The growing inadequacy of an open-ended Saffir-Simpson hurricane wind scale in a warming world.

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.

Deep Learning Prediction Boosts Phosphoproteomics-Based Discoveries Through Improved Phosphopeptide Identification.

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.

Excess methane emissions from shallow water platforms elevate the carbon intensity of US Gulf of Mexico oil and gas production.

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.

Biodiversity and pollination benefits trade off against profit in an intensive farming system.

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.

Neurophysiology of Effortful Listening: Decoupling Motivational Modulation from Task Demands.

In demanding listening situations, a listener's motivational state may affect their cognitive investment. Here, we aim to delineate how domain-specific sensory processing, domain-general neural alpha power, and pupil size as a proxy for cognitive investment encode influences of motivational state under demanding listening. Participants (male and female) performed an auditory gap-detection task while the pupil size and the magnetoencephalogram were simultaneously recorded. Task demand and a listener's motivational state were orthogonally manipulated through changes in gap duration and monetary-reward prospect, respectively. Whereas task difficulty impaired performance, reward prospect enhanced it. The pupil size reliably indicated the modulatory impact of an individual's motivational state. At the neural level, the motivational state did not affect auditory sensory processing directly but impacted attentional postprocessing of an auditory event as reflected in the late evoked-response field and alpha-power change. Both pregap pupil dilation and higher parietal alpha power predicted better performance at the single-trial level. The current data support a framework wherein the motivational state acts as an attentional top-down neural means of postprocessing the auditory input in challenging listening situations.

Impacts of altered exercise volume, intensity, and duration on the activation of AMPK and CaMKII and increases in PGC-1α mRNA.

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.

Improvement in photosynthesis under different light intensities is highly linked to domestication stages in cotton.

Domestication has dramatically increased crop size and biomass, reflecting the enhanced accumulation of photosynthates. However, we still lack solid empirical data on the impacts of domestication on photosynthetic rates at different light intensities and on leaf anatomy, and of the relationships of photosynthesis with aboveground biomass. In this study, we measured the photosynthetic rate at three photosynthetic photon flux densities of 2000 (high), 1000 (moderate) and 400 µmol m-2 sec-1 (low light intensity), dark respiration, relative chlorophyll content (SPAD), leaf morphology, and aboveground biomass in 40 wild, 91 semiwild, and 42 domesticated cotton genotypes. The study was replicated for two years (growing years 2018 and 2019). During the first domestication stage (transition from wild to semiwild genotypes), domestication led to higher photosynthetic rates measured under high light intensity, higher SPAD, larger leaf area (LA), and lower leaf mass per unit area (LMA), contributing to greater aboveground biomass accumulation in both study years. During the second domestication stage (transition from semiwild to domesticated genotypes), domestication significantly enhanced photosynthesis under low light intensity and reduced LMA, which were associated with increased aboveground biomass in both study years. In conclusion, photosynthesis improvement at different light intensities has been a gradual domestication phase specific process with the rate of photosynthesis enhanced under high light during the first domestication stage, and under low light during the second domestication stage. We argue that these differences reflect a higher proportion of LA photosynthesizing under low light due to enhanced canopy expansion at the second domestication stage.

Histotripsy: A Method for Mechanical Tissue Ablation with Ultrasound.

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.

Membrane-Localized Orientation of NONPHOTOTROPIC HYPOCOTYL3 Affects the Necessity of Its Phosphorylation for Phototropism.

NONPHOTOTROPIC HYPOCOTYL3 (NPH3) is a key regulator of hypocotyl phototropism under both low- and high-intensity blue light (LBL/HBL), mediating phototropin1 (phot1) and phot2 signaling. NPH3 undergoes dephosphorylation and is released from the plasma membrane (PM) upon blue light irradiation. However, how its phosphorylation status and PM localization mediate phot1 and phot2 signaling in Arabidopsis (Arabidopsis thaliana) remains elusive. In this study, we found that fusing NPH3 with GFP at its C terminus (N3G) impaired its release from the PM, a defect exacerbated by a phosphorylation-deficient mutation, resulting in a dephosphorylated NPH3-GFP (N3AG). Unlike N3G, transgenic lines expressing N3AG exhibited defective hypocotyl phototropism under HBL, which could be rescued by myristoylation at the N-terminus of N3AG (mN3AG), indicating that NPH3 phosphorylation is not essential for HBL-induced phototropic responses when it is artificially anchored at the PM via its N terminus. Furthermore, genetic analysis revealed that N3AG anchored to the PM by its N terminus (as in mN3AG) only rescues phot1-mediated HBL responses, which require RPT2. However, N3AG failed to regulate phot2-mediated HBL signaling, regardless of its PM orientation. Taken together, our results revealed that NPH3 phosphorylation is essential for phot2-mediated hypocotyl phototropism under HBL, but is not required for phot1-mediated HBL signaling when the NPH3 N terminus is PM-anchored.

High-intensity interval training improves hypothalamic inflammation by suppressing HIF-1α signaling in microglia of male C57BL/6J mice.

