ABSTRACT
Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and future therapeutic interventions.
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Stroke is the leading cause of disability and the second cause of death worldwide. The increasing burden of stroke underscores the importance of optimising rehabilitation protocols. Virtual reality (VR) can improve poststroke prognosis. A VR software combining gamification, full immersion and stroke specificity (ie, the Development and validation of a novel viRtual rEality software for improving diSability and quality of lifE in patients with sTroke (RESET) software) might substantially improve disability and quality of life (QoL). However, this technology is still very scarce. The RESET trial aims to assess the effects of an early 10-week gamified, fully immersive and stroke-specific VR intervention (ie, starting at week 3 poststroke) on disability and QoL in people with stroke in the subacute phase. People with ischaemic or haemorrhagic stroke (n=94) aged ≥ 18 years will be randomised to receive (1) usual care (UC), (2) commercial VR or (3) gamified, fully immersive and stroke-specific VR (RESET). The three groups will receive UC (ie, three sessions/week of 90 min of standard rehabilitation). The VR groups will additionally receive three VR sessions of 20 min per week. The outcome measures will be assessed at baseline (week 2 from stroke occurrence), week 13 (approximately 90 days from the event) and week 26 (approximately 6 months from the event). The primary outcome is disability measured with the Barthel Index. Secondary outcomes include QoL, upper-extremity and lower-extremity motor function, gross manual dexterity, handgrip strength and cognitive function. This study will unravel the effects of a gamified, fully immersive and stroke-specific VR software on disability and QoL in patients with stroke in the early subacute phase.Trial registration number: NCT06132399.
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This work provides a comprehensive characterization of porcine myocardial tissue, combining true biaxial (TBx), simple triaxial shear (STS) and confined compression (CC) tests to analyze its elastic behavior under cyclic loads. We expanded this study to different zones of the ventricular free wall, providing insights into the local behavior along the longitudinal and radial coordinates. The aging impact was also assessed by comparing two age groups (4 and 8 months). Resulting data showed that the myocardium exhibits a highly nonlinear hyperelastic and incompressible behavior. We observed an anisotropy ratio of 2-2.4 between averaged peak stresses in TBx tests and 1-0.59-0.40 orthotropy ratios for normalised fiber-sheet-normal peak stresses in STS tests. We obtained a highly incompressible response, reaching volumetric pressures of 2-7 MPa for perfused tissue in CC tests, with notable differences when fluid drainage was allowed, suggesting a high permeability. Regional analysis showed reduced stiffness and anisotropy (20-25%) at the apical region compared to the medial, which we attributed to differences in the fiber field dispersion. Compressibility also increased towards the epicardium and apical regions. Regarding age-related variations, 8-month animals showed stiffer response (at least 25% increase), particularly in directions where the mechanical stress is absorbed by collagenous fibers (more than 90%), as supported by a histological analysis. Although compressibility of perfused tissue remained unchanged, permeability significantly reduced in 8-month-old animals. Our findings offer new insights into myocardial properties, emphasizing on local variations, which can help to get a more realistic understanding of cardiac mechanics in this common animal model. STATEMENT OF SIGNIFICANCE: In this work, we conducted a comprehensive analysis of the passive mechanical behavior of porcine myocardial tissue through biaxial, triaxial shear, and confined compression tests. Unlike previous research, we investigated the variation in mechanical response across the left ventricular free wall, conventionally assumed homogeneous, revealing differences in terms of stiffness and compressibility. Additionally, we evaluated agerelated effects on mechanical properties by comparing two age groups, observing significant variations in stiffness and permeability. To date, there has been no such indepth exploration of myocardial elastic response and compressibility considering regional variations along the wall and may contribute to a better understanding of the cardiac tissue's passive mechanical response.
