Export of heme by the feline leukemia virus C receptor regulates mitochondrial biogenesis and redox balance in the hematophagous insect Rhodnius prolixus.

Heme is a prosthetic group of proteins involved in vital physiological processes. It participates, for example, in redox reactions crucial for cell metabolism due to the variable oxidation state of its central iron atom. However, excessive heme can be cytotoxic due to its prooxidant properties. Therefore, the control of intracellular heme levels ensures the survival of organisms, especially those that deal with high concentrations of heme during their lives, such as hematophagous insects. The export of heme initially attributed to the feline leukemia virus C receptor (FLVCR) has recently been called into question, following the discovery of choline uptake by the same receptor in mammals. Here, we found that RpFLVCR is a heme exporter in the midgut of the hematophagous insect Rhodnius prolixus, a vector for Chagas disease. Silencing RpFLVCR decreased hemolymphatic heme levels and increased the levels of intracellular dicysteinyl-biliverdin, indicating heme retention inside midgut cells. FLVCR silencing led to increased expression of heme oxygenase (HO), ferritin, and mitoferrin mRNAs while downregulating the iron importers Malvolio 1 and 2. In contrast, HO gene silencing increased FLVCR and Malvolio expression and downregulated ferritin, revealing crosstalk between heme degradation/export and iron transport/storage pathways. Furthermore, RpFLVCR silencing strongly increased oxidant production and lipid peroxidation, reduced cytochrome c oxidase activity, and activated mitochondrial biogenesis, effects not observed in RpHO-silenced insects. These data support FLVCR function as a heme exporter, playing a pivotal role in heme/iron metabolism and maintenance of redox balance, especially in an organism adapted to face extremely high concentrations of heme.

Current State of Canine Heartworm in Portugal.

The favourable geo-climatic conditions in Portugal have made it highly conducive to the development of Dirofilaria immitis in dogs, leading to its identification as an endemic region. This nematode is rapidly spreading across Europe, particularly in northeastern countries. The objective of this study was to provide an updated assessment of the prevalence of this disease in Portuguese dogs, analysing the results in relation to epidemiological and geo-environmental factors, and to identify potential risk factors. A total of 1367 dogs from all continental and insular districts were included in the study and tested for D. immitis antigens. The overall prevalence was found to be 5.9%. It was observed that the disease is spreading northward, with previously unaffected districts now reporting cases, and that the prevalence in coastal districts exceeded that of inland ones. Notably, the Aveiro district exhibited a significant increase in D. immitis prevalence, while in certain districts such as Setúbal, Santarém, Madeira, or Faro, a stabilisation or decrease in prevalence was noted. Furthermore, outdoor and older dogs were found to be at a higher risk of infection. No positive cases were detected in the Azores. Most of the infected dogs were located in areas of high and medium risk of infection. This study underscores the importance of implementing pharmacological prophylaxis, vector control strategies, and public awareness programs to control the spread of this zoonotic disease.

Do Acoustic Characteristics of Dysarthria in People With Parkinson's Disease Differ Across Languages?

