Effect of acute high-intensity interval exercise on a mouse model of doxorubicin-induced cardiotoxicity: a pilot study.

BACKGROUND: It is unknown whether high-intensity interval exercise (HIIE) may potentiate or attenuate the cardiotoxic effect of chemotherapy agents such as doxorubicin (DOX) when performed shortly after treatment. The study aimed to investigate the effect of acute HIIE on cardiac function and structure performed either 1, 2 or 3 days after DOX injection in an animal model. METHODS: Female C57bl/6 mice (n = 28), 70 days old, received a bolus 20 mg/kg intravenous tail vein DOX injection. Three exercise groups performed 1 HIIE session (16 sets of 1 min at 85-90% of peak running speed) at 1 (n = 7), 2 (n = 7), and 3 days (n = 8) following the DOX injection. A sedentary (SED) group of mice (n = 6) did not exercise. Animals underwent echocardiography under light anesthesia (isoflurane 0.5-1%) before and 7 days after the DOX injection. Animals were sacrificed on day 9 and hearts were collected for morphometric and histological analysis. RESULTS: Animals exercising on day 3 had the smallest pre-post reduction in left ventricular fractional shortening (LVFS) (MΔ= -1.7 ± 3.3; p = 0.406) and the SED group had the largest reduction (MΔ=-6.8 ± 7.5; p = 0.009). After reclassification of animals according to their exercise compliance (performing > 8/16 of high-intensity bouts), LVFS in compliant mice was unchanged over time (LVFS MΔ= -1.3 ± 5.6; p = 0.396) while non-compliant animals had a LVFS reduction similar to sedentary animals. There were no significant differences in myocardial histology between groups. CONCLUSIONS: In this pilot murine study, one single HIIE session did not exacerbate acute doxorubicin-induced cardiotoxicity. The timing of the HIIE session following DOX injection and the level of compliance to exercise could influence the negative impact of DOX on cardiac function.

Freshwater and anadromous fishing in Ice Age Beringia.

While freshwater and anadromous fish have been critical economic resources for late prehistoric and modern Native Americans, the origin and development of fishing is not well understood. We document the earliest known human use of freshwater and anadromous fish in North America by 13,000 and 11,800 years ago, respectively, from primary anthropogenic contexts in central Alaska (eastern Beringia). Fish use appears conditioned by broad climatic factors, as all occurrences but one are within the Younger Dryas chronozone. Earlier Bølling-Allerød and later early Holocene components, while exhibiting similar organic preservation, did not yield evidence of fishing, suggesting that this was a response to changing environmental factors, perhaps reductions in higher ranked resources such as large terrestrial mammals. Late Pleistocene and recent Indigenous peoples harvested similar fish taxa in the region (salmon, burbot, whitefish, and pike). We characterize late Pleistocene fishing in interior Beringia as an important element of broad-spectrum foraging rather than the intensive communal fishing and storage common among recent peoples.

Cardiac remodeling in amateur triathletes after 24 weeks of exercise training for a half-Ironman event: a brief report.

BACKGROUND: Triathletes' physiological adaptations to exercise training can have a different impact on cardiac remodeling based on the extreme exercise preparation. Moreover, cardiac remodeling might be different depending on whether triathletes have trained for many years or if they just decided to be more active. Nevertheless, data are limited in amateur endurance athletes and studies about them are key for their safety. Therefore, we investigated the effects of exercise training for a half-ironman on cardiac remodeling. METHODS: A total of 24 amateur athletes underwent a 24-week exercise program and were followed by three-dimensional echocardiography to assess its global impact on cardiac remodeling. Subanalyses were performed based on participants past-training experience (low versus high). RESULTS: We found significant group effects on the right and left ventricle, significant time effect on the right ventricle. No significant interaction effects were observed. We observed significant correlations between the right ventricle, clinical and performance characteristics where the peak power output explained 38% of the variance, while the body surface area, weight and power at the second ventilatory threshold explained 34%, 31% and 30%, respectively. CONCLUSIONS: Changes in cardiac remodeling in response to an exercise program for a half-ironman are not homogeneous across the ventricles and are influenced by participants' past-training experience. This study strengthens our knowledge of extreme exercise training for a half-ironman to further develop better training programs and medical follow-up in amateur triathletes.

