Physical activity and exercise testing are two key points in sports medicine. Sports medicine is a field of medicine concerned with the prevention and treatment of injuries and disorders that are ...related to participation in sports. Clinical assessment in sports medicine can solve many questions about diagnosis, treatment, and prognosis related to health in sports. Physical activity could be defined as any bodily movement produced by skeletal muscles that requires energy expenditure. Physical activity refers to all movement including during leisure time, for transport to get to and from places, or as part of a person’s work. Both moderate- and vigorous-intensity physical activity improve health. Regular physical activity is proven to help prevent and manage noncommunicable diseases such as heart disease, stroke, diabetes, and several cancers. It also helps prevent hypertension, maintain a healthy body weight, and can improve mental health, quality of life, and well-being. Exercise could be defined as a subset of physical activity that is planned, structured, and repetitive and has as a final or an intermediate objective, such as the improvement or maintenance of physical fitness. Gait and posture analysis, clinical assessment, biomechanical analysis, reliability and repeatability research, force platform and electromyography analysis are key in order to improve our knowledge in this area.
Cystic Fibrosis is an autosomal recessive disorder caused by mutations in the CFTR gene. CRISPR mediated, template-dependent homology-directed gene editing has been used to correct the most common ...mutation, c.1521_1523delCTT / p.Phe508del (F508del) which affects ~70% of individuals, but the efficiency was relatively low. Here, we describe a high efficiency strategy for editing of three different rare CFTR mutations which together account for about 3% of individuals with Cystic Fibrosis. The mutations cause aberrant splicing of CFTR mRNA due to the creation of cryptic splice signals that result in the formation of pseudoexons containing premature stop codons c.1679+1634A>G (1811+1.6kbA>G) and c.3718-2477C>T (3849+10kbC>T), or an out-of-frame 5' extension to an existing exon c.3140-26A>G (3272-26A>G). We designed pairs of Cas9 guide RNAs to create targeted double-stranded breaks in CFTR either side of each mutation which resulted in high efficiency excision of the target genomic regions via non-homologous end-joining repair. When evaluated in a mini-gene splicing assay, we showed that targeted excision restored normal splicing for all three mutations. This approach could be used to correct aberrant splicing signals or remove disruptive transcription regulatory motifs caused by deep-intronic mutations in a range of other genetic disorders.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutation screening of the breast cancer genes BRCA1 and BRCA2 identifies a large fraction of variants of uncertain clinical significance (VUS) whose functional and clinical interpretations pose a ...challenge for genomic medicine. Likewise, an increasing amount of evidence indicates that genetic variants can have deleterious effects on pre-mRNA splicing. Our goal was to investigate the impact on splicing of a set of reported variants of BRCA2 exons 17 and 18 to assess their role in hereditary breast cancer and to identify critical regulatory elements that may constitute hotspots for spliceogenic variants. A splicing reporter minigene with BRCA2 exons 14 to-20 (MGBR2_ex14-20) was constructed in the pSAD vector. Fifty-two candidate variants were selected with splicing prediction programs, introduced in MGBR2_ex14-20 by site-directed mutagenesis and assayed in triplicate in MCF-7 cells. Wild type MGBR2_ex14-20 produced a stable transcript of the expected size (1,806 nucleotides) and structure (V1-BRCA2_exons_14-20-V2). Functional mapping by microdeletions revealed essential sequences for exon recognition on the 3' end of exon 17 (c.7944-7973) and the 5' end of exon 18 (c.7979-7988, c.7999-8013). Thirty out of the 52 selected variants induced anomalous splicing in minigene assays with >16 different aberrant transcripts, where exon skipping was the most common event. A wide range of splicing motifs were affected including the canonical splice sites (15 variants), novel alternative sites (3 variants), the polypyrimidine tract (3 variants) and enhancers/silencers (9 variants). According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), 20 variants could be classified as pathogenic (c.7806-2A>G, c.7806-1G>A, c.7806-1G>T, c.7806-1_7806-2dup, c.7976+1G>A, c.7977-3_7978del, c.7977-2A>T, c.7977-1G>T, c.7977-1G>C, c.8009C>A, c.8331+1G>T and c.8331+2T>C) or likely pathogenic (c.7806-9T>G, c.7976G>C, c.7976G>A, c.7977-7C>G, c.7985C>G, c.8023A>G, c.8035G>T and c.8331G>A), accounting for 30.8% of all pathogenic/likely pathogenic variants of exons 17-18 at the BRCA Share database. The remaining 8 variants (c.7975A>G, c.7977-6T>G, c.7988A>T, c.7992T>A, c.8007A>G, c.8009C>T, c.8009C>G, and c.8072C>T) induced partial splicing anomalies with important ratios of the full-length transcript (≥70%), so that they remained classified as VUS. Aberrant splicing is therefore especially prevalent in BRCA2 exons 17 and 18 due to the presence of active ESEs involved in exon recognition. Splicing functional assays with minigenes are a valuable strategy for the initial characterization of the splicing outcomes and the subsequent clinical interpretation of variants of any disease-gene, although these results should be checked, whenever possible, against patient RNA.
