Sex Differences May Exist for Performance Fatigue but Not Recovery After Single-Joint Upper-Body and Lower-Body Resistance Exercise.

ABSTRACT: Lewis, MH, Siedler, MR, Lamadrid, P, Ford, S, Smith, T, SanFilippo, G, Waddell, B, Trexler, ET, Buckner, S, and Campbell, BI. Sex differences may exist for performance fatigue but not recovery after single-joint upper-body and lower-body resistance exercise. J Strength Cond Res 36(6): 1498-1505, 2022-This study evaluated sex differences in performance recovery and fatigue during dynamic exercise. Twenty-eight resistance-trained males (n = 16) and females (n = 12) completed a repeated-measures, randomized, parallel-groups design. The protocol consisted of a baseline assessment, a recovery period (4, 24, or 48 hours), and a postrecovery assessment. The assessments were identical consisting of 4 sets of 10 repetition maximum (10RM) bicep curls and 4 sets of 10RM leg extensions to failure. Recovery was quantified as the number of total repetitions completed in the postrecovery bout. Fatigue was quantified as the number of repetitions completed set to set within the session. For analysis, we set the level of significance at p ≤ 0.05. No sex differences in performance recovery were observed across any of the investigated time periods for either exercise modality. Regarding fatigue, significant effects were observed for set (p < 0.001) and sex (p = 0.031) for bicep curls. Repetitions dropped in later sets, and females generally completed a greater number of repetitions than males (8.8 ± 0.5 vs. 7.2 ± 0.5). For leg extension, a significant sex × set interaction was observed (p = 0.003), but post hoc tests revealed these sex differences as marginal. Our results suggest that in dynamic bicep curls and leg extensions, other factors unrelated to sex may be more impactful on performance recovery. To optimize an athlete's desired adaptations, it may be more important to consider other variables unrelated to sex such as volume, perceived exertion, and training history when formulating training prescriptions for single-joint exercises.

Cognitive tasks during walking affect cerebral blood flow signal features in middle cerebral arteries and their correlation to gait characteristics.

Gait is a complex process involving both cognitive and sensory ability and is strongly impacted by the environment. In this paper, we propose to study of the impact of a cognitive task during gait on the cerebral blood flow velocity, the blood flow signal features and the correlation of gait and blood flow features through a dual task methodology. Both cerebral blood flow velocity and gait characteristics of eleven participants with no history of brain or gait conditions were recorded using transcranial Doppler on mid-cerebral artery while on a treadmill. The cognitive task was induced by a backward counting starting from 10,000 with decrement of 7. Central blood flow velocity raw and envelope features were extracted in both time, frequency and time-scale domain; information-theoretic metrics were also extracted and statistical significances were inspected. A similar feature extraction was performed on the stride interval signal. Statistical differences between the cognitive and baseline trials, between the left and right mid-cerebral arteries signals and the impact of the antropometric variables where studied using linear mixed models. No statistical differences were found between the left and right mid-cerebral arteries flows or the baseline and cognitive state gait features, while statistical differences for specific features were measured between cognitive and baseline states. These statistical differences found between the baseline and cognitive states show that cognitive process has an impact on the cerebral activity during walking. The state was found to have an impact on the correlation between the gait and blood flow features.

Early toxicology signal generation in the mouse.

The rat has been the preferred rodent toxicology species since before regulatory requirements have been in place, and there exists in the pharmaceutical industry and the regulatory agencies a significant amount of historical data for the rat. The resulting experience base with the rat makes the possibility of replacing it with the mouse for regulated toxicology studies untenable for all but the most extreme circumstances. However, toxicologists are very familiar with the mouse as a model for chronic carcinogenicity studies, and there exist multiple preclinical mouse models of disease. The authors evaluated the use of the mouse for early in vivo toxicology signal generation and prioritization of small molecule lead compounds prior to nomination of a development candidate. In five-day oral gavage studies with three test agents in the mouse, the authors were able to identify the same dose-limiting toxicities as those identified in the rat, including examples of compound-mediated hemolysis as well as microscopic lesions in the alimentary canal, kidney, and pancreas. Performing early signal generation studies in the mouse allows for earlier assessment of the safety liabilities of small molecules, requires significantly less compound, and allows evaluation of more compounds earlier in the project's life cycle.

Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders.

During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

Modifying the N-terminus of polyamides: PyImPyIm has improved sequence specificity over f-ImPyIm.

Seven N-terminus modified derivatives of a previously published minor-groove binding polyamide (f-ImPyIm, 1) were synthesized and the biochemical and biophysical chemistry evaluated. These compounds were synthesized with the aim of attaining a higher level of sequence selectivity over f-ImPyIm (1), a previously published strong minor-groove binder. Two compounds possessing a furan or a benzofuran moiety at the N-terminus showed a footprint of 0.5microM at the cognate ACGCGT site (determined by DNase I footprinting); however, the specificity of these compounds was not improved. In contrast, PyImPyIm (4) produced a footprint of 0.5microM but showed a superior specificity using the same technique. When evaluated by thermal melting experiments and circular dichroism using ACGCGT and the non-cognate AAATTT sequence, all compounds were shown to bind in the minor-groove of DNA and stabilize the cognate sequence much better than the non-cognate (except for the non-amido-compound that did not bind either sequence, as expected). PyImPyIm (4) was interesting as the DeltaT(m) for this compound was only 4 degrees C but the footprint was very selective. No binding was observed for this compound with a third DNA (non-cognate, ACCGGT). ITC studies on compound 4 showed exothermic binding with ACGCGT and no heat change was observed for titrating the compound to the other two DNA sequences. The heat capacity (DeltaC(p)) of the PIPI/ACGCGT complex calculated from the hydrophobic interactions and SASA calculations was comparable to the experimental value obtained from ITC (-146calmol(-1)K(-1)). SPR results provided confirmation of the sequence specificity of PyImPyIm (4), with a K(eq) value determined to be 7.1x10(6) M(-1) for the cognate sequence and no observable binding to AAATTT and ACCGGT. Molecular dynamic simulations affirmed that PyImPyIm (4) binds as a dimer in an overlapped conformation, and it fits snugly in the minor-groove of the ACGCGT oligonucleotide. PyImPyIm (4) is an especially interesting molecule, because although the binding affinity is slightly reduced, the specificity with respect to f-ImPyIm (1) is significantly improved.

Superparamagnetic iron oxide particles transactivator protein-fluorescein isothiocyanate particle labeling for in vivo magnetic resonance imaging detection of cell migration: uptake and durability.

Conjugation of dextran-coated superparamagnetic iron oxide (SPIO) particles with transactivator protein (Tat)-peptide and fluorescein isothiocyanate (FITC) allows cells to readily uptake SPIO particles. This makes possible high-resolution, real-time imaging of these cells by magnetic resonance imaging (MRI). First, we need to understand how various subpopulations take up and maintain SPIO particles. In this report, we have focused on differences in T cells, B cells, and macrophages with respect to cross-linked (CL)-SPIO Tat-FITC particle uptake over 72 hours. We have found that cells quickly take up the particles and that the bead loss that does occur is not related to cell death or apoptosis. In contrast with reports in the literature, we have observed migration of the Tat-peptide conjugates primarily to the cytoplasm rather than the nucleus.