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Global warming increases available sensible and latent heat energy, increasing the thermodynamic potential wind intensity of tropical cyclones (TCs). Supported by theory, observations, and modeling, this causes a shift in mean TC intensity, which tends to manifest most clearly at the greatest intensities. The Saffir-Simpson scale for categorizing damage based on the wind intensity of TCs was introduced in the early 1970s and remains the most commonly used metric for public communication of the level of wind hazard that a TC poses. Because the scale is open-ended and does not extend beyond category 5 (70 m/s windspeed or greater), the level of wind hazard conveyed by the scale remains constant regardless of how far the intensity extends beyond 70 m/s. This may be considered a weakness of the scale, particularly considering that the destructive potential of the wind increases exponentially. Here, we consider how this weakness becomes amplified in a warming world by elucidating the past and future increases of peak wind speeds in the most intense TCs. A simple extrapolation of the Saffir-Simpson scale is used to define a hypothetical category 6, and we describe the frequency of TCs, both past and projected under global warming, that would fall under this category. We find that a number of recent storms have already achieved this hypothetical category 6 intensity and based on multiple independent lines of evidence examining the highest simulated and potential peak wind speeds, more such storms are projected as the climate continues to warm.
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Shotgun phosphoproteomics enables high-throughput analysis of phosphopeptides in biological samples. One of the primary challenges associated with this technology is the relatively low rate of phosphopeptide identification during data analysis. This limitation hampers the full realization of the potential offered by shotgun phosphoproteomics. Here we present DeepRescore2, a computational workflow that leverages deep learning-based retention time and fragment ion intensity predictions to improve phosphopeptide identification and phosphosite localization. Using a state-of-the-art computational workflow as a benchmark, DeepRescore2 increases the number of correctly identified peptide-spectrum matches by 17% in a synthetic dataset and identifies 19% to 46% more phosphopeptides in biological datasets. In a liver cancer dataset, 30% of the significantly altered phosphosites between tumor and normal tissues and 60% of the prognosis-associated phosphosites identified from DeepRescore2-processed data could not be identified based on the state-of-the-art workflow. Notably, DeepRescore2-processed data uniquely identifies EGFR hyperactivation as a new target in poor-prognosis liver cancer, which is validated experimentally. Integration of deep learning prediction in DeepRescore2 improves phosphopeptide identification and facilitates biological discoveries.
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Aprendizado Profundo , Neoplasias Hepáticas , Humanos , Fosforilação , Fosfopeptídeos/metabolismo , ProteômicaRESUMO
The Gulf of Mexico is the largest offshore fossil fuel production basin in the United States. Decisions on expanding production in the region legally depend on assessments of the climate impact of new growth. Here, we collect airborne observations and combine them with previous surveys and inventories to estimate the climate impact of current field operations. We evaluate all major on-site greenhouse gas emissions, carbon dioxide (CO2) from combustion, and methane from losses and venting. Using these findings, we estimate the climate impact per unit of energy of produced oil and gas (the carbon intensity). We find high methane emissions (0.60 Tg/y [0.41 to 0.81, 95% confidence interval]) exceeding inventories. This elevates the average CI of the basin to 5.3 g CO2e/MJ [4.1 to 6.7] (100-y horizon) over twice the inventories. The CI across the Gulf varies, with deep water production exhibiting a low CI dominated by combustion emissions (1.1 g CO2e/MJ), while shallow federal and state waters exhibit an extraordinarily high CI (16 and 43 g CO2e/MJ) primarily driven by methane emissions from central hub facilities (intermediaries for gathering and processing). This shows that production in shallow waters, as currently operated, has outsized climate impact. To mitigate these climate impacts, methane emissions in shallow waters must be addressed through efficient flaring instead of venting and repair, refurbishment, or abandonment of poorly maintained infrastructure. We demonstrate an approach to evaluate the CI of fossil fuel production using observations, considering all direct production emissions while allocating to all fossil products.