ABSTRACT
Background: Marsupials and rodents are the most important wild and synanthropic hosts of Trypanosoma cruzi due to the high frequency of infection, maintenance of diverse genetic populations of the parasite, and their close proximity to interact with both transmission cycles, sylvatic and peridomestic. Our aim was to identify the discrete typing units (DTU) of T. cruzi from different wild and synanthropic hosts in two regions of Mexico and to carry out a review of historical data focusing on current knowledge on the diversity and T. cruzi DTUs of host species. Materials and Methods: One hundred fifteen samples were obtained from two areas in Tabasco and Nayarit state. The presence of T. cruzi was evaluated by PCR. Results: The 12.6% (12/95) of samples from Tabasco and 65% (13/20) from Nayarit were found to be positive for parasite DNA. All the sequences analyzed were grouped in T. cruzi DTU I; low nucleotide diversity was observed in Tabasco (π = 0.00566, and Ï´ = 0.00632), while high genetic diversity was observed in Nayarit sequences, up to 8.63 (π) to 11.10 (Ï´) times greater than Tabasco sequences. Genetic flow and migration between Tabasco, and Nayarit were scarce (FST = 0.37329 and Nm = 0.42), and genetic exchange was observed only between nearby areas. The bibliographic review of hosts in Mexico, together with our data, shows a heterogeneous T. cruzi prevalence in Chiroptera and domestic animals. For Atelidae and Canids, prevalence is generally below 25%. However, a high prevalence, greater than 25% and up to 100%, was recorded in Didelphimorphia, and Rodentia. Few studies in regions of Mexico have been described as infected with the parasite; in these, the genetic group with the highest prevalence is the DTU I. Conclusion: Marsupials and rodents are important reservoirs of T. cruzi; DTU I was frequently reported; however, recent genetic and reservoir studies have demonstrated the presence of greater diversity of genetic groups.
Subject(s)
Chagas Disease , Trypanosoma cruzi , Trypanosoma cruzi/genetics , Trypanosoma cruzi/isolation & purification , Trypanosoma cruzi/classification , Animals , Mexico/epidemiology , Chagas Disease/epidemiology , Chagas Disease/veterinary , Chagas Disease/transmission , Animals, Wild/parasitology , Mammals/parasitology , Genetic Variation , Rodentia/parasitologyABSTRACT
This study investigated how equipment and sex affect the prediction accuracy of the maximum number of repetitions performed to failure (RTF) using the fastest mean velocity of the set (MVfastest). Sixteen men and twelve women completed four sessions (two using free-weight equipment and two sessions using the Smith machine). Each session involved three sets of repetitions to failure against the 65%, 75%, and 85% of the one-repetition maximum, interspersed by 10-min of rest. The goodness-of-fit of the individualized RTF-MVfastest relationships was comparable between both equipment types and sexes (P≥0.510). Moreover, there were not significant differences in the MVfastest associated with RTF between equipment types (P≥0.258). However, the MVfastest associated with RTF was higher for men than for women in repetitions 6 to 15 (P≤0.043; ES≥0.69). In addition, the absolute errors when predicting RTF showed no significant differences between equipment types and loads (P<0.444). Specifically, these RTF estimates were within an acceptable range for men (<2 repetitions), but not for women (≥2 repetitions) (main effect of sex: P≤0.018; ES≥0.58). These findings suggest that individualized RTF-MVfastest equations estimate the RTF with an acceptable precision in men during bench press exercises in both equipment types but exhibit lower precision for women.
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OBJECTIVES: This study assessed the transparency and replicability of exercise-based interventions following bariatric surgery by evaluating the content reporting of exercise-based clinical trials. DESIGN: The study design of the present article is a systematic review. DATA SOURCES: PubMed, Scopus, Web of Sciences, PsycINFO, and Cochrane were searched from their inception to May 2023. ELIGIBILITY CRITERIA: Eligible studies were clinical trials including exercise interventions in participants following bariatric surgery. There were 28 unique exercise interventions. Two independent reviewers applied the exercise prescription components of Frequency, Intensity, Time, and Type (FITT; four items) and the Consensus on Exercise Reporting Template (CERT; 19 items). Exercise interventions were organized into four major exercise components: aerobic training, resistance training, concurrent training, and "others." RESULTS: The FITT assessment revealed that 53% of the trials did not report the training intensity, whereas 25% did not indicate the duration of the major exercise component within the training session. The mean CERT score was 5 out of a possible score of 19. No studies reached CERT score >10, while 13 out of the total 19 CERT items were not adequately reported by ≥75% of the studies. CONCLUSION: This study highlights that the exercise interventions following bariatric surgery are poorly reported, non-transparent, and generally not replicable. This precludes understanding the dose-response association of exercise and health-related effects and requires action to improve this scientific field.
