Search

Intracellular pathogens that replicate in host myeloid cells have devised ways to inhibit the cell's killing machinery. Pyroptosis is one of the host strategies used to reduce the pathogen replicating niche and thereby control its expansion. The intracellular Leishmania parasites can survive and use neutrophils as a silent entry niche, favoring subsequent parasite dissemination into the host. Here, we show that Leishmania mexicana induces NLRP1- and caspase-1-dependent Gasdermin D (GSDMD)-mediated pyroptosis in neutrophils, a process critical to control the parasite-induced pathology. In the absence of GSDMD, we observe an increased number of infected dermal neutrophils two days post-infection. Using adoptive neutrophil transfer in neutropenic mice, we show that pyroptosis contributes to the regulation of the neutrophil niche early after infection. The critical role of neutrophil pyroptosis and its positive influence on the regulation of the disease outcome was further demonstrated following infection of mice with neutrophil-specific deletion of GSDMD. Thus, our study establishes neutrophil pyroptosis as a critical regulator of leishmaniasis pathology. Author summary: Leishmaniases are neglected infectious diseases with around 1 million new cases reported per year. Neutrophils are rapidly and massively recruited to the site of infection. Several Leishmania species including Leishmania mexicana, inhibit the host neutrophil antimicrobial response, using these cells as an entry shelter. Here, we discover a novel host defense mechanism against Leishmania mexicana that controls neutrophil presence at the onset of infection. The inflammasomes are multiprotein signaling complexes that detect infection and induce pyroptotic cell death. We show that the NLRP1 inflammasome is important in the control of lesion development and parasite burden. We identify NLRP1-driven GSDMD pyroptosis in neutrophils as critical in the control of the early neutrophil pool, impacting the outcome of infection. Taken together, we show that neutrophil pyroptosis is an essential player in cutaneous leishmaniasis. [ABSTRACT FROM AUTHOR]

Copyright of Retos: Nuevas Perspectivas de Educación Física, Deporte y Recreación is the property of Federacion Espanola de Asociaciones de Docentes de Educacion Fisica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This study measured the peak force (PF) in cadet inline speed skaters (ISS) and verified the physical measures that determine athletes' performance on the Isometric Mid-Thigh Pull Test (IMTP) through a multivariate regression and discriminant canonical analysis. A total of 36 high-performance male (n= 18; age= 17.4± 1.21 years; body mass= 65.1± 6.18 kg; height= 168.6± 5.1 cm) and female (n= 18; age= 17.4± 1.23 years; body mass= 55.5± 4.4 kg; height= 158.6± 5.2 cm) athletes were measured two times (with a 3-day interval). All participants performed the IMTP and sit-and-reach (SR) tests, and an evaluator performed anthropometric circumference measurements on their thighs and calves. The main results indicated that males showed a higher PF on the test (m= 59.0± 3.9 N/kg vs. f= 50.4± 5.8 N/kg; p≤ 0.001) and retest (m= 59.1± 4.2 N/kg vs. f= 51.9± 6.6 N/kg; p≤ 0.001). In the first, thigh circumference (X2= 29.01, p≤ 0.001, R2= 0.74) had an overall 91.7% prediction. The second model included using the SR and thigh circumference (X2= 49.91, p≤ 0.001, R2= 1.0) showed an overall prediction of 100.0%. The thigh circumference matrix showed better predictive power for (coefficient= 7.158) male and female IMTP performance. In conclusion, despite the gender differences, the thigh circumference is a good predictor for PF in cadet ISS athletes.

Summary: Neutrophils are specialized innate immune cells known for their ability to fight pathogens. However, the mechanisms of neutrophil trafficking to lymph nodes are not fully clear. Using a murine model of dermal infection with Leishmania parasites, we observe a transient neutrophil influx in draining lymph nodes despite sustained recruitment to the infection site. Cell-tracking experiments, together with intravital two-photon microscopy, indicate that neutrophil recruitment to draining lymph nodes occurs minimally through lymphatics from the infected dermis, but mostly through blood vessels via high endothelial venules. Mechanistically, neutrophils do not respond to IL-1β or macrophage-derived molecules. Instead, they are guided by the C5a-C5aR1 axis, using L-selectin and integrins, to extravasate into the draining lymph node parenchyma. We also report that C5, the C5a precursor, is locally produced in the draining lymph node by lymphatic endothelial cells. Our data establish and detail organ-specific mechanisms of neutrophil trafficking.

