Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1-Host Interactions as Antiviral Targets for Flu.

Influenza viruses are responsible for significant morbidity and mortality worldwide in winter seasonal outbreaks and in flu pandemics. Influenza viruses have a high rate of evolution, requiring annual vaccine updates and severely diminishing the effectiveness of the available antivirals. Identifying novel viral targets and developing new effective antivirals is an urgent need. One of the most promising new targets for influenza antiviral therapy is non-structural protein 1 (NS1), a highly conserved protein exclusively expressed in virus-infected cells that mediates essential functions in virus replication and pathogenesis. Interaction of NS1 with the host proteins PI3K and TRIM25 is paramount for NS1's role in infection and pathogenesis by promoting viral replication through the inhibition of apoptosis and suppressing interferon production, respectively. We, therefore, conducted an analysis of the druggability of this viral protein by performing molecular dynamics simulations on full-length NS1 coupled with ligand pocket detection. We identified several druggable pockets that are partially conserved throughout most of the simulation time. Moreover, we found out that some of these druggable pockets co-localize with the most stable binding regions of the protein-protein interaction (PPI) sites of NS1 with PI3K and TRIM25, which suggests that these NS1 druggable pockets are promising new targets for antiviral development.

Círculo de Cultura como estratégia de promoção da saúde: encontros entre educação popular e interdisciplinaridade / Culture Circle as a strategy to promote health: encounters between popular education and interdisciplinarity

RESUMO A promoção da saúde é uma estratégia de cuidado da Atenção Primária à Saúde (APS) que deve entender a saúde como dinâmica sócio-histórica atravessada por determinantes sociais. Além disso, a APS tem o intuito de promover a qualidade de vida, reduzindo vulnerabilidades e riscos à saúde relacionados com os seus determinantes e condicionantes. Nos territórios em saúde, existem grupos que necessitam de busca ativa e atenção integral dos serviços de saúde devido à sua condição de vulnerabilidade. Este relato de experiência apresenta o uso do Círculo de Cultura, proposto por Paulo Freire, como ferramenta para a aproximação entre profissionais de saúde e um agrupamento de famílias em situação de vulnerabilidade no contexto do território de uma unidade de saúde periférica situada em uma capital na região Sul. A estratégia promoveu o fortalecimento do vínculo entre trabalhadores e usuários, ampliando o empoderamento, o acesso à saúde e à dignidade, concomitantemente ao envolvimento dos profissionais da equipe com a Educação Popular em Saúde.

ABSTRACT Health promotion is a care strategy in Primary Health Care (PHC) that must see health as a social-historic dynamic permeated by social determinants. Moreover, PHC aims to promote the quality of life, reducing vulnerabilities and health risks related to determinants and conditions of health. There are groups in health territories that require actively search and integrative care of health services, due to their condition of vulnerability. This experience report presents the use of Culture Circle, as proposed by Paulo Freire, as a tool for health professionals to approach a family agroupment in a vulnerability situation in the territory of a Health Care Unit located in the peripherical region of a city in the south of Brazil. This strategy strengthens the bond between health workers and patients, amplifying empowerment and access to health and dignity, concurrently to the involvement of team workers with Popular Education in Health.

Likely a matter of time for Amyloid-ß immunotherapy.

Amyloid-ß peptide (Aß) deposition in the brain is an early feature of Alzheimers' disease. In a phase II clinical trial recently published in The New England Journal of Medicine, Mintun and colleagues report on the safety and efficacy of an antibody targeting Aß peptide in amyloid plaques for the treatment of participants with early symptomatic Alzheimer's disease.

Trojan mosquitoes control dengue.

Dengue virus is transmitted by Aedes aegypti mosquitoes and causes the disease known as dengue. In a trial published in The New England Journal of Medicine, Utarini and colleagues report that release of wolbachia-infected A. aegypti populations in a dengue endemic area reduces the number of symptomatic cases and of hospitalisations.

Recent major advances in cardiovascular pharmacotherapy.

The field of cardiovascular pharmacotherapy remains extremely active. The aim of this review is to summarize the recent major advances in cardiovascular pharmacotherapy, with a focus on (1) the new approved drug for treatment of heart failure with reduced ejection fraction-sacubitril/valsartan; (2) proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors; (3) the novel reversal agents for non-vitamin K oral anticoagulants (NOACs); and finally, (4) new evidence on pharmacological treatment of coronary artery disease.

Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia.

Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD.

Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors.

Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice.

Immunoregulatory effects of HO-1: how does it work?

The heme-catabolizing enzyme heme oxygenase-1 (HO-1; encoded by the Hmox1 gene) inhibits the pathogenesis of several immune-mediated inflammatory diseases. This unusually broad salutary effect is thought to rely on the immunoregulatory actions of HO-1, exerted on innate and adaptive immune cells. According to this notion, HO-1 'dampens' innate and adaptive immune responses, limiting immune-mediated tissue injury and thus suppressing the pathogenesis of immune-mediated inflammatory diseases. We will argue that the salutary effects of HO-1 are also exerted via its cytoprotective action, which sustains tissue function and prevents unfettered immune activation by endogenous proinflammatory ligands released from injured cells.

