Identification of Factors Contributing to Musculoskeletal Injuries in Military Basic Trainees

Due to the physical activity requirements of the United States (U.S.) Armed Forces, there is a concerning incidence rate of musculoskeletal injuries in military personnel. In the basic trainee population specifically, multiple studies have reported a range of exercise- related injury incidence from 14% to 42% in males and 27% to 61.7% in females. Depending on the severity, these injuries can exclude basic trainees from participation, ultimately altering career trajectory and creating the possibility of long-term disability. The studies of this dissertation examine variations in muscle strength, flexibility, and dynamic postural control as a means to identify those basic trainees with increased odds of reporting a back or lower extremity musculoskeletal injury during U.S. Army Basic Combat Training (BCT). The Star Excursion Balance Test (SEBT) is used in clinical and research settings to assess dynamic postural control. Moderate to excellent intra-rater, inter-rater, and test- retest reliabilities of measures obtained from the SEBT have been published; however, current testing procedures are not time efficient for large-scale application. The first study of this dissertation determined the inter-rater and test-retest reliabilities of the shortened testing version of the SEBT—the Quick Star Excursion Balance Test (QSEBT). Forty-six healthy participants (21 males, 25 females; age = 23.5 ± 4.3 years; height = 170.6 ± 8.3 cm; mass = 72.7 ± 15.4 kg) were evaluated by 2 examiners simultaneously in the performance of 8 tasks of the QSEBT bilaterally, followed by repeating the test to assess test-retest reliability. Intraclass correlation coefficients (ICC) for inter-rater comparisons of the QSEBT for all 8 reach directions ranged from 0.83 to 0.98 for both stance legs. ICCs for test-retest reliability of the QSEBT ranged from 0.64 to 0.88 bilaterally. It was concluded that measures obtained from the QSEBT have moderate to excellent reliability for novice examiners when they are instructed on how to administer the test and provided with oral instructions to read to participants. Researchers and clinicians can use the QSEBT to assess dynamic postural control by recording measurements in real-time. The second study of this dissertation examined the predictive validity between individual and combinations of measures in the reporting of a back or lower extremity musculoskeletal injury to a medical provider during U.S. Army BCT. Four hundred and twenty-seven participants (141 females, 286 males; age: 21.43 ± 3.61 years; height: 171.63± 9.37 cm; mass: 73.55 ± 13.29 kg) completed baseline survey questionnaires, body composition testing, and baseline physical performance measures (QSEBT, Weight- Bearing Lunge Test (WBLT), and Single Leg Wall Squat (SLWS)) and participated in self- report of injury questionnaires throughout BCT. Ultimately, 147 participants reported at least one injury during training. Multiple logistic regression was applied to assess the relationship between the measures taken prior to beginning BCT and the report of musculoskeletal injury. We estimate each centimeter increase in the reach distance of the 3-direction composite QSEBT score (dominant stance leg) is associated with a 2.1% reduction (OR = 0.979, 95% CI [0.958, 1.001], p = 0.06) in the odds of a basic trainee in reporting an injury during BCT, after adjusting for sex, bone mineral density, and the average days of 30 minutes of exercise per week in the two months prior to BCT. The measures obtained on the WBLT and SLWS did not contribute to the final model. Dynamic postural control assessments may contribute to identifying basic trainees at an increased odds of injury during BCT. Future study should examine the predictive validity of the physical performance tests on diagnosed musculoskeletal injury from a medical provider, as well as lost time and attrition from training

Effect of Playing Surface on Knee and Hip Kinematics in Healthy Female Populations

