TOPBP1 missense variant Arg309Cys and breast cancer in a German hospital-based case-control study

The DNA double strand break repair gene TOPBP1 has been suggested as a breast cancer susceptibility gene and a missense variant Arg309Cys was observed at elevated frequency in familial breast cancer cases compared to healthy controls from Finland. We found the Arg309Cys allele at a 13% carrier frequency in a hospital-based series of 1064 German breast cancer patients and at a 14% carrier frequency in 1014 population controls (OR 0.89, 95%CI 0.69-1.15; p = 0.4). Arg309Cys carriers were not enriched among patients with a family history of breast cancer (OR = 0.87, 95%CI 0.53-1.43, p = 0.6) and were slightly underrepresented in patients with bilateral disease (OR = 0.49, 95%CI = 0.24-0.99; p = 0.047). In the latter group, the mean age at diagnosis was 62 years in carriers and 54 years in non-carriers (p = 0.004). We conclude that there is no evidence for the TOPBP1*Arg309Cys variant to confer an increased risk for breast cancer in the German population

A Tunable Two-impurity Kondo system in an atomic point contact

Two magnetic atoms, one attached to the tip of a Scanning Tunneling Microscope (STM) and one adsorbed on a metal surface, each constituting a Kondo system, have been proposed as one of the simplest conceivable systems potentially exhibiting quantum critical behaviour. We have succeeded in implementing this concept experimentally for cobalt dimers clamped between an STM tip and a gold surface. Control of the tip-sample distance with sub-picometer resolution allows us to tune the interaction between the two cobalt atoms with unprecedented precision. Electronic transport measurements on this two-impurity Kondo system reveal a rich physical scenario which is governed by a crossover from local Kondo screening to non-local singlet formation due to antiferromagnetic coupling as a function of separation of the cobalt atoms.Comment: 22 pages, 5 figure

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

Muscle histopathology in nebulin-related nemaline myopathy : ultrastrastructural findings correlated to disease severity and genotype

Peer reviewe

Explaining gender differences in non-fatal suicidal behaviour among adolescents: a population-based study

<p>Abstract</p> <p>Background</p> <p>While suicide is the second leading cause of death among young people in most industrial countries, non-fatal suicidal behaviour is also a very important public health concern among adolescents. The aim of this study was to investigate gender differences in prevalence and emotional and behavioural correlates of suicidal behaviour in a representative school-based sample of adolescents.</p> <p>Methods</p> <p>A cross-sectional design was used to assess suicidal behaviour and various areas of emotional and behavioural problems by using a self-report booklet including the Youth Self-Report. One hundred sixteen schools in a region of Southern Germany agreed to participate. A representative sample of 5,512 ninth-grade students was studied. Mean age was 14.8 years (SD 0.73); 49.8% were female.</p> <p>Results</p> <p>Serious suicidal thoughts were reported by 19.8% of the female students and 10.8% of the females had ever attempted suicide. In the male group, 9.3% had a history of suicidal thoughts and 4.9% had previously attempted suicide. Internalizing emotional and behavioural problems were shown to be higher in the female group (difference of the group means 4.41) while externalizing emotional and behavioural problems slightly predominated in male students (difference of the group means -0.65). However, the total rate of emotional and behavioural problems was significantly higher in the adolescent female group (difference of the group means 4.98). Using logistic regression models with suicidal thoughts or attempted suicide as dependent variables, the pseudo-R² of gender alone was only 2.7% or 2.3%, while it was 30% or 23.2% for emotional and behavioural problems measured by the YSR syndrome scales. By adding gender to the emotional and behavioural problems only an additional 0.3% of information could be explained.</p> <p>Conclusions</p> <p>The findings suggest that gender differences in non-fatal suicidal behaviour among adolescents can to a large extent be explained by the gender differences in emotional and behavioural problems during this age.</p

Physician attitude toward depression care interventions: Implications for implementation of quality improvement initiatives