Subject(s)
Bariatric Surgery , Exercise Therapy , Humans , Exercise Therapy/methods , Exercise , Obesity, Morbid/surgery , Resistance Training/methodsABSTRACT
Introducción y objetivos: La American Heart Association ha desarrollado el índice Life's Essential 8 (LE8) para promover la prevención de la enfermedad cardiovascular (ECV). Este estudio examinó la distribución del LE8 en la población adulta española y su asociación con la mortalidad general y por ECV.MétodosSe analizaron datos de 11.616 personas de edad≥ años (el 50,5% mujeres) del estudio ENRICA, reclutadas en 2008-2010 y seguidas hasta 2020-2022. El LE8 incluye 8 parámetros (dieta, actividad física, exposición a la nicotina, sueño, índice de masa corporal, lípidos y glucosa en sangre y presión arterial) y se puntúa de 0 a 100. La asociación entre LE8 y mortalidad se resumió mediante hazardratio obtenidas de modelos de Cox.ResultadosEl 13,2% de los participantes (del 6,1 al 16,9% según la comunidad autónoma) mostraron mala salud cardiovascular (LE8≤49). Tras una mediana de 12,9 años de seguimiento, ocurrieron 908 muertes totales y, durante una mediana de 11,8 años de seguimiento, 207 muertes por ECV. Tras ajustar por los principales factores de confusión y comparados con el cuartil más bajo (menos saludable) de LE8, los HR (IC 95%) de mortalidad general en el segundo, el tercer y el cuarto cuartil fueron, respectivamente, 0,68 (0,56-0,83), 0,63 (0,51-0,78) y 0,53 (0,39-0,72). Los resultados correspondientes a la mortalidad cardiovascular, considerando riesgos competitivos de muerte, fueron 0,62 (0,39-0,97), 0,55 (0,32-0,93) y 0,38 (0,16-0,89).ConclusionesUna proporción sustancial de los españoles mostraron mala salud cardiovascular. Una mayor puntación de LE8, desde el segundo cuartil, se asocia con menores mortalidad general y cardiovascular. (AU)
Introduction and objectives: The American Heart Association has recently developed the Life's Essential 8 (LE8) score to encourage prevention of cardiovascular disease (CVD). This study assessed the distribution of LE8 in the Spanish adult population and its association with all-cause and CVD death.MethodsWe used data from 11 616 individuals aged 18 years and older (50.5% women) from the ENRICA study, recruited between 2008 and 2010 and followed up until 2020 to 2022. The LE8 score includes 8 metrics (diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids and glucose, and blood pressure) and ranges from 0 to 100. The association of LE8 score with mortality was summarized with hazard ratios (HR), obtained from Cox regression.ResultsIn total, 13.2% of participants (range, 6.1%-16.9% across regions) had low cardiovascular health (LE8≤49). During a median follow-up of 12.9 years, 908 total deaths occurred, and, during a median follow-up of 11.8 years, 207 CVD deaths were ascertained. After adjustment for the main potential confounders and compared with being in the least healthy (lowest) quartile of LE8, the HR (95%CI) of all-cause mortality for the second, third and fourth quartiles were 0.68 (0.56-0.83), 0.63 (0.51-0.78), and 0.53 (0.39-0.72), respectively. The corresponding figures for CVD mortality, after accounting for competing mortality risks, were 0.62 (0.39-0.97), 0.55 (0.32-0.93), and 0.38 (0.16-0.89).ConclusionsA substantial proportion of the Spanish population showed low cardiovascular health. A higher LE8 score, starting from the second quartile, was associated with lower all-cause and CVD mortality. (AU)
Subject(s)
Humans , Body Mass Index , Cardiovascular Diseases/mortality , Cause of Death/trends , Risk Factors , Spain/epidemiologyABSTRACT
Most reported porous materials are either extended networks or monomeric discrete cavities; indeed, porous structures of intermediate size have scarcely been explored. Herein, we present the stepwise linkage of discrete porous metal-organic cages or polyhedra (MOPs) into oligomeric structures with a finite number of MOP units. The synthesis of these new oligomeric porous molecules entails the preparation of 1-connected (1-c) MOPs with only one available azide reactive site on their surface. The azide-terminated 1-c MOP is linked through copper(i)-catalysed azide-alkyne cycloaddition click chemistry with additional alkyne-terminated 1-c MOPs, 4-c clusters, or 24-c MOPs to yield three classes of giant oligomeric molecules: dimeric, tetrameric, or satellite-like, respectively. Importantly, all the giant molecules that we synthesised are soluble in water and permanently porous in the solid state.
