Arterial Smooth Muscle Cell AKAP150 Mediates Exercise-Induced Repression of CaV1.2 Channel Function in Cerebral Arteries of Hypertensive Rats.

BACKGROUND: Hypertension is a major, prevalent risk factor for the development and progression of cerebrovascular disease. Regular exercise has been recommended as an excellent choice for the large population of individuals with mild-to-moderate elevations in blood pressure, but the mechanisms that underlie its vascular-protective and antihypertensive effects remain unknown. Here, we describe a mechanism by which myocyte AKAP150 (A-kinase anchoring protein 150) inhibition induced by exercise training alleviates voltage-dependent L-type Ca2+ channel (CaV1.2) activity and restores cerebral arterial function in hypertension. METHODS: Spontaneously hypertensive rats and newly generated smooth muscle-specific AKAP150 knockin mice were used to assess the role of myocyte AKAP150/CaV1.2 channel in regulating cerebral artery function after exercise intervention. RESULTS: Activation of the AKAP150/PKCα (protein kinase Cα) signaling increased CaV1.2 activity and Ca2+ influx of cerebral arterial myocyte, thus enhancing vascular tone in spontaneously hypertensive rats. Smooth muscle-specific AKAP150 knockin mice were hypertensive with higher CaV1.2 channel activity and increased vascular tone. Furthermore, treatment of Ang II (angiotensin II) resulted in a more pronounced increase in blood pressure in smooth muscle-specific AKAP150 knockin mice. Exercise training significantly reduced arterial myocyte AKAP150 expression and alleviated CaV1.2 channel activity, thus restoring cerebral arterial function in spontaneously hypertensive rats and smooth muscle-specific AKAP150 knockin mice. AT1R (AT1 receptor) and AKAP150 were interacted closely in arterial myocytes. Exercise decreased the circulating Ang II and Ang II-involved AT1R-AKAP150 association in myocytes of hypertension. CONCLUSIONS: The current study demonstrates that aerobic exercise ameliorates CaV1.2 channel function via inhibiting myocyte AKAP150, which contributes to reduced cerebral arterial tone in hypertension.

Genome wide-scale CRISPR-Cas9 knockout screens identify a fitness score for optimized risk stratification in colorectal cancer.

BACKGROUND: The molecular complexity of colorectal cancer poses a significant challenge to the clinical implementation of accurate risk stratification. There is still an urgent need to find better biomarkers to enhance established risk stratification and guide risk-adapted treatment decisions. METHODS: we systematically analyzed cancer dependencies of 17 colorectal cancer cells and 513 other cancer cells based on genome-scale CRISPR-Cas9 knockout screens to identify colorectal cancer-specific fitness genes. A regression model was built using colorectal cancer-specific fitness genes, which was validated in other three independent cohorts. 30 published gene expression signatures were also retrieved. FINDINGS: We defined a total of 1828 genes that were colorectal cancer-specific fitness genes and identified a 22 colorectal cancer-specific fitness gene (CFG22) score. A high CFG22 score represented unfavorable recurrence and mortality rates, which was validated in three independent cohorts. Combined with age, and TNM stage, the CFG22 model can provide guidance for the prognosis of colorectal cancer patients. Analysis of genomic abnormalities and infiltrating immune cells in the CFG22 risk stratification revealed molecular pathological difference between the subgroups. Besides, drug analysis found that CFG22 high patients were more sensitive to clofibrate. INTERPRETATION: The CFG22 model provided a powerful auxiliary prediction tool for identifying colorectal cancer patients with high recurrence risk and poor prognosis, optimizing precise treatment and improving clinical efficacy.

Using machine learning to enlarge the measurement range and promote the compactness of the optical fiber torsion sensor based on the Sagnac interferometer.

