LINE-1 RNA triggers matrix formation in bone cells via a PKR-mediated inflammatory response.

Transposable elements (TEs) are mobile genetic modules of viral derivation that have been co-opted to become modulators of mammalian gene expression. TEs are a major source of endogenous dsRNAs, signaling molecules able to coordinate inflammatory responses in various physiological processes. Here, we provide evidence for a positive involvement of TEs in inflammation-driven bone repair and mineralization. In newly fractured mice bone, we observed an early transient upregulation of repeats occurring concurrently with the initiation of the inflammatory stage. In human bone biopsies, analysis revealed a significant correlation between repeats expression, mechanical stress and bone mineral density. We investigated a potential link between LINE-1 (L1) expression and bone mineralization by delivering a synthetic L1 RNA to osteoporotic patient-derived mesenchymal stem cells and observed a dsRNA-triggered protein kinase (PKR)-mediated stress response that led to strongly increased mineralization. This response was associated with a strong and transient inflammation, accompanied by a global translation attenuation induced by eIF2α phosphorylation. We demonstrated that L1 transfection reshaped the secretory profile of osteoblasts, triggering a paracrine activity that stimulated the mineralization of recipient cells.

Early-life stress and the gut microbiome: A comprehensive population-based investigation.

Early-life stress (ELS) has been robustly associated with a range of poor mental and physical health outcomes. Recent studies implicate the gut microbiome in stress-related mental, cardio-metabolic and immune health problems, but research on humans is scarce and thus far often based on small, selected samples, often using retrospective reports of ELS. We examined associations between ELS and the human gut microbiome in a large, population-based study of children. ELS was measured prospectively from birth to 10 years of age in 2,004 children from the Generation R Study. We studied overall ELS, as well as unique effects of five different ELS domains, including life events, contextual risk, parental risk, interpersonal risk, and direct victimization. Stool microbiome was assessed using 16S rRNA sequencing at age 10 years and data were analyzed at multiple levels (i.e. α- and ß-diversity indices, individual genera and predicted functional pathways). In addition, we explored potential mediators of ELS-microbiome associations, including diet at age 8 and body mass index at 10 years. While no associations were observed between overall ELS (composite score of five domains) and the microbiome after multiple testing correction, contextual risk - a specific ELS domain related to socio-economic stress, including risk factors such as financial difficulties and low maternal education - was significantly associated with microbiome variability. This ELS domain was associated with lower α-diversity, with ß-diversity, and with predicted functional pathways involved, amongst others, in tryptophan biosynthesis. These associations were in part mediated by overall diet quality, a pro-inflammatory diet, fiber intake, and body mass index (BMI). These results suggest that stress related to socio-economic adversity - but not overall early life stress - is associated with a less diverse microbiome in the general population, and that this association may in part be explained by poorer diet and higher BMI. Future research is needed to test causality and to establish whether modifiable factors such as diet could be used to mitigate the negative effects of socio-economic adversity on the microbiome and related health consequences.

Identification of Transcripts with Shared Roles in the Pathogenesis of Postmenopausal Osteoporosis and Cardiovascular Disease.

Epidemiological evidence suggests existing comorbidity between postmenopausal osteoporosis (OP) and cardiovascular disease (CVD), but identification of possible shared genes is lacking. The skeletal global transcriptomes were analyzed in trans-iliac bone biopsies (n = 84) from clinically well-characterized postmenopausal women (50 to 86 years) without clinical CVD using microchips and RNA sequencing. One thousand transcripts highly correlated with areal bone mineral density (aBMD) were further analyzed using bioinformatics, and common genes overlapping with CVD and associated biological mechanisms, pathways and functions were identified. Fifty genes (45 mRNAs, 5 miRNAs) were discovered with established roles in oxidative stress, inflammatory response, endothelial function, fibrosis, dyslipidemia and osteoblastogenesis/calcification. These pleiotropic genes with possible CVD comorbidity functions were also present in transcriptomes of microvascular endothelial cells and cardiomyocytes and were differentially expressed between healthy and osteoporotic women with fragility fractures. The results were supported by a genetic pleiotropy-informed conditional False Discovery Rate approach identifying any overlap in single nucleotide polymorphisms (SNPs) within several genes encoding aBMD- and CVD-associated transcripts. The study provides transcriptional and genomic evidence for genes of importance for both BMD regulation and CVD risk in a large collection of postmenopausal bone biopsies. Most of the transcripts identified in the CVD risk categories have no previously recognized roles in OP pathogenesis and provide novel avenues for exploring the mechanistic basis for the biological association between CVD and OP.