<p>Abstract</p> <p>Background</p> <p>Few individuals with depression treated in the primary care setting receive care consistent with clinical treatment guidelines. Interventions based on the chronic care model (CCM) have been promoted to address barriers and improve the quality of care. A current understanding of barriers to depression care and an awareness of whether physicians believe interventions effectively address those barriers is needed to enhance the success of future implementation.</p> <p>Methods</p> <p>We conducted semi-structured interviews with 23 primary care physicians across the US regarding their experience treating patients with depression, barriers to care, and commonly promoted CCM-based interventions. Themes were identified from interview transcripts using a grounded theory approach.</p> <p>Results</p> <p>Six barriers emerged from the interviews: difficulty diagnosing depression, patient resistance, fragmented mental health system, insurance coverage, lack of expertise, and competing demands and other responsibilities as a primary care provider. A number of interventions were seen as helpful in addressing these barriers – including care managers, mental health integration, and education – while others received mixed reviews. Mental health consultation models received the least endorsement. Two systems-related barriers, the fragmented mental health system and insurance coverage limitations, appeared incompletely addressed by the interventions.</p> <p>Conclusion</p> <p>CCM-based interventions, which include care managers, mental health integration, and patient education, are most likely to be implemented successfully because they effectively address several important barriers to care and are endorsed by physicians. Practices considering the adoption of interventions that received less support should educate physicians about the benefit of the interventions and attend to physician concerns prior to implementation. A focus on interventions that address systems-related barriers is needed to overcome all barriers to care.</p

On the Multi-Language Construction

Modern software is no more developed in a single programming language. Instead, programmers tend to exploit cross-language interoperability mechanisms to combine code stemming from different languages, and thus yielding fully-fledged multi-language programs. Whilst this approach enables developers to benefit from the strengths of each single-language, on the other hand it complicates the semantics of such programs. Indeed, the resulting multi-language does not meet any of the semantics of the combined languages. In this paper, we broaden the boundary functions-based approach a la Matthews and Findler to propose an algebraic framework that provides a constructive mathematical notion of multi-language able to determine its semantics. The aim of this work is to overcome the lack of a formal method (resp., model) to design (resp., represent) a multi-language, regardless of the inherent nature of the underlying languages. We show that our construction ensures the uniqueness of the semantic function (i.e., the multi-language semantics induced by the combined languages) by proving the initiality of the term model (i.e., the abstract syntax of the multi-language) in its category

Protein-Protein Interactions of Tandem Affinity Purified Protein Kinases from Rice

Eighty-eight rice (Oryza sativa) cDNAs encoding rice leaf expressed protein kinases (PKs) were fused to a Tandem Affinity Purification tag (TAP-tag) and expressed in transgenic rice plants. The TAP-tagged PKs and interacting proteins were purified from the T1 progeny of the transgenic rice plants and identified by tandem mass spectrometry. Forty-five TAP-tagged PKs were recovered in this study and thirteen of these were found to interact with other rice proteins with a high probability score. In vivo phosphorylated sites were found for three of the PKs. A comparison of the TAP-tagged data from a combined analysis of 129 TAP-tagged rice protein kinases with a concurrent screen using yeast two hybrid methods identified an evolutionarily new rice protein that interacts with the well conserved cell division cycle 2 (CDC2) protein complex

Eye Development under the control of SRp55/B52-Mediated Alternative Splicing of eyeless

The genetic programs specifying eye development are highly conserved during evolution and involve the vertebrate Pax-6 gene and its Drosophila melanogaster homolog eyeless (ey). Here we report that the SR protein B52/SRp55 controls a novel developmentally regulated splicing event of eyeless that is crucial for eye growth and specification in Drosophila. B52/SRp55 generates two isoforms of eyeless differing by an alternative exon encoding a 60-amino-acid insert at the beginning of the paired domain. The long isoform has impaired ability to trigger formation of ectopic eyes and to bind efficiently Eyeless target DNA sequences in vitro. When over-produced in the eye imaginal disc, this isoform induces a small eye phenotype, whereas the isoform lacking the alternative exon triggers eye over-growth and strong disorganization. Our results suggest that B52/SRp55 splicing activity is used during normal eye development to control eye organogenesis and size through regulation of eyeless alternative splicing