Maximizing anaerobic performance with repeated-sprint training in hypoxia: In search of an optimal altitude based on pulse oxygen saturation monitoring.

Purpose: Repeated-sprint training in hypoxia (RSH) leads to great improvements in anaerobic performance. However, there is no consensus about the optimal level of hypoxia that should be used during training to maximize subsequent performances. This study aimed to establish whether such an optimal altitude can be determined and whether pulse oxygen saturation during RSH is correlated with training-induced improvement in performance. Methods: Peak and mean power outputs of healthy young males [age (mean ± SD) 21.7 ± 1.4 years] were measured during a Wingate (30 s) and a repeated-sprint ability (RSA; 10 x 6-s sprint with 24-s recovery) test before and after RSH. Participants performed six cycling sessions comprising three sets of 8 x 6-s sprint with 24-s recovery in normobaric hypoxia at a simulated altitude of either 1,500 m, 2,100 m, or 3,200 m (n = 7 per group). Heart rate variability was assessed at rest and during recovery from Wingate test before and after RSH. Results: The subjective rating of perceived exertion and the relative exercise intensity during training sessions did not differ between the three groups, contrary to pulse oxygen saturation (p < 0.001 between each group). Mean and peak power outputs were significantly increased in all groups after training, except for the mean power in the RSA test for the 3200 m group. Change in mean power on RSA test (+8.1 ± 6.6%) was the only performance parameter significantly correlated with pulse oxygen saturation during hypoxic training (p < 0.05, r = 0.44). The increase in LnRMSSD during recovery from the Wingate test was enhanced after training in the 1,500 m (+22%) but not in the two other groups (≈- 6%). Moreover, the increase in resting heart rate with standing after training was negatively correlated with SpO2 (p < 0.01, r =-0.63) suggesting that hypoxemia level during training differentially altered autonomic nervous system activity. Conclusion: These data indicate that RSH performed as early as 1,500 m of altitude is effective in improving anaerobic performance in moderately trained subjects without strong association with pulse oxygen saturation monitoring during training.

Rapid assembly of a polar network architecture drives efficient actomyosin contractility.

Actin network architecture and dynamics play a central role in cell contractility and tissue morphogenesis. RhoA-driven pulsed contractions are a generic mode of actomyosin contractility, but the mechanisms underlying how their specific architecture emerges and how this architecture supports the contractile function of the network remain unclear. Here we show that, during pulsed contractions, the actin network is assembled by two subpopulations of formins: a functionally inactive population (recruited) and formins actively participating in actin filament elongation (elongating). We then show that elongating formins assemble a polar actin network, with barbed ends pointing out of the pulse. Numerical simulations demonstrate that this geometry favors rapid network contraction. Our results show that formins convert a local RhoA activity gradient into a polar network architecture, causing efficient network contractility, underlying the key function of kinetic controls in the assembly and mechanics of cortical network architectures.

Effects of Repeated Sprint Training With Progressive Elastic Resistance on Sprint Performance and Anterior-Posterior Force Production in Elite Young Soccer Players.

