Humans can inherently adapt their gait pattern in a way that minimizes the metabolic cost of transport, or walking economy, within a few steps, which is faster than any known direct physiological ...sensor of metabolic energy. Instead, walking economy may be indirectly sensed through mechanoreceptors that correlate with the metabolic cost per step to make such gait adaptations. We tested whether velocity feedback from tibialis anterior (TA) muscle fascicles during the early stance phase of walking could potentially act to indirectly sense walking economy. As participants walked within a range of steady-state speeds and step frequencies, we observed that TA fascicles lengthen on almost every step. Moreover, the average peak fascicle velocity experienced during lengthening reflected the metabolic cost of transport of the given walking condition. We observed that the peak TA muscle activation occurred earlier than could be explained by a short latency reflex response. The activation of the TA muscle just prior to heel strike may serve as a prediction of the magnitude of the ground collision and the associated energy exchange. In this scenario, any unexpected length change experienced by the TA fascicle would serve as an error signal to the nervous system and provide additional information about energy lost per step. Our work helps provide a biomechanical framework to understand the possible neural mechanisms underlying the rapid optimization of walking economy.
The receptor for advanced glycation end products (RAGE) is highly expressed in various cancers and is correlated with poorer outcome in breast and other cancers. Here we tested the role of targeting ...RAGE by multiple approaches in the tumor and tumor microenvironment, to inhibit the metastatic process. We first tested how RAGE impacts tumor cell-intrinsic mechanisms using either RAGE overexpression or knockdown with short hairpin RNAs (shRNAs). RAGE ectopic overexpression in breast cancer cells increased MEK-EMT (MEK-epithelial-to-mesenchymal transition) signaling, transwell invasion and soft agar colony formation, and in vivo promoted lung metastasis independent of tumor growth. RAGE knockdown with multiple independent shRNAs in breast cancer cells led to decreased transwell invasion and soft agar colony formation, without affecting proliferation. In vivo, targeting RAGE shRNA knockdown in human and mouse breast cancer cells, decreased orthotopic tumor growth, reduced tumor angiogenesis and recruitment of inflammatory cells, and markedly decreased metastasis to the lung and liver in multiple xenograft and syngeneic mouse models. To test the non-tumor cell microenvironment role of RAGE, we performed syngeneic studies with orthotopically injected breast cancer cells in wild-type and RAGE-knockout C57BL6 mice. RAGE-knockout mice displayed striking impairment of tumor cell growth compared with wild-type mice, along with decreased mitogen-activated protein kinase signaling, tumor angiogenesis and inflammatory cell recruitment. To test the combined inhibition of RAGE in both tumor cell-intrinsic and non-tumor cells of the microenvironment, we performed in vivo treatment of xenografted tumors with FPS-ZM1 (1 mg/kg, two times per week). Compared with vehicle, FPS-ZM1 inhibited primary tumor growth, inhibited tumor angiogenesis and inflammatory cell recruitment and, most importantly, prevented metastasis to the lung and liver. These data demonstrate that RAGE drives tumor progression and metastasis through distinct tumor cell-intrinsic and -extrinsic mechanisms, and may represent a novel and therapeutically viable approach for treating metastatic cancers.
Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1α stimulates glycolytic energy production ...and promotes tumour growth. Sirtuins are NAD(+)-dependent protein deacetylases that regulate cellular metabolism in response to stress; however, their involvement in the hypoxic response remains unclear. In this study, it is shown that SIRT2-mediated deacetylation of HIF-1α regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1α under hypoxic conditions, whereas HIF-1α protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1α and deacetylated Lys709 of HIF-1α. Deacetylation of HIF-1α by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1α stability, and increased HIF-1α hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD(+)/NADH ratio led to the degradation of HIF-1α by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1α deacetylation is critical for the destablization of HIF-1α and the hypoxic response of tumour cells.
