HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.

The anti-cancer drug target poly(ADP-ribose) polymerase 1 (PARP1) and its close homologue, PARP2, are early responders to DNA damage in human cells1,2. After binding to genomic lesions, these enzymes use NAD+ to modify numerous proteins with mono- and poly(ADP-ribose) signals that are important for the subsequent decompaction of chromatin and the recruitment of repair factors3,4. These post-translational modifications are predominantly serine-linked and require the accessory factor HPF1, which is specific for the DNA damage response and switches the amino acid specificity of PARP1 and PARP2 from aspartate or glutamate to serine residues5-10. Here we report a co-structure of HPF1 bound to the catalytic domain of PARP2 that, in combination with NMR and biochemical data, reveals a composite active site formed by residues from HPF1 and PARP1 or PARP2 . The assembly of this catalytic centre is essential for the addition of ADP-ribose moieties after DNA damage in human cells. In response to DNA damage and occupancy of the NAD+-binding site, the interaction of HPF1 with PARP1 or PARP2 is enhanced by allosteric networks that operate within the PARP proteins, providing an additional level of regulation in the induction of the DNA damage response. As HPF1 forms a joint active site with PARP1 or PARP2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors.

Structural insights into functional amyloid inhibition in Gram -ve bacteria.

Amyloids are proteinaceous aggregates known for their role in debilitating degenerative diseases involving protein dysfunction. Many forms of functional amyloid are also produced in nature and often these systems require careful control of their assembly to avoid the potentially toxic effects. The best-characterised functional amyloid system is the bacterial curli system. Three natural inhibitors of bacterial curli amyloid have been identified and recently characterised structurally. Here, we compare common structural features of CsgC, CsgE and CsgH and discuss the potential implications for general inhibition of amyloid.

Structural insights into the biogenesis and biofilm formation by the Escherichia coli common pilus.

Bacteria have evolved a variety of mechanisms for developing community-based biofilms. These bacterial aggregates are of clinical importance, as they are a major source of recurrent disease. Bacterial surface fibers (pili) permit adherence to biotic and abiotic substrates, often in a highly specific manner. The Escherichia coli common pilus (ECP) represents a remarkable family of extracellular fibers that are associated with both disease-causing and commensal strains. ECP plays a dual role in early-stage biofilm development and host cell recognition. Despite being the most common fimbrial structure, relatively little is known regarding its biogenesis, architecture, and function. Here we report atomic-resolution insight into the biogenesis and architecture of ECP. We also derive a structural model for entwined ECP fibers that not only illuminates interbacteria communication during biofilm formation but also provides a useful foundation for the design of novel nanofibers.

Implications for conservation assessment from flux in the botanical record over 20 years in southwest Ghana.

At best, conservation decisions can only be made using the data available at the time. For plants and especially in the tropics, natural history collections remain the best available baseline information upon which to base conservation assessments, in spite of well-documented limitations in their taxonomic, geographic, and temporal coverage. We explore the extent to which changes to the plant biological record over 20 years have changed our conception of the conservation importance of 931 plant taxa, and 114 vegetation samples, recorded in forest reserves of the southwest Ghana biodiversity hotspot. 36% of species-level assessments changed as a result of new distribution data. 12% of species accepted in 2016 had no assessment in 1996: of those, 20% are new species publications, 60% are new records for SW Ghana, and 20% are taxonomic resolutions. Apparent species ranges have increased over time as new records are made, but new species publications are overwhelmingly of globally rare species, keeping the balance of perceived rarity in the flora constant over 20 years. Thus, in spite of considerable flux at the species record level, range size rarity scores calculated for 114 vegetation samples of the reserves in 1996 and 2016 are highly correlated with each other: r(112) = 0.84, p < .0005, and showed no difference in mean score over 20 years: paired t(113) = -0.482, p = .631. This consistency in results at the area level allows for worthwhile conservation priority setting over time, and we argue is the better course of action than taking no action at all.

