Relationships Between Physical Ability Test Performance and Fitness in Recruits From a Southeastern U.S. Police Department.

ABSTRACT: Lockie, RG, Orr, RM, Sanchez, KJ, Gonzales, SM, Viramontes, E, Kennedy, K, and Dawes, JJ. Relationships between physical ability test performance and fitness in recruits from a southeastern U.S. police department. J Strength Cond Res XX(X): 000-000, 2024-Police recruit occupational ability may be predicted by a physical ability test (PAT). This study determined relationships between a department-specific PAT and fitness test performance among police recruits. Retrospective analysis was conducted on recruit data (1,069 men and 404 women) from one department collected during 2005-2009 and 2016-2020. The following data were provided: grip strength; sit-and-reach; 60-second push-ups; 60-second sit-ups; 2.4-km run; and the PAT. The PAT involved exiting a vehicle and opening the trunk; running ∼201 m; completing an obstacle course; dragging a 68-kg dummy 31 m; completing an obstacle course and running ∼201 m; dry firing a weapon 6 times with each hand; and trunk item placement and vehicle reentry. Relationships between the PAT and fitness tests were measured by partial correlations and stepwise linear regression, both controlling for sex. The PAT was completed in a mean time of 4:16 ± 1:07 minutes:seconds. The PAT significantly (p < 0.001) related to all fitness tests. Moderate relationships were found for push-ups (r = -0.35), sit-ups (r = -0.41), and the 2.4-km run (r = -0.43). Small relationships were found with grip strength (r = -0.19) and the sit-and-reach (r = -0.17). The final regression model, which included sex and all fitness tests except the sit-and-reach, explained ∼53% of the variance. Sex and the 2.4-km run explained ∼47% of the variance. Aerobic fitness appeared to have the greatest impact on PAT performance, which may have related to the PAT design and duration. Tasks completed in succession, and the use of a relatively light dummy, may stress aerobic fitness and muscular endurance to a greater extent.

A Retrospective Analysis of Southeastern U.S. Police Recruit Health and Fitness From 4 Points in Time Within a 16-Year Period: Implications for Physical Fitness Training.

ABSTRACT: Gonzales, SM, Orr, RM, Coburn, JW, Hoffmann, MD, Kennedy, K, Dawes, JJ, and Lockie, RG. A retrospective analysis of southeastern U.S. police recruit health and fitness from 4 points in time within a 16-year period: Implications for physical fitness training. J Strength Cond Res 38(6): 1118-1126, 2024-Drawing from the general population for its recruiting needs, police departments often employ academy curricula to improve a recruit's fitness so they can perform occupational tasks. Recently, obesity and physical inactivity have increased in the general population, potentially influencing the health and fitness of incoming recruits. This study involved a retrospective, cross-sectional analysis of health and fitness data of police recruits. Data from 1 police department in southeastern United States were analyzed at 4 specific time points, splitting the recruits into natural immerging groups; 2003 (n = 93), 2006 (n = 137), 2009 (n = 74), and 2019 (n = 242). Health and fitness data for all recruits included age, height, body mass, and body mass index (BMI); systolic and diastolic blood pressure (BP); sit-and-reach; combined grip strength; push-ups and sit-ups completed in 60 seconds; physical ability test time; and 2.4-km run time. Several univariate analyses, with sex and age as covariates (analyses of covariance), and a Bonferroni's post hoc, determined whether there were significant between-group differences. Effect sizes (d) were also calculated. Key results demonstrated that 2019 recruits were heavier than the recruits in 2006 and 2009 (p ≤ 0.032; d = 0.14-0.38); had a greater BMI (p ≤ 0.028; d = 0.24-0.75) and systolic BP (p < 0.001; d = 0.47-0.65), and lesser sit-and-reach distance (p ≤ 0.020; d = 0.26-0.46), than all recruit groups; completed fewer sit-up repetitions than the recruits in 2006 and 2009 (p ≤ 0.025; d = 0.42-0.48); and were slower in the 2.4-km run than the recruits in 2006 (p = 0.009; d = 0.36). Police training staff may need to address lesser health (BMI, BP) and fitness (hamstring flexibility, abdominal endurance, aerobic fitness) in incoming recruits.

Total Synthesis of (-)-Nodulisporic Acids D, C, and B: Evolution of a Unified Synthetic Strategy.