An accurate trunk muscle strength assessment seems very important to design and individualize training and rehabilitation programs in clinical and sport settings. Hand-held dynamometers (HHDs) are interesting alternatives to isokinetic dynamometers for assessing trunk isometric muscle strength because they are inexpensive instruments and easy to use. This cross-sectional observational study aimed to examine the reliability of two novel sitting tests for assessing trunk flexion and extension isometric strength using an HHD and their relationship with two other novel isometric tests that use an isokinetic dynamometer. Twenty-four female amateur athletes (age: 24.5 ± 2.64 years; body height: 164.45 ± 6.33 cm; body mass: 63.17 ± 10.35 kg) participated in this study. A test-retest design was carried out one-week apart to examine the reliability. The relationship and the degree of agreement between the HHD and the isokinetic dynamometer measurements were analysed using Pearson correlation and Bland-Altman analysis, respectively. In general, the reliability of all isometric strength tests was good, with ICCs ranging from 0.65 to 0.87 and typical error < 15%. Pearson correlations were moderate, with values of r = 0.47 (R² = 0.22) and r = 0.42 (R² = 0.18) for flexion and extension strength, respectively. Bland-Altman plots showed no agreement between HHDs and isokinetic measurements. All trunk isometric tests using both, an isokinetic dynamometer and HHDs, provide reliable measurements for assessing trunk flexion and extension strength. According to the comparative analysis, both measurement types are different and cannot be used interchangeably. Health and sport professionals should choose the test that best suits the biomechanical characteristics required for functional goals or success in a given sport. [ABSTRACT FROM AUTHOR]

BACKGROUND: Body tilt changes could affect the intensity/difficulty of core stability exercises, but there is still a lack of knowledge about its impact. OBJECTIVE: To analyse the trunk muscles activation during prone plank exercises at different body tilts. METHODS: Twenty-four young adults who performed recreational gymnastic activities participated in this study. Electromyography activity of the rectus abdominis (RA), external oblique (EO), internal oblique (IO) and erector spinae (ES) was recorded during the performance of six variations of the prone plank exercise (planking with feet supported on the ground [conventional horizontal position] and planking with feet supported on wall bars at five different heights increasing the angle tilt) and an inverted position exercise. RESULTS: The RA, EO and IO activation in all prone plank variations were higher than those observed in the conventional prone plank. In addition, the coefficient of variation of the muscle activation increased with the declination angle, reaching the highest values in the inverted position for the RA and ES muscles. CONCLUSION: The results seem to indicate that the body tilt variation could be used as an easy and inexpensive strategy for modulating the neuromuscular demands and the motor control challenge during planking exercises. [ABSTRACT FROM AUTHOR]

Neutrophils are the first line of defence against invading pathogens. Although neutrophils are well-known professional killers, some pathogens including Leishmania (L.) parasites survive in neutrophils, using these cells to establish infection. Manipulation of neutrophil recruitment to the infection site is therefore of interest in this cutaneous disease. The c-MET tyrosine kinase receptor was shown to promote neutrophil migration to inflamed sites. Here, we investigated the importance of c-MET expression on neutrophils in their recruitment to the infection site and the role of c-Met expression in the pathology of leishmaniasis. Following infection with L. mexicana, mice with conditional deletion of c-MET in neutrophils controlled significantly better their lesion development and parasite burden compared to similarly infected wild type mice. Our data reveal a specific role for c-MET activation in Leishmania-induced neutrophil infiltration, a process correlating with their negative role in the pathology of the diseases. We further show that c-MET phosphorylation is observed in established cutaneous lesions. Exposure to L. mexicana upregulated c-Met expression predominantly in infected neutrophils and c-Met expression influenced ROS release by neutrophils. In addition, pharmacological inhibition of c-MET, administrated once the lesion is established, induced a significant decrease in lesion size associated with diminished infiltration of neutrophils. Both genetic ablation of c-MET in neutrophils and systemic inhibition of c-MET locally resulted in higher levels of CD4+T cells producing IFNγ, suggesting a crosstalk between neutrophils and these cells. Collectively, our data show that c-MET activation in neutrophils contributes to their recruitment following infection, and that L. mexicana induction of c-MET on neutrophils impacts the local pathology associated with this disease. Our results suggest a potential use for this inhibitor in the control of the cutaneous lesion during this parasitic infection.

Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Ape-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell-mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs., Introduction Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide (1). Patients with stage III or IV CRC have a high risk of recurrence and are [...]