Predisposing, enabling, and need factors associated with high service use in a public mental health system.

The purpose of this study was twofold: (1) To investigate the individual- and system-level characteristics associated with high utilization of acute mental health services according to a widely-used theory of service use-Andersen's Behavioral Model of Health Service Use -in individuals enrolled in a large, public-funded mental health system; and (2) To document service utilization by high use consumers prior to a transformation of the service delivery system. We analyzed data from 10,128 individuals receiving care in a large public mental health system from fiscal years 2000-2004. Subjects with information in the database for the index year (fiscal year 2000-2001) and all of the following 3 years were included in this study. Using logistic regression, we identified predisposing, enabling, and need characteristics associated with being categorized as a single-year high use consumer (HU: >3 acute care episodes in a single year) or multiple-year HU (>3 acute care episodes in more than 1 year). Thirteen percent of the sample met the criteria for being a single-year HU and an additional 8% met the definition for multiple-year HU. Although some predisposing factors were significantly associated with an increased likelihood of being classified as a HU (younger age and female gender) relative to non-HUs, the characteristics with the strongest associations with the HU definition, when controlling for all other factors, were enabling and need factors. Homelessness was associated with 115% increase in the odds of ever being classified as a HU compared to those living independently or with family and others. Having insurance was associated with increased odds of being classified as a HU by about 19% relative to non-HUs. Attending four or more outpatient visits was an enabling factor that decreased the chances of being defined as a HU. Need factors, such as having a diagnosis of schizophrenia, bipolar disorder or other psychotic disorder or having a substance use disorder increased the likelihood of being categorized as a HU. Characteristics with the strongest association with heavy use of a public mental health system were enabling and need factors. Therefore, optimal use of public mental services may be achieved by developing and implementing interventions that address the issues of homelessness, insurance coverage, and substance use. This may be best achieved by the integration of mental health, intensive case management, and supportive housing, as well as other social services.

A large-scale species level dated angiosperm phylogeny for evolutionary and ecological analyses.

Phylogenies are a central and indispensable tool for evolutionary and ecological research. Even though most angiosperm families are well investigated from a phylogenetic point of view, there are far less possibilities to carry out large-scale meta-analyses at order level or higher. Here, we reconstructed a large-scale dated phylogeny including nearly 1/8th of all angiosperm species, based on two plastid barcoding genes, matK (incl. trnK) and rbcL. Novel sequences were generated for several species, while the rest of the data were mined from GenBank. The resulting tree was dated using 56 angiosperm fossils as calibration points. The resulting megaphylogeny is one of the largest dated phylogenetic tree of angiosperms yet, consisting of 36,101 sampled species, representing 8,399 genera, 426 families and all orders. This novel framework will be useful for investigating different broad scale research questions in ecological and evolutionary biology.

The intermediate disturbance hypothesis applies to tropical forests, but disturbance contributes little to tree diversity.

The intermediate disturbance hypothesis (IDH) predicts local species diversity to be maximal at an intermediate level of disturbance. Developed to explain species maintenance and diversity patterns in species-rich ecosystems such as tropical forests, tests of IDH in tropical forest remain scarce, small-scale and contentious. We use an unprecedented large-scale dataset (2504 one-hectare plots and 331,567 trees) to examine whether IDH explains tree diversity variation within wet, moist and dry tropical forests, and we analyse the underlying mechanism by determining responses within functional species groups. We find that disturbance explains more variation in diversity of dry than wet tropical forests. Pioneer species numbers increase with disturbance, shade-tolerant species decrease and intermediate species are indifferent. While diversity indeed peaks at intermediate disturbance levels little variation is explained outside dry forests, and disturbance is less important for species richness patterns in wet tropical rain forests than previously thought.

A longitudinal study of the use of mental health services by persons with serious mental illness: do Spanish-speaking Latinos differ from English-speaking Latinos and Caucasians?

