Kinetochore protein KNL1 links kinetochore-microtubule attachment and checkpoint signaling during mitosis, The

2014 Summer.Mitosis is the phase of the cell cycle in which replicated chromosomes physically separate, resulting in the formation of two genetically identical daughter cells. This process is not only essential for the development of a single fertilized cell into a multicellular organism, but also for replacement of damaged and dying cells during the span life of an organism. The distribution of chromosomes during mitotic cell division requires accurate yet dynamic attachment between the plus-ends of spindle microtubules (MTs) and kinetochores, which are protein structures assembled at the centromeric region of replicated chromatids. The tightly regulated connection between kinetochores and MTs allows for chromosome congression to the metaphase plate and subsequent separation of the replicated chromosomes during anaphase. Not surprisingly, the inability of cells to resolve erroneous kinetochore-MT attachments results in missegregation of chromosomes, which is linked to uncontrolled cell proliferation and cancer. Thus, proper kinetochore-MT attachment during cell division is essential for the maintenance of genetic integrity. Despite a growing understanding of the identity of proteins that compose the kinetochore and the processes for which they are required, the precise functions of many kinetochore proteins are still unknown. KNL1, a large kinetochore scaffolding protein, contributes to several signaling pathways coordinated by the kinetochore. Yet, how KNL1 recruits its various binding partners to the kinetochore, and whether KNL1 directly or indirectly modulates protein function during mitosis are unresolved questions. In this dissertation, I examine the function of KNL1 in the regulation of kinetochore-MT attachment and determine the regions of KNL1 required for the accumulation of an array of kinetochore proteins. By loss of function analyses using a set of KNL1 mutants, combined with functional assays in cells, I demonstrate that the KNL1 N-terminus is essential for Aurora B kinase activity at kinetochores and for correct kinetochore-MT dynamics. Aurora B kinase phosphorylates kinetochore proteins during early mitosis, increasing kinetochore-microtubule (MT) turnover and preventing premature stabilization of kinetochore-MT attachments. Therefore, KNL1 is required for correct Aurora B-mediated kinetochore-MT attachment regulation during mitosis. I provide evidence that the KNL1 N-terminus influences Aurora B activity by mediating the activity of Bub1 kinase, a kinetochore protein required for the spindle assembly checkpoint (SAC). The SAC mediates amplification of an inhibitory signal to prevent mitotic exit until all chromosomes are correctly attached to MTs. Although the SAC is known to be tightly coupled to kinetochore-MT attachment, how such coupling occurs at the kinetochore is a major unanswered question. The finding that KNL1 mediates Aurora B activity through Bub1 establishes KNL1 as a key integrator of multiple signaling pathways at the kinetochore. Finally, I determine the regions of KNL1 required for the accumulation of several kinetochore proteins, providing a broad view and better understanding of kinetochore organization inside the cell. Overall, results from these studies establish KNL1 as a central organizer of kinetochore architecture and function, and demonstrate the direct influence of this scaffolding protein on kinetochore-mediated regulatory processes during mitosis

Surface Energy in Cold Asymmetrical Fermion Superfluids

We derive the energy of the surface between the normal and superfluid components of a mixed phase of a system composed of two particle species with different densities. The surface energy is obtained by the integration of the free energy density in the interface between the two phases. We show that the mixed phase remains as the favored ground state over the gapless phase in weak coupling. We find that the surface energy effects emerge only at strong coupling.Comment: 12 pages, 2 figures, typos corrected, published versio

ATENDIMENTO EM CUIDADOS PALIATIVOS PEDIÁTRICOS: PERSPECTIVAS DOS PROFISSIONAIS DE SAÚDE

ATENDIMENTO EM CUIDADOS PALIATIVOS PEDIÁTRICOS: PERSPECTIVAS DOS PROFISSIONAIS DE SAÚDE Filipa da Conceição Rego1, Sara Filipa Rodrigues1, Vânia Sofia Teixeira1, José Carlos Caldas2 1Curso de Mestrado em Psicologia Clínica e da Saúde, ISCS-N; 2Departamento de Psicologia, ISCS-N / UnIPSa / CICS Instituto Superior de Ciências da Saúde – Norte; Unidade de Investigação em Psicologia e Saúde; Centro de Investigação em Ciências da Saúde Introdução Os cuidados paliativos, segundo a OMS (2002) têm como objectivo proporcionar ao paciente é a sua família uma melhor qualidade de vida. De acordo com Twycross (2003) este tipo de cuidados estão pensados para os pacientes em processo de fim de vida. Reflectir sobre os cuidados paliativos pediátricos remete-nos para a possibilidade de que a morte não somente se relaciona com a velhice mas que esta poderá ocorrer em qualquer idade. Prestar cuidados paliativos pediátricos direcciona-se não só para as crianças em risco de vida, mas também para as famílias. O objectivo deste tipo de cuidados mantém-se mesmo quando se direccionam para crianças, pretendendo-se satisfazer necessidades de ordem física, emocional, psicológica e espiritual, promovendo o bem-estar e qualidade de vida (Himelstein, Hilden, Boldt & Weissman, 2004). Objectivos e Material e Métodos Com o objectivo de explorar e comparar as perspectivas de diferentes profissionais de saúde relativamente aos cuidados paliativos pediátricos reuniu-se uma amostra de Médicos, Enfermeiros, Directores Clínicos, Directores de Serviço e Psicólogos (n=66), das seguintes instituições: Hospital de S. João E.P.E.; Centro Hospitalar do Porto; Centro Hospitalar da Póvoa do Varzim/ Vila do Conde e Instituto Português de Oncologia do Porto, aos quais foi aplicada uma tradução adaptada do questionário ISAT – Institucional Self – Assessment Tool: Unit Form (Levetown, Dokken, Heller, et al. For The Initiative for Pediatric Palliative Care - IPPC). Discussão Os resultados obtidos revelaram comunalidades de perspectivas entre profissionais, mas também diferenças estatisticamente significativas (teste χ2, p<= 0,05), entre os três grupos por nós estudados: Médicos (M); Enfermeiros (E) e Directores de Serviço, Directores Clínicos e Psicólogos (D), quanto às frequências das respostas dadas a algumas das questões colocadas. Perante os resultados obtidos é possível perceber a perspectiva dos profissionais em geral e as diferenças de perspectiva entre grupos profissionais, tendo em conta as funções principais desempenhadas. Conclusões Concluímos, então que os cuidados paliativos pediátricos, apesar de ainda não serem uma realidade no nosso sistema nacional de saúde, representam uma temática que se revela presente entre os profissionais de saúde. Estes esboçam uma perspectiva que nos remete para a necessidade de promover à criança/família a melhor qualidade de vida possível, independentemente dos meios disponíveis, mas também mostram diferir em alguns aspectos da forma de levar à prática este desiderato. Apresentador: Filipa da Conceição Rego, Curso de Mestrado em Psicologia Clínica e da Saúde do Instituto Superior de Ciências da Saúde – Norte