ABSTRACT: Le Scouarnec, J, Samozino, P, Andrieu, B, Thubin, T, Morin, JB, and Favier, FB. Effects of repeated sprint training with progressive elastic resistance on sprint performance and anterior-posterior force production in elite young soccer players. J Strength Cond Res 36(6): 1675-1681, 2022-This study aimed to determine whether repeated sprint training with progressive high elastic resistance could improve sprint performance and anterior-posterior (AP) force production capacities of elite young soccer players. Seven elite U19 soccer players underwent 10 sessions of elastic-resisted repeated sprints on 8 weeks, whereas 8 U17 players from the same academy (control group) followed the same protocol without elastic bands. Sprint performance and mechanical parameters were recorded on a 30-m sprint before and after training. The control group did not show change for any of the measured variables. In contrast, the elastic-resisted training resulted in a significant improvement of the sprint time (-2.1 ± 1.3%; p = 0.026; Hedges' g = -0.49) and maximal velocity (Vmax; +3.9 ± 2%; p = 0.029; Hedges' g = 0.61) reached during the 30-m sprint. These enhancements were concurrent with an increase in the maximal power output related to AP force (Pmax; +4.9 ± 5.1%%; p = 0.026; Hedges' g = 0.42). Although the theoretical maximal AP force (F0) remained unchanged in both groups, there was a medium but nonsignificant increase in theoretical maximal velocity (V0; +3.7 ± 2.5%; p = 0.13; Hedges' g = 0.5) only in the elastic group. Therefore, the present results show that sprint capacity of elite young soccer players can be further improved by adding incremental resistance against runner displacement to raise the ability to produce AP force, rather at high velocity in the final phase of the acceleration.

Hypothalamic-pituitary-adrenal axis activation and glucocorticoid-responsive gene expression in skeletal muscle and liver of Apc mice.

BACKGROUND: Cancer patients at advanced stages experience a severe depletion of skeletal muscle compartment together with a decrease in muscle function, known as cancer cachexia. Cachexia contributes to reducing quality of life, treatment efficiency, and lifespan of cancer patients. However, the systemic nature of the syndrome is poorly documented. Here, we hypothesize that glucocorticoids would be important systemic mediators of cancer cachexia. METHODS: To explore the role of glucocorticoids during cancer cachexia, biomolecular analyses were performed on several tissues (adrenal glands, blood, hypothalamus, liver, and skeletal muscle) collected from ApcMin/+ male mice, a mouse model of intestine and colon cancer, aged of 13 and 23 weeks, and compared with wild type age-matched C57BL/6J littermates. RESULTS: Twenty-three-week-old Apc mice recapitulated important features of cancer cachexia including body weight loss (-16%, P < 0.0001), muscle atrophy (gastrocnemius muscle: -53%, P < 0.0001), and weakness (-50% in tibialis anterior muscle force, P < 0.0001), increased expression of atrogens (7-fold increase in MuRF1 transcript level, P < 0.0001) and down-regulation of Akt-mTOR pathway (3.3-fold increase in 4EBP1 protein content, P < 0.0001), together with a marked transcriptional rewiring of hepatic metabolism toward an increased expression of gluconeogenic genes (Pcx: +90%, Pck1: +85%), and decreased expression of glycolytic (Slc2a2: -40%, Gk: -30%, Pklr: -60%), ketogenic (Hmgcs2: -55%, Bdh1: -80%), lipolytic/fatty oxidation (Lipe: -50%, Mgll: -60%, Cpt2: -60%, Hadh: -30%), and lipogenic (Acly: -30%, Acacb: -70%, Fasn: -45%) genes. The hypothalamic pituitary-adrenal axis was activated, as evidenced by the increase in the transcript levels of genes encoding corticotropin-releasing hormone in the hypothalamus (2-fold increase, P < 0.01), adrenocorticotropic hormone receptor (3.4-fold increase, P < 0.001), and steroid biosynthesis enzymes (Cyp21a1, P < 0.0001, and Cyp11b1, P < 0.01) in the adrenal glands, as well as by the increase in corticosterone level in the serum (+73%, P < 0.05), skeletal muscle (+17%, P < 0.001), and liver (+24%, P < 0.05) of cachectic 23-week-old Apc mice. A comparative transcriptional analysis with dexamethasone-treated C57BL/6J mice indicated that the activation of the hypothalamic-pituitary-adrenal axis in 23-week-old ApcMin/+ mice was significantly associated with the transcription of glucocorticoid-responsive genes in skeletal muscle (P < 0.05) and liver (P < 0.001). The transcriptional regulation of glucocorticoid-responsive genes was also observed in the gastrocnemius muscle of Lewis lung carcinoma tumour-bearing mice and in KPC mice (tibialis anterior muscle and liver). CONCLUSIONS: These findings highlight the role of the hypothalamic-pituitary-adrenal-glucocorticoid pathway in the transcriptional regulation of skeletal muscle catabolism and hepatic metabolism during cancer cachexia. They also provide the paradigm for the design of new therapeutic strategies.