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Agricultural expansion and intensification have boosted global food production but have come at the cost of environmental degradation and biodiversity loss. Biodiversity-friendly farming that boosts ecosystem services, such as pollination and natural pest control, is widely being advocated to maintain and improve agricultural productivity while safeguarding biodiversity. A vast body of evidence showing the agronomic benefits of enhanced ecosystem service delivery represent important incentives to adopt practices enhancing biodiversity. However, the costs of biodiversity-friendly management are rarely taken into account and may represent a major barrier impeding uptake by farmers. Whether and how biodiversity conservation, ecosystem service delivery, and farm profit can go hand in hand is unknown. Here, we quantify the ecological, agronomic, and net economic benefits of biodiversity-friendly farming in an intensive grassland-sunflower system in Southwest France. We found that reducing land-use intensity on agricultural grasslands drastically enhances flower availability and wild bee diversity, including rare species. Biodiversity-friendly management on grasslands furthermore resulted in an up to 17% higher revenue on neighboring sunflower fields through positive effects on pollination service delivery. However, the opportunity costs of reduced grassland forage yields consistently exceeded the economic benefits of enhanced sunflower pollination. Our results highlight that profitability is often a key constraint hampering adoption of biodiversity-based farming and uptake critically depends on society's willingness to pay for associated delivery of public goods such as biodiversity.
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Ecossistema , Polinização , Abelhas , Animais , Fazendas , Biodiversidade , Agricultura/métodos , Produtos Agrícolas , Conservação dos Recursos NaturaisRESUMO
The purpose of this review is to explore and discuss the impacts of augmented training volume, intensity, and duration on the phosphorylation/activation of key signaling protein - AMPK, CaMKII and PGC-1α - involved in the initiation of mitochondrial biogenesis. Specifically, we explore the impacts of augmented exercise protocols on AMP/ADP and Ca2+ signaling and changes in post exercise PGC - 1α gene expression. Although AMP/ADP concentrations appear to increase with increasing intensity and during extended durations of higher intensity exercise AMPK activation results are varied with some results supporting and intensity/duration effect and others not. Similarly, CaMKII activation and signaling results following exercise of different intensities and durations are inconsistent. The PGC-1α literature is equally inconsistent with only some studies demonstrating an effect of intensity on post exercise mRNA expression. We present a novel meta-analysis that suggests that the inconsistency in the PGC-1α literature may be due to sample size and statistical power limitations owing to the effect of intensity on PGC-1α expression being small. There is little data available regarding the impact of exercise duration on PGC-1α expression. We highlight the need for future well designed, adequately statistically powered, studies to clarify our understanding of the effects of volume, intensity, and duration on the induction of mitochondrial biogenesis by exercise.
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Proteínas Quinases Ativadas por AMP , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Fosforilação , RNA Mensageiro/genética , HumanosRESUMO
Histotripsy is a relatively new therapeutic ultrasound technology to mechanically liquefy tissue into subcellular debris using high-amplitude focused ultrasound pulses. In contrast to conventional high-intensity focused ultrasound thermal therapy, histotripsy has specific clinical advantages: the capacity for real-time monitoring using ultrasound imaging, diminished heat sink effects resulting in lesions with sharp margins, effective removal of the treated tissue, a tissue-selective feature to preserve crucial structures, and immunostimulation. The technology is being evaluated in small and large animal models for treating cancer, thrombosis, hematomas, abscesses, and biofilms; enhancing tumor-specific immune response; and neurological applications. Histotripsy has been recently approved by the US Food and Drug Administration to treat liver tumors, with clinical trials undertaken for benign prostatic hyperplasia and renal tumors. This review outlines the physical principles of various types of histotripsy; presents major parameters of the technology and corresponding hardware and software, imaging methods, and bioeffects; and discusses the most promising preclinical and clinical applications.
