Mitochondrial Retrograde Signaling: Triggers, Pathways, and Outcomes

Mitochondria are essential organelles for eukaryotic homeostasis. Although these organelles possess their own DNA, the vast majority (>99%) of mitochondrial proteins are encoded in the nucleus. This situation makes systems that allow the communication between mitochondria and the nucleus a requirement not only to coordinate mitochondrial protein synthesis during biogenesis but also to communicate eventual mitochondrial malfunctions, triggering compensatory responses in the nucleus. Mitochondria-to-nucleus retrograde signaling has been described in various organisms, albeit with differences in effector pathways, molecules, and outcomes, as discussed in this review

BIOÉTICA E ATENÇÃO BÁSICA: UM ESTUDO EXPLORATÓRIO DOS PROBLEMAS ÉTICOS VIVIDOS POR ENFERMEIROS E MÉDICOS NO PSF

Investigación cuantitativa, exploratoria para identificar y verificar la frecuencia de problemas éticos vividos en el Programa Salud de la Familia. Para recoger los datos se utilizó cuestionario autoaplicado, con situaciones generadoras de problemas éticos y escala de cuatro puntos para frecuencia. Trato irrespetuoso del usuario; problemas relacionados a información para usuarios y familias, preservación de privacidad y confidencialidad aparecieron en la mayoría de los cuestionarios, sin embargo con frecuencias distintas. Los resultados plantean para la bioética en atención básica situaciones cotidianas y no dilemas de gran apelo dramático. Esto puede resultar en la no percepción de los problemas. Hace falta capacitar los profesionales para comunicación y acogimiento con vistas a instituir una actitud ética basada en ciudadanía, solidariedad y humanismo.Quantitative exploratory study on ethical problems in primary care. The objectives were to identify and check the frequency of ethical problems experienced by nurses and physicians at the Family Health Program. Data collection used a self- applied questionnaire with ethical problems’ generating situations and a four-point scale for occurrence frequency. Professional disrespect to the patient, problems concerning information to patients and families and those related to privacy and confidentiality appeared in all questionnaires, in different degrees. Results show that ethical problems in primary care deal with typical situations in daily care and not dramatic ones. This reinforces the core role of communication and healing skills in primary care professional practice to foster an ethical attitude based on citizenship, solidarity and humanity.Estudo quantitativo exploratório para identificar e verificar a freqüência dos problemas éticos vividos por enfermeiros e médicos no PSF. Coleta de dados com questionário auto-aplicado, contendo situações geradoras de problemas éticos e escala de quatro pontos para a freqüência. Desrespeito do profissional para com o usuário; problemas relacionados às informações para usuários e famílias e à preservação da privacidade e confidencialidade apareceram na maioria dos questionários, embora com freqüências diferentes. Os resultados indicam que a bioética na atenção básica lida com situações do cotidiano e não com dilemas de maior apelo dramático. A sutileza desse panorama pode levar a não percepção dos problemas, reforçando a necessidade de capacitação dos profissionais em comunicação e acolhimento, para instituir uma atitude ética baseada na cidadania, solidariedade e humanismo

Nature of the band gap of In2O3 revealed by first-principles calculations and x-ray spectroscopy

Bulk and surface sensitive x-ray spectroscopic techniques are applied in tandem to show that the valence band edge for In2O3 is found significantly closer to the bottom of the conduction band than expected on the basis of the widely quoted bulk band gap of 3.75 eV. First-principles theory shows that the upper valence bands of In2O3 exhibit a small dispersion and the conduction band minimum is positioned at Gamma. However, direct optical transitions give a minimal dipole intensity until 0.8 eV below the valence band maximum. The results set an upper limit on the fundamental band gap of 2.9 eV

Electronic structure of In₂O₃ and Sn-doped In₂O₃ by hard x-ray photoemission spectroscopy

The valence and core levels of In₂O₃ and Sn-doped In₂O₃ have been studied by hard x-ray photoemission spectroscopy (hν=6000 eV) and by conventional Al Kα (hν=1486.6 eV) x-ray photoemission spectroscopy. The experimental spectra are compared with density-functional theory calculations. It is shown that structure deriving from electronic levels with significant In or Sn 5s character is selectively enhanced under 6000 eV excitation. This allows us to infer that conduction band states in Sn-doped samples and states at the bottom of the valence band both contain a pronounced In 5s contribution. The In 3d core line measured at hν=1486.6 eV for both undoped and Sn-doped In₂O₃ display an asymmetric lineshape, and may be fitted with two components associated with screened and unscreened final states. The In 3d core line spectra excited at hν=6000 eV for the Sn-doped samples display pronounced shoulders and demand a fit with two components. The In 3d core line spectrum for the undoped sample can also be fitted with two components, although the relative intensity of the component associated with the screened final state is low, compared to excitation at 1486.6 eV. These results are consistent with a high concentration of carriers confined close to the surface of nominally undoped In₂O₃. This conclusion is in accord with the fact that a conduction band feature observed for undoped In₂O₃ in Al Kα x-ray photoemission is much weaker than expected in hard x-ray photoemission

