Role of the anterior temporal lobes in semantic representations: paradoxical results of a cTBS study

According to the 'Semantic Hub' model, which was developed from data gathered in the moderate to advanced stages of semantic dementia (SD), a unitary amodal mechanism, located in the anterior parts of both temporal lobes (ATLs), should support the interactive activation of semantic representations in all modalities and for all semantic categories. This model has been challenged by clinical findings, which show that in the early stages of SD, when important asymmetries can be observed at the level of the right and left ATLs, the semantic impairment can be modality-specific, mainly affecting lexical-semantic knowledge when the left temporal lobe is more atrophic and pictorial representations when atrophy prevails on the right side. On the other hand, findings of experiments conducted in normal subjects with repetitive transcranial magnetic stimulations (rTMS), support the unitary model. In the most compelling of these studies, rTMS was used to investigate the role of right and left ATLs directly, by comparing semantic processing of the same concepts, presented as written words or pictures. The efficiency of semantic processing for words and pictures was reduced to the same degree by rTMS applied to the left and right ATLs. However, to consider more in depth some methodological inconsistencies of these studies and with the aim of discussing the effects of rTMS on high-level cognitive functions, we decided to repeat that experimental paradigm, using the continuous theta burst stimulation (cTBS) protocol over the right ATL, left ATL and vertex (as control site). A significant interaction was found between side of cTBS application and type of stimulus, but, contrary to our predictions, we observed significantly faster (rather than slower) responses to pictures after application of cTBS to the right ATL and no difference between responses to written words after application of cTBS to the left ATL in comparison with the vertex. These unexpected results are discussed with respect to the nature of the semantic representations supported by the right and left ATLs and to re-appraisal of the 'virtual lesion' account to explain results obtained with rTMS experiments on high-level cognitive functions

Redox-dependent dimerization of p38 alpha mitogen-activated protein kinase with mitogen-activated protein kinase kinase 3

The kinase p38α MAPK (p38α) plays a pivotal role in many biological processes. p38α is activated by canonical upstream kinases that phosphorylate the activation region. The purpose of our study was to determine whether such activation may depend on redox-sensing cysteines within p38α. p38α was activated and formed a disulfide-bound heterodimer with MAP2K3 (MKK3) in rat cardiomyocytes and isolated hearts exposed to H2O2 This disulfide heterodimer was sensitive to reduction by mercaptoethanol and was enhanced by the thioredoxin-reductase inhibitor auranofin. We predicted that Cys-119 or Cys-162 of p38α, close to the known MKK3 docking domain, were relevant for these redox characteristics. The C119S mutation decreased whereas the C162S mutation increased the dimer formation, suggesting that these two Cys residues act as vicinal thiols, consistent with C119S/C162S being incapable of sensing H2O2 Similarly, disulfide heterodimer formation was abolished in H9C2 cells expressing both MKK3 and p38α C119S/C162S and subjected to simulated ischemia and reperfusion. However, the p38α C119S/C162S mutants did not exhibit appreciable alteration in activating dual phosphorylation. In contrast, the anti-inflammatory agent 10-nitro-oleic acid (NO2-OA), a component of the Mediterranean diet, reduced p38α activation and covalently modified Cys-119/Cys-162, probably obstructing MKK3 access. Moreover, NO2-OA reduced the dephosphorylation of p38α by hematopoietic tyrosine phosphatase (HePTP). Furthermore, steric obstruction of Cys-119/Cys-162 by NO2-OA pretreatment in Langendorff-perfused murine hearts prevented the p38-MKK3 disulfide dimer formation and attenuated H2O2-induced contractile dysfunction. Our findings suggest that cysteine residues within p38α act as redox sensors that can dynamically regulate the association between p38 and MKK3.</p

Ética médica e bioética no atendimento de adolescentes em ginecologia e obstetrícia / Medical and bioethical ethics in the service of adolescents in gynecology and obstetrics