PURPOSE: Cross-language studies suggest more similarities than differences in how dysarthria affects the speech of people with Parkinson's disease (PwPD) who speak different languages. In this study, we aimed to identify the relative contribution of acoustic variables to distinguish PwPD from controls who spoke varieties of two Romance languages, French and Portuguese. METHOD: This bi-national, cross-sectional, and case-controlled study included 129 PwPD and 124 healthy controls who spoke French or Portuguese. All participants underwent the same clinical examinations, voice/speech recordings, and self-assessment questionnaires. PwPD were evaluated off and on optimal medication. Inferential analyses included Disease (controls vs. PwPD) and Language (French vs. Portuguese) as factors, and random decision forest algorithms identified relevant acoustic variables able to distinguish participants: (a) by language (French vs. Portuguese) and (b) by clinical status (PwPD on and off medication vs. controls). RESULTS: French-speaking and Portuguese-speaking individuals were distinguished from each other with over 90% accuracy by five acoustic variables (the mean fundamental frequency and the shimmer of the sustained vowel /a/ production, the oral diadochokinesis performance index, the relative sound level pressure and the relative sound pressure level standard deviation of the text reading). A distinct set of parameters discriminated between controls and PwPD: for men, maximum phonation time and the oral diadochokinesis speech proportion were the most significant variables; for women, variables calculated from the oral diadochokinesis were the most discriminative. CONCLUSIONS: Acoustic variables related to phonation and voice quality distinguished between speakers of the two languages. Variables related to pneumophonic coordination and articulation rate were the more effective in distinguishing PwPD from controls. Thus, our research findings support that respiration and diadochokinesis tasks appear to be the most appropriate to pinpoint signs of dysarthria, which are largely homogeneous and language-universal. In contrast, identifying language-specific variables with the speech tasks and acoustic variables studied was less conclusive.

Comparison of Polarized Versus Other Types of Endurance Training Intensity Distribution on Athletes' Endurance Performance: A Systematic Review with Meta-analysis.

BACKGROUND: Polarized training intensity distribution (POL) was recently suggested to be superior to other training intensity distribution (TID) regimens for endurance performance improvement. OBJECTIVE: We aimed to systematically review and meta-analyze evidence comparing POL to other TIDs on endurance performance. METHODS: PRISMA guidelines were followed. The protocol was registered at PROSPERO (CRD42022365117). PubMed, Scopus, and Web of Science were searched up to 20 October 2022 for studies in adults and young adults for ≥ 4 weeks comparing POL with other TID interventions regarding VO2peak, time-trial (TT), time to exhaustion (TTE) or speed or power at the second ventilatory or lactate threshold (V/P at VT2/LT2). Risk of bias was assessed with RoB-2 and ROBINS-I. Certainty of evidence was assessed with GRADE. Results were analyzed by random effects meta-analysis using standardized mean differences. RESULTS: Seventeen studies met the inclusion criteria (n = 437 subjects). Pooled effect estimates suggest POL superiority for improving VO2peak (SMD = 0.24 [95% CI 0.01, 0.48]; z = 2.02 (p = 0.040); 11 studies, n = 284; I2 = 0%; high certainty of evidence). Superiority, however, only occurred in shorter interventions (< 12 weeks) (SMD = 0.40 [95% CI 0.08, 0.71; z = 2.49 (p = 0.01); n = 163; I2 = 0%) and for highly trained athletes (SMD = 0.46 [95% CI 0.10, 0.82]; z = 2.51 (p = 0.01); n = 125; I2 = 0%). The remaining endurance performance surrogates were similarly affected by POL and other TIDs: TT (SMD = - 0.01 [95% CI -0.28, 0.25]; z = - 0.10 (p = 0.92); n = 221; I2 = 0%), TTE (SMD = 0.30 [95% CI - 0.20, 0.79]; z = 1.18 (p = 0.24); n = 66; I2 = 0%) and V/P VT2/LT2 (SMD = 0.04 [95% CI -0.21, 0.29]; z = 0.32 (p = 0.75); n = 253; I2 = 0%). Risk of bias for randomized controlled trials was rated as of some concern and for non-randomized controlled trials as low risk of bias (two studies) and some concerns (one study). CONCLUSIONS: POL is superior to other TIDs for improving VO2peak, particularly in shorter duration interventions and highly trained athletes. However, the effect of POL was similar to that of other TIDs on the remaining surrogates of endurance performance. The results suggest that POL more effectively improves aerobic power but is similar to other TIDs for improving aerobic capacity.

Artificial intelligence as a prediction tool for orthognathic surgery assessment.