Avaliação comparativa das regulamentações, diretrizes e normas para a criação das fontes de informação oficiais sobre medicamentos (bulas) para profissionais de saúde disponibilizadas no Brasil, Europa e Estados Unidos / Comparative evaluation of regulations, guidelines and standards for the creation of official medical information sources (medicine leaflet) for health professional available in Brazil, Europe and United States

A bula é um documento técnico-científico que fornece informações sobre medicamentos e é regulada por diferentes legislações ao redor do mundo, criadas por órgãos do governo, os quais determinam os itens necessários que estes escritos devem conter, a fim de sanar as dúvidas de profissionais de saúde e/ou pacientes, reduzindo, dessa forma, o uso inadequado dos medicamentos. As informações contidas nestes escritos evoluíram ao longo dos anos, porém ainda existem limitações ao seu uso, como ausência de atualização continuada e a omissão ou falta de completude de informações relevantes. Esses fatores podem levar a descrença e ao desuso dessa importante fonte de informação aos profissionais de saúde. Dessa forma, é fundamental a avaliação constante das bulas de medicamentos, podendo ser realizado comparações com as legislações de outros países, da Europa e Estados Unidos, a fim de constatar lacunas entre as diferentes regulações. Sendo assim, o objetivo deste trabalho foi avaliar comparativamente as regulamentações, diretrizes e normas para criação de bulas de medicamentos para profissionais de saúde disponíveis no Brasil, Europa e Estados Unidos, analisando, dessa forma, criticamente as legislações. Para isso, foi realizada uma busca e avaliação criteriosa das legislações e orientações fornecidas pelas respectivas agências reguladoras, ANVISA, EMA e FDA e foi observado que a legislação brasileira ainda é vaga no que tange a completude das bulas de medicamentos, apresentando desfalques em relação ao descarte correto de medicamentos, as orientações ao paciente, bem como aos avisos de alerta, quando comparada as legislações europeias e americanas. Logo, percebe-se que a padronização internacional dos requisitos de informação pode garantir o fornecimento de informações relevantes a profissionais de diferentes países, reduzindo erros e melhorando a prática clínica de diferentes profissionais de saúde.

Sarcolemma-localized nNOS is required to maintain activity after mild exercise

Many neuromuscular conditions are characterized by an exaggerated exercise- induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients(1), and some patients experience severe fatigue without any demonstrable somatic disease(2). Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown(2). With no treatment available, this form of inactivity is a major determinant of disability(3). Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase ( nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS- null mice do not have muscle pathology and have no loss of muscle- specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction- induced signalling from sarcolemma- localized nNOS, which decreases cGMP- mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise- induced signalling.Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant ; University of Iowa Cardiovascular Interdisciplinary Research ; National Research Service Award ; National Institute of Arthritis and Musculoskeletal and Skin Diseases ; National Institutes of Health ; Senator Paul D. Wellstone Fellowship ; Muscular Dystrophy Association Development Grant ; Howard Hughes Medical InstituteWe thank M. Anderson and M. Henry for comments, and M. M. Kilburg, K. Uppal, B. J. Steinmann and S. Watkins and members of the Campbell laboratory for scientific contributions. This work was supported in part by a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant. Y.M.K. was supported by grants from the University of Iowa Cardiovascular Interdisciplinary Research/ National Research Service Award (NRSA) Fellowship, from an individual NRSA Fellowship from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, from the National Institutes of Health (NIH), and from a Senator Paul D. Wellstone Fellowship. E.P.R. was supported by a Muscular Dystrophy Association Development Grant. R.M.W. was supported by the NIH. K.P.C. is an investigator of the Howard Hughes Medical Institute.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62850/1/nature07414.pd

Nature of the Band Gap of In₂O₃ Revealed by First-Principles Calculations and X-Ray Spectroscopy

Bulk and surface sensitive x-ray spectroscopic techniques are applied in tandem to show that the valence band edge for In₂O₃ is found significantly closer to the bottom of the conduction band than expected on the basis of the widely quoted bulk band gap of 3.75 eV. First-principles theory shows that the upper valence bands of In₂O₃ exhibit a small dispersion and the conduction band minimum is positioned at Γ. However, direct optical transitions give a minimal dipole intensity until 0.8 eV below the valence band maximum. The results set an upper limit on the fundamental band gap of 2.9 eV