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Ablação por Ultrassom Focalizado de Alta Intensidade , Humanos , Animais , Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Masculino , Neoplasias/terapia , Neoplasias/diagnóstico por imagem , Desenho de Equipamento , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/diagnóstico por imagemRESUMO
Repeated bouts of high-intensity interval training (HIIT) induce an improvement in metabolism via plasticity of melanocortin circuits and attenuated hypothalamic inflammation. HIF-1α, which plays a vital role in hypothalamus-mediated regulation of peripheral metabolism, is enhanced in the hypothalamus by HIIT. This study aimed to investigate the effects of HIIT on hypothalamic HIF-1α expression and peripheral metabolism in obese mice and the underlying molecular mechanisms. By using a high-fat diet (HFD)-induced obesity mouse model, we determined the effect of HIIT on energy balance and the expression of the hypothalamic appetite-regulating neuropeptides, POMC and NPY. Moreover, hypothalamic HIF-1α signaling and its downstream glycolytic enzymes were explored after HIIT intervention. The state of microglia and microglial NF-κB signaling in the hypothalamus were also examined in vivo. In vitro by using an adenovirus carrying shRNA-HIF1ß, we explored the impact of HIF-1 signaling on glycolysis and NF-κB inflammatory signaling in BV2 cells. Food intake was suppressed and whole-body metabolism was improved in exercised DIO mice, accompanied by changes in the expression of POMC and NPY. Moreover, total and microglial HIF-1α signaling were obviously attenuated in the hypothalamus, consistent with the decreased levels of glycolytic enzymes. Both HFD-induced microglial activation and hypothalamic NF-κB signaling were significantly suppressed following HIIT in vivo. In BV2 cells, after HIF-1 complex knockdown, glycolysis and NF-κB inflammatory signaling were significantly attenuated. The data indicate that HIIT improves peripheral metabolism probably via attenuated HFD-induced microglial activation and microglial NF-κB signaling in the hypothalamus, which could be mediated by suppressed microglial HIF-1α signaling.
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Hipotálamo , Subunidade alfa do Fator 1 Induzível por Hipóxia , Inflamação , Camundongos Endogâmicos C57BL , Microglia , Transdução de Sinais , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Microglia/metabolismo , Masculino , Camundongos , Hipotálamo/metabolismo , Inflamação/metabolismo , Treinamento Intervalado de Alta Intensidade , Obesidade/metabolismo , Dieta Hiperlipídica/efeitos adversos , Condicionamento Físico Animal/fisiologia , NF-kappa B/metabolismo , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética , Neuropeptídeo Y/metabolismoRESUMO
Human brain organoids represent a remarkable platform for modeling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses reveal that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays reveal that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage.
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Prior investigations have established that the manipulation of neural activity has the potential to influence both rapid eye movement and non-rapid eye movement sleep. Low-intensity retinal ultrasound stimulation has shown effectiveness in the modulation of neural activity. Nevertheless, the specific effects of retinal ultrasound stimulation on rapid eye movement and non-rapid eye movement sleep, as well as its potential to enhance overall sleep quality, remain to be elucidated. Here, we found that: In healthy mice, retinal ultrasound stimulation: (i) reduced total sleep time and non-rapid eye movement sleep ratio; (ii) changed relative power and sample entropy of the delta (0.5-4 Hz) in non-rapid eye movement sleep; and (iii) enhanced relative power of the theta (4-8 Hz) and reduced theta-gamma coupling strength in rapid eye movement sleep. In Alzheimer's disease mice with sleep disturbances, retinal ultrasound stimulation: (i) reduced the total sleep time; (ii) altered the relative power of the gamma band during rapid eye movement sleep; and (iii) enhanced the coupling strength of delta-gamma in non-rapid eye movement sleep and weakened the coupling strength of theta-fast gamma. The results indicate that retinal ultrasound stimulation can modulate rapid eye movement and non-rapid eye movement-related neural activity; however, it is not beneficial to the sleep quality of healthy and Alzheimer's disease mice.
