A comparison of the effects of fatigue on subjective and objective assessment of situation awareness in cycling

Maximal effort on a 30 km Time Trial (TT30) was examined to assess whether it would elicit changes in objective and subjective tests of the participants’ perception of the environment and their ability to anticipate future occurrences (situation awareness; SA) and to determine the effect of post-exercise recovery on SA. Nine experienced (5.22 ± 2.77 years) road cyclists had their objective and subjective levels of SA assessed prior to and at the completion of two TT30. The participants’ results were compared to measurements of maximal oxygen uptake (VO2max), peak power output (PPO), age and years of competitive cycle racing experience. Fatigue resulting from maximal effort on a TT30 produced significant changes in both the objective and subjective test of SA. Effect sizes of 0.93 and 0.99 indicated that the first and second TT30 were likely or almost certain to have a beneficial effect on the objective assessment of SA. However, the effect sizes of 0.97 and 0.95 relating to the subjective assessment of cognitive performance on the first and second TT30 showed that it was very likely the participants’ had an increased difficulty in maintaining SA. A recovery period of up to three minutes post TT30 had no effect on SA. Changes in SA had no relationship with measurements of VO2max, peak power output (PPO), age and years of competitive cycle racing experience. The findings suggest that within a laboratory environment, participants consistently underestimate their ability to make accurate assessments of their cycling environment compared to objective measures of their SA

Consistent Point Data Assimilation in Firedrake and Icepack

We present methods and tools that significantly improve the ability to estimate quantities and fields which are difficult to directly measure, such as the fluidity of ice, using point data sources, such as satellite altimetry. These work with both sparse and dense point data with estimated quantities and fields becoming more accurate as the number of measurements are increased. Such quantities and fields are often used as inputs to mathematical models that are used to make predictions so improving their accuracy is of vital importance. We demonstrate how our methods and tools can increase the accuracy of results, ensure posterior consistency, and aid discourse between modellers and experimenters. To do this, we bring point data into the finite element method ecosystem as discontinuous fields on meshes of disconnected vertices. Point evaluation can then be formulated as a finite element interpolation operation (dual-evaluation). Our new abstractions are well-suited to automation. We demonstrate this by implementing them in Firedrake, which generates highly optimised code for solving PDEs with the finite element method. Our solution integrates with dolfin-adjoint/pyadjoint which allows PDE-constrained optimisation problems, such as data assimilation, to be solved through forward and adjoint mode automatic differentiation. We demonstrate our new functionality through examples in the fields of groundwater hydrology and glaciology

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

Preserving skeletal muscle function is essential to maintain life quality at high age. Calorie restriction (CR) potently extends health and lifespan, but is largely unachievable in humans, making "CR mimetics" of great interest. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, is considered a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Here we show that long-term CR and rapamycin unexpectedly display distinct gene expression profiles in geriatric mouse skeletal muscle, despite both benefiting aging muscles. Furthermore, CR improves muscle integrity in mice with nutrient-insensitive, sustained muscle mTORC1 activity and rapamycin provides additive benefits to CR in naturally aging mouse muscles. We conclude that rapamycin and CR exert distinct, compounding effects in aging skeletal muscle, thus opening the possibility of parallel interventions to counteract muscle aging

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

As global life expectancy continues to climb, maintaining skeletal muscle function is increasingly essential to ensure a good life quality for aging populations. Calorie restriction (CR) is the most potent and reproducible intervention to extend health and lifespan, but is largely unachievable in humans. Therefore, identification of "CR mimetics" has received much attention. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, has been proposed as a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Contrary to our expectation, long-term CR and rapamycin-treated geriatric mice display distinct skeletal muscle gene expression profiles despite both conferring benefits to aging skeletal muscle. Furthermore, CR improved muscle integrity in a mouse with nutrient-insensitive sustained muscle mTORC1 activity and rapamycin provided additive benefits to CR in aging mouse muscles. Therefore, RM and CR exert distinct, compounding effects in aging skeletal muscle, opening the possibility of parallel interventions to counteract muscle aging

BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle

Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases

Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated PKB/Akt inhibition and point to juxtaposed roles of the UPS in atrophy and proteome integrity

Disruption of endosomal trafficking with EGA alters TLR9 cytokine response in human plasmacytoid dendritic cells

Plasmacytoid dendritic cells (pDCs) exhibit bifurcated cytokine responses to TLR9 agonists, an IRF7-mediated type 1 IFN response or a pro-inflammatory cytokine response via the activation of NF-κB. This bifurcated response has been hypothesized to result from either distinct signaling endosomes or endo-lysosomal trafficking delay of TLR9 agonists allowing for autocrine signaling to affect outcomes. Utilizing the late endosome trafficking inhibitor, EGA, we assessed the bifurcated cytokine responses of pDCs to TLR9 stimulation. EGA treatment of pDCs diminished both IFNα and pro-inflammatory cytokine expression induced by CpG DNAs (D- and K-type), CpG-DNAs complexed with DOTAP, and genomic DNAs complexed with LL37. Mechanistically, EGA suppressed phosphorylation of IKKα/β, STAT1, Akt, and p38, and decreased colocalization of CpG oligodeoxynucleotides with LAMP+ endo-lysosomes. EGA also diminished type 1 IFN expression by pDCs from systemic lupus erythematosus patients. Therefore, our findings help understand mechanisms for the bifurcated cytokine responses by pDCs and support future examination of the potential benefit of EGA in treating type 1 IFN-associated inflammatory diseases in the future

The Higgs sector of the munuSSM and collider physics

The $\mu\nu$SSM is a supersymmetric standard model that accounts for light neutrino masses and solves the $\mu$ problem of the MSSM by simply using right-handed neutrino superfields. Since this mechanism breaks R-parity, a peculiar structure for the mass matrices is generated. The neutral Higgses are mixed with the right- and left-handed sneutrinos producing 8$\times$8 neutral scalar mass matrices. We analyse the Higgs sector of the $\mu\nu$SSM in detail, with special emphasis in possible signals at colliders. After studying in general the decays of the Higges, we focus on those processes that are genuine of the $\mu\nu$SSM, and could serve to distinguish it from other supersymmetric models. In particular, we present viable benchmark points for LHC searches. For example, we find decays of a MSSM-like Higgs into two lightest neutralinos, with the latter decaying inside the detector leading to displaced vertices, and producing final states with 4 and 8 $b$-jets plus missing energy. Final states with leptons and missing energy are also found.Comment: Final version to appear in JHEP. The discussion on signals at colliders, expanded. 33 pages, 8 figures and 9 table