Search Results (61)

Background: Duchenne/Becker muscular dystrophy (DMD/BMD) is associated with a wide spectrum of brain-related comorbidities. Methods: This retrospective study assesses the neuropsychiatric profile of DMD/BMD patients and the hypothesis of a functional-versus-structural approach of dystrophin gene variants/impaired isoforms in relation to brain comorbidities. Patients with documented mutation in the DMD gene and neuropsychiatric assessments were included. Seven comorbidities were analyzed based on variant location and dystrophin brain isoform disruption. The clustering of comorbidities and genotype–phenotype correlations were studied. Results: 264 DMD/BMD patients met inclusion criteria. 22 variants have never been described before. A high prevalence of neuropsychiatric comorbidities was identified in the cohort with higher values in patients with distal mutations. The number of comorbidities increased with the number of brain dystrophin isoforms predicted to be lost. Functional-versus-structural comparison revealed that Dp140 5′UTR variants might not affect protein expression. Epilepsy and intellectual disability (ID) showed significant association in this cohort. Neuropsychiatric phenotype varied greatly in patients with identical variants, even between siblings. Conclusions: This is one of the largest European cohorts for which all these comorbidities were studied in association with DMD gene mutation site and the first study of this kind performed on the Eastern European DMD/BMD population. Our group analyzed, for the first time, Dp140 5′UTR variants in relation to all neuropsychiatric phenotypes and showed that epilepsy and ID are strongly associated in DMD/DMB patients. Full article

TANGO2 deficiency disorder is a rare autosomal recessive disease (~100 cases reported worldwide). Despite being caused by loss-of-function variants in the TANGO2 gene, patients exhibit marked phenotypic variability, including intrafamilial differences among individuals carrying identical variants. To uncover potential modifier mechanisms influencing disease severity, we developed an integrative Systems biology framework, combining exome sequencing, transcriptomics, variant effect prediction, and Human Phenotype Ontology mapping. This approach was applied to two siblings carrying identical compound heterozygous TANGO2 variants but opposite clinical outcomes: one severely affected and one asymptomatic. Personalized protein–protein interaction networks and combined univariate and multivariate analyses were employed to maximize specificity in this single-family comparison. In the affected sibling, a cumulative burden of common APOB variants, together with altered VLDLR, NTN1, and LDHA expression, implicated disrupted lipid metabolism and neurodevelopmental pathways. The asymptomatic sibling harbored a potentially protective 3′-UTR variant in EP300 and no APOB variant burden, supporting enhanced post-transcriptional regulation within developmental biology networks. These findings highlight lipid metabolism as a key pathway in TANGO2 deficiency pathophysiology and suggest autophagy and mitophagy as additional modifier mechanisms influencing phenotypic variability. Our integrative multi-omics framework provides a valuable strategy for elucidating genotype-phenotype relationships in rare diseases and supports personalized therapeutic approaches. Full article

The intermuscular-bone-free crucian carp (Carassius auratus, WUCI), developed through CRISPR/Cas9-mediated bmp6a and bmp6b knockout, offers advantages in consumer acceptance and processing efficiency. However, its effects on muscle texture and nutritional quality have not been fully elucidated. In this study, we compared the F3 generation of WUCI with its sibling wild-type crucian carp (Carassius auratus, WT), Songpu silver crucian carp (Carassius gibelio var. Songpu, SPYJ), and Fangzheng silver crucian carp (Carassius gibelio var. Fangzheng, FZYJ), focusing on muscle texture characteristics and nutritional attributes. WUCI exhibited significantly higher shear force but lower hardness than most comparison groups, with no substantial differences in muscle fiber morphology. Amino acid profiles were similar among all groups. WUCI showed lower crude fat content than WT but higher than FZYJ, and comparable levels of polyunsaturated fatty acids (PUFA), n-3 fatty acids, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) to WT and SPYJ. These findings indicate that the knockout of bmp6a and bmp6b does not alter muscle mass in crucian carp, supporting the potential of WUCI for commercial adoption as a gene-edited consumer-oriented fish product. Full article