For the controller of wearable lower-limb assistive devices, quantitative understanding of human locomotion serves as the basis for human motion intent recognition and joint-level motion control. ...Traditionally, the required gait data are obtained in gait research laboratories, utilizing marker-based optical motion capture systems. Despite the high accuracy of measurement, marker-based systems are largely limited to laboratory environments, making it nearly impossible to collect the desired gait data in real-world daily-living scenarios. To address this problem, the authors propose a novel exoskeleton-based gait data collection system, which provides the capability of conducting independent measurement of lower limb movement without the need for stationary instrumentation. The basis of the system is a lightweight exoskeleton with articulated knee and ankle joints. To minimize the interference to a wearer's natural lower-limb movement, a unique two-degrees-of-freedom joint design is incorporated, integrating a primary degree of freedom for joint motion measurement with a passive degree of freedom to allow natural joint movement and improve the comfort of use. In addition to the joint-embedded goniometers, the exoskeleton also features multiple positions for the mounting of inertia measurement units (IMUs) as well as foot-plate-embedded force sensing resistors to measure the foot plantar pressure. All sensor signals are routed to a microcontroller for data logging and storage. To validate the exoskeleton-provided joint angle measurement, a comparison study on three healthy participants was conducted, which involves locomotion experiments in various modes, including overground walking, treadmill walking, and sit-to-stand and stand-to-sit transitions. Joint angle trajectories measured with an eight-camera motion capture system served as the benchmark for comparison. Experimental results indicate that the exoskeleton-measured joint angle trajectories closely match those obtained through the optical motion capture system in all modes of locomotion (correlation coefficients of 0.97 and 0.96 for knee and ankle measurements, respectively), clearly demonstrating the accuracy and reliability of the proposed gait measurement system.
The effect of the volume fraction (0.6–8.4%) of the icosahedral phase (I-phase) on the microstructure, texture and mechanical properties of extruded Mg-Zn-Y alloys was examined. During extrusion, the ...eutectic and divorced eutectic I-phase in the cast microstructures was broken into small particles, and the particles were dispersed along the extrusion direction, forming parallel particle bands. The broken I-phase particles promoted grain refinement via a particle-stimulated nucleation mechanism and led to basal texture weakening through dynamic recrystallization. The work hardening rate increased with an increase in the volume fraction of I-phase. However, the strength decreased with an increase in the volume fraction of I-phase due to the texture softening effect. To incorporate the texture softening effect into the Hall-Petch relation, a modified Hall-Petch equation, which simultaneously considers the effects of grain size and texture on strength, was developed using the Schmid factors for basal slip. The proposed equation predicts smaller Hall-Petch slope, friction stress and yield strength with easier activation of basal slip, agreeing with the experimental observations.
•The volume fraction effect of I-phase on the extruded Mg-Zn-Y alloys was examined.•The work hardening rate increased with increasing the volume fraction of I-phase.•The strength decreased with increasing volume fraction of I-phase.•Texture effect on strength was incorporated into the Hall-Petch relation.•Smaller Hall-Petch slope and friction stress with easier activation of basal slip.
Accurate predictive abilities are important for a wide variety of animal behaviors. Inherent to many of these predictions is an understanding of the physics that underlie the behavior. Humans are ...specifically attuned to the physics on Earth but can learn to move in other environments (e.g., the surface of the Moon). However, the adjustments made to their physics-based predictions in the face of altered gravity are not fully understood. The current study aimed to characterize the locomotor adaptation to a novel paradigm for simulated reduced gravity. We hypothesized that exposure to simulated hypogravity would result in updated predictions of gravity-based movement. Twenty participants took part in a protocol that had them perform vertically targeted countermovement jumps before (PRE), during, and after (POST) a physical simulation of hypogravity. Jumping in simulated hypogravity had different neuromechanics from the PRE condition, with reduced ground impulses ( p ≤ .009) and muscle activity prior to the time of landing (i.e., preactivation; p ≤ .016). In the 1 g POST condition, muscle preactivation remained reduced ( p ≤ .033) and was delayed ( p ≤ .008) by up to 33% for most muscles of the triceps surae, reflecting an expectation of hypogravity. The aftereffects in muscle preactivation, along with little-to-no change in muscle dynamics during ground contact, point to a neuromechanical adaptation that affects predictive, feed-forward systems over feedback systems. As such, we conclude that the neural representation, or internal model, of gravity is updated after exposure to simulated hypogravity.