Bone health index in the assessment of bone health: The Generation R Study.

Bone Health Index (BHI) has been proposed as a useful instrument for assessing bone health in children. However, its relationship with fracture risk remains unknown. We aimed to investigate whether BHI is associated with bone mineral density (BMD) and prevalent fracture odds in children from the Generation R Study. We also implemented genome-wide association study (GWAS) and polygenic score (PGS) approaches to improve our understanding of BHI and its potential. In total, 4150 children (49.4 % boys; aged 9.8 years) with genotyped data and bone assessments were included in this study. BMD was measured across the total body (less head following ISCD guidelines) using a GE-Lunar iDXA densitometer; and BHI was determined from the hand DXA scans using BoneXpert®. Fractures were self-reported collected with home questionnaires. The association of BHI with BMD and fractures was evaluated using linear models corrected for age, sex, ethnicity, height, and weight. We observed a positive correlation between BHI and BMD (ρ = 0.32, p-value<0.0001). Further, every SD decrease in BHI was associated with an 11 % increased risk of prevalent fractures (OR:1.11, 95 % CI 1.00-1.24, p-value = 0.05). Our BHI GWAS identified variants (lead SNP rs1404264-A, p-value = 2.61 × 10-14) mapping to the ING3/CPED1/WNT16 locus. Children in the extreme tails of the BMD PGS presented a difference in BHI values of -0.10 standard deviations (95% CI -0.14 to -0.07; p-value<0.0001). On top of the demonstrated epidemiological association of BHI with both BMD and fracture risk, our results reveal a partially shared biological background between BHI and BMD. These findings highlight the potential value of using BHI to screen children at risk of fracture.

Oral microbiota of adolescents with dental caries: A systematic review.

OBJECTIVE: This systematic review summarizes the current knowledge on the association between the oral microbiota and dental caries in adolescents. DESIGN: An electronic search was carried out across five databases. Studies were included if they conducted research on generally healthy adolescents, applied molecular-based microbiological analyses and assessed caries status. Data extraction was performed by two reviewers and the Newcastle-Ottawa Scale was applied for quality assessment. RESULTS: In total, 3935 records were reviewed which resulted in a selection of 20 cross-sectional studies (published 2005-2022) with a sample size ranging from 11 to 614 participants including adolescents between 11 and 19 years. The studies analyzed saliva, dental biofilm or tongue swabs with Checkerboard DNA-DNA hybridization, (q)PCR or Next-Generation Sequencing methods. Prevotella denticola, Scardoviae Wiggsiae, Streptococcus sobrinus and Streptococcus mutans were the most frequently reported species presenting higher abundance in adolescents with caries. The majority of the studies reported that the microbial diversity was similar between participants with and without dental caries. CONCLUSION: This systematic review is the first that shows how the oral microbiota composition in adolescents appears to differ between those with and without dental caries, suggesting certain taxa may be associated with increased caries risk. However, there is a need to replicate and expand these findings in larger, longitudinal studies that also focus on caries severity and take adolescent-specific factors into account.

Defining type 2 diabetes polygenic risk scores through colocalization and network-based clustering of metabolic trait genetic associations.