The lack of training load control, mainly exercise intensity, is one of the main limitations of core stability (CS) programs, which makes the training individualization and the analysis of the dose-response relationship difficult. The objectives of this study were to assess the inter-and intra-rater agreement when using new observational screening guidelines to decide if a core stability exercise represents an adequate training intensity level for a given participant. Besides, the relationship between experts' ratings based on these criteria and pelvic accelerations recorded with a smartphone accelerometer was also analyzed. Ten healthy physically active participants with a smartphone accelerometer placed on their pelvis were video-taped while performing a progression of seven variations of the front bridge, back bridge, side bridge and bird-dog exercises. Two expert and four non-expert raters watched the videos and used the observational screening guidelines to decide for each exercise variation if it represented an adequate training intensity level or not. In order to analyze the inter-and intra-rater agreement, several Kappa (κ) statistics were used. Receiver operating characteristic (ROC) curves to explore if the accelerometry allowed to establish pelvic acceleration thresholds representing the minimum level of exercise intensity for CS training. Cut-off acceleration values were calculated balancing sensitivity (Se) and 1-specifity (1-Sp) indexes (i.e., Youden index) or minimizing 1-Sp. The intra-and inter-rater analysis showed a substantial-high level of agreement with a prevalence-adjusted bias-adjusted Kappa > 0.69. The ROC curves showed that the acceleration thresholds for the bridging exercises were very similar, with global cut-off values of 0.35 m/s2 (Se = 82%; 1-Sp = 15%) when using the Youden Index and of 0.50 m/s2 when minimizing 1-Sp (Se = 31%), whilst the bird-dog exercise showed lower cut-off values (Youden Index: 0.21 m/s2, Se = 90%, 1-Sp = 16%; minimizing 1-Sp: 0.32 m/s2, Se = 40%). Overall, this study provides observational screening guidelines and smartphone accelerometer thresholds to facilitate the decision-making process when setting the intensity of some of the most popular core stability exercises in young physically active individuals.

Heredia-Elvar, JR, Juan-Recio, C, Prat-Luri, A, Barbado, D, R'ıos-Calonge, Jdl, and Vera-Garcia, FJ. Exercise intensity progressions and criteria to prescribe core stability exercises in young physically active men: a smartphone accelerometer-based study. J Strength Cond Res 38(2): 266-273, 2024--The establishment of core stability (CS) exercise intensity progressions in sport and clinical settings is normally based on subjective criteria. Therefore, this study aimed to develop exercise intensity progressions for some of the most common CS exercises through smartphone accelerometry and to analyze the effect of the subjects' lumbopelvic postural control on these progressions. Fifty-seven healthy young physically active male students performed 7 isometric variations of front bridge, back bridge, side bridge, and bird-dog exercises with a smartphone accelerometer placed on the pelvis. Mean pelvic accelerations were calculated during each variation to evaluate the lumbopelvic postural control challenge imposed on the subjects as an index of exercise intensity of difficulty. For the bridge exercises, long bridging produced higher pelvic accelerations than short bridging, bridging with single-leg support was more intense than bridging with double-leg support (even with both legs on a hemisphere ball for the back and front bridge), and the most difficult variations were those performed on a Swiss ball, mainly the variations with single-leg support. For the bird-dog exercise, the 2-point positions weremore intense than the 3-point positions, the variations performed with a knee on the hemisphere ball produced higher pelvic accelerations than similar variations performed with the forearm on the hemisphere ball, and the variationswith limbmotions generated higher pelvic accelerations than similar variations performed without limbmotions. Although the CS exercise progressionswere very similar across subjects, our results showed the need to individualize the prescription of theCS exercise progressions based on the subjects' lumbopelvic postural control level. [ABSTRACT FROM AUTHOR]

The side bridge test (SBT) is one of the most popular tests to assess isometric trunk lateral flexor endurance. The aim of this study was to assess the validity and reliability of the SBT in healthy females. Twenty-four (24.58 ± 3.92 years) physically active (1–2 h of moderate physical activity, 2–3 times a week) females voluntarily participated in this study. The surface electromyography (EMG) of eight abdominal, back, shoulder and hip muscles was measured during the SBT. Normalized median frequency slopes (NMFslope) were calculated to analyze the muscle fatigue. The EMG amplitudes were normalized to maximum EMG values to assess muscle activity intensity. A one-week test-retest design was performed to evaluate the SBT reliability through the ICC3,1 and typical error. Higher NMFslopes and normalized EMG amplitudes were found in deltoids, abdominal obliques, rectus abdominis, and erector spinae in comparison to latissimus dorsi, gluteus medius, and rectus femoris. However, no significant differences were found between the trunk lateral flexors and the deltoids. Linear regression analysis showed that SBT performance could be significantly predicted by external oblique and deltoid NMFslope (adjusted R2 = 0.673) and by body mass and trunk height (adjusted R2 = 0.223). Consistency analysis showed a high intraclass correlation coefficient (0.81) and a relatively high typical error (10.95 s). Despite the good relative reliability of the SBT, its absolute reliability was low and its validity questionable, as the shoulder muscle activation and fatigue and the individuals’ anthropometric characteristics played an important role in SBT performance.