The support vector regression (SVR) algorithm is presented to demodulate the torsion angle of an optical fiber torsion sensor based on the Sagnac interferometer with the panda fiber. Experimental results demonstrate that with the aid of SVR algorithm, the information in the transmission spectrum of the sensor can be used fully to realize the regression prediction of the directional torsion angle. The full torsion angle ranges from -360° to 360° can be predicted with a mean absolute error (MAE) of 2.24° and determination coefficient (R2) of 0.9996. The impact of the angle sampling interval and wavelength resolution of the spectrometer on the prediction accuracy of the directional torsion angle and the suitability of the SVR algorithm for compact optical fiber sensor and other optical fiber torsion sensors based on the Sagnac interferometer are discussed. Moreover, the multi-objective SVR algorithm is used to eliminate the interference of strain during torsion angle measurement. The SVR algorithm can efficiently enlarge the measurement range of the torsion angle and break through the challenge of demodulating sensing signal for compact fiber torsion sensor. Compared to the prediction accuracy of common machine learning algorithms of artificial neural network (ANN) algorithm, random forest (RF) algorithm, and K-nearest neighbor (KNN) algorithm, the SVR algorithm has the advantages of higher measurement accuracy and shorter testing time.

Quorum sensing-induced transition from colloidal waves to Turing-like patterns in chemorepulsive active colloids.

The study of active systems, especially in the presence of a chemical background field, is garnering significant attention. Traditionally, the self-propelled velocity of active colloids was assumed to be constant, independent of the local density of colloids. In this work, we introduce a chemotactic active system that features quorum sensing (QS), wherein particles act as chemorepellents. Interestingly, these particles lose their activity in regions of high local particle density. Our findings reveal that QS leads to a transition from an oscillatory colloidal wave to a Turing-like pattern, with the observation of an intermediate state. With the variation of the sensing threshold, both the mean oscillation frequency of the system and the number of clusters exhibit non-monotonic dependence. Furthermore, the QS-induced pattern differs markedly from systems without QS, primarily due to the competitive interplay between diffusion and chemotaxis. The dynamics of this phenomenon are explained using a coarse-grained mean field model.

Age at menarche and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study.

BACKGROUND: Sex difference in the incidence rate of idiopathic pulmonary fibrosis (IPF) indicates that estrogen has a certain protective effect on the disease. Nevertheless, there is a dearth of study investigating the association between factors pertaining to endogenous estrogen exposure level, such as age at menarche (AAM) in women, and IPF. Our study intended to employ Mendelian randomization (MR) method to elucidate the causal association between AAM and IPF. METHODS: Our study utilized AAM as a measure of endogenous estrogen exposure and investigated its causal effect on the risk of IPF through MR. We employed the inverse variance weighted (IVW) method to assess the causal relationship between AAM and IPF risk, with supplementary analyses conducted using the weighted median estimator (WME) and MR-Egger method. Several sensitivity analyses were performed to assess the dependability of MR estimates. RESULTS: A total of 9 selected single nucleotide polymorphisms (SNPs) significantly associated with AAM were selected as instrumental variables. The IVW method showed that genetically later AAM was associated with an increased risk of IPF (odds ratio [OR] = 1.0014, 95%confidence interval [CI] = 1.0005-1.0023, p = 0.001). The median weighting method and the MR-Egger method obtained similar estimates, and no heterogeneity or pleiotropy was found, indicating that the results were robust. CONCLUSIONS: Our MR study suggested a causal relationship between a later onset of menarche and a heightened susceptibility to IPF.

Genome-wide identification and expression analysis of the NRT genes in Ginkgo biloba under nitrate treatment reveal the potential roles during calluses browning.

