Control of hyperpnoea and pulmonary gas exchange during prolonged exercise: The role of group III/IV muscle afferent feedback.

It remains unclear whether feedback from group III/IV muscle afferents is of continuous significance for regulating the pulmonary response during prolonged (>5 min), steady-state exercise. To elucidate the influence of these sensory neurons on hyperpnoea, gas exchange efficiency, arterial oxygenation and acid-base balance during prolonged locomotor exercise, 13 healthy participants (4 females; 21 (3) years, V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ : 46 (8) ml/kg/min) performed consecutive constant-load cycling bouts at ∼50% (20 min), ∼75% (20 min) and ∼100% (5 min) of V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ with intact (CTRL) and pharmacologically attenuated (lumbar intrathecal fentanyl; FENT) group III/IV muscle afferent feedback from the legs. Pulmonary responses were continuously recorded and arterial blood (radial catheter) periodically collected throughout the exercise. Pulmonary gas exchange efficiency was evaluated using the alveolar-arterial P O 2 ${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ difference ( A - a D O 2 ${\mathrm{A - a}}{{D}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ). There were no differences in any of the variables of interest between conditions before the start of the exercise. Pulmonary ventilation was up to 20% lower across all intensities during FENT compared to CTRL exercise (P < 0.001) and this hypoventilation was accompanied by an up to 10% lower arterial P O 2 ${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ and a 2-4 mmHg higher P C O 2 ${{P}_{{\mathrm{C}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ (both P < 0.001). The exercise-induced widening of A - a D O 2 ${\mathrm{A - a}}{{D}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ was up to 25% larger during FENT compared to CTRL (P < 0.001). Importantly, the differences developed within the first minute of each stage and persisted, or further increased, throughout the remainder of each bout. These findings reflect a critical and time-independent significance of feedback from group III/IV leg muscle afferents for continuously regulating the ventilatory response, gas exchange efficiency, arterial oxygenation and acid-base balance during human locomotion. KEY POINTS: Feedback from group III/IV leg muscle afferents reflexly contributes to hyperpnoea during short duration (i.e. <5 min) locomotor exercise. Whether continuous feedback from these sensory neurons is obligatory to ensure adequate pulmonary responses during steady-state exercise of longer duration remains unknown. Lumbar intrathecal fentanyl was used to attenuate the central projection of group III/IV leg muscle afferents during prolonged locomotor exercise (i.e. 45 min) at intensities ranging from 50% to 100% of V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ . Without affecting the metabolic rate, afferent blockade compromised pulmonary ventilation and gas exchange efficiency, consistently impairing arterial oxygenation and facilitating respiratory acidosis throughout exercise. These findings reflect the time-independent significance of feedback from group III/IV muscle afferents for regulating exercise hyperpnoea and gas exchange efficiency, and thus for optimizing arterial oxygenation and acid-base balance, during prolonged human locomotion.

Hypertension Restricts Leg Blood Flow and Aggravates Neuromuscular Fatigue during Human Locomotion in Males.

Patients with hypertension (HTN) are characterized by exaggerated vascular resistance and mean arterial pressure (MAP), and a compromised leg blood flow (QL) response to exercise recruiting a small muscle mass. However, the impact of hypertension on peripheral hemodynamics and the development of neuromuscular fatigue during locomotor activities, which critically depends on QL, remain unknown. Eight HTN (143±11mmHg / 95±6mmHg; 45±13years) and 8 matched (age, activity) controls (120±6mmHg / 77±7mmHg; CTRL) performed constant-load cycling exercise at 25, 50, and 75W (for 4-min each), and at 165±41W (for 5-min). Exercise-induced locomotor muscle fatigue was quantified as the pre- to post-exercise change in quadriceps twitch-torque (∆Qtw, peripheral fatigue) and voluntary activation (∆VA%, central fatigue). QL (Doppler-ultrasound) and leg vascular conductance (LVC) were determined during cycling at 25, 50, and 75W. Heart Rate and ventilatory responses were recorded during all intensities. MAP during exercise was, on average, ~21mmHg higher (P=0.002) and LVC ~39% lower (P=0.001) in HTN compared to CTRL. QL was consistently between 20-30% lower (P=0.004) and heart rate was significantly higher in HTN. Exercise-induced peripheral (∆Qtw: -53±19% vs -25±23%) and central (∆VA%: -7±5% vs -3±2%) fatigue were significantly greater in HTN compared to CTRL. In addition to an exaggerated MAP, LVC and QL were lower during exercise in HTN compared to CTRL. Given the critical role of QL in determining the development of neuromuscular fatigue, these hemodynamic impairments likely accounted for the faster development of neuromuscular fatigue characterizing hypertensive individuals during locomotor exercise.

