Ubiquitin-proteasome signaling in lung injury

Cell homeostasis requires precise coordination of cellular proteins function. Ubiquitination is a post-translational modification that modulates protein half-life and function and is tightly regulated by ubiquitin E3 ligases and deubiquitinating enzymes. Lung injury can progress to acute respiratory distress syndrome that is characterized by an inflammatory response and disruption of the alveolocapillary barrier resulting in alveolar edema accumulation and hypoxemia. Ubiquitination plays an important role in the pathobiology of acute lung injury as it regulates the proteins modulating the alveolocapillary barrier and the inflammatory response. Better understanding of the signaling pathways regulated by ubiquitination may lead to novel therapeutic approaches by targeting specific elements of the ubiquitination pathways.Fil: Magnani, Natalia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Programa de Radicales Libres; Argentina. Northwestern University; Estados UnidosFil: Dada, Laura Andrea. Northwestern University; Estados UnidosFil: Sznajder, Jacob I.. Northwestern University; Estados Unido

A Scoping Review to Assess Sexual and Reproductive Health Outcomes, Challenges and Recommendations in the Context of Climate Migration

Background: As growing numbers of people may be forced to migrate due to climate change and variability, it is important to consider the disparate impacts on health for vulnerable populations, including sexual and reproductive health (SRH). This scoping review aims to explore the relationship between climate migration and SRH. Methods: We searched PubMed/MEDLINE, CINAHL Plus, EMBASE, Web of Science, Scopus, Global Health and Google for peer-reviewed and gray literature published before 2nd July 2021 in English that reported on SRH in the context of climate migration. Data were extracted using a piloted extraction tool and findings are reported in a narrative synthesis. Results: We screened 1,607 documents. Ten full-text publications were included for analysis: five peer-reviewed articles and five gray literature documents. Reported SRH outcomes focused on maternal health, access to family planning and antiretroviral therapy, sexual and gender-based violence, transactional sex, and early/forced marriage. Recommendations to improve SRH in the context of climate migration called for gender-transformative health systems, education and behavior change programmes, and the involvement of local women in policy planning and programme implementation. Discussion: While the disparate impacts of climate change and migration are well-established, primary data on the scope of impact due to climate migration is limited. The SRH outcomes reported in the literature focus on a relatively narrow range of SRH domains, emphasizing women and girls, over men. Achieving holistic and equitable SRH in the context of climate migration requires engaging all genders across the range of SRH outcomes and migration contexts. This review highlights the need for further empirical evidence on the effect of climate migration on SRH, with research that is context-specific and engages communities in order to reflect the heterogeneity of outcomes and impact in the climate-migration-SRH nexus

Optimizing Pandemic Preparedness and Response Through Health Information Systems: Lessons Learned From Ebola to COVID-19.

Strengthening health systems and maintaining essential service delivery during health emergencies response is critical for early detection and diagnosis, prompt treatment, and effective control of pandemics, including the novel coronavirus disease 2019 (COVID-19). Health information systems (HIS) developed during recent Ebola outbreaks in West Africa and the Democratic Republic of the Congo (DRC) provided opportunities to collect, analyze, and distribute data to inform both day-to-day and long-term policy decisions on outbreak preparedness. As COVID-19 continues to sweep across the globe, HIS and related technological advancements remain vital for effective and sustained data sharing, contact tracing, mapping and monitoring, community risk sensitization and engagement, preventive education, and timely preparedness and response activities. In reviewing literature of how HIS could have further supported mitigation of these Ebola outbreaks and the ongoing COVID-19 pandemic, 3 key areas were identified: governance and coordination, health systems infrastructure and resources, and community engagement. In this concept study, we outline scalable HIS lessons from recent Ebola outbreaks and early COVID-19 responses along these 3 domains, synthesizing recommendations to offer clear, evidence-based approaches on how to leverage HIS to strengthen the current pandemic response and foster community health systems resilience moving forward

Linear ubiquitin assembly complex regulates lung epithelial–driven responses during influenza infection

Influenza A virus (IAV) is among the most common causes of pneumonia-related death worldwide. Pulmonary epithelial cells are the primary target for viral infection and replication and respond by releasing inflammatory mediators that recruit immune cells to mount the host response. Severe lung injury and death during IAV infection result from an exuberant host inflammatory response. The linear ubiquitin assembly complex (LUBAC), composed of SHARPIN, HOIL-1L, and HOIP, is a critical regulator of NF-κB–dependent inflammation. Using mice with lung epithelial–specific deletions of HOIL-1L or HOIP in a model of IAV infection, we provided evidence that, while a reduction in the inflammatory response was beneficial, ablation of the LUBAC-dependent lung epithelial–driven response worsened lung injury and increased mortality. Moreover, we described a mechanism for the upregulation of HOIL-1L in infected and noninfected cells triggered by the activation of type I IFN receptor and mediated by IRF1, which was maladaptive and contributed to hyperinflammation. Thus, we propose that lung epithelial LUBAC acts as a molecular rheostat that could be selectively targeted to modulate the immune response in patients with severe IAV-induced pneumonia.Fil: Brazee, Patricia L.. Northwestern University; Estados UnidosFil: Morales Nebreda, Luisa. Northwestern University; Estados UnidosFil: Magnani, Natalia Daniela. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Garcia, Joe G. N.. University of Arizona; Estados UnidosFil: Misharin, Alexander V.. Northwestern University; Estados UnidosFil: Ridge, Karen M.. Northwestern University; Estados UnidosFil: Budinger, G.R. Scott. Northwestern University; Estados UnidosFil: Iwai, Kazuhiro. Kyoto University; JapónFil: Dada, Laura Andrea. Northwestern University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Sznajder, Jacob I.. Northwestern University; Estados Unido

A Scoping Review to Assess Sexual and Reproductive Health Outcomes, Challenges and Recommendations in the Context of Climate Migration.