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Doença de Alzheimer , Animais , Camundongos , Entropia , Nível de Saúde , Luz , Qualidade do SonoRESUMO
Recent advances in mass spectrometry-based proteomics enable the acquisition of increasingly large datasets within relatively short times, which exposes bottlenecks in the bioinformatics pipeline. Although peptide identification is already scalable, most label-free quantification (LFQ) algorithms scale quadratic or cubic with the sample numbers, which may even preclude the analysis of large-scale data. Here we introduce directLFQ, a ratio-based approach for sample normalization and the calculation of protein intensities. It estimates quantities via aligning samples and ion traces by shifting them on top of each other in logarithmic space. Importantly, directLFQ scales linearly with the number of samples, allowing analyses of large studies to finish in minutes instead of days or months. We quantify 10,000 proteomes in 10 min and 100,000 proteomes in less than 2 h, a 1000-fold faster than some implementations of the popular LFQ algorithm MaxLFQ. In-depth characterization of directLFQ reveals excellent normalization properties and benchmark results, comparing favorably to MaxLFQ for both data-dependent acquisition and data-independent acquisition. In addition, directLFQ provides normalized peptide intensity estimates for peptide-level comparisons. It is an important part of an overall quantitative proteomic pipeline that also needs to include high sensitive statistical analysis leading to proteoform resolution. Available as an open-source Python package and a graphical user interface with a one-click installer, it can be used in the AlphaPept ecosystem as well as downstream of most common computational proteomics pipelines.
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Proteoma , Proteômica , Proteoma/análise , Proteômica/métodos , Ecossistema , Peptídeos/análise , Espectrometria de Massas/métodos , SoftwareRESUMO
The physics of mutual interaction of phonon quasiparticles with electronic spin degrees of freedom, leading to unusual transport phenomena of spin and heat, has been a subject of continuing interests for decades. Despite its pivotal role in transport processes, the effect of spin-phonon coupling on the phonon system, especially acoustic phonon properties, has so far been elusive. By means of inelastic neutron scattering and first-principles calculations, anomalous scattering spectral intensity from acoustic phonons was identified in the exemplary collinear antiferromagnetic nickel (II) oxide, unveiling strong spin-lattice correlations that renormalize the polarization of acoustic phonon. In particular, a clear magnetic scattering signature of the measured neutron scattering intensity from acoustic phonons is demonstrated by its momentum transfer and temperature dependences. The anomalous scattering intensity is successfully modeled with a modified magneto-vibrational scattering cross-section, suggesting the presence of spin precession driven by phonon. The renormalization of phonon eigenvector is indicated by the observed "geometry-forbidden" neutron scattering intensity from transverse acoustic phonon. Importantly, the eigenvector renormalization cannot be explained by magnetostriction but instead, it could result from the coupling between phonon and local magnetization of ions.
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In this study, we investigated the role of the super-relaxed (SRX) state of myosin in the structure-function relationship of sarcomeres in the hearts of mouse models of cardiomyopathy-bearing mutations in the human ventricular regulatory light chain (RLC, MYL2 gene). Skinned papillary muscles from hypertrophic (HCM-D166V) and dilated (DCM-D94A) cardiomyopathy models were subjected to small-angle X-ray diffraction simultaneously with isometric force measurements to obtain the interfilament lattice spacing and equatorial intensity ratios (I11/I10) together with the force-pCa relationship over a full range of [Ca2+] and at a sarcomere length of 2.1 µm. In parallel, we studied the effect of mutations on the ATP-dependent myosin energetic states. Compared with wild-type (WT) and DCM-D94A mice, HCM-D166V significantly increased the Ca2+ sensitivity of force and left shifted the I11/I10-pCa relationship, indicating an apparent movement of HCM-D166V cross-bridges closer to actin-containing thin filaments, thereby allowing for their premature Ca2+ activation. The HCM-D166V model also disrupted the SRX state and promoted an SRX-to-DRX (super-relaxed to disordered relaxed) transition that correlated with an HCM-linked phenotype of hypercontractility. While this dysregulation of SRX â DRX equilibrium was consistent with repositioning of myosin motors closer to the thin filaments and with increased force-pCa dependence for HCM-D166V, the DCM-D94A model favored the energy-conserving SRX state, but the structure/function-pCa data were similar to WT. Our results suggest that the mutation-induced redistribution of myosin energetic states is one of the key mechanisms contributing to the development of complex clinical phenotypes associated with human HCM-D166V and DCM-D94A mutations.