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Characterizing the subtle changes of functional brain networks associated with the pathological cascade of Alzheimer's disease (AD) is important for early diagnosis and prediction of disease ...progression prior to clinical symptoms. We developed a new deep learning method, termed multiple graph Gaussian embedding model (MG2G), which can learn highly informative network features by mapping high-dimensional resting-state brain networks into a low-dimensional latent space. These latent distribution-based embeddings enable a quantitative characterization of subtle and heterogeneous brain connectivity patterns at different regions, and can be used as input to traditional classifiers for various downstream graph analytic tasks, such as AD early stage prediction, and statistical evaluation of between-group significant alterations across brain regions. We used MG2G to detect the intrinsic latent dimensionality of MEG brain networks, predict the progression of patients with mild cognitive impairment (MCI) to AD, and identify brain regions with network alterations related to MCI.
Abstract
Obstructive sleep apnea (OSA) is associated with increased risk for end-organ morbidities, which can collectively be viewed as accelerated aging. Vascular senescence is an important ...contributor to end-organ dysfunction. Exosomes are released ubiquitously into the circulation, and transfer their cargo to target cells facilitating physiological and pathological processes. Plasma exosomes from 15 patients with polysomnographically diagnosed OSA at baseline (OSA-T1) after 12 months of adherent continuous positive airway pressure (CPAP) treatment (OSA-T2), 13 untreated OSA patients at 12-month intervals (OSA-NT1, OSA-NT2), and 12 controls (CO1 and CO2) were applied on naïve human microvascular endothelialcells-dermal (HMVEC-d). Expression of several senescence gene markers including p16 (CDKN2A), SIRT1, and SIRT6 and immunostaining for β-galactosidase activity (x-gal) were performed. Endothelial cells were also exposed to intermittent hypoxia (IH) or normoxia (RA) or treated with hydrogen peroxide (H2O2), stained with x-gal and subjected to qRT-PCR. Exosomes from OSA-T1, OSA-NT1, and OSA-NT2 induced significant increases in x-gal staining compared to OSA-T2, CO1, and CO2 (p-value < 0.01). p16 expression was significantly increased (p < 0.01), while SIRT1 and SIRT6 expression levels were decreased (p < 0.02 and p < 0.009). Endothelial cells exposed to IH or to H2O2 showed significant increases in x-gal staining (p < 0.001) and in senescence gene expression. Circulating exosomes in untreated OSA induce marked and significant increases in senescence of naïve endothelial cells, which are only partially reversible upon long-term adherent CPAP treatment. Furthermore, endothelial cells exposed to IH or H2O2 also elicit similar responses. Thus, OSA either directly or indirectly via exosomes may initiate and exacerbate cellular aging, possibly via oxidative stress-related pathways.
Modern Elekta Neuromag MEG devices include 102 sensor triplets containing one magnetometer and two planar gradiometers. The first processing step is often a signal space separation (SSS), which ...provides a powerful noise reduction. A question commonly raised by researchers and reviewers relates to which data should be employed in analyses: (1) magnetometers only, (2) gradiometers only, (3) magnetometers and gradiometers together. The MEG community is currently divided with regard to the proper answer.
First, we provide theoretical evidence that both gradiometers and magnetometers result from the backprojection of the same SSS components. Then, we compare resting state and task-related sensor and source estimations from magnetometers and gradiometers in real MEG recordings before and after SSS.
SSS introduced a strong increase in the similarity between source time series derived from magnetometers and gradiometers (r² = 0.3-0.8 before SSS and r² > 0.80 after SSS). After SSS, resting state power spectrum and functional connectivity, as well as visual evoked responses, derived from both magnetometers and gradiometers were highly similar (Intraclass Correlation Coefficient > 0.8, r² > 0.8).
After SSS, magnetometer and gradiometer data are estimated from a single set of SSS components (usually ≤ 80). Equivalent results can be obtained with both sensor types in typical MEG experiments.
