Description of a utrophin associated protein complex in lipid raft domains of human artery smooth muscle cells

AbstractThe dystrophin-associated protein complex (DAPC) is a multimeric complex that links the extracellular matrix to the actin cytoskeleton, and in some cases dystrophin can be substituted by its autosomal homologue utrophin to form the utrophin-associated protein complex (UAPC). Both complexes maintain the stability of plasma membrane during contraction process and play an important role in transmembrane signaling. Mutations in members of the DAPC are associated with muscular dystrophy and dilated cardiomyopathy. In a previous study with human umbilical cord vessels, we observed that utrophin colocalize with caveolin-1 (Cav-1) which proposed the presence of UAPC in the plasma membrane of vascular smooth muscle (VSM). In the current study, we demonstrated by immunofluorescence analysis, co-immunoprecipitation assays, and subcellular fractionation by sucrose gradients, the existence of an UAPC in lipid raft domains of human umbilical artery smooth muscle cells (HUASMC). This complex is constituted by utrophin, β-DG, ε-SG, α-smooth muscle actin, Cav-1, endothelial nitric oxide synthase (eNOS) and cavin-1. It was also observed the presence of dystrophin, utrophin Dp71, β-SG, δ-SG, δ-SG3 and sarcospan in non-lipid raft fractions. Furthermore, the knockdown of α/β-DG was associated with the decrease in both the synthesis of nitric oxide (NO) and the presence of the phosphorylated (active) form of eNOS; and with a reduction in the downstream activation of some cGMP signaling transduction pathway components. Together these results show the presence of an UAPC complex in HUASMC that may participate in the activity regulation of eNOS and in the vascular function

The Ship of Theseus Puzzle

Does the Ship of Theseus present a genuine puzzle about persistence due to conflicting intuitions based on “continuity of form” and “continuity of matter” pulling in opposite directions? Philosophers are divided. Some claim that it presents a genuine puzzle but disagree over whether there is a solution. Others claim that there is no puzzle at all since the case has an obvious solution. To assess these proposals, we conducted a cross-cultural study involving nearly 3,000 people across twenty-two countries, speaking eighteen different languages. Our results speak against the proposal that there is no puzzle at all and against the proposal that there is a puzzle but one that has no solution. Our results suggest that there are two criteria—“continuity of form” and “continuity of matter”— that constitute our concept of persistence and these two criteria receive different weightings in settling matters concerning persistence

Renal Complications Due to SARS-CoV-2 Infection in Pediatric Population

Background and Aim: COVID-19 pandemic originated in Wuhan City, China, in 2019.The disease spectrum ranges from asymptomatic to severe respiratory failure leadingto death. Although in a lower percentage, pediatric patients also have complications,not only pulmonary but also systemic, affecting other organs. This article aims to studythe renal involvement of pediatric patients infected by the Severe Acute RespiratorySyndrome Coronavirus 2 (SARS-CoV-2).Methods: We designed a retrospective observational cohort study of patientshospitalized in the emergency department and intensive care unit of a tertiary medicalfacility hospital Infantil de México Federico Gomez in Mexico City, from March 1,2020, to May 16, 2021. The inclusion criteria included patients younger than 18 yearswho had a positive Reverse Transcription-Polymerase Chain Reaction (RT-PCR) test ora positive rapid antigen test of nasopharyngeal sample for SARS-CoV-2 at admission.Results: We included 165 patients, of whom 29(17.6%) patients developed renalcomplications during hospitalization. In these patients, 12(41.3%) patients developedproteinuria, 10(34.5%) developed any type of Acute Kidney Injury (AKI), i.e., AcuteKidney Injury Network (AKIN-1) in 26.6%, AKIN-2 in 40% and AKIN-3 in 33.3%.Also, 5(17.2%) patients had arterial hypertension, 2(6.9%) required renal replacementtherapy, 4(13.8%) had hematuria. Only 1(3.4%) patient had developed rapidlyprogressive glomerulonephritis.Conclusion: COVID-19 infection within its spectrum can cause kidney disease; themost common complications are proteinuria and AKI. Older age and admission to theintensive care unit are risk factors for kidney damage

Comprehensive description of clinical characteristics of a large systemic Lupus Erythematosus Cohort from the Spanish Rheumatology Society Lupus Registry (RELESSER) with emphasis on complete versus incomplete lupus differences