OBJECTIVE: Reports of mental health care use by Latinos compared to Caucasians have been mixed. To the authors' knowledge, no large-scale studies have examined the effects of language on mental health service use for Latinos who prefer Spanish compared to Latinos who prefer English and to Caucasians. Language is the most frequently used proxy measure of acculturation. The authors used the administrative database of a mental health system to conduct a longitudinal examination of mental health service use among Spanish-speaking versus English-speaking Latinos and Caucasians with serious mental illness. METHOD: There were 539 Spanish-speaking Latinos, 1,144 English-speaking Latinos, and 4,638 Caucasians initiating treatment for schizophrenia, bipolar disorder, or major depression during 2001-2004. Using multivariate regressions, the authors examined the differences among the groups in the type of service first used. The authors also examined the probability of use of each of four types of mental health services and the intensity of outpatient treatment. RESULTS: Spanish-speaking Latinos differed from both English-speaking Latinos and Caucasians on most measures. Compared to patients in the other groups, the Spanish-speaking Latinos were less likely to enter care through emergency or jail services and more likely to enter care through outpatient services. There were no group differences in the proportion that stayed in treatment or used inpatient hospitalization. CONCLUSIONS: This study suggests that for Latinos, preferred language may be more important than ethnicity in mental health service use. Future studies comparing mental health use may need to differentiate between Spanish- and English-speaking Latinos.

Anxiety disorders in a public mental health system: clinical characteristics and service use patterns.

BACKGROUND: Anxiety disorders are among the most common forms of psychiatric disorder, yet few investigations have examined the prevalence or service use of clients with anxiety disorders in the public mental health sector. METHODS: We examined demographics, clinical information, and service use in clients with anxiety disorders enrolled in San Diego County Adult and Older Adult Mental Health Services in fiscal 2002-2003. RESULTS: Almost 15% of the sample had a diagnosis of an anxiety disorder based on administrative billing data. Most anxiety disorder clients had additional psychiatric diagnoses, most commonly depression. Clients with both anxiety disorders and depression were more likely than those with anxiety or depression alone to use emergency psychiatric services and outpatient services than those with depression alone. Those with anxiety disorders alone used more outpatient services than those with depression alone. LIMITATION: Data were taken from an administrative database. CONCLUSIONS: Data indicate that anxiety disorders are not uncommon in public mental health settings and are associated with higher utilization of outpatient mental health services.

A new class of hybrid secretion system is employed in Pseudomonas amyloid biogenesis.

Gram-negative bacteria possess specialised biogenesis machineries that facilitate the export of amyloid subunits for construction of a biofilm matrix. The secretion of bacterial functional amyloid requires a bespoke outer-membrane protein channel through which unfolded amyloid substrates are translocated. Here, we combine X-ray crystallography, native mass spectrometry, single-channel electrical recording, molecular simulations and circular dichroism measurements to provide high-resolution structural insight into the functional amyloid transporter from Pseudomonas, FapF. FapF forms a trimer of gated ß-barrel channels in which opening is regulated by a helical plug connected to an extended coil-coiled platform spanning the bacterial periplasm. Although FapF represents a unique type of secretion system, it shares mechanistic features with a diverse range of peptide translocation systems. Our findings highlight alternative strategies for handling and export of amyloid protein sequences.Gram-negative bacteria assemble biofilms from amyloid fibres, which translocate across the outer membrane as unfolded amyloid precursors through a secretion system. Here, the authors characterise the structural details of the amyloid transporter FapF in Pseudomonas.

Diagnostic variability for schizophrenia and major depression in a large public mental health care system dataset.

