Designer Extracellular Vesicles Modulate Pro-Neuronal Cell Responses and Improve Intracranial Retention.

Gene/oligonucleotide therapies have emerged as a promising strategy for the treatment of different neurological conditions. However, current methodologies for the delivery of neurogenic/neurotrophic cargo to brain and nerve tissue are fraught with caveats, including reliance on viral vectors, potential toxicity, and immune/inflammatory responses. Moreover, delivery to the central nervous system is further compounded by the low permeability of the blood brain barrier. Extracellular vesicles (EVs) have emerged as promising delivery vehicles for neurogenic/neurotrophic therapies, overcoming many of the limitations mentioned above. However, the manufacturing processes used for therapeutic EVs remain poorly understood. Here, we conducted a detailed study of the manufacturing process of neurogenic EVs by characterizing the nature of cargo and surface decoration, as well as the transfer dynamics across donor cells, EVs, and recipient cells. Neurogenic EVs loaded with Ascl1, Brn2, and Myt1l (ABM) are found to show enhanced neuron-specific tropism, modulate electrophysiological activity in neuronal cultures, and drive pro-neurogenic conversions/reprogramming. Moreover, murine studies demonstrate that surface decoration with glutamate receptors appears to mediate enhanced EV delivery to the brain. Altogether, the results indicate that ABM-loaded designer EVs can be a promising platform nanotechnology to drive pro-neuronal responses, and that surface functionalization with glutamate receptors can facilitate the deployment of EVs to the brain.

In Situ Deployment of Engineered Extracellular Vesicles into the Tumor Niche via Myeloid-Derived Suppressor Cells.

Extracellular vesicles (EVs) have emerged as a promising carrier system for the delivery of therapeutic payloads in multiple disease models, including cancer. However, effective targeting of EVs to cancerous tissue remains a challenge. Here, it is shown that nonviral transfection of myeloid-derived suppressor cells (MDSCs) can be leveraged to drive targeted release of engineered EVs that can modulate transfer and overexpression of therapeutic anticancer genes in tumor cells and tissue. MDSCs are immature immune cells that exhibit enhanced tropism toward tumor tissue and play a role in modulating tumor progression. Current MDSC research has been mostly focused on mitigating immunosuppression in the tumor niche; however, the tumor homing abilities of these cells present untapped potential to deliver EV therapeutics directly to cancerous tissue. In vivo and ex vivo studies with murine models of breast cancer show that nonviral transfection of MDSCs does not hinder their ability to home to cancerous tissue. Moreover, transfected MDSCs can release engineered EVs and mediate antitumoral responses via paracrine signaling, including decreased invasion/metastatic activity and increased apoptosis/necrosis. Altogether, these findings indicate that MDSCs can be a powerful tool for the deployment of EV-based therapeutics to tumor tissue.

Nanochannel-Based Poration Drives Benign and Effective Nonviral Gene Delivery to Peripheral Nerve Tissue.

While gene and cell therapies have emerged as promising treatment strategies for various neurological conditions, heavy reliance on viral vectors can hamper widespread clinical implementation. Here, the use of tissue nanotransfection as a platform nanotechnology to drive nonviral gene delivery to nerve tissue via nanochannels, in an effective, controlled, and benign manner is explored. TNT facilitates plasmid DNA delivery to the sciatic nerve of mice in a voltage-dependent manner. Compared to standard bulk electroporation (BEP), impairment in toe-spread and pinprick response is not caused by TNT, and has limited to no impact on electrophysiological parameters. BEP, however, induces significant nerve damage and increases macrophage immunoreactivity. TNT is subsequently used to deliver vasculogenic cell therapies to crushed nerves via delivery of reprogramming factor genes Etv2, Foxc2, and Fli1 (EFF). The results indicate the TNT-based delivery of EFF in a sciatic nerve crush model leads to increased vascularity, reduced macrophage infiltration, and improved recovery in electrophysiological parameters compared to crushed nerves that are TNT-treated with sham/empty plasmids. Altogether, the results indicate that TNT can be a powerful platform nanotechnology for localized nonviral gene delivery to nerve tissue, in vivo, and the deployment of reprogramming-based cell therapies for nerve repair/regeneration.

Active duty firefighters can improve Functional Movement Screen (FMS) scores following an 8-week individualized client workout program.