The exercise pressor reflex - a pressure-raising mechanism with a limited role in regulating leg perfusion during locomotion in young healthy men.

We investigated the role of the exercise pressor reflex (EPR) in regulating the haemodynamic response to locomotor exercise. Eight healthy participants (23 ± 3 years, V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ : 49 ± 6 ml/kg/min) performed constant-load cycling exercise (∼36/43/52/98% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ; 4 min each) without (CTRL) and with (FENT) lumbar intrathecal fentanyl attenuating group III/IV locomotor muscle afferent feedback and, thus, the EPR. To avoid different respiratory muscle metaboreflex and arterial chemoreflex activation during FENT, subjects mimicked the ventilatory response recorded during CTRL. Arterial and leg perfusion pressure (femoral arterial and venous catheters), femoral blood flow (Doppler-ultrasound), microvascular quadriceps blood flow index (indocyanine green), cardiac output (inert gas breathing), and systemic and leg vascular conductance were quantified during exercise. There were no cardiovascular and ventilatory differences between conditions at rest. Pulmonary ventilation, arterial blood gases and oxyhaemoglobin saturation were not different during exercise. Furthermore, cardiac output (-2% to -12%), arterial pressure (-7% to -15%) and leg perfusion pressure (-8% to -22%) were lower, and systemic (up to 16%) and leg (up to 27%) vascular conductance were higher during FENT compared to CTRL. Leg blood flow, microvascular quadriceps blood flow index, and leg O2 -transport and utilization were not different between conditions (P > 0.5). These findings reflect a critical role of the EPR in the autonomic control of the heart, vasculature and, ultimately, arterial pressure during locomotor exercise. However, the lack of a net effect of the EPR on leg blood flow challenges the idea of this cardiovascular reflex as a key determinant of leg O2 -transport during locomotor exercise in healthy, young individuals. KEY POINTS: The role of the exercise pressor reflex (EPR) in regulating leg O2 -transport during human locomotion remains uncertain. We investigated the influence of the EPR on the cardiovascular response to cycling exercise. Lumbar intrathecal fentanyl was used to block group III/IV leg muscle afferents and debilitate the EPR at intensities ranging from 30% to 100% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ . To avoid different respiratory muscle metaboreflex and arterial chemoreflex activation during exercise with blocked leg muscle afferents, subjects mimicked the ventilatory response recorded during control exercise. Afferent blockade increased leg and systemic vascular conductance, but reduced cardiac output and arterial-pressure, with no net effect on leg blood flow. The EPR influenced the cardiovascular response to cycling exercise by contributing to the autonomic control of the heart and vasculature, but did not affect leg blood flow. These findings challenge the idea of the EPR as a key determinant of leg O2 -transport during locomotor exercise in healthy, young individuals.

Autonomic cardiovascular control during exercise.