BACKGROUND: Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations. METHODS: We applied colocalization between T2D and 20 related metabolic traits, across 243 loci, to obtain inferences of shared casual variants. Network-based unsupervised hierarchical clustering was performed on variant-trait associations. Partitioned polygenic risk scores (PRSs) were generated for each cluster using T2D summary statistics and validated in 21,742 individuals with T2D from 3 cohorts. Inferences of directionality and causality were obtained by applying Mendelian randomization Steiger's Z-test and further validated in a pediatric cohort without diabetes (aged 9-12 years old, n = 3866). RESULTS: We identified 146 T2D loci that colocalized with at least one metabolic trait locus. T2D variants within these loci were grouped into 5 clusters. The clusters corresponded to the following pathways: obesity, lipodystrophic insulin resistance, liver and lipid metabolism, hepatic glucose metabolism, and beta-cell dysfunction. We observed heterogeneity in associations between PRSs and metabolic measures across clusters. For instance, the lipodystrophic insulin resistance (Beta - 0.08 SD, 95% CI [- 0.10-0.07], p = 6.50 × 10-32) and beta-cell dysfunction (Beta - 0.10 SD, 95% CI [- 0.12, - 0.08], p = 1.46 × 10-47) PRSs were associated to lower BMI. Mendelian randomization Steiger analysis indicated that increased T2D risk in these pathways was causally associated to lower BMI. However, the obesity PRS was conversely associated with increased BMI (Beta 0.08 SD, 95% CI 0.06-0.10, p = 8.0 × 10-33). Analyses within a pediatric cohort supported this finding. Additionally, the lipodystrophic insulin resistance PRS was associated with a higher odds of chronic kidney disease (OR 1.29, 95% CI 1.02-1.62, p = 0.03). CONCLUSIONS: We successfully partitioned T2D genetic variants into phenotypic pathways using a colocalization first approach. Partitioned PRSs were associated to unique metabolic and clinical outcomes indicating successful partitioning of disease heterogeneity. Our work expands on previous approaches by providing stronger inferences of shared causal variants, causality, and directionality of GWAS variant-trait associations.

Association between BMD and coronary artery calcification: an observational and Mendelian randomization study.

Observational studies have reported inconsistent associations between bone mineral density (BMD) and coronary artery calcification (CAC). We examined the observational association of BMD with CAC in 2 large population-based studies and evaluated the evidence for a potential causal relation between BMD and CAC using polygenic risk scores (PRS), 1- and 2-sample Mendelian randomization (MR) approaches. Our study populations comprised 1414 individuals (mean age 69.9 yr, 52.0% women) from the Rotterdam Study and 2233 individuals (mean age 56.5 yr, 50.9% women) from the Framingham Heart Study with complete information on CAC and BMD measurements at the total body (TB-), lumbar spine (LS-), and femoral neck (FN-). We used linear regression models to evaluate the observational association between BMD and CAC. Subsequently, we compared the mean CAC across PRSBMD quintile groups at different skeletal sites. In addition, we used the 2-stage least squares regression and the inverse variance weighted (IVW) model as primary methods for 1- and 2-sample MR to test evidence for a potentially causal association. We did not observe robust associations between measured BMD levels and CAC. These results were consistent with a uniform random distribution of mean CAC across PRSBMD quintile groups (P-value > .05). Moreover, neither 1- nor 2-sample MR supported the possible causal association between BMD and CAC. Our results do not support the contention that lower BMD is (causally) associated with an increased CAC risk. These findings suggest that previously reported epidemiological associations of BMD with CAC are likely explained by unmeasured confounders or shared etiology, rather than by causal pathways underlying both osteoporosis and vascular calcification processes.

