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Background: Private sector acting in healthcare does not remove the public nature of a health system, nor mitigate the right to health as a human right., Methods: This scoping review aims to answer the question: what factors influence the pattern of lawsuits seeking to enforce the right to health in private healthcare systems? The search was carried out in Pubmed, SciELO, DOAJ and Scopus., Results: Out of 464 articles found, after inclusion and exclusion criteria, 30 articles were included. The survey covered 36 different countries and four main factors were identified. The socioeconomic context, the health system model, the incorporation of the right to health in legislation, and the model of regulation of private health., Conclusions: Understanding these patterns help understanding the difficulties of implementing and guaranteeing universal health. Health systems must be based on responsibility, solidarity, equity, and distributive justice, since the sum of these values generates mutualism. Judicial decision-making regarding to health access must be reasoned on equity and distributive justice, scientific evidence and ethical factors. Even private health systems must be funded in a well-defined ethical platform and social moral valuation., Competing Interests: Declaration of interest statement The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Most human proteins lack chemical probes, and several large-scale and generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such "binding-first" assays affect protein function, nonetheless, often remains unclear. Here, we describe a "function-first" proteomic strategy that uses size exclusion chromatography (SEC) to assess the global impact of electrophilic compounds on protein complexes in human cells. Integrating the SEC data with cysteine-directed activity-based protein profiling identifies changes in protein-protein interactions that are caused by site-specific liganding events, including the stereoselective engagement of cysteines in PSME1 and SF3B1 that disrupt the PA28 proteasome regulatory complex and stabilize a dynamic state of the spliceosome, respectively. Our findings thus show how multidimensional proteomic analysis of focused libraries of electrophilic compounds can expedite the discovery of chemical probes with site-specific functional effects on protein complexes in human cells., Competing Interests: Declaration of interests G.M.S., V.F.V., and L.R.W. are employees of Vividion Therapeutics, and B.F.C. is a founder and member of the Board of Directors of Vividion Therapeutics. G.W.Y. is a co-founder, member of the Board of Directors, on the SAB, equity holder, and paid consultant for Locanabio and Eclipse BioInnovations. G.W.Y.’s interests have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. A US provisional patent has been filed related to the work disclosed in this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase Cγ2 (PLCγ2 or PLCG2)-mutations in which are associated with autoinflammatory disorders and Alzheimer's disease-serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 in mouse microglia suppressed DAGL/MGLL-mediated endocannabinoid-eicosanoid cross-talk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2 -/- mice showed generally normal proinflammatory cytokine and chemokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLCγ2 function in innate immune cells, delineating a role in cross-talk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli., Competing Interests: The authors declare no competing interest.

PHARC (polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa, and cataract) is a human neurological disorder caused by deleterious mutations in the ABHD12 gene, which encodes an integral membrane lyso-phosphatidylserine (lyso-PS) lipase. Pharmacological or genetic disruption of ABHD12 leads to higher levels of lyso-PS lipids in human cells and the central nervous system (CNS) of mice. ABHD12 loss also causes rapid rewiring of PS content, resulting in selective increases in the level of arachidonoyl (C20:4) PS and decreases in the levels of other PS species. The biochemical basis for ABHD12-dependent PS remodeling and its pathophysiological significance remain unknown. Here, we show that genetic deletion of the lysophospholipid acyltransferase LPCAT3 blocks accumulation of brain C20:4 PS in mice lacking ABHD12 and concurrently produces hyper-increases in the level of lyso-PS in these animals. These lipid changes correlate with exacerbated auditory dysfunction and brain microgliosis in mice lacking both ABHD12 and LPCAT3. Taken together, our findings reveal that ABHD12 and LPCAT3 coordinately regulate lyso-PS and C20:4 PS content in the CNS and point to lyso-PS lipids as the likely bioactive metabolites contributing to PHARC-related neuropathologies.