The cardiovascular response to exercise is largely determined by neurocirculatory control mechanisms that help to raise blood pressure and modulate vascular resistance which, in concert with regional vasodilatory mechanisms, promote blood flow to active muscle and organs. These neurocirculatory control mechanisms include a feedforward mechanism, known as central command, and three feedback mechanisms, namely, 1) the baroreflex, 2) the exercise pressor reflex, and 3) the arterial chemoreflex. The hemodynamic consequences of these control mechanisms result from their influence on the autonomic nervous system and subsequent alterations in cardiac output and vascular resistance. Although stimulation of the baroreflex inhibits sympathetic outflow and facilitates parasympathetic activity, central command, the exercise pressor reflex, and the arterial chemoreflex facilitate sympathetic activation and inhibit parasympathetic drive. Despite considerable understanding of the cardiovascular consequences of each of these mechanisms in isolation, the circulatory impact of their interaction, which occurs when various control systems are simultaneously activated (e.g., during exercise at altitude), has only recently been recognized. Although aging and cardiovascular disease (e.g., heart failure, hypertension) have both been recognized to alter the hemodynamic consequences of these regulatory systems, this review is limited to provide a brief overview on the action and interaction of neurocirculatory control mechanisms in health.

Critical considerations of the contribution of the corticomotoneuronal pathway to central fatigue.

Neural drive originating in higher brain areas reaches exercising limb muscles through the corticospinal-motoneuronal pathway, which links the motor cortex and spinal motoneurones. The properties of this pathway have frequently been observed to change during fatiguing exercise in ways that could influence the development of central fatigue (i.e. the progressive reduction in voluntary muscle activation). However, based on differences in motor cortical and motoneuronal excitability between exercise modalities (e.g. single-joint vs. locomotor exercise), there is no characteristic response that allows for a categorical conclusion about the effect of these changes on functional impairments and performance limitations. Despite the lack of uniformity in findings during fatigue, there is strong evidence for marked 'inhibition' of motoneurones as a direct result of voluntary drive. Endogenous forms of neuromodulation, such as via serotonin released from neurones, can directly affect motoneuronal output and central fatigue. Exogenous forms of neuromodulation, such as brain stimulation, may achieve a similar effect, although the evidence is weak. Non-invasive transcranial direct current stimulation can cause transient or long-lasting changes in cortical excitability; however, variable results across studies cast doubt on its claimed capacity to enhance performance. Furthermore, with these studies, it is difficult to establish a cause-and-effect relationship between brain responsiveness and exercise performance. This review briefly summarizes changes in the corticomotoneuronal pathway during various types of exercise, and considers the relevance of these changes for the development of central fatigue, as well as the potential of non-invasive brain stimulation to enhance motor cortical excitability, motoneuronal output and, ultimately, exercise performance.

On the role of skeletal muscle acidosis and inorganic phosphates as determinants of central and peripheral fatigue: A 31 P-MRS study.

Intramuscular hydrogen ion (H+ ) and inorganic phosphate (Pi) concentrations were dissociated during exercise to challenge their relationships with peripheral and central fatigue in vivo. Ten recreationally active, healthy men (27 ± 5 years; 180 ± 4 cm; 76 ± 10 kg) performed two consecutive intermittent isometric single-leg knee-extensor trials (60 maximal voluntary contractions; 3 s contraction, 2 s relaxation) interspersed with 5 min of rest. Phosphorus magnetic resonance spectroscopy (31 P-MRS) was used to continuously quantify intramuscular [H+ ] and [Pi] during both trials. Using electrical femoral nerve stimulation, quadriceps twitch force (Qtw ) and voluntary activation (VA) were quantified at rest and throughout both trials. Decreases in Qtw and VA from baseline were used to determine peripheral and central fatigue, respectively. Qtw was strongly related to both [H+ ] (ß coefficient: -0.9, P < 0.0001) and [Pi] (-1.1, P < 0.0001) across trials. There was an effect of trial on the relationship between Qtw and [H+ ] (-0.5, P < 0.0001), but not Qtw and [Pi] (0.0, P = 0.976). This suggests that, unlike the unaltered association with [Pi], a given level of peripheral fatigue was associated with a different [H+ ] in Trial 1 vs. Trial 2. VA was related to [H+ ] (-0.3, P < 0.0001), but not [Pi] (-0.2, P = 0.243), across trials and there was no effect of trial (-0.1, P = 0.483). Taken together, these results support intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents in the interstitial space, as a contributor to central fatigue during exercise. KEY POINTS: We investigated the relationship between intramuscular metabolites and neuromuscular function in humans performing two maximal, intermittent, knee-extension trials interspersed with 5 min of rest. Concomitant measurements of intramuscular hydrogen (H+ ) and inorganic phosphate (Pi) concentrations, as well as quadriceps twitch-force (Qtw ) and voluntary activation (VA), were made throughout each trial using phosphorus magnetic resonance spectroscopy (31 P-MRS) and electrical femoral nerve stimulations. Although [Pi] fully recovered prior to the onset of the second trial, [H+ ] did not. Qtw was strongly related to both [H+ ] and [Pi] across both trials. However, the relationship between Qtw and [H+ ] shifted leftward from the first to the second trial, whereas the relationship between Qtw and [Pi] remained unaltered. VA was related to [H+ ], but not [Pi], across both trials. These in vivo findings support the hypotheses of intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents, as a contributor to central fatigue.