Decreased bone mineral density, the determinant of osteoporosis, and increased coronary artery calcification are common in people at an advanced age and share some common risk factors. Some studies have reported a higher risk for coronary artery calcification in people with osteoporosis than in people without, whereas others failed to find evidence for this relationship. Recently, Mendelian randomization has emerged as an important epidemiological tool that offers a simple way to distinguish causation, minimizing the confounding present in observational studies, leveraging individual genetic data and the findings from robust genome-wide association studies. We combined data from the participants of both the Rotterdam Study and the Framingham Heart Study, and did not observe sufficient evidence for the association between bone mineral density at different skeletal sites and coronary artery calcification. Also, when using Mendelian randomization, we concluded there was no causal relation between bone deterioration and the build-up of calcium in the coronary arteries. Although more research is needed, we conclude that the associations between decreased bone mineral density and increased coronary artery calcification reported in previous studies are likely attributed to other confounders rather than a causal relationship between these traits.

Glaucoma Patients Have a Lower Abundance of Butyrate-Producing Taxa in the Gut.

Purpose: Glaucoma is an eye disease that is the most common cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro-inflammatory cytokines that may travel from the gastric mucosa to distal sites, for example, the optic nerve head or trabecular meshwork. There is evidence for a gut-eye axis, as microbial dysbiosis has been associated with retinal diseases. We investigated the microbial composition in patients with glaucoma and healthy controls. Moreover, we analyzed the association of the gut microbiome with intraocular pressure (IOP; risk factor of glaucoma) and vertical cup-to-disc ratio (VCDR; quantifying glaucoma severity). Methods: The discovery analyses included participants of the Rotterdam Study and the Erasmus Glaucoma Cohort. A total of 225 patients with glaucoma and 1247 age- and sex-matched participants without glaucoma were included in our analyses. Stool samples were used to generate 16S rRNA gene profiles. We assessed associations with 233 genera and species. We used data from the TwinsUK and the Study of Health in Pomerania (SHIP) to replicate our findings. Results: Several butyrate-producing taxa (e.g. Butyrivibrio, Caproiciproducens, Clostridium sensu stricto 1, Coprococcus 1, Ruminococcaceae UCG 007, and Shuttleworthia) were less abundant in people with glaucoma compared to healthy controls. The same taxa were also associated with lower IOP and smaller VCDR. The replication analyses confirmed the findings from the discovery analyses. Conclusions: Large human studies exploring the link between the gut microbiome and glaucoma are lacking. Our results suggest that microbial dysbiosis plays a role in the pathophysiology of glaucoma.

A perspective on muscle phenotyping in musculoskeletal research.

Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term 'osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action 'Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse.

Destrezas académicas y velocidad de procesamiento. Modelos predictivos del rendimiento escolar en básica primaria / Academic skills and processing speed. Predictive models of school achievement in primary school

Resumen El modelo de inteligencia de Cattell-Horn-Carroll (CHC) propone que los procesos cognitivos que componen la inteligencia pueden conceptualizarse como habilidades específicas, implicadas en tareas particulares, y habilidades generales, relacionadas con una amplia cantidad de contextos. Entre las habilidades más estudiadas bajo este modelo se encuentra la velocidad de procesamiento, identificada como uno de los mejores predictores del rendimiento académico y de la capacidad cognitiva general. En este artículo se presentan los resultados del análisis de la relación entre la velocidad de procesamiento y rendimiento académico general. Se evaluó una muestra de 223 estudiantes (53% mujeres) de Preescolar y básica primaria. Los resultados muestran una diferencia en la capacidad predictiva del componente perceptual (β =.76, p < .001) y conceptual (β =.09; p = .121) de la velocidad de procesamiento en procesos académicos básicos de lectura y matemática, así como ajustes similares en modelos de regresión a partir de su conceptualización como habilidad general (R2 = .68) o específica (R2 = .69). El análisis de la relación grado a grado mostró cambios en la capacidad predictiva de la velocidad de procesamiento sobre las habilidades académicas conforme avanza el proceso educativo, apoyando modelos previamente establecidos en el área (Cai, Li & Deng, 2013; Demetriou, Spanodius & Shayer, 2014). Finalmente, es generó un modelo de ecuaciones estructurales (X 2=1.431; p=.232; CFI=1.000; TLI=.999; NFI=.999; RFI=.996; RMSEA=.044) que permitió probar el ajuste de los modelos propuestos a los datos.