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BACKGROUND: The increasing prevalence of obesity worldwide poses a significant threat to reproductive function owing, in part, to hormonal disturbances caused by negative feedback between excess adiposity and the hypothalamic-pituitary-ovarian axis. Consequently, finding the most appropriate strategies to lose weight and improve ovulation in women with overweight or obesity is a clinically relevant matter that needs to be investigated. A comprehensive comparison of the independent and combined efficacy of lifestyle and/or pharmacological interventions on BMI, ovulation, and hormonal profile in women with overweight or obesity at risk of anovulatory infertility would facilitate improving fertility strategies in this population. OBJECTIVE AND RATIONALE: This study aimed to evaluate the comparative efficacy of exercise, diet, and pharmacological interventions on BMI, ovulation, and hormonal profile in reproductive-aged women with overweight or obesity. SEARCH METHODS: A systematic review was performed by searching PubMed, Scopus, Web of Science, PsycINFO, and Cochrane Library up to 14 December 2023, for randomized controlled trials assessing the effects of exercise, diet and/or pharmacological interventions (i.e. weight-lowering drugs or ovulation inducers) on BMI, ovulation, and/or hormonal profile in reproductive-aged women with overweight or obesity. We performed frequentist random-effect network meta-analyses and rated the certainty of the evidence. The primary outcomes were BMI and ovulation rate, and the secondary outcomes were serum reproductive hormone levels (gonadotrophins, androgens, or oestrogens). We performed sensitivity analyses, including the studies that only involved women with PCOS. OUTCOMES: Among 1190 records screened, 148 full texts were assessed for eligibility resulting in 95 trials (9910 women), of which 53% presented a high or unclear risk of bias. The network meta-analyses revealed that, compared to control: diet combined with weight-lowering drugs (mean difference (MD) -2.61 kg/m2; 95% CI -3.04 to -2.19; τ2 = 0.22) and adding exercise (MD -2.35 kg/m2; 95% CI -2.81 to -1.89; τ2 = 0.22) led to the greatest decrease in BMI; exercise combined with diet and ovulation inducers (risk ratio (RR) 7.15; 95% CI 1.94-26.40; τ2 = 0.07) and exercise combined with diet and weight-lowering drugs (RR 4.80; 95% CI 1.67-13.84; τ2 = 0.07) produced the highest increase in ovulation rate; and exercise combined with diet and weight-lowering drugs was the most effective strategy in reducing testosterone levels (standardized mean difference (SMD) -2.91; 95% CI -4.07 to -1.74; τ2 = 2.25), the third most effective strategy in increasing sex hormone-binding globulin levels (SMD 2.37; 95% CI 0.99-3.76; τ2 = 2.48), and it was coupled with being ranked first in terms of free androgen index reduction (SMD -1.59; 95% CI -3.18 to 0.01; τ2 = 1.91). The surface under the cumulative ranking curve scores suggested that: diet combined with weight-lowering drugs is the strategy most likely (94%) to produce the highest BMI reduction; and exercise combined with diet and ovulation inducers is the strategy most likely (89%) to produce the highest ovulation rate improvement. The sensitivity analyses, which exclusively included studies involving women diagnosed with PCOS, were consistent with the results presented above. WIDER IMPLICATIONS: Overall, the findings of this network meta-analysis indicate that the combination of exercise, diet, and pharmacological interventions is effective for weight loss, improving ovulation, and normalizing the androgen levels of women with overweight or obesity. Although higher quality studies are needed, these results support that the optimal treatment strategy for women with overweight or obesity wishing to conceive must consider exercise, diet, and pharmacological interventions during the shared decision-making process.