Previous research implicates specific hip and knee kinematics during functional tasks as increasing the risk of ACL injury. Since a large number of severe knee injuries in females are non-contact, the purpose of this study is to determine if knee and hip kinematics during a jump landing cutting task in healthy female populations differ between third generation artificial turf and natural grass playing surfaces. We hypothesized that the task performed on the artificial turf would place the subjects in a biomechanical position that places a greater load on the ACL. Thirty-one female varsity and club soccer athletes performed a 90 degree cutting maneuver immediately after landing from a box jump on a natural grass and a 3rd generation artificial turf playing surface while 3D hip and knee kinematics were assessed. Subjects showed significantly different hip excursions in the frontal (p = 0.038) and transverse (p = 0.048) planes and knee excursions in the frontal plane (p = 0.014) between surface conditions, resulting in increased hip adduction and relatively more internal rotation on artificial turf. Such movements with functional tasks may increase the load placed on the ACL. Therefore, future research is needed to determine the ideal in-fill percentage and type of synthetic fiber, leading to further advancements and improvements in the safety of an artificial surface. In addition, further study into muscle recruitment patterns and the effect of experience on artificial turf surfaces could lead to the development of an intervention program and analysis of its long-term effect on injury prevention.Master of Art

Substrate Scope Analysis of Biocatalytic Halogenation on Complex Substrates

Malbrancheamide is a fungal natural product with significant vasorelaxation effects and potential as a cardiovascular therapeutic. The dichlorination of the indole ring is key for its biological activity, and this transformation is performed by the flavin dependent halogenase MalA. This enzyme utilizes a proposed chloramine lysine intermediate to iteratively and selectively chlorinate its natural substrate premalbrancheamide. Halogenases can provide orthogonal selectivity to many chemical methods, making them useful for pharmaceutical applications, while providing selective methods for late-stage functionalization. This investigation focuses on the substrate scope of the halogenase on complex pharmaceutically relevant substrates in collaboration with the Novartis Institutes for Biomedical Research. The bromination and chlorination reaction conditions were optimized, and the products were structurally characterized by NMR spectroscopy to gain further understanding of the versatility of the wild type enzyme and its mutants

Substrate Scope Analysis of Biocatalytic Halogenation on Complex Substrates

Malbrancheamide is a fungal natural product with significant vasorelaxation effects and potential as a cardiovascular therapeutic. The dichlorination of the indole ring is key for its biological activity, and this transformation is performed by the flavin dependent halogenase MalA. This enzyme utilizes a proposed chloramine lysine intermediate to iteratively and selectively chlorinate its natural substrate premalbrancheamide. Halogenases can provide orthogonal selectivity to many chemical methods, making them useful for pharmaceutical applications, while providing selective methods for late-stage functionalization. This investigation focuses on the substrate scope of the halogenase on complex pharmaceutically relevant substrates in collaboration with the Novartis Institutes for Biomedical Research. The bromination and chlorination reaction conditions were optimized, and the products were structurally characterized by NMR spectroscopy to gain further understanding of the versatility of the wild type enzyme and its mutants

Structural and stereochemical diversity in prenylated indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring system from marine and terrestrial fungi

Various fungi of the generaAspergillus,Penicillium, andMalbrancheaproduce prenylated indole alkaloids possessing a bicyclo[2.2.2]diazaoctane ring system.</p

Machine learning uncovers the most robust self-report predictors of relationship quality across 43 longitudinal couples studies

Given the powerful implications of relationship quality for health and well-being, a central mission of relationship science is explaining why some romantic relationships thrive more than others. This large-scale project used machine learning (i.e., Random Forests) to 1) quantify the extent to which relationship quality is predictable and 2) identify which constructs reliably predict relationship quality. Across 43 dyadic longitudinal datasets from 29 laboratories, the top relationship-specific predictors of relationship quality were perceived-partner commitment, appreciation, sexual satisfaction, perceived-partner satisfaction, and conflict. The top individual-difference predictors were life satisfaction, negative affect, depression, attachment avoidance, and attachment anxiety. Overall, relationship-specific variables predicted up to 45% of variance at baseline, and up to 18% of variance at the end of each study. Individual differences also performed well (21% and 12%, respectively). Actor-reported variables (i.e., own relationship-specific and individual-difference variables) predicted two to four times more variance than partner-reported variables (i.e., the partner’s ratings on those variables). Importantly, individual differences and partner reports had no predictive effects beyond actor-reported relationship-specific variables alone. These findings imply that the sum of all individual differences and partner experiences exert their influence on relationship quality via a person’s own relationship-specific experiences, and effects due to moderation by individual differences and moderation by partner-reports may be quite small. Finally, relationship-quality change (i.e., increases or decreases in relationship quality over the course of a study) was largely unpredictable from any combination of self-report variables. This collective effort should guide future models of relationships