Abstract The Cattell-Horn-Carroll (CHC) intelligence model proposes that the cognitive processes that make up intelligence can be conceptualized as specific skills, involved in particular tasks, and general skills, related to a wide variety of contexts. Among the most studied skills under this model is the speed of processing, identified as one of the best predictors of academic performance and general cognitive ability. This article presents the results of the analysis of the relationship between processing speed and general academic performance. A sample of 223 students (53% women) of preschool and primary school was evaluated. The results show a difference in the predictive capacity of the perceptual component (β = .76, p < .001) and conceptual (β = .09; p = .121) of the processing speed in basic academic processes of reading and mathematics, as well as similar adjustments in regression models from their conceptualization as general (R 2 = .68) or specific (R 2 = .69) ability. The analysis of the grade-to-grade relationship showed changes in the predictive capacity of processing speed over academic skills as the educational process progresses, supporting previously established models in the area (Cai, Li & Deng, 2013; Demetriou, Spanodius & Shayer, 2014). Finally, a model of structural equations (X 2 = 1.431, p = .232, CFI = 1.000, TLI = .999, NFI = .999, RFI = .996, RMSEA = .044) was used to prove the adjustment of the proposed models to data.

Diagnóstico prenatal de hidrops fetal no inmune. Serie de nueve casos. Revisión de la literatura / Prenatal diagnosis of non-immune fetal hydrops: a series of nine cases and a literature review

Objetivo: se presenta una serie de casos de hidrops fetal no inmune (HFNI) con el objetivo de revisar la literatura sobre su etiología y pronóstico. Materiales y métodos: serie de casos diagnosticados por ultrasonografía en el Servicio de Perinatología del Hospital Dr. Adolfo Prince Lara, Venezuela, hospital público de referencia de atención perinatal regional que atiende población de medios y bajos ingresos, en el periodo 2005-2009, y se realiza una revisión de la literatura en la base de datos Medline vía Pubmed, y en la base latinoamericana SciELO desde el año 1995 hasta 2011, y en libros de la especialidad. La palabra clave usada fue hidrops fetal. Resultados: se revisaron 2195 historias clínicas encontrándose nueve casos de HFNI, resultando una prevalencia de (0,41 por ciento). Hubo dos casos de monosomías, un caso asociado a proceso infeccioso, dos casos de malformaciones cardiacas, un caso de malformaciones múltiples, y en tres no se precisó etiología. Todos los productos fallecieron, ya sea in utero o en el periodo neonatal. Se encontraron 1584 publicaciones, incluyéndose 14 referencias, 6 revisiones, 6 presentaciones de casos y 2 artículos originales. Conclusión: HFNI está asociado a diversas patologías fetales y tiene alta mortalidad.

Objective: A series of cases of non-immune fetal hydrops (NIFH) is presented, aimed at reviewing the literature concerning its etiology and prognosis. Materials and methods: A series of cases diagnosed by ultrasonography at the Dr. Adolfo Prince Lara Hospital Perinatology Service in Venezuela, 20052009, is presented; this is a public reference hospital providing regional perinatal attention for the poorest strata of the population. A literature review was made using the Medline database via PubMed and the SciELO Latin-American database from 1995 to 2011, and in specialized books on the topic. Fetal hydrops was the key word used in the search. Results: 2,195 clinical histories were reviewed, finding 9 cases of NIFH (0.41 percent prevalence). There were two cases of monosomy, one infectionassociated case, two cases of cardiac malformation, a case of multiple malformations and etiology was not specified in three cases. Death occurred in all cases, whether in the uterus or during the neonatal period. 1,584 publications were found, including 14 references, 6 reviews, 6 case presentations and 2 original articles. Conclusion: NIFH is associated with differing fetal pathologies and involves high mortality.