High-resolution dynamic mapping of the C. elegans intestinal brush border.

The intestinal brush border is made of an array of microvilli that increases the membrane surface area for nutrient processing, absorption and host defense. Studies on mammalian cultured epithelial cells have uncovered some of the molecular players and physical constraints required to establish this apical specialized membrane. However, the building and maintenance of a brush border in vivo has not yet been investigated in detail. Here, we combined super-resolution imaging, transmission electron microscopy and genome editing in the developing nematode Caenorhabditis elegans to build a high-resolution and dynamic localization map of known and new brush border markers. Notably, we show that microvilli components are dynamically enriched at the apical membrane during microvilli outgrowth and maturation, but become highly stable once microvilli are built. This new toolbox will be instrumental for understanding the molecular processes of microvilli growth and maintenance in vivo, as well as the effect of genetic perturbations, notably in the context of disorders affecting brush border integrity.

A focus on the association of Apol1 with kidney disease in children.

Individuals of African origin have an increased risk of developing various progressive chronic kidney diseases (CKD). This risk has been attributed to genetic variants (G1, G2) in apolipoprotein-L1 (APOL1) gene. In the pediatric population, especially in children affected by sickle cell disease (SCD), by human immunodeficiency virus (HIV), or with various glomerular diseases, APOL1 risk variants have been associated with the development of hypertension, albuminuria, and more rapid decline of kidney function. The present review focuses on existing APOL1-related epidemiological data in children with CKD. It also includes data from studies addressing racial disparities in CKD, the APOL1-related innate immunity, and the relationship between APOL1 and CKD and pathogenic pathways mediating APOL1-related kidney injury.

Prevalence, Location, and Determinants of Valvular Calcifications in Congolese Patients on Chronic Hemodialysis: A Multicenter Cross-Sectional Study.

Valvular calcifications (VCs) are one of the major cardiovascular complications in patients on chronic hemodialysis (HD) due to its prevalence and predictive morbidity and mortality. The current study assessed the prevalence, location, and risk factors of VC among chronic HD Congolese patients in Kinshasa. This observational study involved three HD centers in Kinshasa between March and August 2016. Consecutive consenting adults on maintenance HD for at least six months were recruited. VCs were defined as a luminous echo on one or more cusps of the aortic or mitral valve. Risk factors of VC were determined by multivariate analysis. Sixty patients (mean age: 52.5 ± 15.9 years) were enrolled. The mean serum calcium and phosphorus were7.9 ± 1.3 mg/dL and 5.7 ± 1.7 mg/dL, respectively. VCs were encountered in 38% of the whole group in aortic and mitral valvular location in 64% and 23%, respectively. Hypertension, age >60 years, tobacco use, and hyperphosphatemia were independently associated with VC. Despite a young age of patients, VCs were a common finding and associated with both traditional and chronic kidney disease-specific risk factors.

First Case of COVID-19-Associated Collapsing Glomerulopathy in Sub-Saharan Africa.

Although the lungs remain the main target of SARS-CoV-2, other organs, such as kidneys, can be affected, which has a negative impact on the outcomes of COVID-19 patients. Although previous studies of kidney disease in COVID-19 reported mainly SARS-CoV-2-induced tubular and interstitial injury, there is growing evidence coming out of Africa of glomerular involvement, especially collapsing glomerulopathy seen particularly in people of African descent. We report a case of collapsing glomerulopathy revealed by acute kidney injury and a new onset of full blown nephrotic syndrome in a black Congolese patient coinfected with COVID-19 and malaria.

Is REDD1 a metabolic double agent? Lessons from physiology and pathology.

