The degree of brain injury is the governing factor for the magnitude of the patient's psycho- and physiological deficits post-injury, and the associated long-term consequences. The present scaling method used to segregate the patients among mild, moderate and severe phases of traumatic brain injury (TBI) has major limitations; however, a more continuous stratification of TBI is still elusive. With the anticipation that differentiating molecular markers could be the backbone of a robust method to triage TBI, we used a modified closed-head injury (CHI) Marmarou model with two impact heights (IH). By definition, IH directly correlates with the impact force causing TBI. In our modified CHI model, the rat skull was fitted with a helmet to permit a diffuse axonal injury. With the frontal cortex as the focal point of injury, the adjacent brain regions (hippocampus, HC and cerebellum, CB) were susceptible to diffuse secondary shock injury. At 8 days post injury (po.i.), rats impacted by 120 cm IH (IH120) took a longer time to find an escape route in the Barnes maze as compared to those impacted by 100 cm IH (IH100). Using a time-resolved interrogation of the transcriptomic landscape of HC and CB tissues, we mined those genes that altered their regulations in correlation with the variable IHs. At 14 days po.i., when all rats demonstrated nearly normal visuomotor performance, the bio-functional analysis suggested an advanced healing mechanism in the HC of IH100 group. In contrast, the HC of IH120 group displayed a delayed healing with evidence of active cell death networks. Combining whole genome rat microarrays with behavioral analysis provided the insight of neuroprotective signals that could be the foundation of the next generation triage for TBI patients.

Prolonged residence of mice in spaceflight is a scientifically robust and ethically ratified model of muscle atrophy caused by continued unloading. Under the Rodent Research Program of NASA, we assayed the large scale mRNA and metabolomic perturbations in the quadriceps of C57BL/6j male mice that lived in spaceflight (FLT) or on the Ground (Control or CTR) for approximately four weeks. The wet weights of the quadriceps were significantly reduced in FLT mice. Next generation sequencing and untargeted mass spectroscopic assays interrogated the gene‐metabolite landscape of the quadriceps. A majority of top ranked differentially suppressed genes in FLT encoded proteins from the myosin or troponin families, suggesting sarcomere alterations in space. Significantly enriched gene‐metabolite networks were found linked to sarcomeric integrity, immune fitness, and oxidative stress response; all inhibited in space as per in silico prediction. A significant loss of mitochondrial DNA copy numbers in FLT mice underlined the energy deprivation associated with spaceflight induced stress. This hypothesis was reinforced by the transcriptomic sequencing‐metabolomics integrative analysis that showed inhibited networks related to protein, lipid and carbohydrate metabolism, and ATP synthesis and hydrolysis. Finally, we discovered important upstream regulators, which could be targeted for next generation therapeutic intervention for chronic disuse of the musculoskeletal system.

Clinical, epidemiological, and experimental evidence demonstrate non-cancer, cardiovascular, and endocrine effects of ionizing radiation exposure including growth hormone deficiency, obesity, metabolic syndrome, diabetes, and hyperinsulinemia. Insulin-like growth factor-1 (IGF-1) signaling perturbations are implicated in development of cardiovascular disease and metabolic syndrome. The minipig is an emerging model for studying radiation effects given its high analogy to human anatomy and physiology. Here we use a minipig model to study late health effects of radiation by exposing male Göttingen minipigs to 1.9–2.0 Gy X-rays (lower limb tibias spared). Animals were monitored for 120 days following irradiation and blood counts, body weight, heart rate, clinical chemistry parameters, and circulating biomarkers were assessed longitudinally. Collagen deposition, histolopathology, IGF-1 signaling, and mRNA sequencing were evaluated in tissues. Our findings indicate a single exposure induced histopathological changes, attenuated circulating IGF-1, and disrupted cardiac IGF-1 signaling. Electrolytes, lipid profiles, liver and kidney markers, and heart rate and rhythm were also affected. In the heart, collagen deposition was significantly increased and transforming growth factor beta-1 (TGF-beta-1) was induced following irradiation; collagen deposition and fibrosis were also observed in the kidney of irradiated animals. Our findings show Göttingen minipigs are a suitable large animal model to study long-term effects of radiation exposure and radiation-induced inhibition of IGF-1 signaling may play a role in development of late organ injuries.

