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

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

Specialization of an Exonuclease III family enzyme in the repair of 3' DNA lesions during base excision repair in the human pathogen Neisseria meningitidis.

We have previously demonstrated that the two Exonuclease III (Xth) family members present within the obligate human pathogen Neisseria meningitidis, NApe and NExo, are important for survival under conditions of oxidative stress. Of these, only NApe possesses AP endonuclease activity, while the primary function of NExo remained unclear. We now reveal further functional specialization at the level of 3'-PO(4) processing for NExo. We demonstrate that the bi-functional meningococcal glycosylases Nth and MutM can perform strand incisions at abasic sites in addition to NApe. However, no such functional redundancy exists for the 3'-phosphatase activity of NExo, and the cytotoxicity of 3'-blocking lesions is reflected in the marked sensitivity of a mutant lacking NExo to oxidative stress, compared to strains deficient in other base excision repair enzymes. A histidine residue within NExo that is responsible for its lack of AP endonuclease activity is also important for its 3'-phosphatase activity, demonstrating an evolutionary trade off in enzyme function at the single amino acid level. This specialization of two Xth enzymes for the 3'-end processing and strand-incision reactions has not previously been observed and provides a new paradigm within the prokaryotic world for separation of these critical functions during base excision repair

A network of enzymes involved in repair of oxidative DNA damage in Neisseria meningitidis.

Although oxidative stress is a key aspect of innate immunity, little is known about how host-restricted pathogens successfully repair DNA damage. Base excision repair is responsible for correcting nucleobases damaged by oxidative stress, and is essential for bloodstream infection caused by the human pathogen, Neisseria meningitidis. We have characterized meningococcal base excision repair enzymes involved in the recognition and removal of damaged nucleobases, and incision of the DNA backbone. We demonstrate that the bi-functional glycosylase/lyases Nth and MutM share several overlapping activities and functional redundancy. However, MutM and other members of the GO system, which deal with 8-oxoG, a common lesion of oxidative damage, are not required for survival of N. meningitidis under oxidative stress. Instead, the mismatch repair pathway provides back-up for the GO system, while the lyase activity of Nth can substitute for the meningococcal AP endonuclease, NApe. Our genetic and biochemical evidence shows that DNA repair is achieved through a robust network of enzymes that provides a flexible system of DNA repair. This network is likely to reflect successful adaptation to the human nasopharynx, and might provide a paradigm for DNA repair in other prokaryotes

Structural basis for the recognition and cleavage of abasic DNA in Neisseria meningitidis.

Base excision repair (BER) is a highly conserved DNA repair pathway throughout all kingdoms from bacteria to humans. Whereas several enzymes are required to complete the multistep repair process of damaged bases, apurinic-apyrimidic (AP) endonucleases play an essential role in enabling the repair process by recognizing intermediary abasic sites cleaving the phosphodiester backbone 5' to the abasic site. Despite extensive study, there is no structure of a bacterial AP endonuclease bound to substrate DNA. Furthermore, the structural mechanism for AP-site cleavage is incomplete. Here we report a detailed structural and biochemical study of the AP endonuclease from Neisseria meningitidis that has allowed us to capture structural intermediates providing more complete snapshots of the catalytic mechanism. Our data reveal subtle differences in AP-site recognition and kinetics between the human and bacterial enzymes that may reflect different evolutionary pressures

Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS CoV 2 nsp14 methyltransferase

Monkeypox is a disease with pandemic potential. It is caused by the monkeypox virus MPXV , a double stranded DNA virus from the Poxviridae family, that replicates in the cytoplasm and must encode for its own RNA processing machinery including the capping machinery. Here, we present crystal structures of its 2 amp; 8242; O RNA methyltransferase MTase VP39 in complex with the pan MTase inhibitor sinefungin and a series of inhibitors that were discovered based on it. A comparison of this 2 amp; 8242; O RNA MTase with enzymes from unrelated single stranded RNA viruses SARS CoV 2 and Zika reveals a conserved sinefungin binding mode, implicating that a single inhibitor could be used against unrelated viral families. Indeed, several of our inhibitors such as TO507 also inhibit the coronaviral nsp14 MTas

Lung transplantation in telomerase mutation carriers with pulmonary fibrosis

Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined. We gathered an international series of telomerase mutation carriers who underwent lung transplant in the USA, Australia and Sweden. The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p,0.0001). Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients