Nonsense mutations introduce premature termination codons and underlie 11% of genetic disease cases. High concentrations of aminoglycosides can restore gene function by eliciting premature termination codon readthrough but with low efficiency. Using a high-throughput screen, we identified compounds that potentiate readthrough by aminoglycosides at multiple nonsense alleles in yeast. Chemical optimization generated phthalimide derivative CDX5-1 with activity in human cells. Alone, CDX5-1 did not induce readthrough or increase TP53 mRNA levels in HDQ-P1 cancer cells with a homozygous TP53 nonsense mutation. However, in combination with aminoglycoside G418, it enhanced readthrough up to 180-fold over G418 alone. The combination also increased readthrough at all three nonsense codons in cancer cells with other TP53 nonsense mutations, as well as in cells from rare genetic disease patients with nonsense mutations in the CLN2, SMARCAL1 and DMD genes. These findings open up the possibility of treating patients across a spectrum of genetic diseases caused by nonsense mutations.

We suggest that in preterm infants, furosemide should be prescribed with caution and close monitoring of calcium excretions is advisable. Some guidelines for infant respiratory distress syndrome now favor calcium-sparing thiazides if diuretics are considered.

Mutations in NR5A1 have been reported as a frequent cause of 46,XY disorders of sex development (DSD) associated to a broad phenotypic spectrum ranging from infertility, ambiguous genitalia, anorchia to gonadal dygenesis and female genitalia. Here we present the clinical follow up of four 46,XY DSD patients with three novel heterozygous mutations in the NR5A1 gene leading to a p.T40P missense mutation and a p.18DKVSG22del nonframeshift deletion in the DNA-binding domain and a familiar p.Y211Tfs*83 frameshift mutation. Functional analysis of the missense and nonframeshift mutation revealed a deleterious character with loss of DNA-binding and transactivation capacity. Both, the mutations in the DNA-binding domain, as well as the familiar frameshift mutation are associated with highly variable endocrine values and phenotypic appearance. Phenotypes vary from males with spontaneous puberty, substantial testosterone production and possible fertility to females with and without Müllerian structures and primary amenorrhea. Exome sequencing of the sibling’s family revealed TBX2 as a possible modifier of gonadal development in patients with NR5A1 mutations.

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This article examines the determinants of perceived job security in German standard employment relationships (SER). Although SERs still dominate and shape the labour market, they have undergone several modifications in the recent past. Using survey data from 2006, the article examines how work organizations and particularly multiple workplace demands influence the perceived job security of employees in SERs. The article also asks whether -20 years after reunification -structural and cultural differences still exist between East and West Germany. The results show that employees in East German SERs are more willing to accept flexibility and performance requirements. The article suggests that a new psychological contract has emerged, which promises long-term employment only if employees eventually meet the new workplace demands. Yet the overall lower job security of East Germans, fuelled by lower trust in their employers' information policies, indicates the fragile nature of this arrangement.

No abstract

Children with GHD or born SGA may benefit from GH by growth acceleration and reduction of cardiovascular long-term risks.

Past studies have shown that various aspects of occupational attainment (unemployment, job instability, low occupational status, and low earnings) are associated with poor mental health, but each of these studies focused on one or two aspects of occupational attainment. Consequently, it remains unclear whether their associations are independent of each other. Further, little is known about whether negative self‐assessments of occupational attainment are linked to poor mental health. We sought to overcome these limitations of past research while focusing on depressive symptoms as a mental health outcome and young adulthood as a life stage context. The study analysed U.S. data from the National Longitudinal Study of Adolescent to Adult Health (n = 13,178) using ordinary least square models. The analysis showed that all aspects of occupational attainment were associated with depressive symptoms in the expected directions. Further, unemployment, job instability, and negative self‐assessment of career progress showed stronger associations, and those associations were independent of other occupational attainment variables. Overall, the results suggested that understanding the association between occupational attainment and mental health requires close attention to the life stage context.