The pathways to psychiatric care: a cross-cultural study

This paper describes the referral pathways taken by 1554 patients newly referred to the mental health services in 11 countries, and documents factors associated with delays in referral. The pathways in centres relatively well provided with psychiatric staff were dominated by general practitioners and to a lesser extent hospital doctors: the relatively less well resourced centres showed a variety of pathways with native healers often playing an important part. Delays were remarkably short in all centres regardless of psychiatric resources, but in some centres we found longer delays on pathways involving native healers. Somatic problems were a common presentation in all centres, and in some centres there was a tendency for patients presenting with somatic problems to have longer delays than those with symptoms of depression or anxiety. The implications of these findings are discussed in the context of an ongoing programme of WHO research activities aimed at improving the quality of mental illness care available in community setting

Conformal geometry of the supercotangent and spinor bundles

We study the actions of local conformal vector fields X∈conf(M,g) on the spinor bundle of (M,g) and on its classical counterpart: the supercotangent bundle M of (M,g). We first deal with the classical framework and determine the Hamiltonian lift of conf(M,g) to M. We then perform the geometric quantization of the supercotangent bundle of (M,g), which constructs the spinor bundle as the quantum representation space. The Kosmann Lie derivative of spinors is btained by quantization of the comoment map. The quantum and classical actions of conf(M,g) turn, respectively, the space of differential operators acting on spinor densities and the space of their symbols into conf(M,g)-modules. They are filtered and admit a common associated graded module. In the conformally flat case, the latter helps us determine the conformal invariants of both conf(M,g)-modules, in particular the conformally odd powers of the Dirac operator.Peer reviewe

Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair

SLX4 binds to three nucleases (XPF-ERCC1, MUS81-EME1, and SLX1), and its deficiency leads to genomic instability, sensitivity to DNA crosslinking agents, and Fanconi anemia. However, it is not understood how SLX4 and its associated nucleases act in DNA crosslink repair. Here, we uncover consequences of mouse Slx4 deficiency and reveal its function in DNA crosslink repair. Slx4-deficient mice develop epithelial cancers and have a contracted hematopoietic stem cell pool. The N-terminal domain of SLX4 (mini-SLX4) that only binds to XPF-ERCC1 is sufficient to confer resistance to DNA crosslinking agents. Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity up to 100-fold, directing specificity toward DNA forks. Mini-SLX4-XPF-ERCC1 also vigorously stimulates dual incisions around a DNA crosslink embedded in a synthetic replication fork, an essential step in the repair of this lesion. These observations define vertebrate SLX4 as a tumor suppressor, which activates XPF-ERCC1 nuclease specificity in DNA crosslink repairope

Redirecting research efforts on the diversification-performance linkage: The search for synergy

We review the literature on the diversification-performance (D-P) relationship to a) propose that the time is ripe for a renewed attack on understanding the relationship between diversification and firm performance, and b) outline a new approach to attacking the question. Our paper makes four main contributions. First, through a review of the literature we establish the inherent complexities in the D-P relationship and the methodological challenges confronted by the literature in reaching its current conclusion of a non-linear relationship between diversification and performance. Second, we argue that to better guide managers the literature needs to develop along a complementary path – whereas past research has often focused on answering the big question of does diversification affect firm performance, this second path would focus more on identifying the precise micro-mechanisms through which diversification adds or subtracts value. Third, we outline a new approach to the investigation of this topic, based on (a) identifying the precise underlying mechanisms through which diversification affects performance; (b) identifying performance outcomes that are “proximate” to the mechanism that the researcher is studying, and (c) identifying an appropriate research design that can enable a causal claim. Finally, we outline a set of directions for future research

Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5,6,7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision—analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions—instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism

On the predictive benefits of Form 10-K backlog information / BEBR No.911

"DO NOT QUOTE WITHOUT THE PERMISSION OF THE AUTHORS"Includes bibliographical references (p. 17)

Conformational changes of DNA repair glycosylase MutM triggered by DNA binding

Bacterial MutM is a DNA repair glycosylase removing DNA damage generated from oxidative stress and, therefore, preventing mutations and genomic instability. MutM belongs to the Fpg Nei family of prokaryotic enzymes sharing structural and functional similarities with their eukaryotic counterparts, for example, NEIL1 NEIL3. Here, we present two crystal structures of MutM from pathogenic Neisseria meningitidis a MutM holoenzyme and MutM bound to DNA. The free enzyme exists in an open conformation, while upon binding to DNA, both the enzyme and DNA undergo substantial structural changes and domain rearrangement. Our data show that not only NEI glycosylases but also the MutMs undergo dramatic conformational changes. Moreover, crystallographic data support the previously published observations that MutM enzymes are rather flexible and dynamic molecule

Invariant Prolongation of . . . PDES IN PROJECTIVE, CONFORMAL AND GRASSMANNIAN GEOMETRY

This is the second in a series of papers on natural modification of the normal tractor connection in a parabolic geometry, which naturally prolongs an underlying overdetermined system of invariant differential equations. We give a short review of the general procedure developed in [5] and then compute the prolongation covariant derivatives for a number of interesting examples in projective, conformal and Grassmannian geometries