INTRODUCTION: An ideal orthodontic treatment involves qualitative and quantitative measurements of dental and skeletal components to evaluate patients' discrepancies, such as facial, occlusal, and functional characteristics. Deciding between orthodontics and orthognathic surgery remains challenging, especially in borderline patients. Advances in technology are aiding clinical decisions in orthodontics. The increasing availability of data and the era of big data enable the use of artificial intelligence to guide clinicians' diagnoses. This study aims to test the capacity of different machine learning (ML) models to predict whether orthognathic surgery or orthodontics treatment is required, using soft and hard tissue cephalometric values. METHODS: A total of 920 lateral radiographs from patients previously treated with either conventional orthodontics or in combination with orthognathic surgery were used, comprising n = 558 Class II and n = 362 Class III patients, respectively. Thirty-two measures were obtained from each cephalogram at the initial appointment. The subjects were randomly divided into training (n = 552), validation (n = 183), and test (n = 185) datasets, both as an entire sample and divided into Class II and Class III sub-groups. The extracted data were evaluated using 10 machine learning models and by a four-expert panel consisting of orthodontists (n = 2) and surgeons (n = 2). RESULTS: The combined prediction of 10 models showed top-ranked performance in the testing dataset for accuracy, F1-score, and AUC (entire sample: 0.707, 0.706, 0.791; Class II: 0.759, 0.758, 0.824; Class III: 0.822, 0.807, 0.89). CONCLUSIONS: The proposed combined 10 ML approach model accurately predicted the need for orthognathic surgery, showing better performance in Class III patients.

Dual-Tasks in Soccer: Effects of Players' Experience and Task Condition on Physical Performance.

In this study, we examined whether experience level and various dual motor and cognitive or single tasks influenced young soccer players' physical performance during small-sided games. Participants were 72 players from U-13 (n = 36) and U-17 (n = 36) groups who participated in 3-to-a-side small-sided games under four experimental conditions: control, a secondary motor task, an additional related secondary cognitive task, and an additional secondary non-specific task. We used GPS devices to measure physical performance in terms of distances covered and accelerations at different thresholds. We found no significant interaction effect between player experience and task condition (p = .540), meaning that dual tasks had comparable effects on players of different experience levels. There were significant main effects of both experience level (p < .001) and condition (p < .001) on most physically related variables. Older players outperformed younger ones, particularly in high-intensity actions. While secondary motor tasks decreased physical performance, secondary cognitive tasks, irrespective of specificity, did not impair players' performances. In conclusion, experience level did not influence the players' physical response to dual tasks, and a secondary motor task was more disruptive to physical performance than either of two types of secondary cognitive tasks. Cognitive tasks can be incorporated into soccer training without compromising physical performance.

Are deciduous upper molars and lower canines useful for sex estimation?

OBJECTIVE: This paper investigates whether deciduous upper molars and lower canines have sexual dimorphic features, exploring these teeth' dimensions and the presence of Zuckerkandl's tubercle and Carabelli's cusp on the first and second upper molars. DESIGN: We analyzed 64 pairs of dental plaster casts from 34 females and 30 males aged between 3 and 12 years. We measured the first and second deciduous upper molars and the lower deciduous canines (maximum mesiodistal and buccolingual length), and we registered the presence of the Zuckerkandl's tubercle and the Carabelli's cusp on the first and second upper molars, respectively. RESULTS: Regarding the differentiation between sexes using Carabelli's cusp and Zuckerkandl's tubercle, the classification was not independent of Carabelli's cusp presence only for tooth 65 (p = 0.035). In all other teeth, whether for Carabelli's cusp or Zuckerkandl's tubercle, their presence was similar for both sexes. There were statistically significant differences between sexes (p < 0.05) for the buccolingual measurements of both upper second molars, the first right upper molar, and the right canine. The developed model allowed for a 64.1% accuracy in sex estimation. CONCLUSIONS: The study suggests that while Carabelli's cusp and Zuckerkandl's tubercle in upper deciduous molars don't consistently differ between sexes, tooth size, particularly the buccolingual measurements of certain teeth, including upper deciduous molars and lower canines, may provide a more reliable criterion for sex estimation. The developed model depicted moderate accuracy, underscoring the need for a multifactorial approach when estimating sex from skeletal remains. It suggests that while dental features can contribute to sex estimation, they should be used in conjunction with other skeletal or molecular markers to improve accuracy.