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement and pronounced racial and ethnic heterogeneity. The aims of the present work were (1) to describe the cumulative clinical characteristics of those patients included in the Spanish Rheumatology Society SLE Registry (RELESSER), focusing on the differences between patients who fulfilled the 1997 ACR-SLE criteria versus those with less than 4 criteria (hereafter designated as incomplete SLE (iSLE)) and (2) to compare SLE patient characteristics with those documented in other multicentric SLE registries. RELESSER is a multicenter hospital-based registry, with a collection of data from a large, representative sample of adult patients with SLE (1997 ACR criteria) seen at Spanish rheumatology departments. The registry includes demographic data, comprehensive descriptions of clinical manifestations, as well as information about disease activity and severity, cumulative damage, comorbidities, treatments and mortality, using variables with highly standardized definitions. A total of 4.024 SLE patients (91% with ≥4 ACR criteria) were included. Ninety percent were women with a mean age at diagnosis of 35.4 years and a median duration of disease of 11.0 years. As expected, most SLE manifestations were more frequent in SLE patients than in iSLE ones and every one of the ACR criteria was also associated with SLE condition; this was particularly true of malar rash, oral ulcers and renal disorder. The analysis-adjusted by gender, age at diagnosis, and disease duration-revealed that higher disease activity, damage and SLE severity index are associated with SLE [OR: 1.14; 95% CI: 1.08-1.20 (P < 0.001); 1.29; 95% CI: 1.15-1.44 (P < 0.001); and 2.10; 95% CI: 1.83-2.42 (P < 0.001), respectively]. These results support the hypothesis that iSLE behaves as a relative stable and mild disease. SLE patients from the RELESSER register do not appear to differ substantially from other Caucasian populations and although activity [median SELENA-SLEDA: 2 (IQ: 0-4)], damage [median SLICC/ACR/DI: 1 (IQ: 0-2)], and severity [median KATZ index: 2 (IQ: 1-3)] scores were low, 1 of every 4 deaths was due to SLE activity. RELESSER represents the largest European SLE registry established to date, providing comprehensive, reliable and updated information on SLE in the southern European population

Fortalecimiento del manejo y conservación de corales en Áreas Naturales Protegidas del Pacífico mexicano mediante una red colaborativa

Most of the coral communities of the Mexican Pacific Ocean are located in Natural Protected Areas (NPAs); nevertheless, they are in risk for climatic and anthropogenic threats. In order to promote the conservation of coral reefs in the Mexican Pacific Ocean, one has formed the Coral Conservation Network of the Mexican Pacific. The efforts of collaboration have focused on four principal axes a) strengthening of the management in NPAs, b) training and diffusion of good tourism practices, c) evaluation of the state of conservation of the coral reefs, and d) environmental sensitization. There has been achieved the publication and diffusion of the State of Conservation of the Corals of the Mexican Pacific, in which there are estimated the indicators of coral coverage, abundance and biomass of fish, abundance of invertebrates, and the calculation of the Integrated Index of Reef Health. These indicators reflect the management implemented in the ANPs, participants of these analyses; the utility of standardized protocols that allow comparisons in the time and between NPAs, as well as the need to carry out the monitoring, adapted to the region, and coherent with the capacities of the actors on each ANP. On the other hand, sensitization has been carried out on the importance and the threats towards the corals to persons of different sectors across campaigns of environmental sensitization that reached 5,000 students, as well as the distribution of 12,000 guides of the identification of species and good tourism practices in NPAs. These efforts have been important, nevertheless the creation and permanence of the Coral Conservation Network of the Mexican Pacific Ocean has been perhaps the most impactful achievement on management and conservation in the Region.La mayoría de las comunidades coralinas del Pacífico mexicano están ubicadas en Áreas Naturales Protegidas (ANPs); sin embargo, están en riesgo por amenazas climáticas y antropogénicas. Con el fin de promover la conservación de arrecifes de coral en el Pacífico mexicano, se ha formado la Red de Conservación de los Corales del Pacífico mexicano. Los esfuerzos de colaboración se han enfocado en cuatro ejes principales a) fortalecimiento del manejo de ANPs, b) capacitación y difusión de buenas prácticas turísticas, c) evaluación del estado de conservación de los sistemas arrecifales, y d) sensibilización ambiental. Se ha logrado la publicación y difusión del Estado de Conservación de los Corales del Pacífico mexicano, en el cual se estiman los indicadores de cobertura de coral, abundancia y biomasa de peces, abundancia de invertebrados y el cálculo del Índice Integrado de Salud Arrecifal. Estos indicadores reflejan las medidas de manejo en las ANPs que participaron, la utilidad de protocolos estandarizados que permiten realizar comparaciones en el tiempo y entre ANPs, así como la necesidad de llevar a cabo los monitoreos de forma adaptada a la región y congruente con las capacidades de los actores en cada ANP. Por otro lado, también se ha llevado a cabo la sensibilización sobre la importancia y las amenazas hacia los corales a personas de diferentes sectores, a través de campañas de sensibilización ambiental que han alcanzado 5,000 estudiantes, así como de la distribución de 12,000 guías de identificación de especies y buenas prácticas turísticas en ANPs. Estos esfuerzos han sido importantes, sin embargo la creación y permanencia de la Red de Conservación de los Corales del Pacífico mexicano ha sido quizás el mayor logro de manejo y conservación en la Región

