Evaluation of outreach services for primary care and mental health; assessing the impact

Objectives: This paper reports an evaluation, carried out for London Health Libraries, of the impact of outreach services to primary care and mental health workers in thirteen different settings. The main aims of the project were to identify the impact being made by the service, and to produce best practice guidelines for outreach services in this kind of ‘difficult’ community setting. Methods: Methods used were: analysis of documents (all 13 services); analysis of any evaluation already performed by or for the service (all 13 services); interviews with outreach librarians (11 services); questionnaire survey of a representative sample of users (8 services, with 66 returned questionnaires, 35% response rate). The services evaluated were very diverse, in terms of setting, structure, functions and activities, and extent and nature of self-evaluation and reporting. The evaluation was therefore largely qualitative, in order to deal with the lack of a consistent ‘template’ for analysis. Emphasis was placed on trying to identify critical incidents , where it could be shown unambiguously that the outreach services made a difference to practice. Study limitations included the difficulty of summarising and comparing very different situations and diverse services, difficulty in identifying critical incidents, and an inability to study ‘non-users’. Findings: Service recipients felt better informed, more up- to-date, more aware of resources, more confident and supported in their work, and saved time. Services contributed to a richer information environment. Direct impacts, demonstrably improved patient care, cost savings etc., were more difficult to establish

Inhibition of Inducible Nitric Oxide Synthase Expression by a Novel Small Molecule Activator of the Unfolded Protein Response

The transcription of inducible nitric oxide synthase (iNOS) is activated by a network of proinflammatory signaling pathways. Here we describe the identification of a small molecule that downregulates the expression of iNOS mRNA and protein in cytokine-activated cells and suppresses nitric oxide production in vivo. Mechanistic analysis suggests that this small molecule, erstressin, also activates the unfolded protein response (UPR), a signaling pathway triggered by endoplasmic reticulum stress. Erstressin induces rapid phosphorylation of eIF2α and the alternative splicing of XBP-1, hallmark initiating events of the UPR. Further, erstressin activates the transcription of multiple genes involved in the UPR. These data suggest an inverse relationship between UPR activation and iNOS mRNA and protein expression under proinflammatory conditions

The composition of the protosolar disk and the formation conditions for comets

Conditions in the protosolar nebula have left their mark in the composition of cometary volatiles, thought to be some of the most pristine material in the solar system. Cometary compositions represent the end point of processing that began in the parent molecular cloud core and continued through the collapse of that core to form the protosun and the solar nebula, and finally during the evolution of the solar nebula itself as the cometary bodies were accreting. Disentangling the effects of the various epochs on the final composition of a comet is complicated. But comets are not the only source of information about the solar nebula. Protostellar disks around young stars similar to the protosun provide a way of investigating the evolution of disks similar to the solar nebula while they are in the process of evolving to form their own solar systems. In this way we can learn about the physical and chemical conditions under which comets formed, and about the types of dynamical processing that shaped the solar system we see today. This paper summarizes some recent contributions to our understanding of both cometary volatiles and the composition, structure and evolution of protostellar disks.Comment: To appear in Space Science Reviews. The final publication is available at Springer via http://dx.doi.org/10.1007/s11214-015-0167-

Insetos em presépios e as "formigas vestidas" de Jules Martin (1832-1906): uma curiosa manufatura paulistana do final do século XIX

Encontrados no Brasil desde os primórdios da colonização portuguesa, os presépios logo tiveram de adaptar-se à realidade local, circunstância muito propícia ao aparecimento de concepções heterodoxas e ao emprego de elementos exóticos da fauna e flora de cada região. Como registros envolvendo insetos são muito pouco comuns, chama a atenção que fêmeas de saúva, Atta sp. (Hymenoptera, Formicidae), tenham sido aproveitadas na composição de presépios no estado de São Paulo. Tendo subsistido pelo menos até a década 1960, os "presépios de formigas" existentes em cidades como Embu das Artes poderiam estar relacionados às "formigas vestidas" criadas por Jules Martin, curiosa manufatura paulistana do último quartel do século XIX.Present in Brazil since the beginning of Portuguese colonization, crèche nativity scenes were soon adapted to local reality, a propitious circumstance for the appearance of heterodox conceptions and the use of exotic elements of the fauna and flora peculiar to each region. As records about insects are very uncommon, it is noteworthy that females of leaf-cutting ants, Atta sp. (Hymenoptera, Formicidae), were used to compose crèche nativity scenes in São Paulo State. Having subsisted at least up to the decade of 1960, the "ant crèches" of cities such as Embu das Artes could be related to the then famous "dressed ants" created by Jules Martin, a curious manufacture of the city of São Paulo in the last quarter of the 19th century