The influence of the loading mode on the stress distribution on the connector region of metal-ceramic and all-ceramic fixed partial denture.

Studies pertaining to the mechanical behavior of fixed partial dentures (FPDs) frequently found the highest tensile stress values at the connector region when load is applied at the pontic central region. The connector region is considered the weakest point of the prosthesis with the greatest potential of fractures, regardless of the material used. This 2D finite element study compared the stress distribution on three-element all-ceramic and metal-ceramic FPDs with different loading conditions. Three FPD models were designed: (i) metal-ceramic FPD; (ii) all-ceramic FPD with the veneering porcelain only on the occlusal face; and (iii) all-ceramic FPD with the veneering porcelain on the occlusal and cervical face of the pontic. Loads of 100 N were applied following these simulations: (i) distributed on all working cusps; (ii) only on the abutment teeth; and (iii) only on the pontic. There is a significant change on the stress distribution and on the tensile stress values when the load configuration is changed. The stress distribution from the load applied on the abutments was significantly better compared with the other two load simulations. When the loads were applied on the pontic and distributed on all working cusps, the highest tensile stress values appeared on the cervical region of the connectors between the abutments and the pontic. However, when the load was applied on the abutment teeth, the maximum tensile stress value significantly decreased and was located on the occlusal region of the connectors. In fact, the load applied on the pontic region does not simulate the clinical situation. Studies using this load configuration have overestimated the connector regions as having the highest probability of failures.

All-ceramic and porcelain-fused-to-metal fixed partial dentures: a comparative study by 2D finite element analyses

All-ceramic fixed partial dentures (FPDs) have an esthetic approach for oral rehabilitation. However, metal-ceramic FPDs are best indicated in the posterior area where the follow-up studies found a lower failure rate. This 2D finite element study compared the stress distribution on 3-unit all-ceramic and metal-ceramic FPDs and identified the areas of major risk of failure. Three FPD models were designed: (1) metal-ceramic FPD; (2) All-ceramic FPD with the veneering porcelain on the occlusal and cervical surface of the abutment tooth; (3) All-ceramic FPD with the veneering porcelain only on the occlusal surface. A 100 N load was applied in an area of 0.5 mm² on the working cusps, following these simulations: (1) on the abutment teeth and the pontic; (2) only on the abutment teeth; and (3) only on the pontic. Relative to the maximum stress values found for the physiological load, all-ceramic FPD with only occlusal veneering porcelain produced the lowest stress value (220 MPa), followed by all-ceramic FPD with cervical veneering porcelain (322 MPa) and metal-ceramic FPD (387 MPa). The stress distribution of the load applied on the abutments was significantly better compared to the other two load simulations. The highest principal stress values were low and limited in a small area for the three types of models under this load. When the load was applied on the pontic, the highest stress values appeared on the connector areas between the abutments and pontic. In conclusion, the best stress values and distribution were found for the all-ceramic FPD with the veneering porcelain only on the occlusal surface. However, in under clinical conditions, fatigue conditions and restoration defects must be considered.

Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation.

Heme oxygenase-1 (HO-1, encoded by HMOX1) dampens inflammatory reactions via the catabolism of heme into CO, Fe, and biliverdin. We report that expression of HO-1 dictates the pathologic outcome of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Induction of EAE in Hmox1(-/- )C57BL/6 mice led to enhanced CNS demyelination, paralysis, and mortality, as compared with Hmox1(+/+) mice. Induction of HO-1 by cobalt protoporphyrin IX (CoPPIX) administration after EAE onset reversed paralysis in C57BL/6 and SJL/J mice and disease relapse in SJL/J mice. These effects were not observed using zinc protoporphyrin IX, which does not induce HO-1. CoPPIX protection was abrogated in Hmox1(-/-) C57BL/6 mice, indicating that CoPPIX acts via HO-1 to suppress EAE progression. The protective effect of HO-1 was associated with inhibition of MHC class II expression by APCs and inhibition of Th and CD8 T cell accumulation, proliferation, and effector function within the CNS. Exogenous CO mimicked these effects, suggesting that CO contributes to the protective action of HO-1. In conclusion, HO-1 or exposure to its end product CO counters autoimmune neuroinflammation and thus might be used therapeutically to treat MS.

All-ceramic and porcelain-fused-to-metal fixed partial dentures: a comparative study by 2D finite element analyses.

