Cone photoreceptor phosphodiesterase PDE6H inhibition regulates cancer cell growth and metabolism, replicating the dark retina response.

BACKGROUND: PDE6H encodes PDE6γ', the inhibitory subunit of the cGMP-specific phosphodiesterase 6 in cone photoreceptors. Inhibition of PDE6, which has been widely studied for its role in light transduction, increases cGMP levels. The purpose of this study is to characterise the role of PDE6H in cancer cell growth. METHODS: From an siRNA screen for 487 genes involved in metabolism, PDE6H was identified as a controller of cell cycle progression in HCT116 cells. Role of PDE6H in cancer cell growth and metabolism was studied through the effects of its depletion on levels of cell cycle controllers, mTOR effectors, metabolite levels, and metabolic energy assays. Effect of PDE6H deletion on tumour growth was also studied in a xenograft model. RESULTS: PDE6H knockout resulted in an increase of intracellular cGMP levels, as well as changes to the levels of nucleotides and key energy metabolism intermediates. PDE6H knockdown induced G1 cell cycle arrest and cell death and reduced mTORC1 signalling in cancer cell lines. Both knockdown and knockout of PDE6H resulted in the suppression of mitochondrial function. HCT116 xenografts revealed that PDE6H deletion, as well as treatment with the PDE5/6 inhibitor sildenafil, slowed down tumour growth and improved survival, while sildenafil treatment did not have an additive effect on slowing the growth of PDE6γ'-deficient tumours. CONCLUSIONS: Our results indicate that the changes in cGMP and purine pools, as well as mitochondrial function which is observed upon PDE6γ' depletion, are independent of the PKG pathway. We show that in HCT116, PDE6H deletion replicates many effects of the dark retina response and identify PDE6H as a new target in preventing cancer cell proliferation and tumour growth.

Bdellovibrio bacteriovorus uses chimeric fibre proteins to recognize and invade a broad range of bacterial hosts.

Predatory bacteria, like the model endoperiplasmic bacterium Bdellovibrio bacteriovorus, show several adaptations relevant to their requirements for locating, entering and killing other bacteria. The mechanisms underlying prey recognition and handling remain obscure. Here we use complementary genetic, microscopic and structural methods to address this deficit. During invasion, the B. bacteriovorus protein CpoB concentrates into a vesicular compartment that is deposited into the prey periplasm. Proteomic and structural analyses of vesicle contents reveal several fibre-like proteins, which we name the mosaic adhesive trimer (MAT) superfamily, and show localization on the predator surface before prey encounter. These dynamic proteins indicate a variety of binding capabilities, and we confirm that one MAT member shows specificity for surface glycans from a particular prey. Our study shows that the B. bacteriovorus MAT protein repertoire enables a broad means for the recognition and handling of diverse prey epitopes encountered during bacterial predation and invasion.

Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation.

Propiogenic substrates and gut bacteria produce propionate, a post-translational protein modifier. In this study, we used a mouse model of propionic acidaemia (PA) to study how disturbances to propionate metabolism result in histone modifications and changes to gene expression that affect cardiac function. Plasma propionate surrogates were raised in PA mice, but female hearts manifested more profound changes in acyl-CoAs, histone propionylation and acetylation, and transcription. These resulted in moderate diastolic dysfunction with raised diastolic Ca2+, expanded end-systolic ventricular volume and reduced stroke volume. Propionate was traced to histone H3 propionylation and caused increased acetylation genome-wide, including at promoters of Pde9a and Mme, genes related to contractile dysfunction through downscaled cGMP signaling. The less severe phenotype in male hearts correlated with ß-alanine buildup. Raising ß-alanine in cultured myocytes treated with propionate reduced propionyl-CoA levels, indicating a mechanistic relationship. Thus, we linked perturbed propionate metabolism to epigenetic changes that impact cardiac function.

Gestão descentralizada no SUS: a experiência de implantaçãodas Regiões Intramunicipais de Saúde em Guarulhos (SP) / Decentralized Management in the NHS: the experience of the implementation

Relata-se, aqui, o recente processo de construção e implantação das Regiões Intramunicipais de Saúde no município de Guarulhos, São Paulo, na ótica do Pacto de Gestão. Apresenta-se o método dessa construção, os eixos, diretrizes, princípios e resultados desse processo que o nortearam, além de referências que lhe serviram de base teórica para o desenvolvimento do trabalho em campo. Salienta-se a importância do processo participativo e o envolvimento das gerências de serviços, assim como uma construção ascendente a partir da leitura da demanda local por serviços de saúde, compondo com a oferta existente a informação essencial para definição de sistemas locais de saúde e sua organização intramunicipal na metrópole, sob a égide da descentralização.

The current article describes the recent process of construction andimplementation of the Intramunicipal Health Regions in the city of Guarulhos,São Paulo, Brazil, under the perspective of the Management Pact. The articlealso presents the method of this construction, the axis, guidelines, principles andresults of this process, as well as references that have served as theoretical base forthe development of the field work. The importance of the participation processand the involvement of service managers should be emphasized, as well as theascending construction through the interpretation of local demand of healthservices, which compose with the existent offer, the essential information forthe definition of local health systems and intramunicipal organization in themetropolis, under the aegis of decentralization.