Repeated exposure to blast overpressure remains a major cause of adverse health for military personnel who, as a consequence, are at a higher risk for neurodegenerative disease and suicide. Acute, early tracking of blast related effects holds the promise of rapid health assessment prior to onset of chronic problems. Current techniques used to determine blastrelated effects rely upon reporting of symptomology similar to that of concussion and neurocognitive assessment relevant to operational decrement. Here, we describe the results of a cross sectional study with pared observations. The concentration of multiple TBI-related proteins was tested in serum collected within one hour of blast exposure as a quantitative and minimally invasive strategy to augment assessment of blast-exposure effects that are associated with concussion-like symptomology and reaction time decrements. We determined that median simple reaction time (SRT) was slowed in accordance with serum Nf-L, tau, Aβ-40, and Aβ-42 elevation after overpressure exposure. In contrast, median levels of serum GFAP decreased. Individual, inter-subject analysis revealed positive correlations between changes in Nf-L and GFAP, and in Aβ-40 compared to Aβ-42. The change in Nf-L was negatively associated with tau, Aβ-40, and Aβ-42. Participants reported experiencing headaches, dizziness and taking longer to think. Dizziness was associated with reaction time decrements, GFAP or NfL suppression, as well as Aβ peptide elevation. UCH-L1 elevation had a weak association with mTBI/concussion history. Multiplexed serum biomarker quantitation, coupled with reaction time assessment and symptomology determined before and after blast exposure, may serve as a platform for tracking adverse effects in the absence of a head wound or diagnosed concussion. We propose further evaluation of serum biomarkers, which are often associated with TBI, in the context of acute operational blast exposures.
This cohort study evaluates associations between exposure to low-level overpressure, elevated serum levels of neurotrauma biomarkers, and concussion-like symptoms in military and law enforcement personnel without a diagnosed traumatic brain injury.
Homoserine O-acetyltransferase (HTA) catalyzes the formation of L-O-acetyl-homoserine from L-homoserine through the transfer of an acetyl group from acetyl-CoA. This is the first committed step required for the biosynthesis of methionine in many fungi, Gram-positive bacteria and some Gram-negative bacteria. The structure of HTA from Staphylococcus aureus (SaHTA) has been determined to a resolution of 2.45 Å. The structure belongs to the α/β-hydrolase superfamily, consisting of two distinct domains: a core α/β-domain containing the catalytic site and a lid domain assembled into a helical bundle. The active site consists of a classical catalytic triad located at the end of a deep tunnel. Structure analysis revealed some important differences for SaHTA compared with the few known structures of HTA.
The aspartate pathway is essential for the production of the amino acids required for protein synthesis and of the metabolites needed in bacterial development. This pathway also leads to the production of several classes of quorum-sensing molecules that can trigger virulence in certain microorganisms. The second enzyme in this pathway, aspartate β-semialdehyde dehydrogenase (ASADH), is absolutely required for bacterial survival and has been targeted for the design of selective inhibitors. Fragment-library screening has identified a new set of inhibitors that, while they do not resemble the substrates for this reaction, have been shown to bind at the active site of ASADH. Structure-guided development of these lead compounds has produced moderate inhibitors of the target enzyme, with some selectivity observed between the Gram-negative and Gram-positive orthologs of ASADH. However, many of these inhibitor analogs and derivatives have not yet achieved the expected enhanced affinity. Structural characterization of these enzyme-inhibitor complexes has provided detailed explanations for the barriers that interfere with optimal binding. Despite binding in the same active-site region, significant changes are observed in the orientation of these bound inhibitors that are caused by relatively modest structural alterations. Taken together, these studies present a cautionary tale for issues that can arise in the systematic approach to the modification of lead compounds that are being used to develop potent inhibitors.
Severe traumatic brain injury (TBI) is a risk factor for neurodegenerative diseases. Yet, the molecular events involving dysregulated miRNAs that may be associated with protein degradation in the brain remains elusive. Quantitation of more than 800 miRNAs was conducted using rat ipsilateral coronal brain tissues collected 1, 3, or 7 days after penetrating ballistic-like brain injury (PBBI). As a control for each time-point, Sham-operated animals received craniotomy alone. Microarray and systems biology analysis indicated that the amplitude and complexity of miRNAs affected were greatest 7 day after PBBI. Arrays and Q-PCR inferred that dysregulation of miR-135a, miR-328, miR-29c, and miR-21 were associated with altered levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), PSEN1, PSEN2, and amyloid precursor protein (APP) genes. These events were followed by increased levels of mature BACE1 protein and concomitant loss of full length APP within 3-7 days, then elevation of amyloid beta (Aβ)-40 7 days after PBBI. This study indicates that miRNA arrays, coupled with systems biology, may be used to guide study design prior validation of miRNA dysregulation. Associative analysis of miRNAs, mRNAs, and proteins within a proposed pathway are poised for further validation as biomarkers and therapeutic targets relevant to TBI-induced APP loss and subsequent Aβ peptide generation during neurodegeneration.
Background: Overpressure (OP) is an increase in air pressure above normal atmospheric levels. Military personnel are repeatedly exposed to low levels of OP caused by various weapon systems. Repeated OP may increase risk of neurological disease or psychological disorder diagnoses. A means to detect early phase effects that may be relevant to brain trauma remain elusive. Therefore, development of quantitative and objective OP-mediated effects during acute timeframes would vastly augment point-of-care or field-based decisions. This pilot study evaluated the amplitude of traumatic brain injury (TBI)-associated biomarkers in serum as a consequence of repeated OP exposure from .50-caliber rifle use over training multiple days. Objective: To determine the acute temporal profile of TBI-associated serum biomarkers and their relationship with neurocognitive decrements or self-reported symptoms among participants exposed to low-level, repeated OP from weapons used in a training environment. Methods: Study participants were enrolled in .50-caliber sniper rifle training and exposed to mild OP (peak pressure 3.8-4.5 psi, impulse 19.27-42.22 psi-ms per day) for three consecutive days (D1-D3). Defense automated neurobehavioral assessment (DANA) neurocognitive testing, symptom reporting, and blood collection were conducted 2-3 h before (pre-) and again 0.45-3 h after (post-) OP exposure. The TBI-associated serum biomarkers, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light (Nf-L), tau, and amyloid beta peptides (Aβ-40 and Aβ-42) were measured using digital ELISAs. Results: Serum GFAP decreased on D1 and D3 but not D2 after OP exposure. Nf-L was suppressed on D3 alone. Aβ-40 was elevated on D2 alone while Aβ-42 was elevated each day after OP exposure. Suppression of GFAP and elevation of Aβ-42 correlated to OP-mediated impulse levels measured on D3. Thangavelu et al. Amyloid Beta Peptides After Overpressure Conclusions: Acute measurement of Aβ-peptides may have utility as biomarkers of subconcussive OP caused by rifle fire. Fluctuation of GFAP, Nf-L, and particularly Aβ peptide levels may have utility as acute, systemic responders of subconcussive OP exposure caused by rifle fire even in the absence of extreme operational deficits or clinically defined concussion.
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