Nitrate is a primary nitrogen source for plant growth, and previous studies have indicated a correlation between nitrogen and browning. Nitrate transporters (NRTs) are crucial in nitrate allocation. Here, we utilized a genome-wide approach to identify and analyze the expression pattern of 74 potential GbNRTs under nitrate treatments during calluses browning in Ginkgo, including 68 NITRATE TRANSPORTER 1 (NRT1)/PEPTIDE TRANSPORTER (PTR) (NPF), 4 NRT2 and 2 NRT3. Conserved domains, motifs, phylogeny, and cis-acting elements (CREs) were analyzed to demonstrate the evolutionary conservation and functional diversity of GbNRTs. Our analysis showed that the NPF family was divided into eight branches, with the GbNPF2 and GbNPF6 subfamilies split into three groups. Each GbNRT contained 108-214 CREs of 19-36 types, especially with binding sites of auxin and transcription factors v-myb avian myeloblastosis viral oncogene homolog (MYB) and basic helix-loop-helix (bHLH). The E1X1X2E2R motif had significant variations in GbNPFs, indicating changes in the potential dynamic proton transporting ability. The expression profiles of GbNRTs indicated that they may function in regulating nitrate uptake and modulating the signaling of auxin and polyphenols biosynthesis, thereby affecting browning in Ginkgo callus induction. These findings provide a better understanding of the role of NRTs during NO3- uptake and utilization in vitro culture, which is crucial to prevent browning and develop an efficient regeneration and suspension production system in Ginkgo.

Advanced Composite Lithium Metal Anodes with 3D Frameworks: Preloading Strategies, Interfacial Optimization, and Perspectives.

Lithium (Li) metal is regarded as the most promising anode candidate for next-generation rechargeable storage systems due to its impeccable capacity and the lowest electrochemical potential. Nevertheless, the irregular dendritic Li, unstable interface, and infinite volume change, which are the intrinsic drawbacks rooted in Li metal, give a seriously negative effect on the practical commercialization for Li metal batteries. Among the numerous optimization strategies, designing a 3D framework with high specific surface area and sufficient space is a convincing way out to ameliorate the above issues. Due to the Li-free property of the 3D framework, a Li preloading process is necessary before the 3D framework that matches with the electrolyte and cathode. How to achieve homogeneous integration with Li and 3D framework is essential to determine the electrochemical performance of Li metal anode. Herein, this review overviews the recent general fabrication methods of 3D framework-based composite Li metal anode, including electrodeposition, molten Li infusion, and pressure-derived fabrication, with the focus on the underlying mechanism, design criteria, and interfacial optimization. These results can give specific perspectives for future Li metal batteries with thin thickness, low N/P ratio, lean electrolyte, and high energy density (>350 Wh Kg-1 ).

High sensitivity twist sensor based on suspended core fiber Sagnac interferometer with temperature calibration.

A high sensitivity optical fiber twist sensor based on Suspend Core Fiber Sagnac Interference (SCFSI) is proposed and experimentally demonstrated. By filling the air hole of the Suspend Core Fiber (SCF) with alcohol, the twist sensitivity of the twist sensor is greatly improved to 8.37 nm/°. Moreover, the valid angle measurement range of the sensor can be expanded by utilizing the combination of intensity demodulation and wavelength demodulation. The sensor not only has high twist angle sensitivity but also exhibits a capability of temperature calibration. Since the wavelength shifts of the interference fringes of Mach-Zehnder Interferometer (MZI) formed in the suspend core of SCF appears insensitive to twist angle, the parasitic interference formed by MZI can be used for temperature calibration. Due to compact structure, easy fabrication and low temperature cross sensitivity, the proposed sensor has a great potential for structural health monitoring, such as buildings, towers, bridges, and many other infrastructures.

Machine-learning-assisted omnidirectional bending sensor based on a cascaded asymmetric dual-core PCF sensor.

An omnidirectional bending sensor comprising cascaded asymmetric dual-core photonic crystal fibers (ADCPCFs) is designed and demonstrated experimentally. Upon cascading and splicing two ADCPCFs at a lateral rotation angle, the transmission spectrum of the sensor becomes highly dependent on the bending direction. Machine learning (ML) is employed to predict the curvature and bending orientation of the bending sensor for the first time, to the best of our knowledge. The experimental results demonstrate that the ADCPCF sensor used in combination with machine learning can predict the curvature and omnidirectional bending orientation within 360° without requiring any post-processing fabrication steps. The prediction accuracy is 99.85% with a mean absolute error (MAE) of 2.7° for bending direction measurement and 98.08% with an MAE of 0.03 m-1 for the curvature measurement. This promising strategy utilizes the global features (full spectra) in combination with machine learning to overcome the dependence of the sensor on high-quality transmission spectra, the wavelength range, and a special wavelength dip in the conventional dip tracking method. This excellent omnidirectional bending sensor has large potential for structural health monitoring, robotic arms, medical instruments, and wearable devices.