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Miosinas Cardíacas/genética , Cardiomiopatias/metabolismo , Cadeias Leves de Miosina/genética , Actinas/metabolismo , Animais , Miosinas Cardíacas/metabolismo , Cardiomiopatias/genética , Cardiomiopatia Hipertrófica/genética , Modelos Animais de Doenças , Feminino , Humanos , Hipertrofia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Contração Miocárdica/genética , Cadeias Leves de Miosina/metabolismo , Miosinas/metabolismo , Miosinas/fisiologia , Fenótipo , Fosforilação , Sarcômeros/metabolismo , Relação Estrutura-Atividade , Difração de Raios X/métodosRESUMO
The quaternary organization of rhodopsin-like G protein-coupled receptors in native tissues is unknown. To address this we generated mice in which the M1 muscarinic acetylcholine receptor was replaced with a C-terminally monomeric enhanced green fluorescent protein (mEGFP)-linked variant. Fluorescence imaging of brain slices demonstrated appropriate regional distribution, and using both anti-M1 and anti-green fluorescent protein antisera the expressed transgene was detected in both cortex and hippocampus only as the full-length polypeptide. M1-mEGFP was expressed at levels equal to the M1 receptor in wild-type mice and was expressed throughout cell bodies and projections in cultured neurons from these animals. Signaling and behavioral studies demonstrated M1-mEGFP was fully active. Application of fluorescence intensity fluctuation spectrometry to regions of interest within M1-mEGFP-expressing neurons quantified local levels of expression and showed the receptor was present as a mixture of monomers, dimers, and higher-order oligomeric complexes. Treatment with both an agonist and an antagonist ligand promoted monomerization of the M1-mEGFP receptor. The quaternary organization of a class A G protein-coupled receptor in situ was directly quantified in neurons in this study, which answers the much-debated question of the extent and potential ligand-induced regulation of basal quaternary organization of such a receptor in native tissue when present at endogenous expression levels.
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Córtex Cerebral , Hipocampo , Receptor Muscarínico M1 , Animais , Córtex Cerebral/metabolismo , Proteínas de Fluorescência Verde , Hipocampo/metabolismo , Ligantes , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Imagem Óptica , Receptor Muscarínico M1/química , Receptor Muscarínico M1/genética , Receptor Muscarínico M1/metabolismoRESUMO
BACKGROUND: Numerous insect species undertake long-distance migrations on an enormous scale, with great implications for ecosystems. Given that take-off is the point where it all starts, whether and how the external light and internal circadian rhythm are involved in regulating the take-off behaviour remains largely unknown. Herein, we explore this issue in a migratory pest, Cnaphalocrocis medinalis, via behavioural observations and RNAi experiments. RESULTS: The results showed that C. medinalis moths took off under conditions where the light intensity gradually weakened to 0.1 lx during the afternoon or evening, and the take-off proportions under full spectrum or blue light were significantly higher than that under red and green light. The ultraviolet-A/blue light-sensitive type 1 cryptochrome gene (Cmedcry1) was significantly higher in take-off moths than that of non-take-off moths. In contrast, the expression of the light-insensitive CRY2 (Cmedcry2) and circadian genes (Cmedtim and Cmedper) showed no significant differences. After silencing Cmedcry1, the take-off proportion significantly decreased. Thus, Cmedcry1 is involved in the decrease in light intensity induced take-off behaviour in C. medinalis. CONCLUSIONS: This study can help further explain the molecular mechanisms behind insect migration, especially light perception and signal transmission during take-off phases.