The Akt/mechanistic target of rapamycin (mTOR) signaling pathway governs macromolecule synthesis, cell growth, and metabolism in response to nutrients and growth factors. Regulated in development and DNA damage response (REDD)1 is a conserved and ubiquitous protein, which is transiently induced in response to multiple stimuli. Acting like an endogenous inhibitor of the Akt/mTOR signaling pathway, REDD1 protein has been shown to regulate cell growth, mitochondrial function, oxidative stress, and apoptosis. Recent studies also indicate that timely REDD1 expression limits Akt/mTOR-dependent synthesis processes to spare energy during metabolic stresses, avoiding energy collapse and detrimental consequences. In contrast to this beneficial role for metabolic adaptation, REDD1 chronic expression appears involved in the pathogenesis of several diseases. Indeed, REDD1 expression is found as an early biomarker in many pathologies including inflammatory diseases, cancer, neurodegenerative disorders, depression, diabetes, and obesity. Moreover, prolonged REDD1 expression is associated with cell apoptosis, excessive reactive oxygen species (ROS) production, and inflammation activation leading to tissue damage. In this review, we decipher several mechanisms that make REDD1 a likely metabolic double agent depending on its duration of expression in different physiological and pathological contexts. We also discuss the role played by REDD1 in the cross talk between the Akt/mTOR signaling pathway and the energetic metabolism.

Ancient Beringian paleodiets revealed through multiproxy stable isotope analyses.

The earliest Native Americans have often been portrayed as either megafaunal specialists or generalist foragers, but this debate cannot be resolved by studying the faunal record alone. Stable isotope analysis directly reveals the foods consumed by individuals. We present multi-tissue isotope analyses of two Ancient Beringian infants from the Upward Sun River site (USR), Alaska (~11,500 years ago). Models of fetal bone turnover combined with seasonally-sensitive taxa show that the carbon and nitrogen isotope composition of USR infant bone collagen reflects maternal diets over the summer. Using comparative faunal isotope data, we demonstrate that although terrestrial sources dominated maternal diets, salmon was also important, supported by carbon isotope analysis of essential amino acids and bone bioapatite. Tooth enamel samples indicate increased salmon use between spring and summer. Our results do not support either strictly megafaunal specialists or generalized foragers but indicate that Ancient Beringian diets were complex and seasonally structured.

Analysis of blood pressure and selected cardiovascular risk factors in the Democratic Republic of the Congo: the May Measurement Month 2018 results.

Hypertension (HT) is the largest contributor to cardiovascular disease mortality and is characterized by high prevalence and low awareness, treatment, and control rates in sub-Saharan Africa. May Measurement Month (MMM) is an international campaign intended to increase awareness of high blood pressure (BP) among the population and advocate for its importance to the health authorities. This study aimed to increase awareness of raised BP in a country where its nationwide prevalence is yet unestablished. Investigators trained and tested how to use the campaign materials, collected participants' demographic data, lifestyle habits, and obtained from each one three BP measurements. Hypertension was defined as a BP ≥140/90 mmHg, or use of antihypertensive medication. Of the 18 719 screened (mean age 41 years; 61.4% men), 26.1% were found to be hypertensive of whom 46.3% were aware of their condition and 29.6% were taking antihypertensive medication. The control rate of HT was 43.0% in those on medication and 12.7% among all hypertensive respondents. Comorbidities found were-diabetes (3.3%), overweight/obesity (35.5%); and a previous stroke and a previous myocardial infarction were reported by 1.2% and 2.0%, respectively. Imputed age- and sex-standardized BP was higher in treated hypertensive individuals (135/85 mmHg) than those not treated (124/78 mmHg). Based on linear regression models adjusted for age and sex (and an interaction) and antihypertensive medication, stroke survivors, those who drank once or more per week (vs. never/rarely), and overweight/obese participants were associated with higher BP. MMM18 results in the Democratic Republic of the Congo corroborated the high prevalence of HT in Kinshasa screenees with low rates of treatment and control. Extension of the MMM campaign to other parts of the country is advisable.

Multi-temporal scale analysis of complementarity between hydro and solar power along an alpine transect.