All-ceramic fixed partial dentures (FPDs) have an esthetic approach for oral rehabilitation. However, metal-ceramic FPDs are best indicated in the posterior area where the follow-up studies found a lower failure rate. This 2D finite element study compared the stress distribution on 3-unit all-ceramic and metal-ceramic FPDs and identified the areas of major risk of failure. Three FPD models were designed: (1) metal-ceramic FPD; (2) All-ceramic FPD with the veneering porcelain on the occlusal and cervical surface of the abutment tooth; (3) All-ceramic FPD with the veneering porcelain only on the occlusal surface. A 100 N load was applied in an area of 0.5 mm(2) on the working cusps, following these simulations: (1) on the abutment teeth and the pontic; (2) only on the abutment teeth; and (3) only on the pontic. Relative to the maximum stress values found for the physiological load, all-ceramic FPD with only occlusal veneering porcelain produced the lowest stress value (220 MPa), followed by all-ceramic FPD with cervical veneering porcelain (322 MPa) and metal-ceramic FPD (387 MPa). The stress distribution of the load applied on the abutments was significantly better compared to the other two load simulations. The highest principal stress values were low and limited in a small area for the three types of models under this load. When the load was applied on the pontic, the highest stress values appeared on the connector areas between the abutments and pontic. In conclusion, the best stress values and distribution were found for the all-ceramic FPD with the veneering porcelain only on the occlusal surface. However, in under clinical conditions, fatigue conditions and restoration defects must be considered.

The antiapoptotic effect of heme oxygenase-1 in endothelial cells involves the degradation of p38 alpha MAPK isoform.

Heme oxygenase-1 (HO-1) protects endothelial cells (EC) from undergoing apoptosis. This effect is mimicked by CO, generated via the catabolism of heme by HO-1. The antiapoptotic effect of CO in EC was abrogated when activation of the p38alpha and p38beta MAPKs was inhibited by the pyridinyl imidazole SB202190. Using small interfering RNA, p38beta was found to be cytoprotective in EC, whereas p38alpha was not. When overexpressed in EC, HO-1 targeted specifically the p38alpha but not the p38beta MAPK isoform for degradation by the 26S proteasome, an effect reversed by the 26S proteasome inhibitors MG-132 or lactacystin. Inhibition of p38alpha expression was also observed when HO-1 was induced physiologically by iron protoporphyrin IX (hemin). Inhibition of p38alpha no longer occurred when HO activity was inhibited by tin protoporphyrin IX, suggesting that p38alpha degradation was mediated by an end product of heme catabolism. Exogenous CO inhibited p38alpha expression in EC, suggesting that CO is the end product that mediates this effect. The antiapoptotic effect of HO-1 was impaired when p38alpha expression was restored ectopically or when its degradation by the 26S proteasome was inhibited by MG-132. Furthermore, the antiapoptotic effect of HO-1 was lost when p38beta expression was targeted by a specific p38beta small interfering RNA. In conclusion, the antiapoptotic effect of HO-1 in EC is dependent on the degradation of p38alpha by the 26S proteasome and on the expression of p38beta.

Variação da glicemia após sessão de escleroterapia realizada com 10 ml de glicose hipertônica a 75 por cento / Variation in level of glycemia after sclerotherapy performed with 10 ml of 75 per cent hypertonic glucose

Objetivo: Medir a variação da glicemia após uma sessão de escleroterapia de varizes realizada com glicose hipertônica a 75 por cento. Método: Colheu-se a glicemia antes e imediatamente após uma sessão de escleroterapia química convencional, utilizando-se uma ampola de 10 ml de solução de glicose hipertônica a 75 por cento em 35 pacientes classe C1(CEAP), não diabéticas, com idade média de 43,8 anos, em jejum. Resultados: a glicemia sofreu uma variação média de 42,8 mg/dl, ou seja, 49 por cento.

Pseudo-aneurisma idiopático da artéria poplítea / Idiopathic pseudoaneurysm of the popliteal artery

Pseudo-aneurismas da artéria poplítea são raros. Getalmente são secundários a traumatismos locais, incluindo aqueles causados por procedimentos ortopédicos (artroscopias). Outras causas incluem deiscência anastomótica e processos ósseos expansíveis, localizados na fossa poplítea (exostoses e osteocondromas). Os autotes desctevem dois casos de pseudo-aneutisma espontâneo da artéria poplítea. Após exaustiva investigação, não fotam evidenciados história de trauma, ptocedimentos invasivos, vasculites ou quaisquer fatores que pudessem ser a ptovável causa do pseudo-aneurisma.

Vólvulo da vesícula biliar tratado por colecistectomia laparoscópica / Volvulus of the gallbladder treated by laparoscopic cholecystectomy

Our objective is to report a case of gallbladder torsion treated by laparoscopic cholecystectomy. A 87 year old patient presented with intense right upper quadrant pain, anorexia, nausea and vomiting. Murphy's sign was present at physical examination. Hemogram showed 9.200 leukocytes/mm3, with six bands. Ultrassonography showed a distended gallbladder, perivesicular fluid collection, wall edema, and sludge with stones inside. At laparoscopic cholecystectomy, there was a complete gallbladder torsion with areas of necrosis. There was no postoperative complication. Pathologic examination confirmed the diagnosis of acute calculous cholecystitis with areas of necrosis