Summary: Calcineurin/NFAT signaling is active in endothelial cells and is proposed to be an essential component of the tumor angiogenic response. Here, we investigated the role of endothelial calcineurin signaling in vivo in physiological and pathological angiogenesis and tumor metastasis. We show that this pathway is dispensable for retinal and tumor angiogenesis, but it is implicated in vessel stabilization. While ablation of endothelial calcineurin does not affect the progression of primary tumors or tumor cell extravasation, it does potentiate the outgrowth of lung metastases. We identify Bmp2 as a downstream target of the calcineurin/NFAT pathway in lung endothelium, potently inhibiting cancer cell growth by stimulating differentiation. We reveal a dual role of calcineurin/NFAT signaling in vascular regression or stabilization and in the tissue-specific production of an angiocrine factor restraining cancer cell outgrowth. Our results suggest that, besides targeting the immune system, post-transplantation immunosuppressive therapy with calcineurin inhibitors directly targets the endothelium, contributing to aggressive cancer progression. : Hendrikx et al. show that endothelial calcineurin signaling is dispensable for physiological and tumor angiogenesis. Instead, it promotes vascular stabilization and, in cancer, restrains metastatic outgrowth. Immunosuppressive therapy with calcineurin inhibitors thus also directly affects the endothelium, which may contribute to aggressive cancer progression in organ transplant recipients. Keywords: angiogenesis, calcineurin, NFAT, BMP2, endothelial, metastasis, melanoma

Although core stability (CS) training is largely used to enhance motor performance and prevent musculoskeletal injuries, the lack of methods to quantify CS training intensity hinders the design of CS programs and the comparison and generalization of their effects. The aim of this study was to analyze the reliability of accelerometers integrated into smartphones to quantify the intensity of several CS isometric exercises. Additionally, this study analyzed to what extent the pelvic acceleration data represent the local stability of the core structures or the whole-body postural control. Twenty-three male and female physically-active individuals performed two testing-sessions spaced one week apart, each consisting of two 6-second trials of five variations of frontal bridge, back bridge, lateral bridge and bird-dog exercises. In order to assess load intensity based on the postural control challenge of CS exercises, a smartphone accelerometer and two force platforms were used to measure the mean pelvic linear acceleration and the mean velocity of the centre of pressure displacement, respectively. Reliability was assessed through the intra-class correlation coefficient (ICC3,1) and the standard error of measurement (SEM). In addition, Pearson coefficient was used to analyze the correlation between parameters. The reliability analysis showed that most CS exercise variations obtained moderate-to-high reliability scores for pelvic acceleration (0.71

This study measured the peak force (PF) in cadet inline speed skaters (ISS) and verified the physical measures that determine athletes' performance on the Isometric Mid- Thigh Pull Test (IMTP) through a multivariate regression and discriminant canonical analysis. A total of 36 high-performance male (n= 18; age= 17.4± 1.21 years; body mass= 65.1± 6.18 kg; height= 168.6± 5.1 cm) and female (n= 18; age= 17.4± 1.23 years; body mass= 55.5± 4.4 kg; height= 158.6± 5.2 cm) athletes were measured two times (with a 3-day interval). All participants performed the IMTP and sit-and-reach (SR) tests, and an evaluator performed anthropometric circumference measurements on their thighs and calves. The main results indicated that males showed a higher PF on the test (m= 59.0± 3.9 N/kg vs. f= 50.4± 5.8 N/kg; p≤ 0.001) and retest (m= 59.1± 4.2 N/kg vs. f= 51.9± 6.6 N/kg; p≤ 0.001). In the first, thigh circumference (X2= 29.01, p≤ 0.001, R2= 0.74) had an overall 91.7% prediction. The second model included using the SR and thigh circumference (X2= 49.91, p≤ 0.001, R2= 1.0) showed an overall prediction of 100.0%. The thigh circumference matrix showed better predictive power for (coefficient= 7.158) male and female IMTP performance. In conclusion, despite the gender differences, the thigh circumference is a good predictor for PF in cadet ISS athletes. [ABSTRACT FROM AUTHOR]