Patients with non-small cell lung cancers that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR whereby the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities. Using chemical proteomics, we show here that individual T790M-EGFR inhibitors exhibit strikingly distinct off-target profiles in human cells. The FDA-approved drug osimertinib (AZD9291), in particular, was found to covalently modify cathepsins in cell and animal models, which correlated with lysosomal accumulation of the drug. Our findings thus show how chemical proteomics can be used to differentiate covalent kinase inhibitors based on global selectivity profiles in living systems and identify specific off-targets of these inhibitors that may affect drug activity and safety., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sulfonyl fluoride (SF)-based activity probes have become important tools in chemical biology. Herein, exploiting the relative chemical stability of SF to carry out a number of unprecedented SF-sparing functional group manipulations, we report the chemoselective synthesis of a toolbox of highly functionalized aryl SF monomers that we used to quickly prepare SF chemical biology probes. In addition to SF, the monomers bear an embedded click handle (a terminal alkyne that can perform copper(I)-mediated azide-alkyne cycloaddition). The monomers can be used either as fragments to prepare clickable SF analogues of drugs (biologically active compounds) bearing an aryl ring or, alternatively, attached to drugs as minimalist clickable aryl SF substituents., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: The purpose of this study is to study the practice of sedation by Portuguese palliative care teams., Methods: The teams included on the website of the Portuguese Association for Palliative Care were invited to participate. Data from all the patients sedated between April and June 2010 were recorded. Sedation was defined as the intentional administration of sedative drugs for symptom control, except insomnia, independently of the consciousness level reached., Results: Of the 19 teams invited only 4 actually participated. During the study period, 181 patients were treated: 171 (94 %) were cancer patients and 10 non-cancer patients. Twenty-seven (16 %) patients were sedated: 13 intermittently, 11 continuously, and 3 intermittently at first then continuously. The rate of sedation varied substantially among the teams. Delirium was the most frequent reason for sedation. Midazolam was the drug used in most cases. In 21 cases of sedation, the decision was made unilaterally by the professionals; in 16 (76 %) of those, the situation was deemed to be emergent. From the patients on continuous sedation, 9 (64 %) patients maintained oxygen, 13 (93 %) hydration, and 6 (43 %) nutrition. Two patients who had undergone intermittent sedation were discharged home and one was transferred to another institution; the reason for sedation in the three cases was delirium., Conclusion: There is a substantial variation in the sedation rate among the teams. One of the most important aspects was the decision-making process which should be object of reflection and discussion in the teams.

A role for dynamin in clathrin-mediated endocytosis is now well established. However, mammals express three closely related, tissue-specific dynamin isoforms, each with multiple splice variants. Thus, an important question is whether these isoforms and splice variants function in vesicle formation from distinct intracellular organelles. There are conflicting data as to a role for dynamin-2 in vesicle budding from the TGN. To resolve this issue, we compared the effects of overexpression of dominant-negative mutants of dynamin-1 (the neuronal isoform) and dynamin-2 (the ubiquitously expressed isoform) on endocytic and biosynthetic membrane trafficking in HeLa cells and polarized MDCK cells. Both dyn1(K44A) and dyn2(K44A) were potent inhibitors of receptor-mediated endocytosis; however neither mutant directly affected other membrane trafficking events, including transport mediated by four distinct classes of vesicles budding from the TGN. Dyn2(K44A) more potently inhibited receptor-mediated endocytosis than dyn1(K44A) in HeLa cells and at the basolateral surface of MDCK cells. In contrast, dyn1(K44A) more potently inhibited endocytosis at the apical surface of MDCK cells. The two dynamin isoforms have redundant functions in endocytic vesicle formation, but can be targeted to and function differentially at subdomains of the plasma membrane.

Proximal airway obstruction and acute life-threatening asphyxia is the most important complication of foreign body aspiration. Small foreign bodies that transverse the larynx may be initially asymptomatic appearing serious respiratory disturbances only later. Three patients with different clinical evolutions are reported and the diagnostic and therapeutic approaches, discussed.