Asp-297–CO2− is ΔG‡ = 11.7 kcal/mol, which is comparable with the experimental value of 8.5 kcal/mol. The calculated ΔG‡ when MeOH is hydrogen bonded to Asp-297–CO2− is >50 kcal/mol. The Asp-297–CO2−···Wat1 complex is very stable. Molecular dynamics (MD) simulations on MDH·PQQ·Wat1 complex in TIP3P water for 5 ns does not result in interchange of Asp-297–CO2− bound Wat1 for a solvent water. Starting with Wat1 removed and MeOH hydrogen bonded to Asp-297–CO2−, we find that MeOH returns to be hydrogen bonded to Glu-171–CO2− and Asp-297–CO2− coordinates to Ca2+ during 3 ns simulation. The Asp-297–CO2−···Wat1 of reactant complex does play a crucial role in catalysis. By QM/MM calculation ΔG‡ = 1.1 kcal/mol for Asp-297–CO2− general-base catalysis of Wat1 hydration of the immediate CH2O product → CH2(OH)2. By this means, the endothermic oxidation-reduction reaction is pulled such that the overall conversion of MeOH to CH2(OH)2 is exothermic

A Diagnosis of Insomnia Is Associated With Differential Expression of Sleep-Regulating Genes in Military Personnel

Sleep disturbance is a common and disturbing symptom in military personnel, with many individuals progressing to the development of insomnia, which is characterized by increased arousals, wakefulness after sleep onset, and distorted sleep architecture. The molecular mechanisms underlying insomnia remain elusive, limiting future therapeutic development to address this critical issue. We examined whole gene expression profiles associated with insomnia. We compared subjects with insomnia (n = 25) to controls (n = 13) without insomnia using microarray gene expression profiles obtained from peripheral samples of whole blood obtained from military personnel. Compared to controls, participants with insomnia had differential expression of 44 transcripts from 43 identified genes. Among the identified genes, urotensin 2 was downregulated by more than 6 times in insomnia participants, and the fold-change remained significant after controlling for depression, posttraumatic stress disorder, and medication use. Urotensin 2 is involved in regulation of orexin A and B activity and rapid eye movement during sleep. These findings suggest that differential expression of these sleep-regulating genes contributes to symptoms of insomnia and, specifically, that switching between rapid eye movement and nonrapid eye movement sleep stages underlies insomnia symptoms. Future work to identify therapeutic agents that are able to regulate these pathways may provide novel treatments for insomnia