BACKGROUND: Firefighting is a dangerous occupation that requires adequate functional movement patterns to help reduce injury risk. Structured programs for improving movement quality have not been studied in firefighters. OBJECTIVE: To examine the effects of an 8-week individualized corrective exercise training program on Functional Movement Screen (FMS) scores in active duty firefighters. METHODS: Fifty-six male firefighters volunteered to participate in the study. All subjects completed baseline FMS testing and scores were entered into the FMS Pro360 system, subscription-based software which generates an individualized corrective exercise workout based on each independent test score. Two, 4-week corrective exercise programs were generated for each participant based on baseline testing. Following the 8-weeks, participants completed follow-up FMS testing. RESULTS: A significant increase in total FMS score (pre = 12.09±2.75, post = 13.66±2.28) was found after the program. A significant increase in stability (pre = 4.13±1.21, post = 4.55±0.83) and advanced movements (pre = 4.45±1.28, post = 5.36±1.29) were also found, however, no difference was observed in mobility tests (3.52±1.09, post = 3.75±0.90). CONCLUSIONS: The results suggest an 8-week individualized corrective exercise program was effective at improving scores on the FMS. Providing corrective exercise programs specific to improving levels of dysfunction or maintaining/enhancing function, may increase firefighter preparedness and attempt to minimize injury risk.

Injuries, changes in fitness, and medical demands in deployed National Guard soldiers.

PURPOSE: To characterize noncombat injury/illness, determine changes in physical fitness, and evaluate the influence of these changes on medical resource utilization by National Guard (NG) Soldiers. METHODS: Fifty-four Soldiers from the Arizona NG completed pre- and postdeployment fitness testing. Additionally, individual deployment medical records were inventoried. RESULTS: The majority of noncombat-related medical visits (41%) were musculoskeletal in nature, followed by miscellaneous (33%) and respiratory (13%). Soldiers experienced significant decreases in percent fat mass (-11.1%, p < 0.001) and VO2 peak (-10.8%, p < 0.001). There were significant increases in push-ups (16.4%, p < 0.001), sit-ups (11.0%, p = 0.001), bench-press (10.2%, p < 0.001), and back squat (14.2%, p < 0.001) measures. VO2 peak was inversely correlated to medical resource utilization (r = -0.45 to -0.28, p < or = 0.05). The tertile of Soldiers experiencing the sharpest declines in VO2 peak had significantly more medical visits over the course of the deployment than the other two tertiles (8.0 vs. 2.6 vs. 3.1 medical visits/Soldier, p < or = 0.05). CONCLUSION: The predominate noncombat medical issue was musculoskeletal injury. NG Soldiers improved their body composition, strength, and endurance but experienced significant declines in aerobic fitness while deployed. These data document the association between declining aerobic fitness and increased utilization of medical resources.

How do they compare?: an assessment of predeployment fitness in the Arizona National Guard.

Currently, there is a paucity of literature that describes physical fitness levels in deploying service members. There has been no data collected that evaluate the Army National Guard or Reserves. This descriptive study will provide physical fitness data for soldiers in the Arizona National Guard (AZNG), allowing for a comparison between the active and reserve components. Sixty soldiers from the AZNG were tested before deployment. Body composition was measured by using air displacement plethysmography. Flexibility testing included the sit and reach (SNR), trunk extension (TE), and shoulder elevation (SE) assessments. Muscular strength was determined by the completion of 1 repetition maximum (1RM) bench press and back squat. Muscular endurance was determined by the completion of the Army push-up (P/U) and sit-up (S/U) test. Muscular power was assessed by the completion of the Wingate cycle test and the standing broad jump (SBJ). Cardiorespiratory fitness was determined by the completion of a VO2peak test. The AZNG soldiers demonstrated a fat mass of 22.7 ± 8.9%, SNR, TE, and SE of 30.0 ± 8.9, 117.1 ± 25.2, and 145.5 ± 50.3 cm, 1RM bench press and back squat of 82.2 ± 29.9 and 104.6 ± 29.0 kg, P/U and S/U of 50 ± 18 and 53 ± 14 reps, peak power of 660.9 ± 177.8 W, SBJ of 191.8 ± 28.4 cm, and VO2peak of 48.9 ± 8.8 ml·kg(-1)·min(-1). This is the first study that provides descriptive data for physical fitness in a reserve component. The data demonstrate that these AZNG soldiers are relatively fit and have comparable results to their active duty counterparts. This descriptive data will provide military leadership a better understanding of the condition of soldiers before deployment and will assist them in better preparing soldiers for future conflicts.

The effect of warm-up with whole-body vibration vs. cycle ergometry on isokinetic dynamometry.