Recruitment of a SAP18-HDAC1 Complex into HIV-1 Virions and Its Requirement for Viral Replication

HIV-1 integrase (IN) is a virally encoded protein required for integration of viral cDNA into host chromosomes. INI1/hSNF5 is a component of the SWI/SNF complex that interacts with HIV-1 IN, is selectively incorporated into HIV-1 (but not other retroviral) virions, and modulates multiple steps, including particle production and infectivity. To gain further insight into the role of INI1 in HIV-1 replication, we screened for INI1-interacting proteins using the yeast two-hybrid system. We found that SAP18 (Sin3a associated protein 18 kD), a component of the Sin3a-HDAC1 complex, directly binds to INI1 in yeast, in vitro and in vivo. Interestingly, we found that IN also binds to SAP18 in vitro and in vivo. SAP18 and components of a Sin3A-HDAC1 complex were specifically incorporated into HIV-1 (but not SIV and HTLV-1) virions in an HIV-1 IN–dependent manner. Using a fluorescence-based assay, we found that HIV-1 (but not SIV) virion preparations harbour significant deacetylase activity, indicating the specific recruitment of catalytically active HDAC into the virions. To determine the requirement of virion-associated HDAC1 to HIV-1 replication, an inactive, transdominant negative mutant of HDAC1 (HDAC1H141A) was utilized. Incorporation of HDAC1H141A decreased the virion-associated histone deacetylase activity. Furthermore, incorporation of HDAC1H141A decreased the infectivity of HIV-1 (but not SIV) virions. The block in infectivity due to virion-associated HDAC1H141A occurred specifically at the early reverse transcription stage, while entry of the virions was unaffected. RNA-interference mediated knock-down of HDAC1 in producer cells resulted in decreased virion-associated HDAC1 activity and a reduction in infectivity of these virions. These studies indicate that HIV-1 IN and INI1/hSNF5 bind SAP18 and selectively recruit components of Sin3a-HDAC1 complex into HIV-1 virions. Furthermore, HIV-1 virion-associated HDAC1 is required for efficient early post-entry events, indicating a novel role for HDAC1 during HIV-1 replication

The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis.

How the proto-oncogene c-Myc balances the processes of stem-cell self-renewal, proliferation and differentiation in adult tissues is largely unknown. We explored c-Myc's transcriptional roles at the epidermal differentiation complex, a locus essential for skin maturation. Binding of c-Myc can simultaneously recruit (Klf4, Ovol-1) and displace (Cebpa, Mxi1 and Sin3a) specific sets of differentiation-specific transcriptional regulators to epidermal differentiation complex genes. We found that Sin3a causes deacetylation of c-Myc protein to directly repress c-Myc activity. In the absence of Sin3a, genomic recruitment of c-Myc to the epidermal differentiation complex is enhanced, and re-activation of c-Myc-target genes drives aberrant epidermal proliferation and differentiation. Simultaneous deletion of c-Myc and Sin3a reverts the skin phenotype to normal. Our results identify how the balance of two transcriptional key regulators can maintain tissue homeostasis through a negative feedback loop