Subject(s)
Body Mass Index , Exercise , Obesity , Overweight , Ovulation , Adult , Female , Humans , Diet , Network Meta-Analysis , Obesity/diet therapy , Obesity/therapy , Obesity/complications , Obesity/blood , Overweight/therapy , Overweight/diet therapy , Overweight/complications , Overweight/blood , Ovulation/drug effectsABSTRACT
The application of robotic devices is being used as Assistive Technology (AT) for improving rehabilitation interventions. The purposes of this research were to (1) test a novel low-cost robotic AT to support interventions for people with Cerebral Palsy (CP); (2) determine its usability; and (3) analyze its impact. It was a pilot study with prospective, longitudinal and analytical cohorts was done. Intervention was developed in one association (NGO) of people with CP. Participants were 6 women and 3 men with CP, with a mean age of 51.67. Intervention with LOLA2 (a robotic platform, not wearable, equipped with artificial intelligence) was implemented for training some activities of daily life (ADL) of participants. Functional Independence Measure (FIM), Psychosocial Impact of Assistive Technology Scale (PIADS), and Assistive Technology Device Predisposition Assessment (ATPA) were used for outcome measures. Level of participants' independence was high (FIM = 98). Psychosocial impact of the robotic platform in terms of competence (M = 0.25), adaptability (M = 0.33), and self-esteem (M = 0.25), was positive, but low. The mean in ATDPA (M = 3) reflects a moderate match. No significant variations concerning the changes in functional independence were detected. The robotic platform is applicable and complementary AT for rehabilitation. This study leads to implementing some improvements in its design, proposed activities, human-robot interaction, and system for registering information.
Robotic devices such as LOLA2 show promise as complementary tools in rehabilitation for individuals with Cerebral Palsy (CP), highlighting the potential for improved outcomes in clinical practice.There is a clear need for enhancements in the usability, universal design, and technical specifications of robotic platforms like LOLA2 to ensure their full functionality and quality, underscoring the importance of ongoing development and refinement.Utilizing specific outcome measures tailored to assess the efficacy and applicability of assistive technologies (AT), including robotic devices, is crucial for comprehensive evaluation and informed decision-making in rehabilitation interventions.Further research with higher validity is necessary to expand the evidence base surrounding the use of robotic devices in assistive technology, guiding specialized technical decisions and enhancing their integration into rehabilitation practices.
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Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell-limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.