Background: As growing numbers of people may be forced to migrate due to climate change and variability, it is important to consider the disparate impacts on health for vulnerable populations, including sexual and reproductive health (SRH). This scoping review aims to explore the relationship between climate migration and SRH. Methods: We searched PubMed/MEDLINE, CINAHL Plus, EMBASE, Web of Science, Scopus, Global Health and Google for peer-reviewed and gray literature published before 2nd July 2021 in English that reported on SRH in the context of climate migration. Data were extracted using a piloted extraction tool and findings are reported in a narrative synthesis. Results: We screened 1,607 documents. Ten full-text publications were included for analysis: five peer-reviewed articles and five gray literature documents. Reported SRH outcomes focused on maternal health, access to family planning and antiretroviral therapy, sexual and gender-based violence, transactional sex, and early/forced marriage. Recommendations to improve SRH in the context of climate migration called for gender-transformative health systems, education and behavior change programmes, and the involvement of local women in policy planning and programme implementation. Discussion: While the disparate impacts of climate change and migration are well-established, primary data on the scope of impact due to climate migration is limited. The SRH outcomes reported in the literature focus on a relatively narrow range of SRH domains, emphasizing women and girls, over men. Achieving holistic and equitable SRH in the context of climate migration requires engaging all genders across the range of SRH outcomes and migration contexts. This review highlights the need for further empirical evidence on the effect of climate migration on SRH, with research that is context-specific and engages communities in order to reflect the heterogeneity of outcomes and impact in the climate-migration-SRH nexus

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

The harmonization of the general interest and the private interest protected by Law 256 of 1996 : a pending conflict of interest

La Ley 256 de 1996, al implementar el modelo social de competencia desleal, protege tanto el interés particular como el interés general. Sin embargo, esta protección dual ha ocasionado diversas complejidades en su aplicación para las autoridades jurisdiccionales y administrativas, así como para las partes, en los procesos de competencia desleal. En esta investigación, buscamos una armonización de estos intereses mediante la identificación de los mecanismos procesales disponibles en el ordenamiento jurídico para proteger uno u otro.Law 256 of 1996, by implementing the social model of unfair competition, protects both the private interest and the general interest. However, this dual protection has caused several complexities in its application for the jurisdictional and administrative authorities, as well as for the parties, in unfair competition proceedings. In this research, we seek to harmonize these interests by identifying the procedural mechanisms available in the legal system to protect one or the other.Abogado (a)Pregrad

P-type ATPases in Health and Disease

P-type ATPases are a large group of evolutionary related ion and lipid pumps that have in common that they catalyze a transient phosphorylated intermediate at a key conserved aspartate residue within the pump in order to function. While all the P-type ATPases perform active transport across cellular membranes, they have different transport specificities and serve diverse physiological functions. The ion pumps of the P-type ATPase family create electrochemical gradients that are essential for transepithelial transport, nutrient uptake and membrane potential. They mediate cellular signaling and provide the ligands for metalloenzymes. Phospholipid flippases, also members of the P-type ATPase superfamily, regulate the asymmetric lipid distribution across the lipid bilayer and are critical for the biogenesis of cell membranes. Since all of these ATPases serve fundamental cellular functions, malfunctioning is associated with various pathophysiological processes and dysfunctions of P-type ATPases are known to contribute to cardiovascular, neurological, renal and metabolic diseases. However, with the ever growing knowledge about the diseases associated with the malfunction of P-type ATPases, they are also promising targets for future drug development. In eukaryotes the most prominent examples of P-type ATPases are the Na+,K+-ATPase (sodium pump), the H+-ATPase (proton pump), the H+,K+-ATPase (proton-potassium pump) and the Ca2+-ATPases (calcium pumps). Mutations in the alpha2 and alpha3 subunit of Na,K-ATPase have been associated with neurological diseases, including rapid-onset dystonia-parkinsonism, familial hemiplegic migraine and alternating hemiplegia of childhood. Dysregulation and loss of expression of Na,K-ATPase and plasma membrane Ca-ATPases may be involved in cancer progression. Malfunctioning of the Ca-ATPases is also thought to contribute to hypertension and neurodegenerative diseases and mutations can cause cardiac dysfunction, deafness, hypertension and cerebellar ataxia. Mutations in the SERCA calcium pumps can cause heart failure, Brody myopathy and Darier disease and mutations in the Cu-ATPase genes cause Menkes and Wilson disease. Deficiencies in phospholipid flippases have been linked to progressive familial intrahepatic cholestasis, obesity, diabetes, hearing loss and neurological diseases