Administrative datasets can provide information about mental health treatment in real world settings; however, an important limitation in using these datasets is the uncertainty regarding psychiatric diagnosis. To better understand the psychiatric diagnoses, we investigated the diagnostic variability of schizophrenia and major depression in a large public mental health system. Using schizophrenia and major depression as the two comparison diagnoses, we compared the variability of diagnoses assigned to patients with one recorded diagnosis of schizophrenia or major depression. In addition, for both of these diagnoses, the diagnostic variability was compared across seven types of treatment settings. Statistical analyses were conducted using t tests for continuous data and chi-square tests for categorical data. We found that schizophrenia had greater diagnostic variability than major depression (31% vs. 43%). For both schizophrenia and major depression, variability was significantly higher in jail and the emergency psychiatric unit than in inpatient or outpatient settings. These findings demonstrate that the variability of psychiatric diagnoses recorded in the administrative dataset of a large public mental health system varies by diagnosis and by treatment setting. Further research is needed to clarify the relationship between psychiatric diagnosis, diagnostic variability and treatment setting.

Bioquality Hotspots in the Tropical African Flora.

Identifying areas of high biodiversity is an established way to prioritize areas for conservation [1-3], but global approaches have been criticized for failing to render global biodiversity value at a scale suitable for local management [4-6]. We assembled 3.1 million species distribution records for 40,401 vascular plant species of tropical Africa from sources including plot data, herbarium databases, checklists, and the Global Biodiversity Information Facility (GBIF) and cleaned the records for geographic accuracy and taxonomic consistency. We summarized the global ranges of tropical African plant species into four weighted categories of global rarity called Stars. We applied the Star weights to summaries of species distribution data at fine resolutions to map the bioquality (range-restricted global endemism) of areas [7]. We generated confidence intervals around bioquality scores to account for the remaining uncertainty in the species inventory. We confirm the broad significance of the Horn of Africa, Guinean forests, coastal forests of East Africa, and Afromontane regions for plant biodiversity but also reveal the variation in bioquality within these broad regions and others, particularly at local scales. Our framework offers practitioners a quantitative, scalable, and replicable approach for measuring the irreplaceability of particular local areas for global biodiversity conservation and comparing those areas within their global and regional context.

Electrostatically-guided inhibition of Curli amyloid nucleation by the CsgC-like family of chaperones.

Polypeptide aggregation into amyloid is linked with several debilitating human diseases. Despite the inherent risk of aggregation-induced cytotoxicity, bacteria control the export of amyloid-prone subunits and assemble adhesive amyloid fibres during biofilm formation. An Escherichia protein, CsgC potently inhibits amyloid formation of curli amyloid proteins. Here we unlock its mechanism of action, and show that CsgC strongly inhibits primary nucleation via electrostatically-guided molecular encounters, which expands the conformational distribution of disordered curli subunits. This delays the formation of higher order intermediates and maintains amyloidogenic subunits in a secretion-competent form. New structural insight also reveal that CsgC is part of diverse family of bacterial amyloid inhibitors. Curli assembly is therefore not only arrested in the periplasm, but the preservation of conformational flexibility also enables efficient secretion to the cell surface. Understanding how bacteria safely handle amyloidogenic polypeptides contribute towards efforts to control aggregation in disease-causing amyloids and amyloid-based biotechnological applications.

Prevalence and risk factors for homelessness and utilization of mental health services among 10,340 patients with serious mental illness in a large public mental health system.

OBJECTIVE: The authors examined the prevalence of and risk factors for homelessness among all patients treated for serious mental illnesses in a large public mental health system in a 1-year period. The use of public mental health services among homeless persons was also examined. METHOD: The study included 10,340 persons treated for schizophrenia, bipolar disorder, or major depression in the San Diego County Adult Mental Health Services over a 1-year period (1999-2000). Analytic methods that adjusted for potentially confounding variables were used. Multivariate logistic regression analyses were used to calculate odds ratios for the factors associated with homelessness, including age, gender, ethnicity, substance use disorder, Medicaid insurance, psychiatric diagnosis, and level of functioning. Similarly, odds ratios were computed for utilization of mental health services by homeless versus not-homeless patients. RESULTS: The prevalence of homelessness was 15%. Homelessness was associated with male gender, African American ethnicity, presence of a substance use disorder, lack of Medicaid, a diagnosis of schizophrenia or bipolar disorder, and poorer functioning. Latinos and Asian Americans were less likely to be homeless. Homeless patients used more inpatient and emergency-type services and fewer outpatient-type services. CONCLUSIONS: Homelessness is a serious problem among patients with severe mental illness. Interventions focusing on potentially modifiable factors such as substance use disorders and a lack of Medicaid need to be studied in this population.