Impact of infrasound exposure and streptozotocin-induced glucose intolerance on bone composition in Wistar rats.

The elemental composition of chemical elements can vary between healthy and diseased tissues, providing essential insights into metabolic processes in physiological and diseased states. This study aimed to evaluate the calcium (Ca) and phosphorus (P) levels in the bones of rats with/without streptozotocin-induced diabetes and/or exposure to infrasound. X-ray fluorescence spectroscopy was used to determine the concentrations of Ca and P in Wistar rat tibiae samples.The results showed a significant decrease in bone P concentration in streptozotocin-induced diabetic rats compared to untreated animals. Similarly, the Ca/P ratio was higher in the streptozotocin-induced diabetic group. No significant differences were observed in bone Ca concentration between the studied groups or between animals exposed and not exposed to infrasound.Moreover, streptozotocin-induced diabetic rats had lower bone P concentration but unaltered bone Ca concentration compared to untreated rats. Infrasound exposure did not impact bone Ca or P levels. The reduced bone P concentration may be associated with an increased risk of bone fractures in diabetes.

Retinoic Acid-Mediated Control of Energy Metabolism Is Essential for Lung Branching Morphogenesis.

Lung branching morphogenesis relies on intricate epithelial-mesenchymal interactions and signaling networks. Still, the interplay between signaling and energy metabolism in shaping embryonic lung development remains unexplored. Retinoic acid (RA) signaling influences lung proximal-distal patterning and branching morphogenesis, but its role as a metabolic modulator is unknown. Hence, this study investigates how RA signaling affects the metabolic profile of lung branching. We performed ex vivo lung explant culture of embryonic chicken lungs treated with DMSO, 1 µM RA, or 10 µM BMS493. Extracellular metabolite consumption/production was evaluated by using 1H-NMR spectroscopy. Mitochondrial respiration and biogenesis were also analyzed. Proliferation was assessed using an EdU-based assay. The expression of crucial metabolic/signaling components was examined through Western blot, qPCR, and in situ hybridization. RA signaling stimulation redirects glucose towards pyruvate and succinate production rather than to alanine or lactate. Inhibition of RA signaling reduces lung branching, resulting in a cystic-like phenotype while promoting mitochondrial function. Here, RA signaling emerges as a regulator of tissue proliferation and lactate dehydrogenase expression. Furthermore, RA governs fatty acid metabolism through an AMPK-dependent mechanism. These findings underscore RA's pivotal role in shaping lung metabolism during branching morphogenesis, contributing to our understanding of lung development and cystic-related lung disorders.

Molecular Aspects Involved in the Mechanisms of Bothrops jararaca Venom-Induced Hyperalgesia: Participation of NK1 Receptor and Glial Cells.

Accidents caused by Bothrops jararaca (Bj) snakes result in several local and systemic manifestations, with pain being a fundamental characteristic. The inflammatory process responsible for hyperalgesia induced by Bj venom (Bjv) has been studied; however, the specific roles played by the peripheral and central nervous systems in this phenomenon remain unclear. To clarify this, we induced hyperalgesia in rats using Bjv and collected tissues from dorsal root ganglia (DRGs) and spinal cord (SC) at 2 and 4 h post-induction. Samples were labeled for Iba-1 (macrophage and microglia), GFAP (satellite cells and astrocytes), EGR1 (neurons), and NK1 receptors. Additionally, we investigated the impact of minocycline, an inhibitor of microglia, and GR82334 antagonist on Bjv-induced hyperalgesia. Our findings reveal an increase in Iba1 in DRG at 2 h and EGR1 at 4 h. In the SC, markers for microglia, astrocytes, neurons, and NK1 receptors exhibited increased expression after 2 h, with EGR1 continuing to rise at 4 h. Minocycline and GR82334 inhibited venom-induced hyperalgesia, highlighting the crucial roles of microglia and NK1 receptors in this phenomenon. Our results suggest that the hyperalgesic effects of Bjv involve the participation of microglial and astrocytic cells, in addition to the activation of NK1 receptors.