Subject(s)
Multiple Myeloma , Receptors, Chimeric Antigen , Adult , Humans , Multiple Myeloma/pathology , T-Lymphocytes , Immunotherapy, Adoptive/methods , B-Cell Maturation Antigen , Immunologic Memory , Neoplasm Recurrence, Local/metabolism , Receptors, Chimeric Antigen/metabolismABSTRACT
The lethally maltreated body of Vittrup Man was deposited in a Danish bog, probably as part of a ritualised sacrifice. It happened between c. 3300 and 3100 cal years BC, i.e., during the period of the local farming-based Funnel Beaker Culture. In terms of skull morphological features, he differs from the majority of the contemporaneous farmers found in Denmark, and associates with hunter-gatherers, who inhabited Scandinavia during the previous millennia. His skeletal remains were selected for transdisciplinary analysis to reveal his life-history in terms of a population historical perspective. We report the combined results of an integrated set of genetic, isotopic, physical anthropological and archaeological analytical approaches. Strontium signature suggests a foreign birthplace that could be in Norway or Sweden. In addition, enamel oxygen isotope values indicate that as a child he lived in a colder climate, i.e., to the north of the regions inhabited by farmers. Genomic data in fact demonstrates that he is closely related to Mesolithic humans known from Norway and Sweden. Moreover, dietary stable isotope analyses on enamel and bone collagen demonstrate a fisher-hunter way of life in his childhood and a diet typical of farmers later on. Such a variable life-history is also reflected by proteomic analysis of hardened organic deposits on his teeth, indicating the consumption of forager food (seal, whale and marine fish) as well as farmer food (sheep/goat). From a dietary isotopic transect of one of his teeth it is shown that his transfer between societies of foragers and farmers took place near to the end of his teenage years.
Subject(s)
Emigrants and Immigrants , Proteomics , Humans , Male , Child , Animals , Sheep , Adolescent , Agriculture/history , Oxygen Isotopes , DenmarkABSTRACT
PURPOSE: To evaluate the prevalence of dysphagia in survivors of head and neck cancer (sHNC) and to identify the predictors contributing to the development of dysphagia. METHODS: We enrolled 62 sHNC in a cross-sectional study to check the prevalence of dysphagia in sHNC and to evaluate which factors were influencing the presence of this side effect. Besides dysphagia, sociodemographic and clinical characteristics, oral symptoms, maximal mouth opening (MMO), sleep quality and physical condition were evaluated, and a linear regression analysis was performed to verify which of these outcomes impact dysphagia. RESULTS: Among all the sHNC, 85.5% presented dysphagia. The linear regression analysis confirmed that 44.9% of the variance in dysphagia was determined by coughing, MMO and sleep quality, being MMO the most powerful predictor, followed by coughing and sleep quality. CONCLUSION: Dysphagia affected the great majority of sHNC. Moreover, symptoms as coughing, reduced MMO and sleep disorders may act as predictors contributing to the development of dysphagia. Our results emphasize the importance of an early and proper identification of the symptoms as well as an adequate treatment strategy to address the cluster of symptoms that sHNC undergo.
Subject(s)
Deglutition Disorders , Head and Neck Neoplasms , Humans , Deglutition Disorders/epidemiology , Deglutition Disorders/etiology , Cross-Sectional Studies , Quality of Life , Head and Neck Neoplasms/complications , SurvivorsABSTRACT
Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.
Subject(s)
Genetic Predisposition to Disease , Genome, Human , Grassland , Multiple Sclerosis , Humans , Datasets as Topic , Diet/ethnology , Diet/history , Europe/ethnology , Genetic Predisposition to Disease/history , Genetics, Medical , History, 15th Century , History, Ancient , History, Medieval , Human Migration/history , Life Style/ethnology , Life Style/history , Multiple Sclerosis/genetics , Multiple Sclerosis/history , Multiple Sclerosis/immunology , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/history , Neurodegenerative Diseases/immunology , Population DensityABSTRACT
INTRODUCTION: Excessive sun exposure and sunburns are the main preventable causes of skin cancer. The growing popularity of outdoor sports in developed countries has motivated the objective of this work to study the risk of photoexposure and the skin cancer prevention needs of athletes in an extreme race and evaluate an intervention targeted at this population. METHODS: An observational study was conducted during the XXIII edition of the 101 km de Ronda race, which consisted of trail running and mountain biking categories. Environmental and personal dosimetry, monitoring of meteorological conditions, evaluation of the athletes' photoprotection and skin examination habits, a dermatological checkup, and a satisfaction questionnaire were performed. RESULTS: The ultra-endurance race was carried out under adverse conditions (maximum ultraviolet index (UVI) = 9.2, temperatures above 30°C, and relative humidity >35%). The mean effective erythema dose received by race athletes (n = 11) was 2959.2 ± 404.2 J/m2 , equivalent to 29.6 standard erythema doses (SED). The CHACES questionnaire (n = 1145) showed a sunburn rate of 58% and poor protective habits: 62.9% of athletes do not usually use sunscreen and 67.2% do not self-examine their skin. Actinic keratoses (4.7%) and suspicious skin cancer lesions (4.2%) were found in dermatologic screening exams (n = 170). On the satisfaction questionnaire (n = 111), this intervention was rated as excellent (95.5%). CONCLUSION: This research highlights the extreme risk of photoexposure that athletes are subjected to during ultra-endurance competitions. In the same way, it shows the need to carry out interventions aimed at the acquisition of healthy photoprotection habits and skin surveillance in this target group.