A randomized trial of short-term acute residential treatment for veterans.

OBJECTIVE: A variety of alternatives to acute psychiatric hospital care have been developed over the past several decades. including San Diego's short-term acute residential treatment (START) program, now comprising a certified and accredited network of six facilities with a total of 75 beds. This study compared outcomes, patient satisfaction, and episode costs for a sample of 99 veterans who received acute care either at an inpatient unit at a Department of Veterans Affairs (VA) hospital or at a START facility. METHODS: Consenting participants were randomly assigned to one of the two treatment settings. Follow-up was conducted at two months. During the follow-up period, participants received treatment as usual. Multiple standardized measures were used to maximize validity in assessing symptoms, functioning, and quality of life. RESULTS: Participants who were treated in either a hospital or the START program showed significant improvement between admission, discharge, and two-month follow-up, with few statistically significant differences between the groups in symptoms and functioning. There was some evidence that START participants had greater satisfaction with services. Mean costs for the index episode were significantly lower for START participants (65 percent lower) than for those who were treated in the hospital. CONCLUSIONS: The results of this study suggest that the START model provides effective voluntary acute psychiatric care in a non-hospital-based setting at considerably lower cost. Efforts to replicate and evaluate the model at additional locations merit attention.

Ethnic disparities in use of public mental health case management services among patients with schizophrenia.

OBJECTIVES: This study examined case management service use by ethnic group in a sample of 4,249 European-American, Latino, and African-American patients with a diagnosis of schizophrenia or schizoaffective disorder who were receiving services in the public mental health sector of San Diego County during fiscal year 1998-1999. METHODS: Data on demographic and clinical variables were obtained from the public mental health services database of the San Diego County Mental Health Department. Multivariate logistic regression analyses were used to determine the relationship between the demographic and clinical variables and use of case management services. RESULTS: The ethnic composition of the sample was 64 percent European American, 20 percent Latino, and 17 percent African American. Overall, 1,100 patients (26 percent) received case management services. A disproportionately greater percentage of service use occurred among European Americans (30 percent) than among patients from ethnic minorities (19 percent for Latinos and 17 percent for African Americans). The results also indicated that Spanish-speaking Latinos underused case management services; however, the underuse was less dramatic than anticipated. CONCLUSIONS: The results of this study underscore the need for continuing concern about the use of case management and other mental health services by persons from ethnic minorities.

Gender differences in characteristics and service use of public mental health patients with schizophrenia.

The study examined gender differences in sociodemographic, clinical, and mental health service use variables among patients with schizophrenia in a public mental health care system. Data from 1999 to 2000 for 4975 adult patients were analyzed. Women were older and more likely to be married and to have Medicaid insurance and less likely to have a diagnosis of substance abuse than men. More women were living independently, whereas more men resided in assisted living facilities or were homeless. Women were significantly more likely to have had a psychiatric hospitalization than men, which may be related to differential use of services by men and women with the worst level of functioning.

Assisted living and use of health services among medicaid beneficiaries with schizophrenia.