Physical Therapy Services During COVID-19 Pandemic: Perception of Families of Brazilian Children With Physical Disabilities.

PURPOSE: To describe the perspective of caregivers about physical therapy (PT) during the COVID-19 pandemic and the effect of social distancing on the health of children with physical disabilities. METHODS: This survey research used a remote questionnaire to identify the perceptions of caregivers about the effect of the COVID-19 pandemic on the health of children and adolescents with physical disabilities and on PT services. Data were analyzed using the frequency of responses; open-ended questions were analyzed through a hybrid approach to thematic analysis. RESULTS: Caregivers of 47 children with cerebral palsy were included. Although most received regular PT services during the pandemic, worsened children's physical conditions and anxiety were prevalent. Caregivers believed that they lacked technical skills. CONCLUSIONS: Social distancing impacted the health of children with physical disabilities, especially their physical conditions. Identifying facilitators and barriers for PT services can be helpful in future similar scenarios.Video abstract Supplemental Digital Content available at:http://links.lww.com/PPT/A503.

Relevance of real-time analyzers to determine mitochondrial quality in endothelial cells and oxidative stress in preeclampsia.

Oxidative stress and mitochondrial dysfunction are important elements for the pathophysiology of preeclampsia (PE), a multisystemic hypertensive syndrome of pregnancy, characterized by endothelial dysfunction and responsible for a large part of maternal and fetal morbidity and mortality worldwide. Researchers have dedicated their efforts to unraveling the intricate ways in which certain molecules influence both energy metabolism and oxidative stress. Exploring established methodologies from existing literature, shows that these investigations predominantly focus on the placenta, identified as a pivotal source that drives the changes observed in the disease. In this review, we discuss the role of oxidative stress in pathophysiology of PE, as well as metabolic/endothelial dysfunction. We further discuss the use of seahorse analyzers to study real-time bioenergetics of endothelial cells. Although the benefits are clear, few studies have presented results using this method to assess mitochondrial metabolism in these cells. We performed a search on MEDLINE/PubMed using the terms "Seahorse assay and endothelial dysfunction in HUVEC" as well as "Seahorse assay and preeclampsia". From our research, we selected 16 original peer-review papers for discussion. Notably, the first search retrieved studies involving Human Umbilical Vein Endothelial Cells (HUVECs) but none investigating bioenergetics in PE while the second search retrieved studies exploring the technique in PE but none of the studies used HUVECs. Additional studies are required to investigate real-time mitochondrial bioenergetics in PE. Clearly, there is a need for more complete studies to examine the nuances of mitochondrial bioenergetics, focusing on the contributions of HUVECs in the context of PE.

Inferring molecular inhibition potency with AlphaFold predicted structures.

Even though in silico drug ligand-based methods have been successful in predicting interactions with known target proteins, they struggle with new, unassessed targets. To address this challenge, we propose an approach that integrates structural data from AlphaFold 2 predicted protein structures into machine learning models. Our method extracts 3D structural protein fingerprints and combines them with ligand structural data to train a single machine learning model. This model captures the relationship between ligand properties and the unique structural features of various target proteins, enabling predictions for never before tested molecules and protein targets. To assess our model, we used a dataset of 144 Human G-protein Coupled Receptors (GPCRs) with over 140,000 measured inhibition constants (Ki) values. Results strongly suggest that our approach performs as well as state-of-the-art ligand-based methods. In a second modeling approach that used 129 targets for training and a separate test set of 15 different protein targets, our model correctly predicted interactions for 73% of targets, with explained variances exceeding 0.50 in 22% of cases. Our findings further verified that the usage of experimentally determined protein structures produced models that were statistically indistinct from the Alphafold synthetic structures. This study presents a proteo-chemometric drug screening approach that uses a simple and scalable method for extracting protein structural information for usage in machine learning models capable of predicting protein-molecule interactions even for orphan targets.