Polyhalogenation-Facilitated Spirolactonization at the meta-Position of Phenols.

A novel dearomative spirolactonization/polyhalogenation of phenols that employs hypervalent iodine PhICl2 (iodobenzene dichloride) as both an oxidant and chlorine source with an indispensable base, or only using NBS (N-bromosuccinimide) without any additives, is presented. Halide participations are a vital factor in the cascade reaction of 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acids with good selectivities and reactivities and induced the rapid constructions of multiple C-halogen bonds and directional C═O bonds in a one-step operation under mild conditions. In gaining a good understanding of the mechanism, the increase in number of bromine atoms was inferred rationally from the spirolactonization process, assisted by DFT calculations and high-resolution mass spectrometry. Mechanistic experiments suggest that the formation of a stable carbocation intermediate plays a great role in the migration of oxygen to spirolactonization.

Identification and Analysis of MADS-Box Genes Expressed in the Mesocarp of Oil Palm Fruit (Elaeis guineensis Jacq.).

Oil palm (Elaeis guineensis) is the most important tropical oil-bearing crop species worldwide. MADS-box proteins, which play crucial roles in plant growth and development and are involved in various physiological and biochemical processes, compose one of the largest families of plant transcription factors. In this study, 42 MADS-box genes were screened from the mesocarp transcriptome database of oil palm fruit, and their phylogenetic relationships with Arabidopsis thaliana MADS-box genes were analyzed. Based on the results, MADS-box genes from oil palm mesocarp were classified into four groups: MIKCc-type, MIKC*-type, Mα-type, and Mγ-type MADS-box genes. Members of the subfamilies were classified according to the presence of three specific protein motifs. To explore the differential expression of the MADS-box genes, the dynamic expression of all selected MADS-box genes in oil palm was measured by RNA-seq. The high expression of specific MADS-box genes in the mesocarp of oil palm during different developmental stages indicates that those genes may play important roles in the cell division of and metabolite accumulation in the fruit and could become important targets for fruit development and oil accumulation research in oil palm.

Non-trivial Contribution of Carbon Hybridization in Carbon-based Substrates to Electrocatalytic Activities in Li-S Batteries.

Appling an electrochemical catalyst is an efficient strategy for inhibiting the shuttle effect and enhancing the S utilization of Li-S batteries. Carbon-based materials are the most common conductive agents and catalyst supports used in Li-S batteries, but the correlation between the diversity of hybridizations and sulfur reduction reaction (SRR) catalytic activity remains unclear. Here, by establishing two forms of carbon models, i.e., graphitic carbon (GC) and amorphous carbon (AC), we observe that the nitrogen atom doped in the GC possesses a higher local charge density and a lower Gibbs free energy towards the formation of polysulfides than in the AC. And the GC-based electrode consistently inherits considerably enhanced SRR kinetics and superior cycling stability and rate capability in Li-S batteries. Therefore, the function of carbon in Li-S batteries is not only limited as conductive support but also plays an unignorable contribution to the electrocatalytic activities of SRR.

Engineering Single-Atom Active Sites on Covalent Organic Frameworks for Boosting CO2 Photoreduction.