On the haemodynamic consequence of the chemoreflex and muscle mechanoreflex interaction in women and men: two tales, one story.

The cardiovascular response resulting from the individual activation of the muscle mechanoreflex (MMR) or the chemoreflex (CR) is different between men and women. Whether the haemodynamic consequence resulting from the interaction of these sympathoexcitatory reflexes is also sex-dependent remains unknown. MMR and CR were activated by passive leg movement (LM) and exposure to hypoxia (O2 -CR) or hypercapnia (CO2 -CR), respectively. Twelve young men and 12 young women completed two experimental protocols: (1) resting in normoxia (PET O2 : ∼83 mmHg, PET CO2 : ∼34 mmHg), normocapnic hypoxia (PET O2 : ∼48 mmHg, PET CO2 : ∼34 mmHg) and hyperoxic hypercapnia (PET O2 : ∼524 mmHg, PET CO2 : ∼44 mmHg); (2) LM under the same gas conditions. During the MMR:O2 -CR coactivation, in men, the observed mean arterial pressure (MAP) and cardiac output (CO) were not different (additive effect), while the observed leg blood flow (LBF) and vascular conductance (LVC) were significantly lower (hypo-additive), compared with the sum of the responses elicited by each reflex alone. In women, the observed MAP was not different (additive) while the observed CO, LBF and LVC were significantly greater (hyper-additive), compared with the summated responses. During the MMR:CO2 -CR coactivation, in men, the observed MAP, CO and LBF were not different (additive), while the observed LVC was significantly lower (hypo-additive), compared with the summated responses. In women, the observed MAP was significantly higher (hyper-additive), while the observed CO, LBF and LVC were not different (additive), compared with the summated responses. The interaction of the MMR and CR has a pronounced influence on the autonomic cardiovascular control, with the haemodynamic consequences differing between men and women. KEY POINTS: The cardiovascular response resulting from the activation of the muscle mechanoreflex (MMR) or the chemoreflex (CR) was previously shown to be different between women and men; this study focused on the haemodynamic consequence of the interaction of these two sympathoexcitatory reflexes. MMR and CR were activated by passive leg movement and exposure to hypoxia (O2 -CR) or hypercapnia (CO2 -CR), respectively. Individual and interactive reflex effects on central and peripheral haemodynamics were quantified in healthy young women and men. In men, the MMR:O2 -CR and MMR:CO2 -CR interactions restricted peripheral haemodynamics, likely by potentiating sympathetic vasoconstriction. In women, the MMR:O2 -CR interaction facilitated central and peripheral haemodynamics, likely by potentiating sympathetic vasodilatation; however, the MMR:CO2 -CR interaction was simply additive for the central and peripheral haemodynamics. The interaction between the MMR and the CR exerts a profound influence on the autonomic control of cardiovascular function in humans, with the haemodynamic consequences differing between women and men.