Hot compressive characteristics and processing maps of a cast Mg-9.5Zn-2.0Y alloy with I-phase (ZW92) were studied in the temperature range between 523 and 723 K and in the strain rate range between ...10 super(-3) and 10 s super(-1). According to the analysis of deformation behavior, the rate-controlling mechanism governing deformation during entire compression process was lattice diffusion controlled dislocation climb creep and power-law breakdown. Comparison of the processing maps of ZW92 with those of the cast Mg-Zn-Y alloys with different types of intermetallic compounds (W- and long period stacking ordered phases) and the cast Mg-Al-Zn alloy (AZ80) alloy with beta -Mg sub(17)Al sub(12) phase in terms of eta values and the domain sizes of the unstable regime indicated that ZW92 exhibited a better hot workability at high strain rates above 1 s super(-1). This result was attributed to the suppression of power law breakdown in ZW92 due to occurrence of extensive dynamic recrystallization at high strain rates, which was facilitated by the effective fragmentation and dispersion of I-phase during deformation at high strain rates. A fully recrystallized microstructure composed of defect-free fine grains (9.34 mu m) with high fraction of high angle grain boundaries (0.81) was obtained at 623 K - 10 s super(-1).
Otolith microchemistry was applied to quantify migratory variation and the proportion of native Caribbean stream fishes that undergo full or partial marine migration. Strontium and barium water ...chemistry in four Puerto Rico, U.S.A., rivers was clearly related to a salinity gradient; however, variation in water barium, and thus fish otoliths, was also dependent on river basin. Strontium was the most accurate index of longitudinal migration in tropical diadromous fish otoliths. Among the four species examined, bigmouth sleeper Gobiomorus dormitor, mountain mullet Agonostomus monticola, sirajo goby Sicydium spp. and river goby Awaous banana, most individuals were fully amphidromous, but 9–12% were semi‐amphidromous as recruits, having never experienced marine or estuarine conditions in early life stages and showing no evidence of marine elemental signatures in their otolith core. Populations of one species, G. dormitor, may have contained a small contingent of semi‐amphidromous adults, migratory individuals that periodically occupied marine or estuarine habitats (4%); however, adult migratory elemental signatures may have been confounded with those related to diet and physiology. These findings indicate the plasticity of migratory strategies of tropical diadromous fishes, which may be more variable than simple categorization might suggest.
Powered prosthetic feet require customized tuning to ensure comfort and long-term success for the user, but tuning in both clinical and research settings is subjective, time intensive, and the ...standard for tuning can vary depending on the patient's and the prosthetist's experience levels.
Therefore, we studied eight different metrics of gait quality associated with use of a research-grade powered prosthetic foot in seven individuals with transtibial amputation during treadmill walking. We compared clinically tuned and untuned conditions with the goal of identifying performance-based metrics capable of distinguishing between good (as determined by a clinician) from poor gait quality.
Differences between the tuned and untuned conditions were reflected in ankle power, both the vertical and anterior-posterior impulse symmetry indices, limb-force alignment, and positive ankle work, with improvements seen in all metrics during use of the tuned prosthesis.
Notably, all of these metrics relate to the timing of force generation during walking which is information not directly accessible to a prosthetist during a typical tuning process. This work indicates that relevant, real-time biomechanical data provided to the prosthetist through the future provision of wearable sensors may enhance and improve future clinical tuning procedures associated with powered prostheses as well as their long-term outcomes.
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