Quantum normal-to-inhomogeneous superconductor phase transition in nearly two-dimensional metals

In multi-band systems, electrons from different orbitals coexist at the Fermi surface. An attractive interaction among these quasi-particles gives rise to inter-band or hybrid pairs which eventually condense in a superconducting state. These quasi-particles have a natural mismatch of their Fermi wave-vectors, $\delta k_F$, which depends on the strength of the hybridization between their orbitals. The existence of this natural scale suggests the possibility of inhomogeneous superconducting ground states in these systems, even in the absence of an applied magnetic field. Furthermore, since hybridization $V$ depends on pressure, this provides an external parameter to control the wave-vectors mismatch at the Fermi surface. In this work, we study the phase diagram of a two-dimensional, two-band metal with inter-band pairing. We show that as the mismatch between the Fermi wave-vectors of the two hybrid bands is reduced, the system presents a normal-to-inhomogeneous superconductor quantum phase transition at a critical value of the hybridization $V_c=\Delta_0$. The superconducting ground state for $V<V_c$ is characterized by a wave-vector with magnitude $|\mathbf{q}_c|=q_c=2 \Delta_0/\bar{v}_f$. Here $\Delta_0$ is the superconducting gap in the homogeneous state and $\bar{v}_f$ the average Fermi velocity. We discuss the nature of the quantum critical point (QCP) at $V_c$ and obtain the associated quantum critical exponents.Comment: 6 pages, 4 figure

Finite Temperature Phase Diagram of Quasi-Two-Dimensional Imbalanced Fermi Gases Beyond Mean-Field

We investigate the superfluid transition temperature of quasi-two-dimensional imbalanced Fermi gases beyond the mean-field approximation, through the second-order (or induced) interaction effects. For a balanced Fermi system the transition temperature is suppressed by a factor $\approx 2.72$. For imbalanced Fermi systems, the polarization and transition temperature of the tricritical point are significantly reduced as the two-body binding energy $|\epsilon_B|$ increases.Comment: 6 pages, 3 figure

Asymmetric Fermion Superfluid with Inter- and Intra-Species Pairings

We investigate the phase structure of an asymmetric fermion superfluid with inter- and intra-species pairings. The introduction of the intra-species pairing mechanism in canonical ensemble changes significantly the phase diagram and brings in a new state with coexisting inter- and intra-species pairings. Different from the case with only inter-species pairing, all the fermion excitations are fully gapped in the region with intra-species pairing.Comment: 5 pages, 4 figure

Acute Generalized Exanthematous Pustulosis Associated with Diltiazem

Acute generalized exanthematous pustulosis (AGEP) usually presents with the acute appearance of oedematous and erythematous lesions, on which multiple sterile pustules appear, associated with fever. Almost 90% of cases are associated with drugs, with antibiotics (penicillins and macrolides) being the most frequent causative agents. We describe a 36-year-old female patient, which started diltiazem 120mg/day for hypertension. After 6 days of therapy, multiple erythematous and oedematous lesions appeared, with associated multiple small non-follicular pustules. Oral corticosteroids were started, with progressive and complete improvement. Patch-tests were performed, which revealed positivity for diltiazem. Although a rare entity, AGEP must be considered in cases of acute eruptions with disseminated pustules and fever. The use of patch tests in this disease may be useful as positive reactions are frequent

Functional genomics approaches to improve pre-clinical drug screening and biomarker discovery.

Funder: European Society for Medical Oncology (ESMO); Id: http://dx.doi.org/10.13039/501100007075Funder: American Society of Clinical Oncology (ASCO); Id: http://dx.doi.org/10.13039/100006293Advances in sequencing technology have enabled the genomic and transcriptomic characterization of human malignancies with unprecedented detail. However, this wealth of information has been slow to translate into clinically meaningful outcomes. Different models to study human cancers have been established and extensively characterized. Using these models, functional genomic screens and pre-clinical drug screening platforms have identified genetic dependencies that can be exploited with drug therapy. These genetic dependencies can also be used as biomarkers to predict response to treatment. For many cancers, the identification of such biomarkers remains elusive. In this review, we discuss the development and characterization of models used to study human cancers, RNA interference and CRISPR screens to identify genetic dependencies, large-scale pharmacogenomics studies and drug screening approaches to improve pre-clinical drug screening and biomarker discovery