The Influence of Corrective Exercises on Functional Movement Screen and Physical Fitness Performance in Army ROTC Cadets.

Context: The functional movement screen (FMS) is a tool designed to identify limitations between sections of the body during fundamental movements. However, there is limited evidence on the effectiveness of corrective exercises to improve FMS scores. Objective: To examine the effects of individualized corrective exercises on improving FMS scores in Reserve Officers' Training Corps cadets and to correlate these changes with physical fitness performance as established with the standard Army Physical Fitness Test (APFT). Design: Cluster randomized, cohort study. Setting: Controlled laboratory setting (FMS) and a field-based setting (APFT). Participants: Forty-four healthy, physically active cadets met all inclusion and exclusion criteria. Intervention: Participants were randomly assigned to the experimental (n = 24) or control (n = 20) group by cluster. Personalized intervention programs were developed through the FMS Pro360 system, a subscription-based software that generates corrective exercises based on individual FMS test scores. The experimental group performed the individualized programs 3 times per week for 4 weeks prior to morning physical training regime. The control group continued to participate in the standard warm-up drills as part of morning physical training. Main Outcome Measures: The dependent variables included the individual and composite FMS and APFT scores. Scores were reported and analyzed in several ways to determine the efficacy of corrective exercises. Results: Group FMS and APFT scores were similar at pretest. The experimental group had a significantly greater improvement in FMS composite score at 4 weeks post (U = 87; z = -3.83; P = .001; effect size = 1.33; 95% confidence interval, 0.69-1.98). No significant changes in APFT scores were found (U = 237.5, z = -0.33, P = .74). A nonsignificant weak correlation between the FMS and APFT scores (r = .25, P = .10) was found. Conclusion: Individualized corrective exercises improved FMS scores, but did not change physical fitness performance. FMS composite scores and APFT performance are not related.

Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis.

Centrosomes are orbited by centriolar satellites, dynamic multiprotein assemblies nucleated by Pericentriolar material 1 (PCM1). To study the requirement for centriolar satellites, we generated mice lacking PCM1, a crucial component of satellites. Pcm1-/- mice display partially penetrant perinatal lethality with survivors exhibiting hydrocephalus, oligospermia, and cerebellar hypoplasia, and variably expressive phenotypes such as hydronephrosis. As many of these phenotypes have been observed in human ciliopathies and satellites are implicated in cilia biology, we investigated whether cilia were affected. PCM1 was dispensable for ciliogenesis in many cell types, whereas Pcm1-/- multiciliated ependymal cells and human PCM1-/- retinal pigmented epithelial 1 (RPE1) cells showed reduced ciliogenesis. PCM1-/- RPE1 cells displayed reduced docking of the mother centriole to the ciliary vesicle and removal of CP110 and CEP97 from the distal mother centriole, indicating compromised early ciliogenesis. Similarly, Pcm1-/- ependymal cells exhibited reduced removal of CP110 from basal bodies in vivo. We propose that PCM1 and centriolar satellites facilitate efficient trafficking of proteins to and from centrioles, including the departure of CP110 and CEP97 to initiate ciliogenesis, and that the threshold to trigger ciliogenesis differs between cell types.

Engineered Extracellular Vesicles Derived from Dermal Fibroblasts Attenuate Inflammation in a Murine Model of Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) represents a significant burden to the healthcare system, with ≈200 000 cases diagnosed annually in the USA. ARDS patients suffer from severe refractory hypoxemia, alveolar-capillary barrier dysfunction, impaired surfactant function, and abnormal upregulation of inflammatory pathways that lead to intensive care unit admission, prolonged hospitalization, and increased disability-adjusted life years. Currently, there is no cure or FDA-approved therapy for ARDS. This work describes the implementation of engineered extracellular vesicle (eEV)-based nanocarriers for targeted nonviral delivery of anti-inflammatory payloads to the inflamed/injured lung. The results show the ability of surfactant protein A (SPA)-functionalized IL-4- and IL-10-loaded eEVs to promote intrapulmonary retention and reduce inflammation, both in vitro and in vivo. Significant attenuation is observed in tissue damage, proinflammatory cytokine secretion, macrophage activation, influx of protein-rich fluid, and neutrophil infiltration into the alveolar space as early as 6 h post-eEVs treatment. Additionally, metabolomics analyses show that eEV treatment causes significant changes in the metabolic profile of inflamed lungs, driving the secretion of key anti-inflammatory metabolites. Altogether, these results establish the potential of eEVs derived from dermal fibroblasts to reduce inflammation, tissue damage, and the prevalence/progression of injury during ARDS via nonviral delivery of anti-inflammatory genes/transcripts.