Background/Objectives: Cardiorespiratory fitness (CRF) is of great interest in children and adolescents. Due to the limited availability of cardiopulmonary exercise testing, simple and reliable alternatives are needed. A stair climbing test (SCT) for the assessment of CRF developed at the Department of Pediatric Cardiology of the LMU University Hospital in Munich showed a strong correlation with VO₂max. The aim of this study is to prove its feasibility in a non-clinical setting and to analyse its results in a larger study population. Methods: During the “Hand aufs Herz” study, a comprehensive cardiovascular examination was carried out on 922 pupils and siblings (13.2 ± 7.8 years) at a high school in Bavaria. The SCT was performed to evaluate CRF: participants had to run up and down a total of four floors (14.8 m) as quickly as possible without skipping steps or holding on to the banister. Absolute time has been normalized over the standard height of 12 m to allow comparisons with different settings. An SCT Index was calculated to adjust results to the different weights of participants and the exact height of the staircase. Results: The SCT proved to be easily feasible and safe in non-clinical contexts. Out of 922 participants, 13 (1.4%) were not able to perform the test, and 3 (0.3%) had to interrupt it following fatigue or stumbling. A total of 827 participants aged from 9 to 17 years (13.1 ± 2.1 years, 45.8% girls) had a mean absolute SCT time of 53.4 ± 6.2 s and 43.3 ± 5.1 s when normalized over 12 m. Conclusions: The SCT represents a simple, cost- and time-saving test that allows a rapid and solid assessment of cardiorespiratory fitness in children and adolescents. We could demonstrate that it is safe and feasible in non-clinical contexts. Its short duration and universal applicability are valuable advantages that could facilitate the establishment of a repetitive cardiovascular screening in the pediatric population, particularly in outpatient departments or settings with low-resource systems. Full article

Background: One of the major challenges for children and adolescents with sickle cell disease (SCD) is academic performance. Objectives: Our study aimed to evaluate the academic performance of children and adolescents with SCD in Benin and compare it to the academic performance of their healthy siblings and paediatric comparisons. Furthermore, we aimed to explore the associations between socio-demographic factors, clinical characteristics, and depressive symptoms, and the academic performance of children and adolescents with SCD. Methods: The study was a cross-sectional study that used convenient sampling. Academic scores were collected during the 2021–2022 academic year. Patients with SCD and paediatric comparisons were recruited during routine hospital consultations. The Children’s Depression Inventory (CDI-S) tool was used to assess depressive symptoms. We compared academic performance scores (ranging from 0 to 20) using independent t-tests and explored associations through linear regression analyses. Results: This study included 209 participants: 100 patients with SCD (aged 6 to 17 years), 46 siblings, and 63 paediatric comparisons. The academic performance of patients with SCD (mean academic score = 13.29) was similar to that of the combined comparison group (mean academic score = 12.8, p = 0.196). Younger patients showed poorer academic performance (coef = −0.169, p = 0.019), and depressive symptoms (‘pessimism’, ‘self-hate’, ‘lack of friends’, and ‘fatigue’) were associated with poorer academic performance as well. Patients with SCD who were treated in Benin performed academically as well as their healthy siblings and peers. Conclusions: Children and adolescents with SCD performed on par academically with their healthy siblings and peers. While overall depressive symptoms were not significantly associated with academic performance, certain symptoms were more common among lower-performing students and should therefore be explored in greater detail. Full article

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the double homeobox 4 (DUX4) gene. In this study, an analysis of human FSHD muscle biopsies revealed differential expressions of six m6A regulators, including writers, readers and eraser proteins. In immortalized human FSHD myoblasts, we found higher levels of mRNA and protein expression of a major m6A regulator, methyltransferase-like protein 3 (METTL3), in comparison with myoblasts from unaffected siblings (UASbs). Quantification of the overall RNA m6A levels in the FSHD myoblasts revealed significant elevation compared with their UASb, which was reversed to UASb levels following treatment with an antisense oligonucleotide targeting the DUX4 mRNA. Using Oxford Nanopore direct-RNA sequencing, we mapped m6A across the transcriptome and identified genes harboring differential methylated m6A sites, including several involved in iron homeostasis. Western blot protein quantification showed that FSHD myoblasts had higher levels of ferritin-heavy chain-207 isoform and mitoferrin-1. In addition, our data showed elevation in mitochondrial ferrous iron in FSHD myoblasts. Our findings suggest that m6A RNA modifications play a pivotal role in FSHD pathophysiology and may serve as biomarker for this disease. Full article