Harnessing carboxymethyl cellulose and Moringa oleifera seed husks for sustainable treatment of a multi-metal real waste.

This study aimed to evaluate effective treatment strategies for laboratory waste with an initial pH of 1.0, containing Cr6+, Mn2+, Co2+, Fe3+, Ni2+, Cu2+, Zn2+, Sr2+, Hg2+, and Pb2+ ions, focusing on flocculation, precipitation, and adsorption techniques. The study utilized microparticles derived from Moringa oleifera seed husks (MS), cryogels of carboxymethyl cellulose (CMC), and hybrid cryogels combining CMC and MS (CMC-MS25 and CMC-MS50) as adsorbents. The optimal strategy involved raising the pH to 7 using NH4OH, leading to the partial precipitation of metal ions. The remaining supernatant was then passed through columns packed with the aforementioned adsorbents. Utilizing CMC-MS25 and CMC-MS50 adsorbents resulted in the simultaneous removal of over 90% of the targeted metal ions. The adsorption of Cu2+ ions onto the adsorbents was facilitated by electrostatic interactions between Cu2+ ions and carboxylate groups, as well as Cu-OH chelation, as confirmed by X-ray photoelectron spectroscopy. Under optimized conditions, the fixed-bed column adsorption capacity was determined as 88.2 mg g-1. The CMC-MS25 adsorbents proved reusable at least 5 times, with the recovered Cu2+ ions potentially suitable for other processes. The scalability and feasibility of producing these novel adsorbents suggest a promising, cost-effective solution for treating complex matrices and recovering high-value metals, as copper.

Exposure to toxicologically relevant atrazine concentrations impair the glycolytic function of mouse Sertoli cells through the downregulation of lactate dehydrogenase.

Atrazine (ATZ), a widely used herbicide with potent endocrine-disrupting properties, has been implicated in hormonal disturbances and fertility issues. Sertoli cells (SCs) play a crucial role in providing mechanical and nutritional support of spermatogenesis. Herein, we aimed to study the effects of environmentally relevant ATZ concentrations on the nutritional support of spermatogenesis provided by SCs. For that, mouse SCs (TM4) were exposed to increasing ATZ concentrations (in µg/L: 0.3, 3, 30, 300, or 3000). After 24 h, cellular proliferation and metabolic activity were assessed. Mitochondrial activity and endogenous reactive oxygen species (ROS) production were evaluated using JC-1 and CM-H2DCFDA probes, respectively. We also analyzed protein levels of lactate dehydrogenase (LDH) using Western Blot and live cells glycolytic function through Seahorse XF Glycolysis Stress Test Kit. ATZ exposure decreased the activity of oxidoreductases in SCs, suggesting a decreased metabolic activity. Although ATZ is reported to induce oxidative stress, we did not observe alterations in mitochondrial membrane potential and ROS production across all tested concentrations. When we evaluated the glycolytic function of SCs, we observed that ATZ significantly impaired glycolysis and the glycolytic capacity at all tested concentrations. These results were supported by the decreased expression of LDH in SCs. Overall, our findings suggest that ATZ impairs the glycolytic function of SCs through LDH downregulation. Since lactate is the preferential energetic substrate for germ cells, exposure to ATZ may detrimentally impact the nutritional support crucial for spermatogenesis, hinting for a relationship between ATZ exposure and male infertility.