ICAM-1-decorated extracellular vesicles loaded with miR-146a and Glut1 drive immunomodulation and hinder tumor progression in a murine model of breast cancer.

Tumor-associated immune cells play a crucial role in cancer progression. Myeloid-derived suppressor cells (MDSCs), for example, are immature innate immune cells that infiltrate the tumor to exert immunosuppressive activity and protect cancer cells from the host's immune system and/or cancer-specific immunotherapies. While tumor-associated immune cells have emerged as a promising therapeutic target, efforts to counter immunosuppression within the tumor niche have been hampered by the lack of approaches that selectively target the immune cell compartment of the tumor, to effectively eliminate "tumor-protecting" immune cells and/or drive an "anti-tumor" phenotype. Here we report on a novel nanotechnology-based approach to target tumor-associated immune cells and promote "anti-tumor" responses in a murine model of breast cancer. Engineered extracellular vesicles (EVs) decorated with ICAM-1 ligands and loaded with miR-146a and Glut1, were biosynthesized (in vitro or in vivo) and administered to tumor-bearing mice once a week for up to 5 weeks. The impact of this treatment modality on the immune cell compartment and tumor progression was evaluated via RT-qPCR, flow cytometry, and histology. Our results indicate that weekly administration of the engineered EVs (i.e., ICAM-1-decorated and loaded with miR-146a and Glut1) hampered tumor progression compared to ICAM-1-decorated EVs with no cargo. Flow cytometry analyses of the tumors indicated a shift in the phenotype of the immune cell population toward a more pro-inflammatory state, which appeared to have facilitated the infiltration of tumor-targeting T cells, and was associated with a reduction in tumor size and decreased metastatic burden. Altogether, our results indicate that ICAM-1-decorated EVs could be a powerful platform nanotechnology for the deployment of immune cell-targeting therapies to solid tumors.

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.

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.

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.

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.

Nanotransfection-based vasculogenic cell reprogramming drives functional recovery in a mouse model of ischemic stroke.

Ischemic stroke causes vascular and neuronal tissue deficiencies that could lead to substantial functional impairment and/or death. Although progenitor-based vasculogenic cell therapies have shown promise as a potential rescue strategy following ischemic stroke, current approaches face major hurdles. Here, we used fibroblasts nanotransfected with Etv2, Foxc2, and Fli1 (EFF) to drive reprogramming-based vasculogenesis, intracranially, as a potential therapy for ischemic stroke. Perfusion analyses suggest that intracranial delivery of EFF-nanotransfected fibroblasts led to a dose-dependent increase in perfusion 14 days after injection. MRI and behavioral tests revealed ~70% infarct resolution and up to ~90% motor recovery for mice treated with EFF-nanotransfected fibroblasts. Immunohistological analysis confirmed increases in vascularity and neuronal cellularity, as well as reduced glial scar formation in response to treatment with EFF-nanotransfected fibroblasts. Together, our results suggest that vasculogenic cell therapies based on nanotransfection-driven (i.e., nonviral) cellular reprogramming represent a promising strategy for the treatment of ischemic stroke.

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.

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.

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.

ZMYND10 functions in a chaperone relay during axonemal dynein assembly.

Molecular chaperones promote the folding and macromolecular assembly of a diverse set of 'client' proteins. How ubiquitous chaperone machineries direct their activities towards specific sets of substrates is unclear. Through the use of mouse genetics, imaging and quantitative proteomics we uncover that ZMYND10 is a novel co-chaperone that confers specificity for the FKBP8-HSP90 chaperone complex towards axonemal dynein clients required for cilia motility. Loss of ZMYND10 perturbs the chaperoning of axonemal dynein heavy chains, triggering broader degradation of dynein motor subunits. We show that pharmacological inhibition of FKBP8 phenocopies dynein motor instability associated with the loss of ZMYND10 in airway cells and that human disease-causing variants of ZMYND10 disrupt its ability to act as an FKBP8-HSP90 co-chaperone. Our study indicates that primary ciliary dyskinesia (PCD), caused by mutations in dynein assembly factors disrupting cytoplasmic pre-assembly of axonemal dynein motors, should be considered a cell-type specific protein-misfolding disease.

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.

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.