BACKGROUND: Considerable attention has been given to the appropriateness of mental and medical health care provided to residents of certain assisted living facilities specialized for the severely mentally ill. However, there exists little objective evidence regarding the level of services provided by these facilities in general. AIMS OF THE STUDY: To compare the use of mental and medical health services among persons with schizophrenia who were residing in assisted living facilities compared to those received by patients living independently and those who were homeless. METHODS: Medicaid claims were combined with person level data on living situation and psychological and social functioning for 1998-2000. Regression models were used to analyze whether living in a board-and-care facility was related to use of outpatient mental health services including case management, therapy, crisis stabilization, medication supervision, day treatment, and drug treatment, the probability of acute psychiatric hospitalization, the probability of hospitalization for physical health, and costs. RESULTS: Residents of board-and-care facilities had greater use of outpatient mental health services and lower rates of psychiatric and medical hospitalization. Pharmacy costs and total health care costs were highest in assisted living. DISCUSSION: Our data was observational, and selection processes related to illness severity likely affect living arrangement. Our analysis suggests that assisted living was related to greater use of outpatient mental health services and lower rates of hospitalization. IMPLICATIONS FOR HEALTH POLICIES: Assisted living facilities may provide a suitable environment though which to provide outpatient mental health services. Policy makers interested in reducing homelessness through interventions might consider subsidizing these facilities. IMPLICATIONS FOR FURTHER RESEARCH: Research studies should be designed to evaluate characteristics of assisted living facilities that lead to improved function and outcomes among residents.

1H, 13C and 15N assignments of Sgt2 N-terminal dimerisation domain and its binding partner, Get5 Ubiquitin-like domain.

The first stage of the GET (guided entry of tail-anchored proteins) mechanism for tail-anchored (TA) membrane protein insertion is thought to occur when Sgt2 (small, glutamine-rich, tetratricopeptide repeat-containing protein 2) binds TA proteins upon their release from the ribosome. It sorts them and passes the majority over to a complex of Get5 and Get4 for transmission along the GET pathway and delivery to their membrane destination. Sgt2 is a 38 kDa protein consisting of three domains. The N-terminal domain effects tight dimerisation of the protein and is also the site for binding with the ubiquitin-like (UBL) domain of Get5. Here we have expressed and purified uniformly-(15)N/(13)C-labelled N-terminal Sgt2 (Sgt2_NT) and its binding partner, Get5 UBL domain (Get5_UBL) and assigned the backbone and side-chain resonances as a basis for structure solution of the individual components and, ultimately, the complex. This will provide detailed molecular insight into the early stages of the GET pathway.

Incarceration among adults who are in the public mental health system: rates, risk factors, and short-term outcomes.

OBJECTIVE: Incarceration of people with mental illness has become a major social, clinical, and economic concern, with an estimated 2.1 million incarcerations in 2007. Prior studies have primarily focused on mental illness rates among incarcerated persons. This study examined rates of and risk factors for incarceration and reincarceration, as well as short-term outcomes after incarceration, among patients in a large public mental health system. METHODS: The data set included 39,463 patient records combined with 4,544 matching incarceration records from the county jail system during fiscal year 2005-2006. Risk factors for incarceration and reincarceration were analyzed with logistic regression. Time after release from the index incarceration until receiving services was examined with survival analysis. RESULTS: During the year, 11.5% of patients (N=4,544) were incarcerated. Risk factors for incarceration included prior incarcerations; co-occurring substance-related diagnoses; homelessness; schizophrenia, bipolar, or other psychotic disorder diagnoses; male gender; no Medicaid insurance; and being African American. Patients older than 45, Medicaid beneficiaries, and those from Latino, Asian, and other non-Euro-American racial-ethnic groups were less likely to be incarcerated. Risk factors for reincarceration included co-occurring substance-related diagnoses; prior incarceration; diagnosed schizophrenia or bipolar disorder; homelessness; and incarceration for three or fewer days. Patients whose first service after release from incarceration was outpatient or case management were less likely to receive subsequent emergency services or to be reincarcerated within 90 days. CONCLUSIONS: Modifiable factors affecting incarceration risk include homelessness, substance abuse, lack of medical insurance, and timely receipt of outpatient or case management services after release from incarceration.