A unified synthetic strategy leading to the total synthesis of (-)-nodulisporic acids D, C, and B is described. Key synthetic transformations include a nickel-chromium-mediated cyclization, an aromatic ring functionalization employing a novel copper-promoted alkylation, a palladium-catalyzed cross-coupling cascade/indole ring construction, and a palladium-mediated regio- and diastereoselective allylic substitution/cyclization reaction, the latter to construct ring D.

Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase.

A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.

Total Synthesis of (-)-Nodulisporic Acid D.

A convergent total synthesis of the architecturally complex indole diterpenoid (-)-nodulisporic acid D has been achieved. Key synthetic transformations include vicinal difunctionalization of an advanced α,ß-unsaturated aldehyde to form the E,F-trans-fused 5,6-ring system of the eastern hemisphere and a cascade cross-coupling/indolization protocol leading to the CDE multisubstituted indole core.

Novel acyl coenzyme A (CoA): diacylglycerol acyltransferase-1 inhibitors: synthesis and biological activities of diacylethylenediamine derivatives.

A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.

Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase.

A series of N-acyl benzothiazoles shows selective and potent cytotoxicity against cancer cell lines expressing cytochrome P450 4F11. A prodrug form is metabolized by cancer cells into an active inhibitor of stearoyl-CoA desaturase (SCD). Substantial variation on the acyl portion of the inhibitors allowed the identification of (R)-27, which balanced potency, solubility, and lipophilicity to allow proof-of-concept studies in mice. The prodrugs were activated inside the tumor, where they can arrest tumor growth. Together, these observations offer promise that a tumor-activated prodrug strategy might exploit the essentiality of SCD for tumor growth, while avoiding toxicity associated with systemic SCD inhibition.

Decidual cells from women with preeclampsia exhibit inadequate decidualization and reduced sFlt1 suppression.

Uterine stromal cell decidualization of maternal tissue is essential for implantation of and local adaptation to the fetal allograft, as well as growth and maintenance of the placenta in healthy pregnancies. Maternal defects in decidualization have been suggested as a possible driver of preeclampsia. Preeclampsia (PE) pregnancies demonstrate shallow implantation, inadequate spiral artery remodeling, and elevated levels of the anti-angiogenic protein, sFlt1. To test whether stromal cells (DSCs) isolated from PE placentas exhibit inadequate re-decidualization and increased expression of sFlt1, DSCs from normotensive (NT-DSCs) and PE (PE-DSCs) placentas were treated for 8 days (D8) with cAMP to induce decidualization and levels of decidualization markers (PRL, IGFBP1, VEGF) and sFlt1 were measured at day 0 (D0), D8, and after reversal of treatment. NT-DSCs achieved statistically significant elevations in PRL and IFGBP1 expression (25.72 [5.78-50.04], p = 0.0008 and 92.09 [1.79-543.10], p = 0.005). PE-DSCs increased PRL and IFGBP1 expression to 6.15 [2.30-10.73] (p = 0.18) and 8.67 [1.64-376.10] (p = 0.04). NT-DSCs reduced sFlt1 expression at D8 to 0.25 [0.17-0.49] (p = 0.0021) compared to 0.31 [0.25-0.82] (p = 0.087) in PE-DSCs. These results show that, when induced to decidualize, PE-DSCs fail to increase expression of decidualization markers to levels achieved by NT-DSCs. sFlt1 expression is higher in PE-DSCs during decidualization, suggesting inadequate suppression during the crucial implantation period. These defects at the maternal fetal interface may lead to the failed spiral artery modification, decreased placental invasion of the uterus, and elevated circulating sFlt1 levels seen in PE pathology.

Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors.

Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes alpha-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.

Villous explants from preeclamptic placentas induce sFlt1 in PBMCs: An ex vivo co-culture study.