Solar carbon dioxide (CO2) conversion is an emerging solution to meet the challenges of sustainable energy systems and environmental/climate concerns. However, the construction of isolated active sites not only influences catalytic activity but also limits the understanding of the structure-catalyst relationship of CO2 reduction. Herein, we develop a universal synthetic protocol to fabricate different single-atom metal sites (e.g., Fe, Co, Ni, Zn, Cu, Mn, and Ru) anchored on the triazine-based covalent organic framework (SAS/Tr-COF) backbone with the bridging structure of metal-nitrogen-chlorine for high-performance catalytic CO2 reduction. Remarkably, the as-synthesized Fe SAS/Tr-COF as a representative catalyst achieved an impressive CO generation rate as high as 980.3 µmol g-1 h-1 and a selectivity of 96.4%, over approximately 26 times higher than that of the pristine Tr-COF under visible light irradiation. From X-ray absorption fine structure analysis and density functional theory calculations, the superior photocatalytic performance is attributed to the synergic effect of atomically dispersed metal sites and Tr-COF host, decreasing the reaction energy barriers for the formation of *COOH intermediates and promoting CO2 adsorption and activation as well as CO desorption. This work not only affords rational design of state-of-the-art catalysts at the molecular level but also provides in-depth insights for efficient CO2 conversion.

Synthesis of fluorinated polycyclic dehydroaltenusin analogs through hypervalent iodine-catalyzed dearomatization.

We developed a method employing stoichiometric meta-chloroperbenzoic acid (m-CPBA) as an oxidant and hydrogen fluoride pyridine (pyr·HF) as a fluoride source with catalytic amounts of iodobenzene (PhI) for the cyclization and fluorination-dearomatization of phenols, leading to a range of fluorocyclohexa-dienones with yields of up to 94%. This reaction provides a convenient method to synthesize fluorine-containing dehydroaltenusin analogs under mild conditions, and without expensive reagents. These analogs have potential application as inhibitors of DNA polymerase.

MOF-Derived Bifunctional Co0.85Se Nanoparticles Embedded in N-Doped Carbon Nanosheet Arrays as Efficient Sulfur Hosts for Lithium-Sulfur Batteries.

Lithium-sulfur batteries possess the merits of low cost and high theoretical energy density but suffer from the shuttle effect of lithium polysulfides and slow redox kinetics of sulfur. Herein, novel Co0.85Se nanoparticles embedded in nitrogen-doped carbon nanosheet arrays (Co0.85Se/NC) were constructed on carbon cloth as the self-supported host for a sulfur cathode using a facile fabrication strategy. The interconnected porous carbon-based structure of the Co0.85Se/NC could facilitate the rapid electron and ion transfer kinetics. The embedded Co0.85Se nanoparticles can effectively capture and catalyze lithium polysulfides, thus accelerating the redox kinetics and stabilizing sulfur cathodes. Therefore, the Co0.85Se/NC-S cathode could maintain a stable cycle performance for 400 cycles at 1C and deliver a high discharge specific capacity of 1361, 1001, and 810 mAh g-1 at current densities of 0.1, 1, and 3C, respectively. This work provides an efficient design strategy for high-performance lithium-sulfur batteries with high energy densities.

Engineering MoOx /MXene Hole Transfer Layers for Unexpected Boosting of Photoelectrochemical Water Oxidation.

The development of semiconductor photoanodes is of great practical interest for the realization of photoelectrochemical (PEC) water splitting. Herein, MXene quantum dots (MQD) were grafted on a BiVO4 substrate, then a MoOx layer by combining an ultrathin oxyhydroxide oxygen evolution cocatalyst (OEC) was constructed as an integrated photoanode. The OEC/MoOx /MQD/BiVO4 array not only achieves a current density of 5.85 mA cm-2 at 1.23 V versus a reversible hydrogen electrode (vs. RHE), but also enhances photostability. From electrochemical analysis and density functional theory calculations, high PEC performance is ascribed to the incorporation of MoOx /MQD as hole transfer layers, retarding charge recombination, promoting hole transfer and accelerating water splitting kinetics. This proof-of-principle work not only demonstrates the potential utilization of hole transfer layers, but also sheds light on rational design and fabrication of integrated photoanodes for feasible solar energy conversion.

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer.

Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2-) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

Proteomic and transcriptomic studies of HBV-associated liver fibrosis of an AAV-HBV-infected mouse model.