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Criptocromos , Proteínas de Insetos , Mariposas , Animais , Migração Animal , Ritmo Circadiano , Criptocromos/genética , Criptocromos/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Luz , Mariposas/fisiologia , Interferência de RNARESUMO
Insulin resistance is a significant contributor to the development of type 2 diabetes (T2D) and is associated with obesity, physical inactivity, and low maximal oxygen uptake. While intense and prolonged exercise may have negative effects, physical activity can have a positive influence on cellular metabolism and the immune system. Moderate exercise has been shown to reduce oxidative stress and improve antioxidant status, whereas intense exercise can increase oxidative stress in the short term. The impact of exercise on pro-inflammatory cytokine production is complex and varies depending on intensity and duration. Exercise can also counteract the harmful effects of ageing and inflamm-ageing. This review aims to examine the molecular pathways altered by exercise in non-obese individuals at higher risk of developing T2D, including glucose utilization, lipid metabolism, mitochondrial function, inflammation and oxidative stress, with the potential to improve insulin sensitivity. The focus is on understanding the potential benefits of exercise for improving insulin sensitivity and providing insights for future targeted interventions before onset of disease.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Antioxidantes/metabolismo , Estresse Oxidativo , Exercício Físico , Insulina/metabolismoRESUMO
In skeletal muscle, glycogen particles are distributed both within and between myofibrils, as well as just beneath the sarcolemma. Their precise localisation may influence their degradation rate. Here, we investigated how exercise at different intensities and durations (1- and 15-min maximal exercise) with known variations in glycogenolytic rate and contribution from anaerobic metabolism affects utilisation of the distinct pools. Furthermore, we investigated how decreased glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise affect the storage of glycogen particles (size, numerical density, localisation). Twenty participants were divided into two groups performing either a 1-min (n = 10) or a 15-min (n = 10) maximal cycling exercise test. In a randomised, counterbalanced, cross-over design, the exercise tests were performed following short-term consumption of two distinct diets with either high or moderate carbohydrate content (10 vs. 4 g kg-1 body mass (BM) day-1) mediating a difference in total energy consumption (240 vs. 138 g kg-1 BM day-1). Muscle biopsies from m. vastus lateralis were obtained before and after the exercise tests. Intermyofibrillar glycogen was preferentially utilised during the 1-min test, whereas intramyofibrillar glycogen was preferentially utilised during the 15-min test. Lowering carbohydrate and energy intake after glycogen-depleting exercise reduced glycogen availability by decreasing particle size across all pools and diminishing numerical density in the intramyofibrillar and subsarcolemmal pools. In conclusion, distinct subcellular glycogen pools were differentially utilised during 1-min and 15-min maximal cycling exercise. Additionally, lowered carbohydrate and energy consumption after glycogen-depleting exercise altered glycogen storage by reducing particle size and numerical density, depending on subcellular localisation. KEY POINTS: In human skeletal muscle, glycogen particles are localised in distinct subcellular compartments, referred to as intermyofibrillar, intramyofibrillar and subsarcolemmal pools. The intermyofibrillar and subsarcolemmal pools are close to mitochondria, while the intramyofibrillar pool is at a distance from mitochondria. We show that 1 min of maximal exercise is associated with a preferential utilisation of intermyofibrillar glycogen, and, on the other hand, that 15 min of maximal exercise is associated with a preferential utilisation of intramyofibrillar glycogen. Furthermore, we demonstrate that reduced glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise is characterised by a decreased glycogen particle size across all compartments, with the numerical density only diminished in the intramyofibrillar and subsarcolemmal compartments. These results suggest that exercise intensity influences the subcellular pools of glycogen differently and that the dietary content of carbohydrates and energy is linked to the size and subcellular distribution of glycogen particles.