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EL ARCAICO ORIGEN DE LOS RITOS Londoño Sanz, David
Cuadernos salmantinos de filosofía,
03/2024, Volume:
51
Journal Article
El filósofo francés R. Girard en su obra La violencia y lo sagrado estudia el fenómeno del chivo expiatorio, es decir la cohesión social de un grupo a partir de un enemigo común, de una víctima ...sacrificial. Esta teoría antropológica de la cultura está en relación con la llamada violencia de recambio de la biología, es decir, la violencia desviada hacia enemigos comunes para protección de la comunidad. Si para S. Freud el desarrollo cultural genera inevitablemente neurosis al imponer al individuo una doble orden contradictoria (satisfacer los deseos y a la vez reprimir los deseos) para R. Girard el desarrollo cultural genera no malestar, sino sanidad en el individuo, protegiéndolo de la violencia indiferenciada de épocas arcaicas. Tal vez las instituciones judiciales modernas han intentado racionalizar la figura de los enemigos comunes de la sociedad a través de leyes penales lo más sensatas posibles.
The ever increasing proportion of aged people in modern societies is leading to a substantial increase in the number of people affected by dementia, and Alzheimer's Disease (AD) in particular, which ...is the most common cause for dementia. Throughout the course of the last decades several different compounds have been tested to stop or slow disease progression with limited success, which is giving rise to a strong interest toward the early stages of the disease. Alzheimer's disease has an extended an insidious preclinical stage in which brain pathology accumulates slowly until clinical symptoms are observable in prodromal stages and in dementia. For this reason, the scientific community is focusing into investigating early signs of AD which could lead to the development of validated biomarkers. While some CSF and PET biomarkers have already been introduced in the clinical practice, the use of non-invasive measures of brain function as early biomarkers is still under investigation. However, the electrophysiological mechanisms and the early functional alterations underlying preclinical Alzheimer's Disease is still scarcely studied. This work aims to briefly review the most relevant findings in the field of electrophysiological brain changes as measured by magnetoencephalography (MEG). MEG has proven its utility in some clinical areas. However, although its clinical relevance in dementia is still limited, a growing number of studies highlighted its sensitivity in these preclinical stages. Studies focusing on different analytical approaches will be reviewed. Furthermore, their potential applications to establish early diagnosis and determine subsequent progression to dementia are discussed.
Genome-wide association studies (GWAS) have great promise for identifying the loci that contribute to adaptive variation, but the complex genetic architecture of many quantitative traits presents a ...substantial challenge.
We measured 14 morphological and physiological traits and identified single nucleotide polymorphism (SNP)-phenotype associations in a Populus trichocarpa population distributed from California, USA to British Columbia, Canada. We used whole-genome resequencing data of 882 trees with more than 6.78 million SNPs, coupled with multitrait association to detect polymorphisms with potentially pleiotropic effects. Candidate genes were validated with functional data.
Broad-sense heritability (H²) ranged from 0.30 to 0.56 for morphological traits and 0.08 to 0.36 for physiological traits. In total, 4 and 20 gene models were detected using the single-trait and multitrait association methods, respectively. Several of these associations were corroborated by additional lines of evidence, including co-expression networks, metabolite analyses, and direct confirmation of gene function through RNAi.
Multitrait association identified many more significant associations than single-trait association, potentially revealing pleiotropic effects of individual genes. This approach can be particularly useful for challenging physiological traits such as water-use efficiency or complex traits such as leaf morphology, for which we were able to identify credible candidate genes by combining multitrait association with gene co-expression and co-methylation data.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
A cross-sectional area (CSA) and thickness reduction of the abductor hallucis (AbH) is shown in subjects with hallux valgus (HV). To date, other soft-tissue structures have not been researched in ...relation with HV. The aim of this study was to compare the CSA and thickness of the intrinsic plantar muscles and fascia (PF) between feet with and without HV. Therefore, a cross-sectional and case-control study was performed using B-mode with an iU22 Philips ultrasound system and a 5 to 17-MHz transducer. The CSA and thickness were measured for the AbH, flexor digitorum brevis (FDB) and flexor hallucis brevis (FHB), and also the thickness for the anterior, middle, and posterior PF portions. A convenience sample of 40 feet, 20 with HV and 20 without HV, was recruited from a clinical and research center. A multivariate regression analysis using linear regression was performed to evaluate the ultrasound imaging measurements (α = 0.05). Consequently, statistically significant differences were observed between the groups (P < 0.05) for the AbH and FHB thickness, and CSA reduction, and also the plantar fascia thickness increase in favor of the HV group. On the contrary, the FDB thickness and CSA did not show statistically significant differences (P ≥ 0.05). In conclusion, the CSA and thickness of the AbH and FHB intrinsic plantar muscles are reduced, whereas the thickness of the anterior, middle, and posterior PF portions are increased, in subjects with HV compared with those without HV.
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