The inhibitory role of sympathetic nervous system in the Ca2+-dependent proteolysis of skeletal muscle

Mammalian cells contain several proteolytic systems to carry out the degradative processes and complex regulatory mechanisms to prevent excessive protein breakdown. Among these systems, the Ca2+-activated proteolytic system involves the cysteine proteases denoted calpains, and their inhibitor, calpastatin. Despite the rapid progress in molecular research on calpains and calpastatin, the physiological role and regulatory mechanisms of these proteins remain obscure. Interest in the adrenergic effect on Ca2+-dependent proteolysis has been stimulated by the finding that the administration of β2-agonists induces muscle hypertrophy and prevents the loss of muscle mass in a variety of pathologic conditions in which calpains are activated. This review summarizes evidence indicating that the sympathetic nervous system produces anabolic, protein-sparing effects on skeletal muscle protein metabolism. Studies are reviewed, which indicate that epinephrine secreted by the adrenal medulla and norepinephrine released from adrenergic terminals have inhibitory effects on Ca2+-dependent protein degradation, mainly in oxidative muscles, by increasing calpastatin levels. Evidence is also presented that this antiproteolytic effect, which occurs under both basal conditions and in stress situations, seems to be mediated by β2- and β3-adrenoceptors and cAMP-dependent pathways. The understanding of the precise mechanisms by which catecholamines promote muscle anabolic effects may have therapeutic value for the treatment of muscle-wasting conditions and may enhance muscle growth in farm species for economic and nutritional purposes.FAPESPCNP

Improving Antibiotic Resistant Infection Transmission Situational Awareness in Enclosed Facilities with a Novel Graphical User Interface for Tactical Biosurveillance

Serious challenges associated with antibiotic resistant infections (ABRIs) force healthcare practitioners (HCP) to seek innovative approaches that will slow the emergence of new ABRIs and prevent their spread. It was realized that traditional approaches to infection prevention based on education, retrospective reports, and biosurveillance often fail to ensure reliable compliance with infection prevention guidelines and real-time problem solving. The objective of this original research was to develop and test the conceptual design of a situational awareness (SA)-oriented information system for coping with healthcare-associated infection transmission. Constantly changing patterns in spatial distribution of patients, prevalence of infectious cases, clustering of contacts, and frequency of contacts may compromise the effectiveness of infection prevention and control in hospitals. It was hypothesized that providing HCPs with a graphical user interface (GUI) to visualize spatial information on the risks of exposure to ABRIs would effectively increase HCPs’ SA. Increased SA may enhance biosurveillance and result in tactical decisions leading to better patient outcomes. The study employed a mixed qualitative-quantitative research method encompassing conceptualization of GUI content, transcription of electronic health record and biosurveillance data into GUI visual artifacts, and evaluation of the GUI’s impact on HCPs’ perception and comprehension of the conditions that increase the risk of ABRI transmission. The study provided pilot evidence that visualization of spatial disease distribution and spatially-linked exposures and interventions significantly increases HCPs’ SA when compared to current practice. The research demonstrates that the SA-oriented GUI enables the HCPs to promptly answer the question, “At a given location, what are the risks of infection transmission there?” This research provides a new form of medical knowledge representation for spatial population-based decision-making within enclosed environments. The next steps include rapid application development and further hypothesis testing concerning the impact of this GUI on decsion-making

O discurso comunista no construtivismo russo: a arte a serviço da propaganda ideológica

ResumoIdeologia é uma palavra que serviu de matéria-prima para teóricos de muitas áreas do conhecimento, principalmente nas ciências humanas. Dentro dessas ciências, o filósofo francês Michel Pêcheux ajudou a desenvolver, foi membro do círculo, e também maior expoente do método chamado Análise do Discurso. Ele afirmava que é na ideologia que o indivíduo se torna sujeito; mas é na ideologia também que os discursos são (re)produzidos historicamente, fazendo o sentido parecer autêntico e verdadeiro. A partir dessa concepção de ideologia que nos propomos a olhar o movimento artístico construtivista russo, usado interpelar sujeitos pela máquina de propaganda do regime comunista soviético.AbstractIdeology is a word that served as raw material for theorists of many areas of knowledge, especially in the humanities. Within these sciences, the French philosopher Michel Pêcheux helped to develop, was member of the circle, and also greater exponent of the method called Discourse Analysis. He affirmed that it is in ideology that the individual becomes subject; but it is also in ideology that discourses are (re) produced historically, making sense to appear authentic and true. From this conception of ideology we set out to look at the Russian constructivist artistic movement, used to question subjects by the propaganda machine of the Soviet communist regime

Gender-affirming hormone therapy decreases d-dimer but worsens insulin sensitivity in transgender women.