The meat yield (MY) is a key economic trait in Pacific whiteleg shrimp (Penaeus vannamei) breeding, necessitating accurate genomic prediction for efficient genetic improvement. In this study, we investigated single-trait (STGMs) and multi-trait genomic models (MTGMs) for predicting MY and related traits, using two cross-validation strategies reflecting different data-availability scenarios. A total of 899 individuals from 63 full-sibling families were phenotyped for MY, net meat weight (MW), body weight (BW), body length (BL), and abdominal segment length (AL). We estimated the genomic heritability and genetic correlations of MY and related traits in P. vannamei, followed by comparing the prediction accuracy of STGMs and MTGMs for MY and MW. Two validation approaches were then applied: CV1 retained auxiliary traits in the validation sets, and CV2 excluded both target and auxiliary traits. Heritability estimates indicated that MY had low heritability (STGM: 0.160; MTGMs: 0.145–0.156), whereas MW, BW, BL, and AL showed low-to-moderate heritability (0.099–0.204). Genetic correlations revealed strong associations between MY and MW/BW/BL (r_g = 0.605–0.783), yet a low positive correlation with AL (r_g = 0.286). Across all comparisons, MTGMs consistently surpassed STGMs. For MY, MTGMs improved the accuracy by 4.8–58.8% relative to STGM (0.187), with the MY-MW model achieving the highest accuracy (0.297) under CV1. Similarly, MTGMs enhanced MW prediction by 36.6–138.2% over STGM (0.254), with the MW-BW model reaching the highest accuracy (0.605) under CV1. Notably, retaining auxiliary traits (CV1) boosted accuracy gains substantially (up to 138.2%), whereas excluding them (CV2) yielded only marginal improvements (≤8.6%). Moreover, incorporating AL as an auxiliary trait increased heritability estimates for MW, BW, and BL by 5.4–7.6%, indicating its synergistic value in MTGMs. Overall, these results demonstrate that MTGMs markedly enhance genomic prediction for carcass traits compared to STGMs, particularly when auxiliary trait data are accessible (CV1). The findings underscore the importance of maintaining auxiliary trait records in breeding populations, offering a robust framework for improving P. vannamei through multi-trait genomic prediction models. Full article

Type VII osteogenesis imperfecta (OI), caused by recessive CRTAP mutations, is predominantly lethal in the first year of life. Due to its early lethality, little is known about bone dysplasia mechanism. RNA-seq analysis of differentiated osteoblasts of siblings with a non-lethal homozygous CRTAP-null variant showed an enrichment of gene ontology terms involved in DNA replication and cell cycle compared to control. BrdU incorporation confirmed a ≈2-fold increase in proliferation in non-lethal proband osteoblasts in comparison to control cells. In addition, the expression of cyclin dependent kinase inhibitor 2A (CDKN2A), encoding a protein involved in cell cycle inhibition, was significantly reduced (>50%) in CRTAP-null osteoblasts, while cyclin B1 (CCNB1), encoding a promoter of the cell cycle, was enhanced. Ossification and bone and cartilage development gene ontology pathways were enriched among upregulated genes throughout osteoblast differentiation, as was protein secretion. Ingenuity pathway analysis indicated an upregulation of BMP2 signaling, supported by increase in both BMP2 and MSX2, an early BMP2-responsive gene, by qPCR. Throughout differentiation, CRTAP-null osteoblasts showed a decrease in transcripts related to cell adhesion and extracellular matrix organization pathways. We propose that increased proliferation and osteogenesis of type VII OI osteoblasts may be stimulated through upregulation of BMP2 signaling, altering bone homeostasis, and leading to weaker bones. Full article

Autism spectrum disorder (ASD) has been associated with disruptions in tryptophan (TRP) metabolism, affecting the production of key neuroactive metabolites. Investigating these metabolic pathways could yield valuable biomarkers for ASD severity and progression. We included 44 children with ASD and 44 healthy children, members of the same family. The average age in the ASD group was 10.7 years, while the average age in the control group was 9.4 years. Urinary tryptophan metabolites were quantified via liquid chromatography—mass spectrometry operating multiple reaction monitoring (MRM). Urinary creatinine was analyzed on an Advia 2400 analyzer using the Jaffe reaction. Statistical comparisons were made between ASD subgroups based on CARS scores. Our findings indicate that children with ASD have higher TRP concentrations (19.94 vs. 16.91; p = 0.04) than their siblings. Kynurenine (KYN) was found at higher levels in children with ASD compared to children in the control group (82.34 vs. 71.20; p = 0.86), although this difference was not statistically significant. The ASD group showed trends of higher KYN/TRP ratios and altered TRP/ indole-3-acetic acid (IAA) and TRP/5-hydroxyindoleacetic acid (5-HIAA) ratios, correlating with symptom severity. Although the numbers of the two groups were different, our findings suggest that mild and severe illnesses involve separate mechanisms. However, further comprehensive studies are needed to validate these ratios as diagnostic tools for ASD. Full article

