Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

A randomized controlled trial of the effect of spironolactone on left ventricular mass in hemodialysis patients

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Cross‐sectional and longitudinal association of sports participation,media consumption and motor competence in youth

The beneficial associations of physical activity (PA) and sports with motor competence have been well documented. Similarly, high media time has been associated with poor motor competence. Limited information, however, is available on the combined effects of sport participation and media consumption on motor competence. The present study followed 213 Austrian middle‐school students (57% male; age at baseline: 10.4 ± 0.6 years) over a 4‐year period. Annual assessments included the German Motor Test 6‐18, along with self‐reported participation in club sports, time spent watching TV and using the computer. There were no interaction effects between sports participation and media time on motor competence. Club sports participation, however, was associated with higher motor competence, while there was an inverse association between media time and motor competence. Further, motor competence affected future participation in club sports while club sports had limited effects on subsequent motor development. High media time, on the other hand, impaired subsequent motor development, while effects of motor competence on media time were limited. Taken together, these results emphasize the importance of motor competence in the facilitation of sports participation during adolescence. Accordingly, a wide variety of movement experiences should be provided at young ages to promote motor development. In addition, the detrimental effects of media time on motor competence warrant that sedentary behaviors are targeted separately, particularly in youth not participating in sports.     

Therapeutische Interventionen bei peri- und postmenopausalen Beschwerden

Die S3-Leitlinie „Peri- und Postmenopause – Diagnostik und Therapie“ beinhaltet Handlungsanweisungen und Empfehlungen für die Hormonersatztherapie (HRT) zur Behandlung klimakterischer Beschwerden, die von etwa 50 % der perimenopausalen Frauen und bei 30–80 % der postmenopausalen Frauen angegeben werden. Eine HRT mit Östrogenen (ET) oder Östrogenen und Gestagenen (EPT) wird als symptomatische Therapie zur Behandlung von klimakterischen Beschwerden mit klinisch relevanter Beeinträchtigung der Lebensqualität eingesetzt. Alternativ können auch Isoflavone, Cimicifuga-Präparate, Serotonin- bzw. Serotonin-Noradrenalin-Wiederaufnahmehemmer, Clonidin, Gabapentin oder kognitive Verhaltenstherapie angewendet werden. Im vorliegenden Artikel werden Effektivität und Sicherheit sowie Nebenwirkungen und systemische Wirkungen dieser unterschiedlichen Therapieformen entsprechend den Vorgaben der S3-Leitlinie „Peri- und Postmenopause – Diagnostik und Therapie“ dargestellt.     

Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.