Immunometabolic crosstalk in Aedes fluviatilis and Wolbachia pipientis symbiosis.

Wolbachia pipientis is a maternally transmitted symbiotic bacterium that mainly colonizes arthropods, potentially affecting different aspects of the host's physiology, e.g., reproduction, immunity, and metabolism. It has been shown that Wolbachia modulates glycogen metabolism in mosquito Aedes fluviatilis (Ae. fluviatilis). Glycogen synthesis is controlled by the enzyme GSK3, which is also involved in immune responses in both vertebrate and invertebrate organisms. Here we investigated the mechanisms behind immune changes mediated by glycogen synthase kinase ß (GSK3ß) in the symbiosis between Ae. fluviatilis and W. pipientis using a GSK3ß inhibitor or RNAi-mediated gene silencing. GSK3ß inhibition or knockdown increased glycogen content and Wolbachia population, together with a reduction in Relish2 and gambicin transcripts. Furthermore, knockdown of Relish2 or Caspar revealed that the immunodeficiency pathway acts to control Wolbachia numbers in the host. In conclusion, we describe for the first time the involvement of GSK3ß in Ae. fluviatilis immune response, acting to control the Wolbachia endosymbiotic population.

A Review of Computational Modeling in Wastewater Treatment Processes.

Wastewater treatment companies are facing several challenges related to the optimization of energy efficiency, meeting more restricted water quality standards, and resource recovery potential. Over the past decades, computational models have gained recognition as effective tools for addressing some of these challenges, contributing to the economic and operational efficiencies of wastewater treatment plants (WWTPs). To predict the performance of WWTPs, numerous deterministic, stochastic, and time series-based models have been developed. Mechanistic models, incorporating physical and empirical knowledge, are dominant as predictive models. However, these models represent a simplification of reality, resulting in model structure uncertainty and a constant need for calibration. With the increasing amount of available data, data-driven models are becoming more attractive. The implementation of predictive models can revolutionize the way companies manage WWTPs by permitting the development of digital twins for process simulation in (near) real-time. In data-driven models, the structure is not explicitly specified but is instead determined by searching for relationships in the available data. Thus, the main objective of the present review is to discuss the implementation of machine learning models for the prediction of WWTP effluent characteristics and wastewater inflows as well as anomaly detection studies and energy consumption optimization in WWTPs. Furthermore, an overview considering the merging of both mechanistic and machine learning models resulting in hybrid models is presented as a promising approach. A critical assessment of the main gaps and future directions on the implementation of mathematical modeling in wastewater treatment processes is also presented, focusing on topics such as the explainability of data-driven models and the use of Transfer Learning processes.

Exploiting the therapeutic potential of contracting skeletal muscle-released extracellular vesicles in cancer: Current insights and future directions.

The health benefits of exercise training in a cancer setting are increasingly acknowledged; however, the underlying molecular mechanisms remain poorly understood. It has been suggested that extracellular vesicles (EVs) released from contracting skeletal muscles play a key role in mediating the systemic benefits of exercise by transporting bioactive molecules, including myokines. Nevertheless, skeletal muscle-derived vesicles account for only about 5% of plasma EVs, with the immune cells making the largest contribution. Moreover, it remains unclear whether the contribution of skeletal muscle-derived EVs increases after physical exercise or how muscle contraction modulates the secretory activity of other tissues and thus influences the content and profile of circulating EVs. Furthermore, the destination of EVs after exercise is unknown, and it depends on their molecular composition, particularly adhesion proteins. The cargo of EVs is influenced by the training program, with acute training sessions having a greater impact than chronic adaptations. Indeed, there are numerous questions regarding the role of EVs in mediating the effects of exercise, the clarification of which is critical for tailoring exercise training prescriptions and designing exercise mimetics for patients unable to engage in exercise programs. This review critically analyzes the current knowledge on the effects of exercise on the content and molecular composition of circulating EVs and their impact on cancer progression.