The purpose of this study was to compare the effects of warm-up protocols using either whole-body vibration (WBV) or cycle ergometry (CE) on peak torque at 3 different isokinetic speeds and on fatigue in the knee extension exercise. Twenty-seven recreationally trained (age = 23.59 ± 3.87 years) men (n = 14) and women (n = 13) were tested at 3 different isokinetic speeds (60, 180, 300°·s-1) after either WBV or CE warm-up. The WBV consisted of intermittent bouts of 30 seconds of isometric squats at various degrees of hip and knee flexion for a total of 5 minutes. The CE consisted of 5 minutes of pedaling a cycle ergometer at 65-85% of age-predicted max heart rate. Comparisons between the warm-up conditions were analyzed using repeated measures analysis of variance. For the fatigue comparison, subjects completed 50 continuous concentric knee extensions at 240°·s-1. Means from the first 3 repetitions were compared to means from the final 3 repetitions to establish a fatigue index. Conditions were compared through an independent T-test. No significant (p > 0.05) differences were discovered between warm-up conditions at any speed or on the fatigue index. Means were virtually identical at 60°·s-1 (WBV = 142.14 ± 43.61 ft lb-1; CE = 140.64 ± 42.72 ft lb-1), 180° s-1 (WBV = 93.88 ± 35.18 ft lb-1; CE = 96.36 ± 31.53 ft lb-1), and 300°·s-1 (WBV = 78.36 ± 26.04 ft lb-1; CE = 80.13 ± 26.08), and on fatigue percentage (WBV = 51.14 ± 10.06%; CE = 52.96 ± 9.19%). These data suggest that the more traditional 5-minute cycle ergometer warm-up elicits results comparable to a less common vibration warm-up. The findings of this study are that these modalities are comparable under the tested conditions.

Undulation training for development of hierarchical fitness and improved firefighter job performance.

Firefighters routinely encounter physical demands that contribute to countless musculoskeletal injuries. Seemingly, a progressive prescription for fitness would offer superior protection against intrinsic job risks. The purpose of this study was to investigate the influence of two resistance training interventions on fitness adaptations among firefighters, and to assess the degree of transfer to job-specific tasks. Firefighter trainees were recruited for participation in this experimental study. Two distinct, periodized training models-undulation training (UT; n = 7) and standard training control (STCo; n = 7)-were used to determine the differential affects for muscular fitness and transference to firefighter performance batteries. Specific tests were administered to evaluate 1) upper- and lower-body muscular strength, 2) lower-body power output, 3) sprint speed and jumping ability, 4) anthropometry, and 5) firefighter Grinder performance (i.e., firefighter-specific job tests). The 9-week UT experimental treatment prescription was characterized by daily "nonlinear" fluctuations in training to preferentially elicit specific and distinct muscular fitness components, whereas the STCo treatment conformed to a traditional model, in which each fitness component was systematically targeted during a specified mesocycle. For both treatments, nearly all fitness and performance measures significantly increased from baseline (p < 0.05), with a trend in favor of UT. Further, the UT group experienced significantly greater improvements (p < 0.05) in Grinder performance over the STCo group. Calculation of effect sizes identified meaningful differences in the magnitude of changes in outcomes (effect size > 0.50) in favor of UT for measures of thigh circumference, vertical jump, 1RM squat, Grinder performance, and peak power output. These findings suggest a potentially greater stimulus for multidimensional muscular fitness development with UT, over a periodized STCo. This study effectively establishes that UT may offer a greater transference to performance for firefighter-specific job tasks.

Analysis of acute explosive training modalities to improve lower-body power in baseball players.

Complex training is the simultaneous combination of heavy resistance training and plyometrics. The objective of this study was to test the effects of complex training vs. heavy resistance or plyometric interventions alone on various power-specific performance measures. Forty-five male division II junior college baseball players participated in 3 separate 4-week resistance training interventions. Subjects were randomly assigned to one of three groups. In a counterbalanced rotation design, each group participated in complex, heavy resistance, and plyometric training interventions. Each individual was tested in 20-yd (SP20), 40-yd (SP40), 60-yd (SP60), vertical jump, standing broad jump, and T-agility measures pre- and post-4-week training interventions. There was no statistical significant difference (p = 0.11) between groups across all performance measures. Review of each distinct training intervention revealed greater percent improvements in SP20 (0.55; -0.49; -0.12), SP40 (0.26; -0.72; -1.33), SP60 (0.27; 0.15; -0.27), standing broad jump (1.80; 0.67; 1.1), and T-agility (2.33; 1.23; -0.04) with complex training interventions than with the heavy resistance or plyometric training interventions, respectively. Plyometric-only training showed greater percent changes in vertical jump (1.90) than with complex (0.97) or heavy resistance training (0.36). The present results indicate that complex training can provide strength and conditioning professionals equal, if not slightly greater, improvements in muscular power than traditional heavy resistance- and plyometric-only interventions in moderately trained athletes. Complex training can be another valuable method for short-term power and speed improvements in athletes in isolation or in conjunction with other power development methods.