The association between the shift in fecal resident microbiome and social conflicts with long-term consequences on psychological plasticity, such as the development of post-traumatic stress disorder (PTSD), is yet to be comprehended. We developed an aggressor-exposed (Agg-E) social stress (SS) mouse model to mimic warzone-like conflicts, where random life-threatening interactions took place between naïve intruder mice and aggressive resident mice. Gradually these Agg-E mice developed distinct characteristics simulating PTSD-like aspects, whereas the control mice not exposed to Agg-E SS demonstrated distinct phenotypes. To further investigate the role of Agg-E SS on the resident microbiome, 16S rRNA gene sequencing was assayed using fecal samples collected at pre-, during, and post-SS time points. A time agonist shift in the fecal microbial composition of Agg-E mice in contrast to its controls suggested a persistent impact of Agg-E SS on resident microbiota. At the taxonomic level, Agg-E SS caused a significant shift in the time-resolved ratios of Firmicutes and Bacteroidetes abundance. Furthermore, Agg-E SS caused diverging shifts in the relative abundances of Verrucomicrobia and Actinobacteria. An in silico estimation of genomic potential identified a potentially perturbed cluster of bioenergetic networks, which became increasingly enriched with time since the termination of Agg-E SS. Supported by a growing number of studies, our results indicated the roles of the microbiome in a wide range of phenotypes that could mimic the comorbidities of PTSD, which would be directly influenced by energy deficiency. Together, the present work suggested the fecal microbiome as a potential tool to manage long-term effects of social conflicts, including the management of PTSD.

Introduction: The glia-operated glymphatic system, analogous to but separate from the lymphatics in the periphery, is unique to brain and retina, where it is very closely aligned with the arteriolar system. This intimate relationship leads to a “blood vessel like” distribution pattern of glymphatic vessels in the brain. The spatial relationship of glymphatics, including their essential component aquaporin-4 with vascular pericytes of brain arterioles is critical to functionality and is termed “polarization”. Materials and Methods: We review the available literature on the factors affecting the resting state of glymphatics under normal conditions, including the important role of sleep in supporting normal glymphatic function (including waste removal) as well as the critical role of “polarization” under normal conditions. We then examine the effects of traumatic brain injury (TBI) or seizures on the glymphatic system and its state of “polarization”. Results: Injury, such as TBI, can disrupt polarization resulting in “depolarization” leading to brain edema. Conclusion: Damage to the glymphatic system might explain the brain edema so often seen following TBI or other insult. Moreover, similar damage should be expected in response to seizures, which can often be associated with chemical exposures as well as with TBI. Military operations, whether night operations or continuous operations, quite often impose limitations on sleep. As glymphatic function is sleep-dependent, sleep deprivation alone could compromise glymphatic function, as well, and might in addition, explain some of the well-known performance deficits associated with sleep deprivation. Possible effects of submarine and diving operations, chemical agents (including seizures), as well as high altitude exposure and other threats should be considered. In addition to the brain, the retina is also served and protected by the glymphatic system. Accordingly, the effect of military-related risks (e.g., exposure to laser or other threats) to retinal glymphatic function should also be considered. An intact glymphatic system is absolutely essential to support normal central nervous system functionality, including cognition. This effects a broad range of military threats on brain and retinal glymphatics should be explored. Possible preventive and therapeutic measures should be proposed and evaluated, as well.

Achieving bone union remains a significant clinical dilemma. The use of osteoinductive agents, specifically bone morphogenetic proteins (BMPs), has gained wide attention. However, multiple side effects, including increased incidence of cancer, have renewed interest in investigating alternatives that provide safer, yet effective bone regeneration. Here we demonstrate the robust bone healing capabilities of the main megakaryocyte (MK) growth factor, thrombopoietin (TPO), and second-generation TPO agents using multiple animal models, including mice, rats, and pigs. This bone healing activity is shown in two fracture models (critical-sized defect [CSD] and closed fracture) and with local or systemic administration. Our transcriptomic analyses, cellular studies, and protein arrays demonstrate that TPO enhances multiple cellular processes important to fracture healing, particularly angiogenesis, which is required for bone union. Finally, the therapeutic potential of thrombopoietic agents is high since they are used in the clinic for other indications (eg, thrombocytopenia) with established safety profiles and act upon a narrowly defined population of cells.