Background: The COVID-19 pandemic may have had long-lasting detrimental effects on children’s physical health. Previous studies have shown that children’s participation in physical activity (PA) declined during the pandemic. This study examined the effect of the COVID-19 pandemic on PA type selection and the influence of gender, number of siblings, residence type, and caregiver education level on PA. Methods: Parents of Saudi children (ages 6–9 years) were recruited through convenience sampling and completed an online survey between July and August 2020. The parent-reported survey included demographics and PA types across three time periods (pre-, during, and post-lockdown). Chi-squared tests and logistic regression with pairwise comparisons were used to analyze the differences. Results: Parents reported that children (n = 361, mean age 7.7 ± 1.1 years) selected different PA types pre-COVID-19 pandemic more often than during the COVID-19 lockdown, such as swimming (16.9% vs. 12.8%), high-intensity jumping (9.8% vs. 6.6%), cycling (12.8% vs. 9.6%), football (14.3% vs. 6.1%), running (9.3% vs. 5.5%), virtual gaming exercise (5% vs. 3.2%), and playground activity (11.3% vs. 5.8%) (p < 0.05). Additionally, PA type was shown to be influenced by gender and residence type, with girls being 55% more likely to be physically active during COVID-19 compared to boys, and participants living in houses without private yards being less physically active compared to those who lived in houses with private yards. Conclusions: Children’s gender (boy vs. girl) and residence type (with private yards vs. without private yards) affected their PA level during the COVID-19 lockdown. These findings suggest that more effort should be directed toward understanding the influence of gender and house types in the selection of PA types. Full article

Human leukocyte antigen (HLA) mismatches in stem cell transplantation can be well-tolerated with the use of post-transplant cyclophosphamide (PTCy) for graft-versus-host-disease (GvHD) prophylaxis. Haploidentical (Haplo) and HLA-mismatched unrelated donors become acceptable donors. This review focuses on Haplo and unrelated donor selection in the context of PTCy-transplant for hematological malignancy, in comparison with conventional GvHD prophylaxis. Evaluating patient’s donor-specific antibody (DSA) is critical in donor selection regardless of donor type or the use of PTCy. High DSA levels and positive C1q increase the risk of engraftment failure and unsuccessful desensitization. On the other hand, the degree of donor HLA matching is less critical under PTCy compared to conventional GvHD prophylaxis. Donor age was found to be important, as younger donors improve survival outcomes. HLA-B leader match appears to be preferable. The impacts of donor gender, donor cytomegalovirus serostatus, and ABO mismatch are unclear or non-significant. Additionally, available studies suggest that, in PTCy-transplant, preferred Haplo-donors are HLA class II mismatched (DRB1 mismatch and DPB1 non-permissive), siblings or offspring over parents, and if parent, father over mother, while preferred unrelated donors are HLA class I matched. Further study is warranted. Full article

In the present review, we summarize genome mining of genomic data obtained from the psychrophilic Antarctic marine ciliate Euplotes focardii and its evolutionary-close mesophilic cosmopolitan counterpart E. crassus. This analysis highlights adaptation strategies that are unique to the Antarctic ciliate, including antioxidant gene duplication and distinctive substitutions that may play roles in increased drug binding affinity and enzyme reaction rate in cold environments. Enzymes from psychrophiles are usually characterized by high activities and reaction rates at low temperatures compared with their counterparts from mesophiles and thermophiles. As a rule, catalyst cold activity derives from an increased structural flexibility that may lead to protein denaturation in response to temperature fluctuation. Molecular thermolability has been a major drawback of using macromolecules from psychrophiles in industrial applications. Here, we report a case study in which the role of peculiar amino acid substitution in cold adaptation is demonstrated by site-directed mutagenesis. Combined with a rational design approach, these substitutions can be used for site-directed mutagenesis to obtain cold-active catalysts that are structurally stable. Furthermore, molecular docking analysis of β-tubulin isotypes extrapolated from E. focardii and E. crassus genomes allowed us to obtain additional insight on the taxol binding site and drug affinity. E. focardii genome mining and the comparison with the mesophilic sibling counterpart can be used as an inspiration for molecular engineering for medical and industrial applications. Full article