The 2020 report of The Lancet Countdown on health and climate change: responding to converging crises.

TRANSLATIONS: For the Chinese, French, German, and Spanish translations of the abstract see Supplementary Materials section.

Gene and protein expression of dorsal root ganglion sensory receptors in normotensive and hypertensive male rats.

The exercise pressor reflex (EPR), a neurocirculatory control mechanism, is exaggerated in hypertensive humans and rats. Disease-related abnormalities within the afferent arm of the reflex loop, including mechano- and metabosensitive receptors located at the terminal end of group III/IV muscle afferents, may contribute to the dysfunctional EPR in hypertension. Using control (WKY) and spontaneous hypertensive (SHR) rats, we examined dorsal root ganglion (DRG) gene and protein expression of molecular receptors recognized as significant determinants of the EPR. Twelve lumbar DRGs (6 left, 6 right) were harvested from each of 10 WKY [arterial blood pressure (MAP): 96 ± 9 mmHg] and 10 SHR (MAP: 144 ± 9 mmHg). DRGs from the left side were used for protein expression (Western blotting; normalized to GAPDH), whereas right-side DRGs (i.e., parallel structure) were used to determine mRNA levels (RNA-sequencing, normalized to TPM). Analyses focused on metabosensitive (ASIC3, Bradykinin receptor B2, EP4, P2X3, TRPv1) and mechanosensitive (Piezo1/2) receptors. Although Piezo1 was similar in both groups (P = 0.75), protein expression for all other receptors was significantly higher in SHR compared with WKY. With the exception of a greater Bradykinin-receptor B2 in SHR (P < 0.05), mRNA expression of all other receptors was not different between groups (P > 0.18). The higher protein content of these sensory receptors in SHR indirectly supports the previously proposed hypothesis that the exaggerated EPR in hypertension is, in part, due to disease-related abnormalities within the afferent arm of the reflex loop. The upregulated receptor content, combined with normal mRNA levels, insinuates that posttranscriptional regulation of sensory receptor protein expression might be impaired in hypertension.

Analysis of the air pollution reduction and climate change mitigation effects of the Three-Year Action Plan for Blue Skies on the "2+26" Cities in China.

City clusters play an important role in air pollutant and greenhouse gas (GHG) emissions reduction in China, primarily due to their high fossil energy consumption levels. The "2 + 26" Cities, i.e., Beijing, Tianjin and 26 other perfectures in northern China, has experienced serious air pollution in recent years. We employ the Greenhouse Gas and Air Pollution Interactions and Synergies model adapted to the "2 + 26" Cities (GAINS-JJJ) to evaluate the impacts of structural adjustments in four major sectors, industry, energy, transport and land use, under the Three-Year Action Plan for Blue Skies (Three-Year Action Plan) on the emissions of both the major air pollutants and CO2 in the "2 + 26" Cities. The results indicate that the Three-Year Action Plan applied in the "2 + 26" Cities reduces the total emissions of primary fine particulate matter with an aerodynamic diameter of ≤ 2.5 µm (PM2.5), SO2, NOx, NH3 and CO2 by 17%, 25%, 21%, 3% and 1%, respectively, from 2017 to 2020. The emission reduction potentials vary widely across the 28 prefectures, which may be attributed to the differences in energy structure, industrial composition, and policy enforcement rate. Among the four sectors, adjustment of industrial structure attains the highest co-benefits of CO2 reduction and air pollution control due to its high CO2 reduction potential, while structural adjustments in energy and transport attain much lower co-benefits, despite their relatively high air pollutant emissions reductions, primarily resulting from an increase in the coal-electric load and associated carbon emissions caused by electric reform policies..

Electrically induced quadriceps fatigue in the contralateral leg impairs ipsilateral knee extensors performance.

