The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions.

Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely \u3b23-Cav2.1 at N-terminus part and \u3b2-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause diseas

Avaliação do projeto minibibliotecas no Semiárido do Nordeste e no Vale do Jequitinhonha, MG: uma pesquisa-ação.

Introdução; As minibibliotecas no contexto da leitura e do aprendizado; Metodologia; Análise e discussão dos dados.bitstream/item/83404/1/Avaliacao-do-projeto-minibibliotecas.pd

Synthesis of 4-substituted-1,2-dihydroquinolines by means of gold-catalyzed intramolecular hydroarylation reaction of n-ethoxycarbonyl-n-propargylanilines

An alternative Au(I)-catalyzed synthetic route to functionalized 1,2-dihydroquinolines is reported. This novel approach is based on the use of N-ethoxycarbonyl protected-Npropargylanilines as building blocks that rapidly undergo the IMHA reaction affording the 6-endo cyclization product in good to high yields. In the presence of N-ethoxycarbonyl-N-propargyl-metasubstituted anilines, the regiodivergent cyclization at the ortho-/para-position is achieved by the means of catalyst fine tuning

AN IN VIVO MODEL OF HYPERACUTE REJECTION: CHARACTERIZATION AND EVALUATION OF THE EFFECT OF TRANSGENIC HUMAN COMPLEMENT INHIBITORS

Hyperacute rejection (HAR) occurring after transplantation within phylogenetically distant species is a severe reaction triggered by preexisting xenoreactive antibodies and complement activation, leading to the destruction of the donor organ. Expression of human complement inhibitors in transgenic pig organs prolongs the survival of xenograft in experimental models. Moreover, the extent of protection from hyperacute rejection is dependent on the level and site of expression of the transgenic molecules and, probably, on the combination of different molecules. In this regard a small animal model to test the efficacy of expression vectors and different human molecules could be very advantageous. A murine model developed in our laboratory was characterized by measurement of several parameters characteristic of HAR in the livers of control and transgenic mice expressing transgenic human DAF (CD55) or MCP (CD46) at the end of 2 h of perfusion with human plasma and after 1 day. The parameters studied were heamatological values of hepatic functions (GOT and GPT), induction of pro-inflammatory molecules and histopathological evaluation. Cytokines (IL-1 alpha, IL-1 beta, IL-6) induction and exposure of P-selectin on the endothelial cell surface, was only observed in control animals after 2 h of perfusion, as an early event. GOT and GPT values increase drammatically after 2 h perfusion and 1 day after the treatment according to the histopathological observation of liver damage. On the contrary, the livers of hDAF or hMCP transgenic mice, under the same treatment were significantly protected although the extent of this protection is dependent on the level of expression of transgenic human molecules

Captorhinid reptiles from the lower Permian Pedra de Fogo Formation, Piauí, Brazil: the earliest herbivorous tetrapods in Gondwana

The Pedra de Fogo Formation in the Parnaíba Basin of northeastern Brazil hosts a recently discovered lacustrine fauna and provides the only known record of the Captorhinidae in South America. Here, new captorhinid remains from this unit are described. Two partial mandibles, including one formerly ascribed to the genus Captorhinus, are here referred to Captorhinikos sp. a genus previously described from North America. The natural mould of a large mandible probably represents a new taxon within the captorhinid subclade Moradisaurinae, and a small skull roof is regarded as Captorhinidae indet. Captorhinids are generally considered to have been herbivores or omnivores. The Pedra de Fogo captorhinids likely played an important ecological role as primary consumers in the palaeoenvironment of this geological unit, which is also known for its extensive record of petrified forests. The new finds reinforce the close relationships between the continental faunas of palaeotropical western Gondwana and palaeoequatorial North America during the Cisuralian

The endocannabinoid system controls food intake via olfactory processes

Comment in Sensory systems: the hungry sense. [Nat Rev Neurosci. 2014] Inhaling: endocannabinoids and food intake. [Nat Neurosci. 2014]; International audience; Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior

Preoperative anaemia and clinical outcomes in the South African Surgical Outcomes Study

