Behavioral and cardiopulmonary effects of dexmedetomidine alone and in combination with butorphanol, methadone, morphine or tramadol in conscious sheep

Objective: To compare cardiopulmonary and sedative effects following administration of dexmedetomidine alone or with butorphanol, methadone, morphine or tramadol in healthy sheep. Study design: Randomized crossover study. Animals: Six Santa Inês sheep, five females, one male, aged 12–28 months and weighing 40.1 ± 6.2 kg. Methods: Sheep were assigned treatments of dexmedetomidine (0.005 mg kg−1; D); D and butorphanol (0.15 mg kg−1; DB); D and methadone (0.5 mg kg−1; DM); D and morphine (0.5 mg kg−1; DMO); or D and tramadol (5.0 mg kg−1; DT). All drugs were administered intravenously with at least 7 days between each treatment. Rectal temperature, heart rate (HR), respiratory rate (fR), invasive arterial pressure, blood gases and electrolytes were measured prior to administration of drugs (baseline, T0) and every 15 minutes following drug administration for 120 minutes (T15–T120). Sedation was scored by three observers blinded to treatment. Results: HR decreased in all treatments and fR decreased in DM at T30 and DMO at T30 and T45. PaCO2 was increased in D, DB and DM compared with baseline, and PaO2 decreased in D at T15 and T45; in DB at T15 to T75; in DM at T15 to T60; in DMO at T15; and in DT at T15, T30 and T75. There was a decrease in temperature in D, DB and DM. An increased pH was measured in D at all time points and in DT at T30–T120. inline image and base excess were increased in all treatments compared with baseline. There were no statistical differences in sedation scores. Conclusions and clinical relevance: The combination of dexmedetomidine with butorphanol, methadone, morphine or tramadol resulted in similar changes in cardiopulmonary function and did not improve sedation when compared with dexmedetomidine alone

Análise das competências necessárias aos membros do colegiado pleno do Programa de Pós-graduação em Administração universitária da UFSC para a realização das ações previstas em seu planejamento estratégico

This study aims to identify the necessary competences of the members of the Collegiate of the Program in University Administration at UFSC to carry out the actions foreseen in its strategic planning. The work is justified by the need to deepen studies on Management by Competencies in the field of universities, seeking to advance discussions on the subject and develop new implications with regard to the necessary competencies of collegiate members in graduate programs. We sought to identify the actions foreseen in the strategic planning of the PPGAU/UFSC; define the competencies foreseen in the Program's strategic planning; map the competences of the members of its Full Collegiate and suggest referral actions for managers and members involved in strategic actions. As for the methodology, it is a research with a qualitative approach, a case study, with bibliographical and documental research, being used interviews and content analysis. The survey results show a considerable amount of skills that were identified and validated by the interviewees and by the PPGAU/UFSC Coordination, which indicates the thoroughness of public service actions and the selection of the most suitable individuals to perform the actions that culminate in the objectives of strategic planning. The conclusions suggest that competency management is a fundamental requirement for achieving excellence within university institutions and that scientific contributions are indispensable for academic managers to expand the range of tools available for professional practice in the daily routine of university management.Este estudo objetiva identificar as competências necessárias dos membros do Colegiado Pleno do Programa de Pós-Graduação em Administração Universitária da UFSC para a realização das ações previstas em seu planejamento estratégico. O trabalho se justifica pela necessidade de aprofundamento dos estudos sobre Gestão por Competências no campo das universidades, ao buscar avançar nas discussões sobre o tema e desenvolver novas implicações no que diz respeito às competências necessárias de membros de colegiado em programas de pós-graduação. Buscou-se identificar as ações previstas no planejamento estratégico do PPGAU/UFSC; definir as competências previstas no planejamento estratégico do Programa; mapear as competências dos membros de seu Colegiado Pleno e sugerir ações de encaminhamento para os gestores e membros envolvidos nas ações estratégicas. Quanto à metodologia, trata-se de uma pesquisa de abordagem qualitativa, estudo de caso, com pesquisas bibliográfica e documental, sendo utilizadas entrevista e análise de conteúdo. Os resultados da pesquisa evidenciam uma quantidade considerável de competências que foram apontadas e validadas pelos entrevistados e pela Coordenação do PPGAU/UFSC, o que indica a minuciosidade das ações do serviço público e a seleção dos indivíduos mais adequados para executar as ações que culminam nos objetivos do planejamento estratégico. As conclusões sugerem a gestão por competências como requisito fundamental para o atingimento da excelência no âmbito das instituições universitárias e que contribuições científicas são indispensáveis aos gestores acadêmicos para ampliar o leque de ferramentas disponíveis para o exercício profissionalizado no cotidiano da gestão universitária

March1-dependent modulation of donor MHC II on CD103+ dendritic cells mitigates alloimmunity.

In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs

Generation of glucocorticoid-producing cells derived from human pluripotent stem cells.