Muscle fatigue induced by voluntary exercise, which requires central motor drive, causes central fatigue that impairs endurance performance of a different, nonfatigued muscle. This study investigated the impact of quadriceps fatigue induced by electrically induced (no central motor drive) contractions on single-leg knee-extension (KE) performance of the subsequently exercising ipsilateral quadriceps. On two separate occasions, eight males completed constant-load (85% of maximal power-output) KE exercise to exhaustion. In a counterbalanced manner, subjects performed the KE exercise with no pre-existing quadriceps fatigue in the contralateral leg on one day (No-PreF), whereas on the other day, the same KE exercise was repeated following electrically induced quadriceps fatigue in the contralateral leg (PreF). Quadriceps fatigue was assessed by evaluating pre- to postexercise changes in potentiated twitch force (ΔQtw,pot; peripheral fatigue), and voluntary muscle activation (ΔVA; central fatigue). As reflected by the 57 ± 11% reduction in electrically evoked pulse force, the electrically induced fatigue protocol caused significant knee-extensors fatigue. KE endurance time to exhaustion was shorter during PreF compared with No-PreF (4.6 ± 1.2 vs 7.7 ± 2.4 min; P < 0.01). Although ΔQtw,pot was significantly larger in No-PreF compared with PreF (-60% vs -52%, P < 0.05), ΔVA was greater in PreF (-14% vs -10%, P < 0.05). Taken together, electrically induced quadriceps fatigue in the contralateral leg limits KE endurance performance and the development of peripheral fatigue in the ipsilateral leg. These findings support the hypothesis that the crossover effect of central fatigue is mainly mediated by group III/IV muscle afferent feedback and suggest that impairments associated with central motor drive may only play a minor role in this phenomenon.

Acute high-intensity exercise and skeletal muscle mitochondrial respiratory function: role of metabolic perturbation.

Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: -67% vs. -82%, Pi: 353% vs. 534%, pH: -0.22 vs. -0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (-3% and -36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (-15% and -33%), complex II (-36% and -23%), complex I + II (-31% and -20%), and state 3CI+CII control ratio (-24% and -39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response.

Giant Nonlinear Circular Dichroism from Intersubband Polaritonic Metasurfaces.

Nonlinear metasurfaces are advancing into a new paradigm of "flat nonlinear optics" owing to the ability to engineer local nonlinear responses in subwavelength-thin films. Recently, attempts have been made to expand the design space of nonlinear metasurfaces through nonlinear chiral responses. However, the development of metasurfaces that display both giant nonlinear circular dichroism and significantly large nonlinear optical response is still an unresolved challenge. Herein, we propose a method that induces giant nonlinear responses with near-unity circular dichroism using polaritonic metasurfaces with optical modes in chiral plasmonic nanocavities coupled with intersubband transitions in semiconductor heterostructures designed to have giant second and third order nonlinear responses. A stark contrast between effective nonlinear susceptibility elements for the two spin states of circularly polarized pump beams was seen in the hybrid structure. Experimentally, near-unity nonlinear circular dichroism and conversion efficiencies beyond 10-4% for second- and third-harmonic generation were achieved simultaneously in a single chip.

The exercise pressor reflex and chemoreflex interaction: cardiovascular implications for the exercising human.