Time variability and heterogeneity in the coma of 67P/Churyumov-Gerasimenko

Comets contain the best-preserved material from the beginning of our planetary system. Their nuclei and comae composition reveal clues about physical and chemical conditions during the early solar system when comets formed. ROSINA (Rosetta Orbiter Spectrometer for Ion and Neutral Analysis) onboard the Rosetta spacecraft has measured the coma composition of comet 67P/Churyumov-Gerasimenko with well-sampled time resolution per rotation. Measurements were made over many comet rotation periods and a wide range of latitudes. These measurements show large fluctuations in composition in a heterogeneous coma that has diurnal and possibly seasonal variations in the major outgassing species: water, carbon monoxide, and carbon dioxide. These results indicate a complex coma-nucleus relationship where seasonal variations may be driven by temperature differences just below the comet surface

Histone deacetylase 1 and 2 differentially regulate apoptosis by opposing effects on extracellular signal-regulated kinase 1/2

Histone deacetylases (HDACs) are epigenetic regulators that are important for the control of various pathophysiological events. We found that HDAC inhibitors completely abolished transforming growth factor-β1 (TGF-β1)-induced apoptosis in AML-12 and primary mouse hepatocytes. Expression of a dominant-negative mutant of HDAC1 or downregulation of HDAC1 by RNAi both suppressed TGF-β1-induced apoptosis. In addition, overexpression of HDAC1 enhanced TGF-β1-induced apoptosis, and the rescue of HDAC1 expression in HDAC1 RNAi cells restored the apoptotic response of cells to TGF-β1. These data indicate that HDAC1 functions as a proapoptotic factor in TGF-β1-induced apoptosis. In contrast, downregulation of HDAC2 by RNAi increased spontaneous apoptosis and markedly enhanced TGF-β1-induced apoptosis, suggesting that HDAC2 has a reciprocal role in controlling cell survival. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) by MEK1 inhibitor PD98059 or expression of a kinase-dead mutant of MEK1 restored the apoptotic response to TGF-β1 in HDAC1 RNAi cells. Strikingly, HDAC2 RNAi caused an inhibition of ERK1/2, and the spontaneous apoptosis can be abolished by reactivation of ERK1/2. Taken together, our data demonstrate that HDAC1 and 2 reciprocally affect cell viability by differential regulation of ERK1/2; these observations provide insight into the roles and potential mechanisms of HDAC1 and 2 in apoptosis

In vitro nuclear interactome of the HIV-1 Tat protein

<p>Abstract</p> <p>Background</p> <p>One facet of the complexity underlying the biology of HIV-1 resides not only in its limited number of viral proteins, but in the extensive repertoire of cellular proteins they interact with and their higher-order assembly. HIV-1 encodes the regulatory protein Tat (86–101aa), which is essential for HIV-1 replication and primarily orchestrates HIV-1 provirus transcriptional regulation. Previous studies have demonstrated that Tat function is highly dependent on specific interactions with a range of cellular proteins. However they can only partially account for the intricate molecular mechanisms underlying the dynamics of proviral gene expression. To obtain a comprehensive nuclear interaction map of Tat in T-cells, we have designed a proteomic strategy based on affinity chromatography coupled with mass spectrometry.</p> <p>Results</p> <p>Our approach resulted in the identification of a total of 183 candidates as Tat nuclear partners, 90% of which have not been previously characterised. Subsequently we applied <it>in silico </it>analysis, to validate and characterise our dataset which revealed that the Tat nuclear interactome exhibits unique signature(s). First, motif composition analysis highlighted that our dataset is enriched for domains mediating protein, RNA and DNA interactions, and helicase and ATPase activities. Secondly, functional classification and network reconstruction clearly depicted Tat as a polyvalent protein adaptor and positioned Tat at the nexus of a densely interconnected interaction network involved in a range of biological processes which included gene expression regulation, RNA biogenesis, chromatin structure, chromosome organisation, DNA replication and nuclear architecture.</p> <p>Conclusion</p> <p>We have completed the <it>in vitro </it>Tat nuclear interactome and have highlighted its modular network properties and particularly those involved in the coordination of gene expression by Tat. Ultimately, the highly specialised set of molecular interactions identified will provide a framework to further advance our understanding of the mechanisms of HIV-1 proviral gene silencing and activation.</p