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Glicogênio , Músculo Esquelético , Humanos , Glicogênio/metabolismo , Músculo Esquelético/fisiologia , Miofibrilas/metabolismo , Exercício Físico/fisiologia , Músculo Quadríceps/metabolismo , Carboidratos da Dieta/metabolismoRESUMO
High-intensity exercise stimulates glycolysis, subsequently leading to elevated lactate production within skeletal muscle. While lactate produced within the muscle is predominantly released into the circulation via the monocarboxylate transporter 4 (MCT4), recent research underscores lactate's function as an intercellular and intertissue signalling molecule. However, its specific intracellular roles within muscle cells remains less defined. In this study, our objective was to elucidate the effects of increased intramuscular lactate accumulation on skeletal muscle adaptation to training. To achieve this, we developed MCT4 knockout mice and confirmed that a lack of MCT4 indeed results in pronounced lactate accumulation in skeletal muscle during high-intensity exercise. A key finding was the significant enhancement in endurance exercise capacity at high intensities when MCT4 deficiency was paired with high-intensity interval training (HIIT). Furthermore, metabolic adaptations supportive of this enhanced exercise capacity were evident with the combination of MCT4 deficiency and HIIT. Specifically, we observed a substantial uptick in the activity of glycolytic enzymes, notably hexokinase, glycogen phosphorylase and pyruvate kinase. The mitochondria also exhibited heightened pyruvate oxidation capabilities, as evidenced by an increase in oxygen consumption when pyruvate served as the substrate. This mitochondrial adaptation was further substantiated by elevated pyruvate dehydrogenase activity, increased activity of isocitrate dehydrogenase - the rate-limiting enzyme in the TCA cycle - and enhanced function of cytochrome c oxidase, pivotal to the electron transport chain. Our findings provide new insights into the physiological consequences of lactate accumulation in skeletal muscle during high-intensity exercises, deepening our grasp of the molecular intricacies underpinning exercise adaptation. KEY POINTS: We pioneered a unique line of monocarboxylate transporter 4 (MCT4) knockout mice specifically tailored to the ICR strain, an optimal background for high-intensity exercise studies. A deficiency in MCT4 exacerbates the accumulation of lactate in skeletal muscle during high-intensity exercise. Pairing MCT4 deficiency with high-intensity interval training (HIIT) results in a synergistic boost in high-intensity exercise capacity, observable both at the organismal level (via a treadmill running test) and at the muscle tissue level (through an ex vivo muscle contractile function test). Coordinating MCT4 deficiency with HIIT enhances both the glycolytic enzyme activities and mitochondrial capacity to oxidize pyruvate.
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Treinamento Intervalado de Alta Intensidade , Transportadores de Ácidos Monocarboxílicos , Músculo Esquelético , Animais , Camundongos , Lactatos , Camundongos Endogâmicos ICR , Camundongos Knockout , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Piruvatos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismoRESUMO
Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Acute mechanical left ventricular (LV) support has been suggested to improve infarct tissue perfusion. However, its regulatory mechanism remains unclear. We investigated the physiological mechanisms in six Yorkshire pigs, which were subjected to 90-min balloon occlusion of the left anterior descending artery. During the acute reperfusion phase, LV support using an Impella heart pump was initiated. LV pressure, coronary flow and pressure of the infarct artery were simultaneously recorded to evaluate the impact of LV support on coronary physiology. Coronary wave intensity was calculated to understand the forces regulating coronary flow. Significant increases in coronary flow velocity and its area under the curve were found after mechanical LV support. Among the coronary flow-regulating factors, coronary pressure was increased mainly during the late diastolic phase with less pulsatility. Meanwhile, LV pressure was reduced throughout diastole resulting in significant and consistent elevation of coronary driving pressure. Interestingly, the duration of diastole was prolonged with LV support. In the wave intensity analysis, the duration between backward suction and pushing waves was extended, indicating that earlier myocardial relaxation and delayed contraction contributed to the extension of diastole. In conclusion, mechanical LV support increases infarct coronary flow by extending diastole and augmenting coronary driving pressure. These changes were mainly driven by reduced LV diastolic pressure, indicating that the key regulator of coronary flow under mechanical LV support is downstream of the coronary artery, rather than upstream. Our study highlights the importance of LV diastolic pressure in infarct coronary flow regulation. KEY POINTS: Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Although mechanical left ventricular (LV) support has been suggested to improve infarct coronary flow, its specific mechanism remains to be clarified. LV support reduced LV pressure, and elevated coronary pressure during the late diastolic phase, resulting in high coronary driving pressure. This study demonstrated for the first time that mechanical LV support extends diastolic phase, leading to increased infarct coronary flow. Future studies should evaluate the correlation between improved infarct coronary flow and resulting infarct size.