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.

Low-intensity ultrasound ameliorates brain organoid integration and rescues microcephaly deficits.

Human brain organoids represent a remarkable platform for modelling 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 revealed 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 revealed 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.

Modulatory effects of low-intensity retinal ultrasound stimulation on rapid and non-rapid eye movement sleep.

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.

Accurate Label-Free Quantification by directLFQ to Compare Unlimited Numbers of Proteomes.

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.

Mutual spin-phonon driving effects and phonon eigenvector renormalization in nickel (II) oxide.

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.

Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin.

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 ↔ 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.

The M1 muscarinic receptor is present in situ as a ligand-regulated mixture of monomers and oligomeric complexes.

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.

CRY1 is involved in the take-off behaviour of migratory Cnaphalocrocis medinalis individuals.

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.

Transcriptomic signatures of human single skeletal muscle fibers in response to high-intensity interval exercise.

The heterogeneous fiber type composition of skeletal muscle makes it challenging to decipher the molecular signaling events driving the health- and performance benefits of exercise. We developed an optimized workflow for transcriptional profiling of individual human muscle fibers before, immediately after, and after 3 h of recovery from high-intensity interval cycling exercise. From a transcriptional point-of-view, we observe that there is no dichotomy in fiber activation, which could refer to a fiber being recruited or nonrecruited. Rather, the activation pattern displays a continuum with a more uniform response within fast versus slow fibers during the recovery from exercise. The transcriptome-wide response immediately after exercise is characterized by some distinct signatures for slow versus fast fibers, although the most exercise-responsive genes are common between the two fiber types. The temporal transcriptional waves further converge the gene signatures of both fiber types toward a more similar profile during the recovery from exercise. Furthermore, a large heterogeneity among all resting and exercised fibers was observed, with the principal drivers being independent of a slow/fast typology. This profound heterogeneity extends to distinct exercise responses of fibers beyond a classification based on myosin heavy chains. Collectively, our single-fiber methodological approach points to a substantial between-fiber diversity in muscle fiber responses to high-intensity interval exercise.NEW & NOTEWORTHY By development of a single-fiber transcriptomics technology, we assessed the transcriptional events in individual human skeletal muscle fibers upon high-intensity exercise. We demonstrate a large variability in transcriptional activation of fibers, with shared and distinct gene signatures for slow and fast fibers. The heterogeneous fiber-specific exercise response extends beyond this traditional slow/fast categorization. These findings expand on our understanding of exercise responses and uncover a profound between-fiber diversity in muscle fiber activation and transcriptional perturbations.

Molecular regulators of exercise-mediated insulin sensitivity in non-obese individuals.

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.

Interleukin-15 and high-intensity exercise: relationship with inflammation, body composition and fitness in cancer survivors.

Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth. These anti-oncogenic effects of exercise were associated with the exercise-mediated release of myokines such as interleukin (IL)-15. However, no study has quantified the acute IL-15 response in human cancer survivors, and whether physiological adaptations to exercise training (i.e. body composition and cardiorespiratory fitness) influence this response. In the present study breast, prostate and colorectal cancer survivors (n = 14) completed a single bout of high-intensity interval exercise (HIIE) [4×4 min at 85-95% heart rate (HR) peak, 3 min at 50-70% HR peak] before and after 7 months of three times weekly high-intensity interval training (HIIT) on a cycle ergometer. At each time point venous blood was sampled before and immediately after HIIE to assess the acute myokine (IL-15, IL-6, IL-10, IL-1ra) responses. Markers of inflammation, cardiorespiratory fitness and measures of body composition were obtained at baseline and 7 months. An acute bout of HIIE resulted in a significant increase in IL-15 concentrations (pre-intervention: 113%; P = 0.013, post-intervention: 102%; P = 0.005). Post-exercise IL-15 concentrations were associated with all other post-exercise myokine concentrations, lean mass (P = 0.031), visceral adipose tissue (P = 0.039) and absolute V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ peak (P = 0.032). There was no significant effect of 7 months of HIIT on pre- or post-HIIE IL-15 concentrations (P > 0.05). This study demonstrates HIIE is a sufficient stimulus to increase circulating IL-15 and other myokines including IL-6, IL-10 and IL-1ra which may be clinically relevant in the anti-oncogenic effect of exercise and repetitive exposure to these effects may contribute to the positive relationship between exercise and cancer recurrence. KEY POINTS: Exercise has been demonstrated to reduce the risk of cancer recurrence. Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth, mediated by exercise-induced myokines (IL-6 and IL-15). High-intensity interval exercise significantly increased myokines associated with the anti-oncogenic effect of exercise and the magnitude of response was associated with lean mass, but training did not appear to influence this response. Given IL-15 has been implicated in the anti-oncogenic effect of exercise and is being explored as an immunotherapy agent, high-intensity interval exercise may improve outcomes for people living beyond cancer through IL-15-mediated pathways. Interventions that increase lean mass may also enhance this response.