Enzyme evolution in fungal indole alkaloid biosynthesis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154936/1/febs15270_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154936/2/febs15270.pd

Molecular Basis for Selective Late-Stage Transformations in Fungal Indole Alkaloid Biosynthesis

The class of fungal indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring is comprised of diverse molecules that display a range of biological activities. While much interest has been garnered due to their therapeutic potential, this class of molecules also displays unique chemical functionality, making them intriguing synthetic targets. Many elegant and intricate total syntheses have been developed to generate these alkaloids, but selectivity and yield have always presented barriers to efficient synthesis. Alternatively, if we can understand the molecular mechanisms behind how the fungi produce these complex molecules, we can leverage the power of nature to perform these chemical transformations. This work has delved into the enzymatic machinery responsible for key biosynthetic transformations in the production of the fungal indole alkaloids. With full mechanistic characterization, these enzymes are now available as biocatalytic tools for generating pre-existing and novel indole alkaloids in the search for the next line of therapeutic molecules. The studies presented in this thesis start with the discovery of the Diels-Alderase enzymes responsible for forming the characteristic bicyclo[2.2.2]diazaoctane ring. This core component is the signature of this class of molecules and we have found that the enzymes responsible for its formation perform multiple roles in the biosynthesis, including reduction and cyclization. Halogen atoms are found within a small number of the fungal indole alkaloids, but the halogen moieties on these molecules significantly contribute to the biological activity. This is particularly true in the case of malbrancheamide, for which the dichlorination is required for its biological activity. This work has thoroughly characterized the iterative late-stage halogenase (MalA) which performs dichlorination as the last step in malbrancheamide biosynthesis. Cocrystal structures and computational studies have led to the generation of site-selective variants produced through structure-based engineering of the halogenase. A collaboration with Novartis Institutes for BioMedical Research led to the discovery that this halogenase has a broad substrate scope, and thus great utility as a biocatalyst for late-stage halogenation. A common functionality of the fungal indole alkaloids is the spirooxindole center. This is another core component of many molecules within this class, and it provides dimension to an otherwise relatively planar structure. This thesis presents the discovery of a flavin monooxygenase that is responsible for the selective spirocyclization of the potent antihelmintic paraherquamides. The natural substrates of this enzyme were identified and cocrystal structures demonstrated that the enzyme binds the molecules in a manner conducive for stereocontrol. The broad substrate scope demonstrated with PhqK provides further evidence that it could be utilized to develop new therapeutic molecules. As mentioned, this class of fungal indole alkaloids has displayed a wide range of biological activities. There has been significant interest in the malbrancheamides because they have displayed a potent vasorelaxant effect, and a complete reversal of the swelling of cardiac tissue. With this in mind, the culmination of my thesis work demonstrated the utility of malbrancheamide as a probe for protein-protein interactions that have been implicated in cardiovascular disease. Malbrancheamide was characterized as a selective inhibitor of calmodulin, and its unique binding mode relieved the effects of Ca2+-calmodulin-induced cardiac hypertropy. We used the in vitro data with malbrancheamide and the Ca2+-CaM·GRK5 complex to validate a much-debated model for this protein-protein interaction, providing valuable insight for the field of Ca2+-calmodulin-dependent kinase signaling.PHDMedicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/151738/1/aefraley_1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151738/2/aefraley_2.pd