Adrenal insufficiency is a life-threatening condition resulting from the inability to produce adrenal hormones in a dose- and time-dependent manner. Establishing a cell-based therapy would provide a physiologically responsive approach for the treatment of this condition. We report the generation of large numbers of human-induced steroidogenic cells (hiSCs) from human pluripotent stem cells (hPSCs). Directed differentiation of hPSCs into hiSCs recapitulates the initial stages of human adrenal development. Following expression of steroidogenic factor 1, activation of protein kinase A signaling drives a steroidogenic gene expression profile most comparable to human fetal adrenal cells, and leads to dynamic secretion of steroid hormones, in vitro. Moreover, expression of the adrenocorticotrophic hormone (ACTH) receptor/co-receptor (MC2R/MRAP) results in dose-dependent ACTH responsiveness. This protocol recapitulates adrenal insufficiency resulting from loss-of-function mutations in AAAS, which cause the enigmatic triple A syndrome. Our differentiation protocol generates sufficient numbers of hiSCs for cell-based therapy and offers a platform to study disorders causing adrenal insufficiency

Black hole thermodynamical entropy

As early as 1902, Gibbs pointed out that systems whose partition function diverges, e.g. gravitation, lie outside the validity of the Boltzmann-Gibbs (BG) theory. Consistently, since the pioneering Bekenstein-Hawking results, physically meaningful evidence (e.g., the holographic principle) has accumulated that the BG entropy $S_{BG}$ of a $(3+1)$ black hole is proportional to its area $L^2$ ($L$ being a characteristic linear length), and not to its volume $L^3$. Similarly it exists the \emph{area law}, so named because, for a wide class of strongly quantum-entangled $d$-dimensional systems, $S_{BG}$ is proportional to $\ln L$ if $d=1$, and to $L^{d-1}$ if $d>1$, instead of being proportional to $L^d$ ($d \ge 1$). These results violate the extensivity of the thermodynamical entropy of a $d$-dimensional system. This thermodynamical inconsistency disappears if we realize that the thermodynamical entropy of such nonstandard systems is \emph{not} to be identified with the BG {\it additive} entropy but with appropriately generalized {\it nonadditive} entropies. Indeed, the celebrated usefulness of the BG entropy is founded on hypothesis such as relatively weak probabilistic correlations (and their connections to ergodicity, which by no means can be assumed as a general rule of nature). Here we introduce a generalized entropy which, for the Schwarzschild black hole and the area law, can solve the thermodynamic puzzle.Comment: 7 pages, 2 figures. Accepted for publication in EPJ

Detection of Carbon Monoxide in the Atmosphere of WASP-39b Applying Standard Cross-Correlation Techniques to JWST NIRSpec G395H Data

Carbon monoxide was recently reported in the atmosphere of the hot Jupiter WASP-39b using the NIRSpec PRISM transit observation of this planet, collected as part of the JWST Transiting Exoplanet Community Early Release Science (JTEC ERS) Program. This detection, however, could not be confidently confirmed in the initial analysis of the higher resolution observations with NIRSpec G395H disperser. Here we confirm the detection of CO in the atmosphere of WASP-39b using the NIRSpec G395H data and cross-correlation techniques. We do this by searching for the CO signal in the unbinned transmission spectrum of the planet between 4.6 and 5.0 $\mu$m, where the contribution of CO is expected to be higher than that of other anticipated molecules in the planet's atmosphere. Our search results in a detection of CO with a cross-correlation function (CCF) significance of $6.6 \sigma$ when using a template with only ${\rm ^{12}C^{16}O}$ lines. The CCF significance of the CO signal increases to $7.5 \sigma$ when including in the template lines from additional CO isotopologues, with the largest contribution being from ${\rm ^{13}C^{16}O}$. Our results highlight how cross-correlation techniques can be a powerful tool for unveiling the chemical composition of exoplanetary atmospheres from medium-resolution transmission spectra, including the detection of isotopologues.Comment: Accepted for publication in The Astrophysical Journal Letter

Wild-Type Phosphoribosylpyrophosphate Synthase (PRS) from Mycobacterium tuberculosis: A Bacterial Class II PRS?

The 5-phospho-α-D-ribose 1-diphosphate (PRPP) metabolite plays essential roles in several biosynthetic pathways, including histidine, tryptophan, nucleotides, and, in mycobacteria, cell wall precursors. PRPP is synthesized from α-D-ribose 5-phosphate (R5P) and ATP by the Mycobacterium tuberculosis prsA gene product, phosphoribosylpyrophosphate synthase (MtPRS). Here, we report amplification, cloning, expression and purification of wild-type MtPRS. Glutaraldehyde cross-linking results suggest that MtPRS predominates as a hexamer, presenting varied oligomeric states due to distinct ligand binding. MtPRS activity measurements were carried out by a novel coupled continuous spectrophotometric assay. MtPRS enzyme activity could be detected in the absence of Pi. ADP, GDP and UMP inhibit MtPRS activity. Steady-state kinetics results indicate that MtPRS has broad substrate specificity, being able to accept ATP, GTP, CTP, and UTP as diphosphoryl group donors. Fluorescence spectroscopy data suggest that the enzyme mechanism for purine diphosphoryl donors follows a random order of substrate addition, and for pyrimidine diphosphoryl donors follows an ordered mechanism of substrate addition in which R5P binds first to free enzyme. An ordered mechanism for product dissociation is followed by MtPRS, in which PRPP is the first product to be released followed by the nucleoside monophosphate products to yield free enzyme for the next round of catalysis. The broad specificity for diphosphoryl group donors and detection of enzyme activity in the absence of Pi would suggest that MtPRS belongs to Class II PRS proteins. On the other hand, the hexameric quaternary structure and allosteric ADP inhibition would place MtPRS in Class I PRSs. Further data are needed to classify MtPRS as belonging to a particular family of PRS proteins. The data here presented should help augment our understanding of MtPRS mode of action. Current efforts are toward experimental structure determination of MtPRS to provide a solid foundation for the rational design of specific inhibitors of this enzyme