OBJECTIVES: Gender-affirming hormonal therapies (GAHT) and HIV increase cardiovascular risk for transgender women (TW), yet there is a paucity of data quantifying cardiometabolic changes following GAHT initiation, particularly among TW with HIV. METHODS: The Féminas study enrolled TW from October 2016 to March 2017 in Lima, Peru. Participants reported sexual activity that was high risk for HIV acquisition or transmission. All were tested for HIV/ sexually transmitted infection and were given access to GAHT (oestradiol valerate and spironolactone), HIV pre-exposure prophylaxis (PrEP) or antiretroviral therapy (ART) for 12 months. Biomarker measurement was done on stored serum, whereas fasting glucose and lipids were measured in real time. RESULTS: In all, 170 TW (32 with HIV, 138 without HIV) had median age 27 years and 70% prior GAHT use. At baseline, PCSK9, sCD14, sCD163, IL-6, sTNFRI/II, CRP and EN-RAGE levels were significantly higher in TW with HIV than in TW without HIV. High-density lipoprotein and total cholesterol were lower and insulin and glucose parameters were similar. All TW with HIV started ART, but only five achieved virological suppression at any time. No TW without HIV initiated PrEP. Over 6 months, all participants initiated GAHT and had worsening insulin, glucose and HOMA-IR. Large d-dimer decreases also occurred. Similar changes occurred in TW with and without HIV. CONCLUSIONS: In this unique cohort of TW, GAHT decreased d-dimer but worsened insulin sensitivity. Because PrEP uptake and ART adherence were very low, observed effects are primarily attributed to GAHT use. Further study is needed to better understand cardiometabolic changes in TW by HIV serostatus

Expression and cellular localization of microRNA-29b and RAX, an activator of the RNA-dependent protein kinase (PKR), in the retina of streptozotocin-induced diabetic rats

Purpose: The apoptosis of retinal neurons plays a critical role in the pathogenesis of diabetic retinopathy (DR), but the molecular mechanisms underlying this phenomenon remain unclear. The purpose of this study was to investigate the cellular localization and the expression of microRNA-29b (miR-29b) and its potential target PKR associated protein X (RAX), an activator of the pro-apoptotic RNA-dependent protein kinase (PKR) signaling pathway, in the retina of normal and diabetic rats. Methods: Retinas were obtained from normal and diabetic rats within 35 days after streptozotocin (STZ) injection. In silico analysis indicated that RAX is a potential target of miR-29b. The cellular localization of miR-29b and RAX was assessed by in situ hybridization and immunofluorescence, respectively. The expression levels of miR-29b and RAX mRNA were evaluated by quantitative reverse transcription PCR (qRT-PCR), and the expression of RAX protein was evaluated by western blot. A luciferase reporter assay and inhibition of endogenous RAX were performed to confirm whether RAX is a direct target of miR-29b as predicted by the in silico analysis. Results: We found that miR-29b and RAX are localized in the retinal ganglion cells (RGCs) and the cells of the inner nuclear layer (INL) of the retinas from normal and diabetic rats. Thus, the expression of miR-29b and RAX, as assessed in the retina by quantitative RT-PCR, reflects their expression in the RGCs and the cells of the INL. We also revealed that RAX protein is upregulated (more than twofold) at 3, 6, 16, and 22 days and downregulated (70%) at 35 days, whereas miR-29b is upregulated (more than threefold) at 28 and 35 days after STZ injection. We did not confirm the computational prediction that RAX is a direct target of miR-29b. Conclusions: Our results suggest that RAX expression may be indirectly regulated by miR-29b, and the upregulation of this miRNA at the early stage of STZ-induced diabetes may have a protective effect against the apoptosis of RGCs and cells of the INL by the pro-apoptotic RNA-dependent protein kinase (PKR) signaling pathway.FAPESP[08/58325-4]FAPESP[08/50294-2]Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Higher insulin sensitivity in EDL muscle of rats fed a low-protein, high-carbohydrate diet inhibits the caspase-3 and ubiquitin-proteasome proteolytic systems but does not increase protein synthesis

