Cortical and spinal mechanisms of task failure of sustained submaximal fatiguing contractions

In this and the subsequent companion paper, results are presented that collectively seek to delineate the contribution that supraspinal circuits have in determining the time to task failure (TTF) of sustained submaximal contractions. The purpose of this study was to compare adjustments in supraspinal and spinal excitability taken concurrently throughout the performance of two different fatigue tasks with identical mechanical demands but different TTF (i.e., force-matching and position-matching tasks). On separate visits, ten healthy volunteers performed the force-matching or position-matching task at 15% of maximum strength with the elbow flexors to task failure. Single-pulse transcranial magnetic stimulation (TMS), paired-pulse TMS, paired cortico-cervicomedullary stimulation, and brachial plexus electrical stimulation were delivered in a 6-stimuli sequence at baseline and every 2–3 minutes throughout fatigue-task performance. Contrary to expectations, the force-matching task TTF was 42% shorter (17.5±7.9 min) than the position-matching task (26.9±15.11 min; p0.05). Therefore, failure occurred after a similar mean decline in motorneuron excitability developed (p0.10) and an index of upstream excitation of the motor cortex remained constant (p>0.40). Together, these results suggest that as fatigue develops prior to task failure, the increase in corticospinal excitability observed in relationship to the decrease in spinal excitability results from a combination of decreasing intracortical inhibition with constant levels of intracortical facilitation and upstream excitability that together eventually fail to provide the input to the motor cortex necessary for descending drive to overcome the spinal cord resistance, thereby contributing to task failure

Preliminary evidence that anodal transcranial direct current stimulation enhances time to task failure of a sustained submaximal contraction.

The purpose of this study was to determine whether anodal transcranial direct current stimulation (tDCS) delivered while performing a sustained submaximal contraction would increase time to task failure (TTF) compared to sham stimulation. Healthy volunteers (n = 18) performed two fatiguing contractions at 20% of maximum strength with the elbow flexors on separate occasions. During fatigue task performance, either anodal or sham stimulation was delivered to the motor cortex for up to 20 minutes. Transcranial magnetic stimulation (TMS) was used to assess changes in cortical excitability during stimulation. There was no systematic effect of the anodal tDCS stimulation on TTF for the entire subject set (n = 18; p = 0.64). Accordingly, a posteriori subjects were divided into two tDCS-time groups: Full-Time (n = 8), where TTF occurred prior to the termination of tDCS, and Part-Time (n = 10), where TTF extended after tDCS terminated. The TTF for the Full-Time group was 31% longer with anodal tDCS compared to sham (p = 0.04), whereas TTF for the Part-Time group did not differ (p = 0.81). Therefore, the remainder of our analysis addressed the Full-Time group. With anodal tDCS, the amount of muscle fatigue was 6% greater at task failure (p = 0.05) and the amount of time the Full-Time group performed the task at an RPE between 8–10 (“very hard”) increased by 38% (p = 0.04) compared to sham. There was no difference in measures of cortical excitability between stimulation conditions (p = 0.90). That the targeted delivery of anodal tDCS during task performance both increased TTF and the amount of muscle fatigue in a subset of subjects suggests that augmenting cortical excitability with tDCS enhanced descending drive to the spinal motorpool to recruit more motor units. The results also suggest that the application of tDCS during performance of fatiguing activity has the potential to bolster the capacity to exercise under conditions required to derive benefits due to overload

Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes

Applications of electrodynamic tethers and the STEP-AIRSEDS mission

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76415/1/AIAA-2001-1144-690.pd

Characterization and Structure of a Zn2+ and [2Fe-2S]-containing Copper Chaperone from Archaeoglobus Fulgidus

Bacterial CopZ proteins deliver copper to P1B-type Cu+-ATPases that are homologous to the human Wilson and Menkes disease proteins. The genome of the hyperthermophile Archaeoglobus fulgidus encodes a putative CopZ copper chaperone that contains an unusual cysteine rich N-terminal domain of 130 amino acids in addition to a C-terminal copper-binding domain with a conserved CXXC motif. The N-terminal domain (CopZ-NT) is homologous to proteins found only in extremophiles and is the only such protein that is fused to a copper chaperone. Surprisingly, optical, electron paramagnetic resonance, and X-ray absorption spectroscopic data indicate the presence of a [2Fe-2S] cluster in CopZ-NT. The intact CopZ protein binds two copper ions, one in each domain. The 1.8 Å resolution crystal structure of CopZ-NT reveals that the [2Fe-2S] cluster is housed within a novel fold and that the protein also binds a zinc ion at a four cysteine site. CopZ can deliver Cu+ to the A. fulgidus CopA N-terminal metal binding domain and is capable of reducing Cu2+ to Cu+. This unique fusion of a redox-active domain with a CXXC-containing copper chaperone domain is relevant to the evolution of copper homeostatic mechanisms and suggests new models for copper trafficking

Particulate methane monooxygenase contains only mononuclear copper centers

Bacteria that oxidize methane to methanol are central to mitigating emissions of methane, a potent greenhouse gas. The nature of the copper active site in the primary metabolic enzyme of these bacteria, particulate methane monooxygenase (pMMO), has been controversial owing to seemingly contradictory biochemical, spectroscopic, and crystallographic results. We present biochemical and electron paramagnetic resonance spectroscopic characterization most consistent with two monocopper sites within pMMO: one in the soluble PmoB subunit at the previously assigned active site (CuB) and one ~2 nanometers away in the membrane-bound PmoC subunit (CuC). On the basis of these results, we propose that a monocopper site is able to catalyze methane oxidation in pMMO

The Grizzly, September 28, 2016

Campus Safety Takes Safety Initiatives • Poet Comes to UC • ESL Program Promotes Community Between Students and Staff • New Club Aims to Get Money Out of Politics • Shakespeare in the Summer of Love • Family Day Branches Out • Opinions: Let\u27s (Finally) Talk About Sex Addiction; Frank Ocean\u27s Blonde was Worth Waiting For • Ursinus Men\u27s and Women\u27s Cross Country Team Off to a Hot Start • Rare Breed: The Two-Sport Athletehttps://digitalcommons.ursinus.edu/grizzlynews/1650/thumbnail.jp