OBJECTIVES: Soluble Flt1 (sFlt1) is an anti-angiogenic protein linked to the pathology of preeclampsia (PE). While the placenta serves as the major organ producing sFlt1 during normal pregnancy, peripheral blood mononuclear cells (PBMCs), endothelial cells, and stromal cells also produce sFlt1. The key question is 'what drives the overexpression of sFlt1 observed during PE?' In the present work we show evidence for sFlt1 over-expression in PBMCs due to interaction with placental villi from PE patients. STUDY DESIGN: sFlt1 production by PBMCs is estimated by using two blood collection methods with different coagulation chemistry. PBMCs were then cultured with homologous villous explants and heterologous villous explants to determine the effects of the interaction between the two tissues. MAIN OUTCOME MEASURES: sFlt1 levels were estimated using real time PCR, ELISA, and gel electrophoresis. RESULTS: Plasma samples obtained using CTAD as anti-coagulant showed 16-23% less sFlt1 compared to plasma collected in EDTA. Preeclamptic PBMCs showed higher basal level of sFlt1 mRNA. In addition, we show evidence of placental interaction as a cause of sFlt1 overexpression in PBMCs using homologous and heterologous co-culture system. However, during co-culture, we observed that while the sFlt1 expression in PE PBMCs is increased, PE villous explants show reduced sFlt1 RNA expression. CONCLUSION: sFlt1 was produced in significant amounts by preeclamptic PBMCs, and ex vivo studies show that the placenta induces this over-expression. In contrast, exposure to PBMCs appears to decrease sFlt1 production by preeclamptic placenta.

Functional Identification of Putrescine C- and N-Hydroxylases.

The small polyamine putrescine (1,4-diaminobutane) is ubiquitously and abundantly found in all three domains of life. It is a precursor, through N-aminopropylation or N-aminobutylation, for biosynthesis of the longer polyamines spermidine, sym-homospermidine, spermine, and thermospermine and longer and branched chain polyamines. Putrescine is also biochemically modified for purposes of metabolic regulation and catabolism, e.g. N-acetylation and N-glutamylation, and for incorporation into specialized metabolites, e.g. N-methylation, N-citrylation, N-palmitoylation, N-hydroxylation, and N-hydroxycinnamoylation. Only one example is known where putrescine is modified on a methylene carbon: the formation of 2-hydroxyputrescine by an unknown C-hydroxylase. Here, we report the functional identification of a previously undescribed putrescine 2-hydroxylase, a Rieske-type nonheme iron sulfur protein from the ß-proteobacteria Bordetella bronchiseptica and Ralstonia solanacearum. Identification of the putrescine 2-hydroxylase will facilitate investigation of the physiological functions of 2-hydroxyputrescine. One known role of 2-hydroxyputrescine has direct biomedical relevance: its role in the biosynthesis of the cyclic hydroxamate siderophore alcaligin, a potential virulence factor of the causative agent of whooping cough, Bordetella pertussis. We also report the functional identification of a putrescine N-hydroxylase from the γ-proteobacterium Shewanella oneidensis, which is homologous to FAD- and NADPH-dependent ornithine and lysine N-monooxygenases involved in siderophore biosynthesis. Heterologous expression of the putrescine N-hydroxylase in E. coli produced free N-hydroxyputrescine, never detected previously in a biological system. Furthermore, the putrescine C- and N-hydroxylases identified here could contribute new functionality to polyamine structural scaffolds, including C-H bond functionalization in synthetic biology strategies.

Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 2.

HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are part of the combination therapy currently used to treat HIV infection. The features of a new NNRTI drug for HIV treatment must include selective potent activity against both wild-type virus as well as against mutant virus that have been selected by use of current antiretroviral treatment regimens. Based on analogy with known HIV-1 NNRTI inhibitors and modeling studies utilizing the X-ray crystal structure of inhibitors bound in the HIV-1 RT, a series of substituted 2-quinolones was synthesized and evaluated as HIV-1 inhibitors.

Identification and structure-activity studies of novel ultrashort-acting benzodiazepine receptor agonists.

The synthesis and evaluation of novel ultrashort-acting benzodiazepine (USA BZD) agonists is described. A BZD scaffold was modified by incorporation of amino acids and derivatives. The propionate side chain of glutamic acid tethers an enzymatically labile functionality where the metabolite carboxylic acid displays markedly reduced BZD receptor affinity. The USA BZDs were characterized by full agonism profiles. Copyright2000 Elsevier Science Ltd.

Relating the structure, activity, and physical properties of ultrashort-acting benzodiazepine receptor agonists.

The ultrashort-acting benzodiazepine (USA BZD) agonists reported previously have been structurally modified to improve aqueous solubility. Lactam-to-amidine modifications, replacement of the C5-haloaryl ring, and annulation of heterocycles are presented. These analogues retain BZD receptor potency and full agonism profiles.