BACKGROUND: Human hepatitis B virus (HBV) infection is an important public health issue in the Asia-Pacific region and is associated with chronic hepatitis, liver fibrosis, cirrhosis and even liver cancer. However, the underlying mechanisms of HBV-associated liver fibrosis remain incompletely understood. RESULTS: In the present study, proteomic and transcriptomic approaches as well as biological network analyses were performed to investigate the differentially expressed molecular signature and key regulatory networks that were associated with HBV-mediated liver fibrosis. RNA sequencing and 2DE-MALDI-TOF/TOF were performed on liver tissue samples obtained from HBV-infected C57BL/6 mouse generated via AAV8-HBV virus. The results showed that 322 genes and 173 proteins were differentially expressed, and 28 HBV-specific proteins were identified by comprehensive proteomic and transcriptomic analysis. GO analysis indicated that the differentially expressed proteins were predominantly involved in oxidative stress, which plays a key role in HBV-related liver fibrosis. Importantly, CAT, PRDX1, GSTP1, NXN and BLVRB were shown to be associated with oxidative stress among the differentially expressed proteins. The most striking results were validated by Western blot and RT-qPCR. The RIG-I like receptor signaling pathway was found to be the major signal pathway that changed during HBV-related fibrosis. CONCLUSIONS: This study provides novel insights into HBV-associated liver fibrosis and reveals the significant role of oxidative stress in liver fibrosis. Furthermore, CAT, BLVRB, NXN, PRDX1, and IDH1 may be candidates for detection of liver fibrosis or therapeutic targets for the treatment of liver fibrosis.

Comparative proteomic study reveals 17ß-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by a massive accumulation of lipid droplets (LDs). The aim of this study was to determine the function of 17ß-hydroxysteroid dehydrogenase-13 (17ß-HSD13), one of our newly identified LD-associated proteins in human subjects with normal liver histology and simple steatosis, in NAFLD development. LDs were isolated from 21 human liver biopsies, including 9 cases with normal liver histology (group 1) and 12 cases with simple steatosis (group 2). A complete set of LD-associated proteins from three liver samples of group 1 or group 2 were determined by 2D LC-MS/MS. By comparing the LD-associated protein profiles between subjects with or without NAFLD, 54 up-regulated and 35 down-regulated LD-associated proteins were found in NAFLD patients. Among them, 17ß-HSD13 represents a previously unidentified LD-associated protein with a significant up-regulation in NAFLD. Because the 17ß-HSD family plays an important role in lipid metabolism, 17ß-HSD13 was selected for validating the proteomic findings and exploring its role in the pathogenesis of NAFLD. Increased hepatic 17ß-HSD13 and its LD surface location were confirmed in db/db (diabetic) and high-fat diet-fed mice. Adenovirus-mediated hepatic overexpression of human 17ß-HSD13 induced a fatty liver phenotype in C57BL/6 mice, with a significant increase in mature sterol regulatory element-binding protein 1 and fatty acid synthase levels. The present study reports an extensive set of human liver LD proteins and an array of proteins differentially expressed in human NAFLD. We also identified 17ß-HSD13 as a pathogenic protein in the development of NAFLD.

Swimming Exercise Protocol and Care Methods for Pregnant Rats.

The developmental origins of health and disease concept highlights the impact of early environments on chronic non-communicable diseases like diabetes, cardiovascular disease, and cancer. Studies using animal models have investigated how maternal factors such as undernutrition, overnutrition, obesity, and exposure to chemicals or hypoxia affect fetal development and offspring health, leading to issues like low birth weight, high blood pressure, dyslipidemia, and insulin resistance. Given the increasing prevalence of overweight and obesity among reproductive-age women, effective interventions are critical. Maternal exercise during pregnancy has emerged as a key intervention, benefiting both mother and offspring and reducing the risk of disease. This study compares the differences of three exercise models on pregnant rats: voluntary wheel running, motorized treadmills, and swimming. Swimming is the most beneficial option due to its safe and controlled intensity levels. This protocol details the rat breeding methods, swimming training during pregnancy, and post-breeding nursing protocols. This model, suitable for various rat and mouse species, is useful for studying the benefits of maternal exercise on offspring health and intergenerational wellness.