Subject(s)
Skin Neoplasms , Sunburn , Humans , Environmental Exposure , Sunburn/prevention & control , Skin Neoplasms/epidemiology , Sunscreening Agents/therapeutic use , Erythema/etiologyABSTRACT
INTRODUCTION: The role of photobiomodulation (PBM) therapy for oral tissue damage induced by cancer treatment is currently unclear, and there is low-quality to moderate-quality evidence supporting the use of this approach for treating xerostomia and/or hyposalivation. Consequently, patients with head and neck cancer increasingly turn to basic oral hygiene to alleviate salivary gland dysfunction, and their adherence can be improved by mobile health (mHealth) education. The primary objective of this study will be to analyse the effects of different doses of PBM therapy (7.5 J/cm2 vs 3 J/cm2) plus mHealth education on quality of life (QoL), oral health, salivary secretion and salivary gland ultrasound assessment at postintervention and at the 6-month follow-up in patients with head and neck cancer after radiotherapy compared with those in control group. METHODS AND ANALYSIS: A prospective, three-arm, randomised, placebo-controlled, double-blinded study will be conducted among patients with head and neck cancer suffering from chronic xerostomia. A total of 20 patients per arm will be included and randomly assigned to receive 7.5 J/cm2 of PBM, 3 J/cm2 of PBM or placebo therapy. PBM therapy will be applied during 24 sessions at 22 points extra and intraorally two times per week for 3 months, combined with a mobile application (https://www.laxer.es). The assessments will be recorded at the beginning of the study, at postintervention and at the 6-month follow-up. The primary outcomes will be QoL, oral health, salivary secretion and salivary gland ultrasound. The pain pressure threshold, functional performance, mood and sleep quality will be secondary indicators. ETHICS AND DISSEMINATION: This study received ethics approval from the Andalusian Biomedical Research Ethics Portal (2402-N-21 CEIM/CEI Provincial de Granada) according to the Declaration of Helsinki for Biomedical Research. The results of this study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05106608.
Subject(s)
Head and Neck Neoplasms , Low-Level Light Therapy , Xerostomia , Humans , Quality of Life , Prospective Studies , Health Education , Xerostomia/etiology , Xerostomia/therapy , Head and Neck Neoplasms/radiotherapy , Randomized Controlled Trials as TopicABSTRACT
The term common variable immunodeficiency (CVID) encompasses a clinically diverse group of disorders, mainly characterized by hypogammaglobulinemia, insufficient specific antibody production, and recurrent infections. The genetics of CVID is complex, and monogenic defects account for only a portion of cases, typically <30%. Other proposed mechanisms include digenic, oligogenic, or polygenic inheritance and epigenetic dysregulation. In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants in BTK (n = 2), CD40LG (n = 1), and IKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant in BTK (p.Tyr418His), patient 3 had a pathogenic variant in CD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant in IKBKG (p.Glu57Lys) and a heterozygous splice variant in TNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics.
Subject(s)
Agammaglobulinemia , Common Variable Immunodeficiency , Humans , Female , Alleles , Antibodies , CD40 Ligand , Chromosomes , I-kappa B KinaseABSTRACT
We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-ß in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2.
Subject(s)
COVID-19 , Interferon Type I , Child , Humans , Interferon-alpha , AutoantibodiesABSTRACT
Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.