Introdução: A sexualidade na adolescência tem impulso fortemente marcado pelas transformações biopsicossociais, ou seja, há nessa fase da vida, inúmeras descobertas e conflitos que podem denotar risco e vulnerabilidade na vida do adolescente. Os riscos são as possibilidades de ocorrência de danos ou agravamentos, como, por exemplo, os casos de infecção pelo HIV e outras DSTs, o início pecoce de atividade sexual, a gravidez não planejada, sem qualquer orientação médica ou familiar, os abortos inseguros, a morbidade materna e os casos de violência sexual. Método: Foram incluídos como referências artigos indexados em português e inglês, disponíveis nos portais de periódicos Scielo, Google Acadêmico e Pubmed, publicados a partir de 2000. Foram localizados 57 artigos a partir dos descritores relacionados:a)”relação médico-paciente+adolescência”; b)”ética médica+atendimento GO”; c)”sigilo+atendimento adolescentes”; d)bioética+atendimento adolescentes”; e)” anticoncepção+ adolescência”; f) “conflitos éticos+ atendimento GO”; g)”relação médico paciente+GO+adolescente”; h)”bioética+DST+adolescente”; i) “bioética+aborto+adolescente”. Resultados: Frente ao elevado número de indivíduos que se encontram na fase de adolescência e aliado à crescente demanda dessa mesma população por serviços de saúde, em especial sobre os direitos sexuais e reprodutivos, visto que a cada dia iniciam as atividades sexuais mais precocemente, o presente estudo justifica-se pela necessidade de se promover a discussão sobre o tema junto aos estudantes e profissionais de saúde, fomentando a ampliação de estudos dessa temática dentro e fora das instituições de ensino e saúde. Conclusões: Os conflitos apontados são rotineiros e graves. No atendimento à saúde dos adolescentes, os profissionais devem: contextualizar seus pacientes; avaliar, na ocasião, as competências dos mesmos; consultar o Ministério Público e as Sociedades Legais; compartilhar e discutir o caso em equipe para que haja maior proteção dessa população adolescente e mais segurança por parte de quem atende. A reflexão bioética, baseada na multidisciplinaridade e no respeito ao pluralismo moral social, ao questionar parâmetros secularmente estagnados, muito pode ajudar no âmbito da saúde do adolescente, e, junto a este último, ir a cada momento e em cada caso estabelecendo novos referenciais éticos, através do abandono de regulamentações imperiosas e cristalizadas.

A unified approach for a posteriori high-order curved mesh generation using solid mechanics

The paper presents a unified approach for the a posteriori generation of arbitrary high-order curvilinear meshes via a solid mechanics analogy. The approach encompasses a variety of methodologies, ranging from the popular incremental linear elastic approach to very sophisticated non-linear elasticity. In addition, an intermediate consistent incrementally linearised approach is also presented and applied for the first time in this context. Utilising a consistent derivation from energy principles, a theoretical comparison of the various approaches is presented which enables a detailed discussion regarding the material characterisation (calibration) employed for the different solid mechanics formulations. Five independent quality measures are proposed and their relations with existing quality indicators, used in the context of a posteriori mesh generation, are discussed. Finally, a comprehensive range of numerical examples, both in two and three dimensions, including challenging geometries of interest to the solids, fluids and electromagnetics communities, are shown in order to illustrate and thoroughly compare the performance of the different methodologies. This comparison considers the influence of material parameters and number of load increments on the quality of the generated high-order mesh, overall computational cost and, crucially, the approximation properties of the resulting mesh when considering an isoparametric finite element formulation

Evolution and Survival on Eutherian Sex Chromosomes

Since the two eutherian sex chromosomes diverged from an ancestral autosomal pair, the X has remained relatively gene-rich, while the Y has lost most of its genes through the accumulation of deleterious mutations in nonrecombining regions. Presently, it is unclear what is distinctive about genes that remain on the Y chromosome, when the sex chromosomes acquired their unique evolutionary rates, and whether X-Y gene divergence paralleled that of paralogs located on autosomes. To tackle these questions, here we juxtaposed the evolution of X and Y homologous genes (gametologs) in eutherian mammals with their autosomal orthologs in marsupial and monotreme mammals. We discovered that genes on the X and Y acquired distinct evolutionary rates immediately following the suppression of recombination between the two sex chromosomes. The Y-linked genes evolved at higher rates, while the X-linked genes maintained the lower evolutionary rates of the ancestral autosomal genes. These distinct rates have been maintained throughout the evolution of X and Y. Specifically, in humans, most X gametologs and, curiously, also most Y gametologs evolved under stronger purifying selection than similarly aged autosomal paralogs. Finally, after evaluating the current experimental data from the literature, we concluded that unique mRNA/protein expression patterns and functions acquired by Y (versus X) gametologs likely contributed to their retention. Our results also suggest that either the boundary between sex chromosome strata 3 and 4 should be shifted or that stratum 3 should be divided into two strata