Technical Design Report - TDR CYGNO-04/INITIUM

The aim of this Technical Design Report is to illustrate the technological choices foreseen to be implemented in the construction of the CYGNO-04 demonstrator, motivate them against the experiment physics goals of CYGNO-30 and demonstrate the financial sustainability of the project. CYGNO-04 represents PHASE 1 of the long term CYGNO roadmap, towards the development of large high precision tracking gaseous Time Projection Chamber (TPC) for directional Dark Matter searches and solar neutrino spectroscopy. The CYGNO project1 peculiarities reside in the optical readout of the light produced during the amplification of the primary ionization electrons in a stack of triple Gas Electron Multipliers (GEMs), thanks to the nice scintillation properties of the chosen He:CF4 gas mixture. To this aim, CYGNO is exploiting the fast progress in commercial scientific Active Pixel Sensors (APS) development for highly performing sCMOS cameras, whose high granularity and sensitivity allow to significantly boost tracking, improve particle identification and lower the energy threshold. The X-Y track project obtained from the reconstruction of the sCMOS images is combined with a PMT measurement to obtain a full 3D track reconstruction. In addition, several synergic R&Ds based on the CYGNO experimental approach are under development in the CYGNO collaboration (see Sec 2) to further enhance the light yield by means of electro luminescence after the amplification stage, to improve the tracking performances by exploiting negative ion drift operation within the INITIUM ERC Consolidator Grant, and to boost the sensitivity to O(GeV) Dark Matter masses by employing hydrogen rich target towards the development of PHASE 2 (see Sec. 1.2). While still under optimization and subject to possible significant improvements, the CYGNO experimental approach performances and capabilities demonstrated so far with prototypes allow to foresee the development of an O(30) m3 experiment by 2026 for a cost of O(10) MEUROs. A CYGNO-30 experiment would be able to give a significant contribution to the search and study of Dark Matter with masses below 10 GeV/c2 for both SI and SD coupling. In case of a Dark Matter observation claim by other experiments, the information provided by a directional detector such as CYGNO would be fundamental to positively confirm the galactic origin of the allegedly detected Dark Matter signal. CYGNO-30 could furthermore provide the first directional measurement of solar neutrinos from the pp chain, possibly extending to lower energies the Borexino measurement2. In order to reach this goal, the CYGNO project is proceeding through a staged approach. The PHASE 0 50 L detector (LIME, recently installed underground LNGS) will validate the full performances of the optical readout via APS commercial cameras and PMTs and the Montecarlo simulation of the expected backgrounds. The full CYGNO-04 demonstrator will be realized with all the technological and material choices foreseen for CYGNO-30, to demonstrate the scalability of the experimental approach and the potentialities of the large PHASE 2 detector to reach the expected physics goals. The first PHASE 1 design anticipated a 1 m3 active volume detector with two back-to-back TPCs with a central cathode and 500 mm drift length. Each 1 m2 readout area would have been composed by 9 + 9 readout modules having the LIME PHASE 0 dimensions and layout. Time (end of INITIUM project by March 2025) and current space availability at underground LNGS (only Hall F) forced the rescaling of the PHASE 1 active volume and design to a 0.4 m3, hence CYGNO-04. CYGNO-04 will keep the back-to-back double TPC layout with 500 mm drift length each, but with an 800 x 500 mm2 readout area covered by a 2 + 2 modules based on LIME design. The reduction of the detector volume has no impact on the technological objectives of PHASE 1, since the modular design with central cathode, detector materials and shieldings and auxiliary systems are independent of the total volume. The physics reach (which is a byproduct of PHASE 1 and NOT an explicit goal) will be only very partially reduced (less than a factor 2 overall) since a smaller detector volume implies also a reduced background from internal materials radioactivity. In addition, the cost reduction of CYGNO-04 of about 1⁄3 with respect to CYGNO-1 illustrated in the CDR effectively makes the overall project more financially sustainable (see CBS in the last section). In summary this document will explain: the physical motivation of the CYGNO project and the technical motivations of the downscale of the PHASE 1 to CYGNO-04, 400 liters of active volume, with respect to the demonstrator presented in the CDR; the results of R&D and the Montecarlo expectations for PHASE 0; the technical choices, procedures and the executive drawings of CYGNO-04 in the Hall F of the LNGS; safety evaluations and the interference/request to the LNGS services; Project management, WBS/WBC, WP, GANTT, ec

LIME -- a gas TPC prototype for directional Dark Matter search for the CYGNO experiment

The CYGNO experiment aims at the development of a large gaseous TPC with GEM-based amplification and an optical readout by means of PMTs and scientific CMOS cameras for 3D tracking down to O(keV) energies, for the directional detection of rare events such as low mass Dark Matter and solar neutrino interactions. The largest prototype built so far towards the realisation of the CYGNO experiment demonstrator is the 50 L active volume LIME, with 4 PMTs and a single sCMOS imaging a 33$\times$33 cm\textsuperscript{2} area for 50 cm drift, that has been installed in underground Laboratori Nazionali del Gran Sasso in February 2022. We will illustrate LIME performances as evaluated overground in Laboratori Nazionali di Frascati by means of radioactive X-ray sources, and in particular the detector stability, energy response and energy resolution. We will discuss the MC simulation developed to reproduce the detector response and show the comparison with actual data. We will furthermore examine the background simulation worked out for LIME underground data taking and illustrate the foreseen expected measurement and results in terms of natural and materials intrinsic radioactivity characterisation and measurement of the LNGS underground natural neutron flux. The results that will be obtained by underground LIME installation will be paramount in the optimisation of the CYGNO demonstrator, since this is foreseen to be composed by multiple modules with the same LIME dimensions and characteristics