Variable renewable energy sources display different space-time variability driving the availability of energy generated from these sources. Complementarity among variable renewable energies in time and space allows reducing the variability of power supply and helps matching the electricity demand curve. This work investigates the temporal structure of complementarity along an alpine transect in North-East Italy, considering a 100% renewable energy mix scenario composed by photovoltaic and run-of-the-river energy. We analyze the dominant scales of variability of variable renewable energy sources and electricity demand. In addition, we introduce a new metric, the wavelet-based complementarity index, to quantify the potential complementarity between two different energy sources. We show that this index varies at different temporal scales and it helps explaining the discrepancy between demand and supply in the study area. Continuous and discrete wavelet analyses are applied to assess the energy balance variability at multiple temporal scales and to identify the optimal mix of renewable energies, respectively. This work describes therefore an effective approach to investigate the temporal-scale dependency of the variance in the energy balance and can be further extended to different and more complex situations.

A promising pediatric peritoneal dialysis experience in a resource-limited setting with the support of saving young lives program.

In the Democratic Republic of Congo (DRC), acute kidney injury (AKI) contributes to the high rate of child mortality owing to the conjunction of poverty, deficiency of qualified health-care providers in pediatric nephrology, and the lack of pediatric dialysis programs. We aimed to describe the recent experience of the first pediatric acute peritoneal dialysis (PD) program in DRC. This is a retrospective cohort study on epidemiology, clinical features and outcomes of children admitted from January 2018 to January 2019 at the University Hospital of Kinshasa for AKI and treated with PD. This pediatric PD program started by a team of one physician and one nurse who were trained in the local production of PD fluids and bedside catheter insertion technique in Benin Republic. The training was jointly supported by the Flemish Inter-University Council (VLIR) TEAM project and Saving Young Lives (SYL) program of ISN, ISPD, EuroPD, and IPNA. From January 2018 to January 2019, 49 children (aged 4 months-15 years) were admitted for AKI mainly due to severe malaria and sepsis. Dialysis was indicated in 35 of 49 (71.4%), 32 of 35 (91.4%) were treated with PD, two with hemodialysis (HD) in adult ward and one died at admission. Data of the two patients transferred for HD were not available for follow-up. The main indications were uremia and prolonged anuria. Of 32 dialyzed patients, 24 (75%) recovered normal renal function 3 months after discharge. Peritonitis was observed in 2 of 32 (6.2%) patients and the mortality was 18.7%. This promising experience proves that with simple means including use of locally produced dialysis fluids and low peritonitis rates, we can effectively save lives of children suffering from AKI.

REDD1 deficiency protects against nonalcoholic hepatic steatosis induced by high-fat diet.

Nonalcoholic fatty liver disease is a chronic liver disease which is associated with obesity and insulin resistance. We investigated the implication of REDD1 (Regulated in development and DNA damage response-1), a stress-induced protein in the development of hepatic steatosis. REDD1 expression was increased in the liver of obese mice and morbidly obese patients, and its expression correlated with hepatic steatosis and insulin resistance in obese patients. REDD1 deficiency protected mice from the development of hepatic steatosis induced by high-fat diet (HFD) without affecting body weight gain and glucose intolerance. This protection was associated with a decrease in the expression of lipogenic genes, SREBP1c, FASN, and SCD-1 in liver of HFD-fed REDD1-KO mice. Healthy mitochondria are crucial for the adequate control of lipid metabolism and failure to remove damaged mitochondria is correlated with liver steatosis. Expression of markers of autophagy and mitophagy, Beclin, LC3-II, Parkin, BNIP3L, was enhanced in liver of HFD-fed REDD1-KO mice. The number of mitochondria showing colocalization between LAMP2 and AIF was increased in liver of HFD-fed REDD1-KO mice. Moreover, mitochondria in liver of REDD1-KO mice were smaller than in WT. These results are correlated with an increase in PGC-1α and CPT-1 expression, involved in fatty acid oxidation. In conclusion, loss of REDD1 protects mice from the development of hepatic steatosis.