KEY POINTS: Although the exercise pressor reflex (EPR) and the chemoreflex (CR) are recognized for their sympathoexcitatory effect, the cardiovascular implication of their interaction remains elusive. We quantified the individual and interactive cardiovascular consequences of these reflexes during exercise and revealed various modes of interaction. The EPR and hypoxia-induced CR interaction is hyper-additive for blood pressure and heart rate (responses during co-activation of the two reflexes are greater than the summation of the responses evoked by each reflex) and hypo-additive for peripheral haemodynamics (responses during co-activation of the reflexes are smaller than the summated responses). The EPR and hypercapnia-induced CR interaction results in a simple addition of the individual responses to each reflex (i.e. additive interaction). Collectively, EPR:CR co-activation results in significant cardiovascular interactions with restriction in peripheral haemodynamics, resulting from the EPR:CR interaction in hypoxia, likely having the most crucial impact on the functional capacity of an exercising human. ABSTRACT: We investigated the interactive effect of the exercise pressor reflex (EPR) and the chemoreflex (CR) on the cardiovascular response to exercise. Eleven healthy participants (5 females) completed a total of six bouts of single-leg knee-extension exercise (60% peak work rate, 4 min each) either with or without lumbar intrathecal fentanyl to attenuate group III/IV afferent feedback from lower limbs to modify the EPR, while breathing either ambient air, normocapnic hypoxia (Sa O2 ∼79%, Pa O2 ∼43 mmHg, Pa CO2 ∼33 mmHg, pH ∼7.39), or normoxic hypercapnia (Sa O2 ∼98%, Pa O2 ∼105 mmHg, Pa CO2 ∼50 mmHg, pH ∼7.26) to modify the CR. During co-activation of the EPR and the hypoxia-induced CR (O2 -CR), mean arterial pressure and heart rate were significantly greater, whereas leg blood flow and leg vascular conductance were significantly lower than the summation of the responses evoked by each reflex alone. During co-activation of the EPR and the hypercapnia-induced CR (CO2 -CR), the haemodynamic responses were not different from the summated responses to each reflex response alone (P ≥ 0.1). Therefore, while the interaction resulting from the EPR:O2 -CR co-activation is hyper-additive for blood pressure and heart rate, and hypo-additive for peripheral haemodynamics, the interaction resulting from the EPR:CO2 -CR co-activation is simply additive for all cardiovascular parameters. Thus, EPR:CR co-activation results in significant interactions between cardiovascular reflexes, with the impact differing when the CR activation is achieved by hypoxia or hypercapnia. Since the EPR:CR co-activation with hypoxia potentiates the pressor response and restricts blood flow to contracting muscles, this interaction entails the most functional impact on an exercising human.

On the Influence of Group III/IV Muscle Afferent Feedback on Endurance Exercise Performance.

This review discusses evidence suggesting that group III/IV muscle afferents affect locomotor performance by influencing neuromuscular fatigue. These neurons regulate the hemodynamic and ventilatory response to exercise and, thus, assure appropriate locomotor muscle O2 delivery, which optimizes peripheral fatigue development and facilitates endurance performance. In terms of central fatigue, group III/IV muscle afferents inhibit motoneuronal output and thereby limit exercise performance.

Reducing global air pollution: the scope for further policy interventions.

Over the last decades, energy and pollution control policies combined with structural changes in the economy decoupled emission trends from economic growth, increasingly also in the developing world. It is found that effective implementation of the presently decided national pollution control regulations should allow further economic growth without major deterioration of ambient air quality, but will not be enough to reduce pollution levels in many world regions. A combination of ambitious policies focusing on pollution controls, energy and climate, agricultural production systems and addressing human consumption habits could drastically improve air quality throughout the world. By 2040, mean population exposure to PM2.5 from anthropogenic sources could be reduced by about 75% relative to 2015 and brought well below the WHO guideline in large areas of the world. While the implementation of the proposed technical measures is likely to be technically feasible in the future, the transformative changes of current practices will require strong political will, supported by a full appreciation of the multiple benefits. Improved air quality would avoid a large share of the current 3-9 million cases of premature deaths annually. At the same time, the measures that deliver clean air would also significantly reduce emissions of greenhouse gases and contribute to multiple UN sustainable development goals. This article is part of a discussion meeting issue 'Air quality, past present and future'.

Giant nonlinear response from plasmonic metasurfaces coupled to intersubband transitions.