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Infarto do Miocárdio , Função Ventricular Esquerda , Animais , Suínos , Diástole/fisiologia , Função Ventricular Esquerda/fisiologia , Pressão Sanguínea , Vasos Coronários , Circulação Coronária/fisiologiaRESUMO
Low-intensity focused ultrasound represents groundbreaking medical advancements, characterized by its noninvasive feature, safety, precision, and broad neuromodulatory capabilities. This technology operates through mechanisms, for example, acoustic radiation force, cavitation, and thermal effects. Notably, with the evolution of medical technology, ultrasound neuromodulation has been gradually applied in treating central nervous system diseases, especially stroke. Furthermore, burgeoning research areas such as sonogenetics and nanotechnology show promising potential. Despite the benefit of low-intensity focused ultrasound the precise biophysical mechanism of ultrasound neuromodulation still need further exploration. This review discusses the recent and ongoing developments of low-intensity focused ultrasound for neurological regulation, covering the underlying rationale to current utility and the challenges that impede its further development and broader adoption of this promising alternative to noninvasive therapy.
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BACKGROUND: Limited evidence supports the effects of short-interval high-intensity interval training (HIIT) for improving cardiorespiratory fitness (VÌO2peak) after stroke. We aimed to compare the effects of 12 weeks of short-interval HIIT versus moderate-intensity continuous training (MICT) on VÌO2peak, cardiovascular risk factors, and mobility outcomes among individuals ≥6 months poststroke. METHODS: This study was a multi-site, 12-week randomized controlled trial (NCT03614585) with an 8-week follow-up. Participants were randomized into 3 d/wk of HIIT (10×1 minute 80%-100% heart rate reserve interspersed with 1 minute 30% heart rate reserve [19 minutes]) or MICT (20-30 minutes 40%-60% heart rate reserve). Secondary outcomes of the trial, including VÌO2peak, cardiovascular risk factors (carotid-femoral pulse wave velocity, blood pressure, and waist-hip ratio), and mobility (6-minute walk test, 10 m gait speed), were reported. Linear mixed model analyses with a group×study time point interaction evaluated between-group differences. RESULTS: Of the 305 potential participants, 82 consented (mean [SD] age 64.9 [9.3] years, 32 females [39%], 1.8 [1.2] years poststroke) and were randomized to HIIT (n=42, mean [SD] baseline VÌO2peak 17.3 [5.9] mL/kg·min) or MICT (n=40, mean [SD] baseline VÌO2peak 17.2 [6.0] mL/kg·min). Participants attended 82% of visits (n=2417/2952). No adverse events occurred during the study period. A significant group×study time point interaction was found (χ2=8.46; P=0.015) for VÌO2peak at 12 weeks (mean difference, 1.81 [95% CI, 0.58-3.04]; P=0.004) whereby the HIIT group had greater gains in VÌO2peak (∆3.52 mL/kg·min [95% CI, 2.47-4.57]; P<0.001) compared with the MICT group (∆1.71 mL/kg·min [95% CI, 0.55-2.86]; P=0.001). There was no between-group difference in VÌO2peak (mean difference, 1.08 [95% CI, -0.26 to 2.42]; P=0.11) at 8-week follow-up. No group×study time point interactions were found for cardiovascular risk factors or mobility outcomes. CONCLUSIONS: Short-interval HIIT may be an effective alternative to MICT for improving VÌO2peak at 12 weeks postintervention. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT03614585.