Background. In high-income countries, preoperative anaemia has been associated with poor postoperative outcomes. To date, no large study has investigated this association in South Africa (SA). The demographics of SA surgical patients differ from those of surgical patients in the European and Northern American settings from which the preoperative anaemia data were derived. These associations between preoperative anaemia and postoperative outcomes are therefore not necessarily transferable to SA surgical patients.Objectives. The primary objective was to determine the association between preoperative anaemia and in-hospital mortality in SA adult non-cardiac, non-obstetric patients. The secondary objectives were to describe the association between preoperative anaemia and (i) critical care admission and (ii) length of hospital stay, and the prevalence of preoperative anaemia in adult SA surgical patients.Methods. We performed a secondary analysis of the South African Surgical Outcomes Study (SASOS), a large prospective observational study of patients undergoing inpatient non-cardiac, non-obstetric surgery at 50 hospitals across SA over a 1-week period. To determine whether preoperative anaemia is independently associated with mortality or admission to critical care following surgery, we conducted a multivariate logistic regression analysis that included all the independent predictors of mortality and admission to critical care identified in the original SASOS model.Results. The prevalence of preoperative anaemia was 1 727/3 610 (47.8%). Preoperative anaemia was independently associated with in-hospital mortality (odds ratio (OR) 1.657, 95% confidence interval (CI) 1.055 - 2.602; p=0.028) and admission to critical care (OR 1.487, 95% CI 1.081 - 2.046; p=0.015).Conclusions. Almost 50% of patients undergoing surgery at government-funded hospitals in SA had preoperative anaemia, which was independently associated with postoperative mortality and critical care admission. These numbers indicate a significant perioperative risk, with a clear need for quality improvement programmes that may improve surgical outcomes. Long waiting lists for elective surgery allow time for assessment and correction of anaemia preoperatively. With a high proportion of patients presenting for urgent or emergency surgery, perioperative clinicians in all specialties should educate themselves in the principles of patient blood management.Â

Preoperative anaemia and clinical outcomes in the South African Surgical Outcomes Study

Background. In high-income countries, preoperative anaemia has been associated with poor postoperative outcomes. To date, no large study has investigated this association in South Africa (SA). The demographics of SA surgical patients differ from those of surgical patients in the European and Northern American settings from which the preoperative anaemia data were derived. These associations between preoperative anaemia and postoperative outcomes are therefore not necessarily transferable to SA surgical patients.Objectives. The primary objective was to determine the association between preoperative anaemia and in-hospital mortality in SA adult non-cardiac, non-obstetric patients. The secondary objectives were to describe the association between preoperative anaemia and (i) critical care admission and (ii) length of hospital stay, and the prevalence of preoperative anaemia in adult SA surgical patients.Methods. We performed a secondary analysis of the South African Surgical Outcomes Study (SASOS), a large prospective observational study of patients undergoing inpatient non-cardiac, non-obstetric surgery at 50 hospitals across SA over a 1-week period. To determine whether preoperative anaemia is independently associated with mortality or admission to critical care following surgery, we conducted a multivariate logistic regression analysis that included all the independent predictors of mortality and admission to critical care identified in the original SASOS model.Results. The prevalence of preoperative anaemia was 1 727/3 610 (47.8%). Preoperative anaemia was independently associated with in-hospital mortality (odds ratio (OR) 1.657, 95% confidence interval (CI) 1.055 - 2.602; p=0.028) and admission to critical care (OR 1.487, 95% CI 1.081 - 2.046; p=0.015).Conclusions. Almost 50% of patients undergoing surgery at government-funded hospitals in SA had preoperative anaemia, which was independently associated with postoperative mortality and critical care admission. These numbers indicate a significant perioperative risk, with a clear need for quality improvement programmes that may improve surgical outcomes. Long waiting lists for elective surgery allow time for assessment and correction of anaemia preoperatively. With a high proportion of patients presenting for urgent or emergency surgery, perioperative clinicians in all specialties should educate themselves in the principles of patient blood management.

AAV Vector-Mediated Overexpression of CB1 Cannabinoid Receptor in Pyramidal Neurons of the Hippocampus Protects against Seizure-Induced Excitoxicity

The CB1 cannabinoid receptor is the most abundant G-protein coupled receptor in the brain and a key regulator of neuronal excitability. There is strong evidence that CB1 receptor on glutamatergic hippocampal neurons is beneficial to alleviate epileptiform seizures in mouse and man. Therefore, we hypothesized that experimentally increased CB1 gene dosage in principal neurons would have therapeutic effects in kainic acid (KA)-induced hippocampal pathogenesis. Here, we show that virus-mediated conditional overexpression of CB1 receptor in pyramidal and mossy cells of the hippocampus is neuroprotective and moderates convulsions in the acute KA seizure model in mice. We introduce a recombinant adeno-associated virus (AAV) genome with a short stop element flanked by loxP sites, for highly efficient attenuation of transgene expression on the transcriptional level. The presence of Cre-recombinase is strictly necessary for expression of reporter proteins or CB1 receptor in vitro and in vivo. Transgenic CB1 receptor immunoreactivity is targeted to glutamatergic neurons after stereotaxic delivery of AAV to the dorsal hippocampus of the driver mice NEX-cre. Increased CB1 receptor protein levels in hippocampal lysates of AAV-treated Cre-mice is paralleled by enhanced cannabinoid-induced G-protein activation. KA-induced seizure severity and mortality is reduced in CB1 receptor overexpressors compared with AAV-treated control animals. Neuronal damage in the hippocampal CA3 field is specifically absent from AAV-treated Cre-transgenics, but evident throughout cortical areas of both treatment groups. Our data provide further evidence for a role of increased CB1 signaling in pyramidal hippocampal neurons as a safeguard against the adverse effects of excessive excitatory network activity