Selective and Specific Activation of Rab5 during Endocytosis of Receptor Tyrosine Kinases

The Rab family of proteins are low molecular weight GTPases that have the ability to switch between GTP- (active) and GDP- (inactive) bound form, and in that sense act as molecular switches. Through distinct localization on various vesicles and organelles and by cycling through GTP/GDP bound forms, Rabs are able to recruit and activate numerous effector proteins, both spatially and temporally, and hence behave as key regulators of trafficking in both endocytic and biosynhtetic pathways. The Rab5 protein has been shown to regulate transport from plasma membrane to the early endosome as well as activate signaling pathways from the early endosome. This dissertation focused on understanding Rab5 activation via endocytosis of receptor tyrosine kinases (RTKs). First, tyrosine kinase activity of RTKs was linked to endosome fusion by demonstrating that tyrosine kinase inhibitors block endosome fusion and activation of Rab5, and a constitutively active form of Rab5 is able to rescue endosome fusion. However, depending on how much ligand is available at the cell surface, the receptor-ligand complexes can be internalized via a number of distinct pathways. Similarly, Rab5 was activated in a ligand-dependent concentration dependent manner via clathrin- and caveolin-mediated pathways, as well as a pathway independent of both. However, overexpression Rabex-5, a nucleotide exchange factor for Rab5, is able to rescue activation even when all of the pathways of EGF-receptor internalization were blocked. Next, the three naturally occurring splice variants of Rabex-5 selectively activated Rab5. Lastly, Rabex-5 inhibits differentiation of 3T3-L1 and PC12 cells through 1) degradation of signaling endosome via Rab5-dependent fusion with the early endosome, 2) and inhibition of signaling cascade via ubiquitination of Ras through the ZnF domain at the N-terminus of Rabex-5. In conclusion, these data shed light on complexity of the endosomal trafficking system where tyrosine kinase activity of the receptor is able to affect endosome fusion; how different endocytic pathways affect activation of one of the key regulators of early endocytic events; and how selective activation of Rab5 via Rabex-5 can control adipogenesis and neurogenesis.

Double blind test series

Braille is a communication tool in decline, in America by 80% since 1950, and in the UK to the extent that only 1% of blind people are now thought to read Braille.1, 2 There are a variety of causal factors, including the phasing out of Braille instruction due to the educational mainstreaming of blind children and the resistance to learning Braille by those who lose sight later in life.3Braille is a writing system of raised dots that allows blind people to read and write tactilely. Each Braille character comprises a cell of six potentially raised dots, two dots across and three dots down. It is designed only to communicate the message and does not convey the tonality provided by visual fonts.However, in his book Design Meets Disability, Graham Pullin, observes that: “Braille is interesting and beautiful, as abstract visual and tactile decoration, intriguing and indecipherable to the nonreader ” and continues; “…braille could be decorative for sighted people.”4I assert that the increasing abandonment of Braille frees it from its restrictive constraints, opening it to exploration and experimentation, and that this may result in Braille becoming dynamic expression for the sighted, as well as the partially sighted and blind.Printmaking is well suited for this exploration. Printmaking processes and techniques can result in prints aesthetically compelling to both senses of sight and touch. Established approaches, such as flocking, varnishes, puff-ink, embossing and die cut, combined with experiments in new techniques in laser cutting and 3D printing, create visually and texturally vibrant prints.In this paper I will detail my systematic investigation of sensually expressive printmaking concentrating on the issues surrounding Braille as a printmaking design element paying particular attention to the approaches and techniques used not only in producing its visual style but to those techniques used to keep it integrally tactile.

Melhoria da Atençao a Saúde do Idoso na UBS Joao Paulo Ii, Caicó/RN

Um envelhecimento de qualidade é direito de toda e qualquer pessoa. Pensar em estratégias de implementação do cuidado ao idoso sob um olhar preventivo, educativo e com redução de riscos e danos, buscando uma melhoria na qualidade de vida, uma vez que é notável o crescimento da expectativa de vida ao observamos os índices de envelhecimento não apenas no Brasil, mas de modo global é suficientemente necessário. Nos países desenvolvidos o envelhecimento está associado à melhoria nas condições de vida, não sendo esta a realidade nos países em desenvolvimento. Diante disso, o objetivo fundamental do desenvolvimento da intervenção em saúde na Unidade de Estratégia de Saúde da Família João Paulo II em Caicó/RN foi direcionado à melhoria da atenção à saúde da pessoa idosa no sentido de promover o envelhecimento ativo e saudável das pessoas com 60 anos ou mais pertencentes à área de abrangência da unidade durante doze semanas, entre os meses de maio e agosto de 2015. Para a realização dessa intervenção, foram planejadas ações nos eixos de Monitoramento e Avaliação, Organização e Gestão do Serviço, Engajamento Público e Qualificação da Prática Clínica, levando-se em consideração as necessidades da população do território de abrangência, a viabilidade de aplicação das ações e a expectativa de obtenção de resultados. Participaram da intervenção um total de 203 (61,5%) idosos pertencentes à unidade de saúde com 60 anos ou mais. Todos os índices de qualidade das ações alcançaram 100% de efetividade. Para um bom desempenho da intervenção foram traçadas metas que por ocasião da conclusão da mesma foram avaliadas mediante os indicadores destinados para cada meta. A intervenção trouxe benefício para os idosos acompanhados, entre os quais há hipertensos, diabéticos, acamados e os que apresentam outras doenças crônicas não transmissíveis e que aprenderam a conviver de forma diferenciada com as mesmas. As ações iniciadas com o processo de intervenção serão mantidas na rotina do serviço para dar continuidade ao processo de qualificação da melhoria da qualidade de vida de todos os idosos acompanhados pela Unidade.