Background/Objectives: Phenylketonuria is a hereditary metabolic disorder characterized by a deficiency of phenylalanine hydroxylase. The main treatment for PKU is a phenylalanine-restricted diet. The exclusion of protein rich natural foods and inclusion of low-Phe substitutes may give rise to an imbalanced diet, and the increased risk of overweight and obesity in PKU is a cause for concern. We aimed to evaluate the body composition and nutritional biochemical biomarkers in adult PKU patients who are on Phe-restricted and essential amino acid-supplemented nutrition therapy and to investigate the relationships between these parameters and patient gender, adherence to dietary therapy, and disease type, defined as mild or classic PKU. Methods: The study group comprised 37 PKU patients and 26 healthy siblings as controls. The participants were assessed based on an analysis of anthropometric parameters, body composition, and biochemical test results. Results: PKU patients do not have a higher incidence of overweight and obesity than healthy controls, the proportion of energy derived from carbohydrates in their diets was below the recommended level, and their total energy intake was below the recommended daily allowance. It was remarkable that patients with a treatment adherence ratio of <50% displayed a higher prevalence of overweight and abdominal obesity in comparison to those with a more favorable treatment adherence ratio. Conclusions: In view of the growing prevalence of overweight in the general population, PKU patients should be kept under close long-term follow-up. Particularly in the group with low treatment compliance, more caution should be taken in terms of adverse outcomes. Full article

Our objective was to harness the power of interactive visualizations by utilizing open-source tools to develop an efficient strategy for visualizing Single Nucleotide Polymorphism data within a livestock population, focusing on tracking the transmission of haplotypes. To achieve this, we simulated a realistic beef cattle population in order to obtain phased haplotypes and generate the necessary inputs for creating our visualizations. The visualization tool was built using Python and the Plotly library, which enables interactivity. We set out to explore three scenarios: trio comparison, visualization of grandparents, and half-sibling evaluation. These scenarios enabled us to trace the inheritance of genetic segments, identify crossover events, and uncover common regions within related and unrelated animals. The potential applications of this approach are significant, particularly for improving genomic selection in smaller breeding programs and farms, and it provides valuable insights for guiding more in-depth genomic region analysis. Beyond its practical applications, we believe this strategy can be a valuable educational tool, helping educators clarify complex concepts like Mendelian sampling and haplotypic diversity. Furthermore, we hope it will encourage livestock producers to adopt advanced technologies like genotyping and genomic selection, thereby contributing to the advancement of livestock genetics. Full article

Asthma and obesity are two of the most common chronic conditions in children and adolescents. There is increasing evidence that sphingolipid metabolism is altered in childhood asthma and is linked to airway hyperreactivity. Dysregulated sphingolipid metabolism is also reported in obesity. However, the functional link between sphingolipid metabolism, asthma, and obesity is not completely understood. This paper describes the protocol of an ongoing study on sphingolipids that aims to examine the pathophysiology of sphingolipids in childhood asthma and obesity. In addition, this study aims to explore the novel biomarkers through a comprehensive multi-omics approach including genomics, genome-wide DNA methylation, RNA-Seq, microRNA (miRNA) profiling, lipidomics, metabolomics, and cytokine profiling. This is a cross-sectional study aiming to recruit 440 children from different groups: children with asthma and normal weight (n = 100), asthma with overweight or obesity (n = 100), overweight or obesity (n = 100), normal weight (n = 70), and siblings of asthmatic children with normal weight, overweight, or obesity (n = 70). These participants will be recruited from the pediatric pulmonology, pediatric endocrinology, and general pediatric outpatient clinics at Sidra Medicine, Doha, Qatar. Information will be obtained from self-reported questionnaires on asthma, quality of life, food frequency (FFQ), and a 3-day food diary that are completed by the children and their parents. Clinical measurements will include anthropometry, blood pressure, biochemistry, bioelectrical impedance, and pulmonary function tests. Blood samples will be obtained for sphingolipid analysis, serine palmitoyltransferase (SPT) assay, whole-genome sequencing (WGS), genome-wide DNA methylation study, RNA-Seq, miRNA profiling, metabolomics, lipidomics, and cytokine analysis. Group comparisons of continuous outcome variables will be carried out by a one-way analysis of variance or the Kruskal–Wallis test using an appropriate pairwise multiple comparison test. The chi-squared test or a Fisher’s exact test will be used to test the associations between categorical variables. Finally, multivariate analysis will be carried out to integrate the clinical data with multi-omics data. This study will help us to understand the role of dysregulated sphingolipid metabolism in obesity and asthma. In addition, the multi-omics data from the study will help to identify novel genetic and epigenetic signatures, inflammatory markers, and mechanistic pathways that link asthma and obesity in children. Furthermore, the integration of clinical and multi-omics data will help us to uncover the potential interactions between these diseases and to offer a new paradigm for the treatment of pediatric obesity-associated asthma. Full article