Intersubband transitions in n-doped multi-quantum-well semiconductor heterostructures make it possible to engineer one of the largest known nonlinear optical responses in condensed matter systems--but this nonlinear response is limited to light with electric field polarized normal to the semiconductor layers. In a different context, plasmonic metasurfaces (thin conductor-dielectric composite materials) have been proposed as a way of strongly enhancing light-matter interaction and realizing ultrathin planarized devices with exotic wave properties. Here we propose and experimentally realize metasurfaces with a record-high nonlinear response based on the coupling of electromagnetic modes in plasmonic metasurfaces with quantum-engineered electronic intersubband transitions in semiconductor heterostructures. We show that it is possible to engineer almost any element of the nonlinear susceptibility tensor of these structures, and we experimentally verify this concept by realizing a 400-nm-thick metasurface with nonlinear susceptibility of greater than 5 × 10(4) picometres per volt for second harmonic generation at a wavelength of about 8 micrometres under normal incidence. This susceptibility is many orders of magnitude larger than any second-order nonlinear response in optical metasurfaces measured so far. The proposed structures can act as ultrathin highly nonlinear optical elements that enable efficient frequency mixing with relaxed phase-matching conditions, ideal for realizing broadband frequency up- and down-conversions, phase conjugation and all-optical control and tunability over a surface.

Identifying the role of group III/IV muscle afferents in the carotid baroreflex control of mean arterial pressure and heart rate during exercise.

KEY POINTS: We investigated the contribution of group III/IV muscle afferents to carotid baroreflex resetting during electrically evoked (no central command) and voluntary (requiring central command) isometric knee extension exercise. Lumbar intrathecal fentanyl was used to attenuate the central projection of µ-opioid receptor-sensitive group III/IV leg muscle afferent feedback. Spontaneous carotid baroreflex control was assessed by loading and unloading the carotid baroreceptors with a variable pressure neck chamber. Group III/IV muscle afferents did not influence spontaneous carotid baroreflex responsiveness at rest or during exercise. Afferent feedback accounted for at least 50% of the exercise-induced increase in the carotid baroreflex blood pressure and heart rate operating points, adjustments that are critical for an appropriate cardiovascular response to exercise. These findings suggest that group III/IV muscle afferent feedback is, independent of central command, critical for the resetting of the carotid baroreflex blood pressure and heart rate operating points, but not for spontaneous baroreflex responsiveness. ABSTRACT: This study sought to comprehensively investigate the role of metabolically and mechanically sensitive group III/IV muscle afferents in carotid baroreflex responsiveness and resetting during both electrically evoked (EVO, no central command) and voluntary (VOL, requiring central command) isometric single-leg knee-extension (15% of maximal voluntary contraction; MVC) exercise. Participants (n = 8) were studied under control conditions (CTRL) and following lumbar intrathecal fentanyl injection (FENT) to inhibit µ-opioid receptor-sensitive lower limb muscle afferents. Spontaneous carotid baroreflex control of mean arterial pressure (MAP) and heart rate (HR) were assessed following rapid 5 s pulses of neck pressure (NP, +40 mmHg) or suction (NS, -60 mmHg). Resting MAP (87 ± 10 mmHg) and HR (70 ± 8 bpm) were similar between CTRL and FENT conditions (P > 0.4). In terms of spontaneous carotid baroreflex responsiveness, FENT did not alter the change in MAP or HR responses to NP (+13 ± 5 mmHg, P = 0.85; +9 ± 3 bpm; P = 0.99) or NS (-13 ± 5 mmHg, P = 0.99; -24 ± 11 bpm; P = 0.49) at rest or during either exercise protocol, which were of a remarkably similar magnitude to rest. In contrast, FENT administration reduced the exercise-induced resetting of the operating point for MAP and HR during both EVO (116 ± 10 mmHg to 100 ± 15 mmHg and 93 ± 14 bpm to 82 ± 10 bpm) and VOL (107 ± 13 mmHg to 100 ± 17 mmHg and 89 ± 10 bpm to 72 ± 10 bpm) exercise bouts. Together, these findings document that group III/IV muscle afferent feedback is critical for the resetting of the carotid baroreflex MAP and HR operating points, independent of exercise-induced changes in central command, but not for spontaneous carotid baroreflex responsiveness.