CD98 Increases Renal Epithelial Cell Proliferation by Activating MAPKs

CD98 heavy chain (CD98hc) is a multifunctional transmembrane spanning scaffolding protein whose extracellular domain binds with light chain amino acid transporters (Lats) to form the heterodimeric amino acid transporters (HATs). It also interacts with β1 and β3 integrins by its transmembrane and cytoplasmic domains. This interaction is proposed to be the mechanism whereby CD98 mediates cell survival and growth via currently undefined signaling pathways. In this study, we determined whether the critical function of CD98-dependent amino acid transport also plays a role in cell proliferation and defined the signaling pathways that mediate CD98-dependent proliferation of murine renal inner medullary collecting duct (IMCD) cells. We demonstrate that downregulating CD98hc expression resulted in IMCD cell death. Utilizing overexpression studies of CD98hc mutants that either lacked a cytoplasmic tail or were unable to bind to Lats we showed that CD98 increases serum-dependent cell proliferation by a mechanism that requires the CD98hc cytoplasmic tail. We further demonstrated that CD98-dependent amino acid transport increased renal tubular epithelial cell proliferation by a mechanism that does not require the CD98hc cytoplasmic tail. Both these mechanisms of increased renal tubular epithelial cell proliferation are mediated by Erk and p38 MAPK signaling. Although increased amino transport markedly activated mTor signaling, this pathway did not alter cell proliferation. Thus, these studies demonstrate that in IMCD cells, the cytoplasmic and extracellular domains of CD98hc regulate cell proliferation by distinct mechanisms that are mediated by common MAPK signaling pathways

Updated measurement of time-dependent CP -violating observables in Bs0→J/ψ^K+^K- decays

The decay-time-dependent $CP$ asymmetry in $B^{0}_{s}\to J/\psi K^{+} K^{-}$ decays is measured using proton-proton collision data, corresponding to an integrated luminosity of $1.9\,\mathrm{fb^{-1}}$, collected with the LHCb detector at a centre-of-mass energy of $13\,\mathrm{TeV}$ in 2015 and 2016. Using a sample of approximately 117\,000 signal decays with an invariant $K^{+} K^{-}$ mass in the vicinity of the $\phi(1020)$ resonance, the $CP$-violating phase $\phi_s$ is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the $B^{0}_{s}$-$\bar{B}^{0}_{s}$ system, $\Delta\Gamma_s$. The difference of the average $B^{0}_{s}$ and $B^{0}$ meson decay widths, $\Gamma_s-\Gamma_d$, is determined using in addition a sample of $B^{0} \to J/\psi K^{+} \pi^{-}$ decays. The values obtained are $\phi_s = -0.083\pm0.041\pm0.006\,\mathrm{rad}$, $\Delta\Gamma_s = 0.077 \pm 0.008 \pm 0.003\, \mathrm{ps^{-1}}$ and $\Gamma_s-\Gamma_d = -0.0041 \pm 0.0024 \pm 0.0015\,\mathrm{ps^{-1}}$, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements of these quantities to date and are consistent with expectations based on the Standard Model and with a previous LHCb analysis of this decay using data recorded at centre-of-mass energies 7 and 8 TeV. Finally, the results are combined with recent results from $B^{0}_{s}\to J/\psi \pi^{+} \pi^{-}$ decays obtained using the same dataset as this analysis, and with previous independent LHCb results

Observation of the Λb0→χc1 (3872) pK⁻ decay

Using proton-proton collision data, collected with the LHCb detector and corresponding to 1.0, 2.0 and 1.9fb$^{-1}$ of integrated luminosity at the centre-of-mass energies of 7, 8, and 13 TeV, respectively, the decay $\Lambda_b^0\to \chi_{c1}(3872)pK^-$ with $\chi_{c1}\to J/\psi\pi^+\pi^-$ is observed for the first time. The significance of the observed signal is in excess of seven standard deviations. It is found that $(58\pm15)\%$ of the decays proceed via the two-body intermediate state $\chi_{c1}(3872)\Lambda(1520)$. The~branching fraction with respect to that of the $\Lambda_b\rightarrow\psi(2S)p K^{-}$ decay mode, where the $\psi(2S)$~meson is reconstructed in the $J/\psi \pi^+\pi^-$ final state, is measured to be: \begin{equation*} \frac{\Lambda_b^0\to\chi_{c1}(3872)pK^-}{\Lambda_b\to\psi(2S)p K^-} \times \frac{\mathcal{B}(\chi_{c1} \to J/\psi \pi^+\pi^-)}{\mathcal{B}(\psi(2S)\to J/\psi \pi^+\pi^-)} = \left(5.4 \pm 1.1 \pm 0.2\right)\times 10^{-2}\,, \end{equation*} where the first uncertainty is statistical and the second is systematic