Compared with the extensor digitorum longus (EDL) muscle of control rats (C), the EDL muscle of rats fed a low-protein, high-carbohydrate diet (LPHC) showed a 36% reduction in mass. Muscle mass is determined by the balance between protein synthesis and proteolysis; thus, the aim of this work was to evaluate the components involved in these processes. Compared with the muscle from C rats, the EDL muscle from LPHC diet-fed rats showed a reduction (34%) in the in vitro basal protein synthesis and a 22% reduction in the in vitro basal proteolysis suggesting that the reduction in the mass can be associated with a change in the rate of the two processes. Soon after euthanasia, in the EDL muscles of the rats fed the LPHC diet for 15 days, the activity of caspase-3 and that of components of the ubiquitin-proteasome system (atrogin-1 content and chymotrypsin-like activity) were decreased. The phosphorylation of p70S6K and 4E-BP1, proteins involved in protein synthesis, was also decreased. We observed an increase in the insulin-stimulated protein content of p-Akt. Thus, the higher insulin sensitivity in the EDL muscle of LPHC rats seemed to contribute to the lower proteolysis in LPHC rats. However, even with the higher insulin sensitivity, the reduction in p-E4-BP1 and p70S6K indicates a reduction in protein synthesis, showing that factors other than insulin can have a greater effect on the control of protein synthesis

Web-Based Virtual Microscopy for Parasitology: A Novel Tool for Education and Quality Assurance

Here, we describe a novel tool to observe parasites by virtual microscopy on the Internet. Microscopy-based identification of parasites is the basis for both diagnostics and epidemiological assessment of parasite burden globally. Yet, quality assessment of diagnostic parasitology laboratories is difficult, as delivering identical educational specimens has been impossible. In this study, a series of parasite specimens on ordinary glass slides were digitized using a recently developed microscope scanner technique. Up to 50,000 images captured at high magnification are digitally stitched together to form a representation of the entire glass slide. These “virtual slides” digitized at a thousand-fold magnification can hold more than 60 gigabytes of data. Handling such large amounts of data was made possible because of efficient compression techniques and a viewing system adopted from the geospatial imaging industry. Viewing the samples on the Internet very much resembles, for example, the use of Google Maps, and puts only modest requirements on the viewer's computer. In addition, we captured image stacks at different focal planes, and developed a web-based viewing system for three-dimensional navigation in the specimens. This novel technique is especially valuable for detailed visualization of large objects such as helminth eggs in stool specimens

Maternal vitamin D deficiency affects the morphology and function of glycolytic muscle in adult offspring rats

Background Fetal stage is a critical developmental window for the skeletal muscle, but little information is available about the impact of maternal vitamin D (Vit. D) deficiency (VDD) on offspring lean mass development in the adult life of male and female animals. Methods Female rats (Wistar Hannover) were fed either a control (1000 IU Vit. D3/kg) or a VDD diet (0 IU Vit. D3/kg) for 6 weeks and during gestation and lactation. At weaning, male and female offspring were randomly separated and received a standard diet up to 180 days old. Results Vitamin D deficiency induced muscle atrophy in the male (M-VDD) offspring at the end of weaning, an effect that was reverted along the time. Following 180 days, fast-twitch skeletal muscles [extensor digitorum longus (EDL)] from the M-VDD showed a decrease (20%; P < 0.05) in the number of total fibres but an increase in the cross-sectional area of IIB (17%; P < 0.05), IIA (19%; P < 0.05) and IIAX (21%; P < 0.05) fibres. The fibre hypertrophy was associated with the higher protein levels of MyoD (73%; P < 0.05) and myogenin (55% %; P < 0.05) and in the number of satellite cells (128.8 ± 14 vs. 91 ± 7.6 nuclei Pax7 + in the M-CTRL; P < 0.05). M-VDD increased time to fatigue during ex vivo contractions of EDL muscles and showed an increase in the phosphorylation levels of IGF-1/insulin receptor and their downstream targets related to anabolic processes and myogenic activation, including Ser 473Akt and Ser 21/9GSK-3β. In such muscles, maternal VDD induced a compensatory increase in the content of calcitriol (two-fold; P < 0.05) and CYP27B1 (58%; P < 0.05), a metabolizing enzyme that converts calcidiol to calcitriol. Interestingly, most morphological and biochemical changes found in EDL were not observed in slow-twitch skeletal muscles (soleus) from the M-VDD group as well as in both EDL and soleus muscles from the female offspring. Conclusions These data show that maternal VDD selectively affects the development of type-II muscle fibres in male offspring rats but not in female offspring rats and suggest that the enhancement of their size and fatigue resistance in fast-twitch skeletal muscle (EDL) is probably due to a compensatory increase in the muscle content of Vit. D in the adult age.FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paul