Immunity and vaccine development efforts against Trypanosoma cruzi

Artículo de revisión especializadoTrypanosoma cruzi (T. cruzi) is the causative agent for Chagas disease (CD). There is a critical lack of methods for prevention of infection or treatment of acute infection and chronic disease. Studies in experimental models have suggested that the protective immunity against T. cruzi infection requires the elicitation of Th1 cytokines, lytic antibodies and the concerted activities of macrophages, T helper cells, and cytotoxic T lymphocytes (CTLs). In this review, we summarize the research efforts in vaccine development to date and the challenges faced in achieving an efficient prophylactic or therapeutic vaccine against human CD.UTM

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Nothing at Stake in Knowledge

Many philosophers hold that stakes affect ordinary knowledge ascriptions. Here’s a version of a pair of cases aimed at supporting this: Bob and his wife are driving home on Friday and considering whether to stop at the bank to deposit a check. The lines at the bank are very long and so Bob considers coming back on Saturday. In the low stakes version, nothing of importance hinges on whether the check is deposited; in the high stakes version, it is very important that the check be deposited. Bob’s wife asks whether the bank will be open on Saturday. Bob says he drove past the bank last Saturday, and it was open. However, his wife points out that banks sometimes change their hours. Bob says “I know the bank will be open tomorrow”. In the low stakes case, many philosophers maintain that Bob does indeed know that the bank will be open; in the high stakes case, these philosophers maintain that Bob is ignorant – his statement that he knows the bank will be open tomorrow is false. These philosophers also maintain that this pattern of judgments is what we would expect from competent speakers confronted with this and similar cases (e.g., Cohen, 1999, 2013; DeRose, 1992, 2009; Fantl and McGrath, 2002; Nagel, 2008; Rysiew, 2001; Stanley, 2005). Though many philosophers agree that stakes play a role in ordinary knowledge ascriptions, there is disagreement about what explains this. One view, epistemic contextualism, holds that “to know” is a context sensitive verb and that the truth conditions for knowledge ascriptions can vary across conversational contexts (e.g., DeRose, 2009). For instance, Bob’s statement “I know the bank will be open tomorrow” can be true in low stakes contexts and false in high stakes contexts. Another view, interest-relative invariantism, denies that “to know” is a context sensitive verb and that the truth conditions for knowledge ascriptions vary according to conversational contexts. Instead, cases like the Bank cases show that practical factors—i.e., stakes—play a distinctive role in determining whether the knowledge relation obtains (e.g., Stanley, 2005). Yet another alternative, which we’ll call classical invariantism, denies that “to know” is a context sensitive verb and that practical factors, such as stakes, play a direct role in determining whether the knowledge relation obtains. Instead, stakes affect knowledge ascriptions only by affecting our assessment of factors that have traditionally been taken to constitute or be necessary for knowledge, such as e.g., belief, quality of evidence, etc. (e.g., Bach, 2005; Weatherson, 2005; Ganson, 2007; Nagel, 2008). If this is right, then the role of stakes in knowledge ascriptions fails to motivate such surprising views as epistemic contextualism or interest-relative invariantism. Naturally, epistemic contextualists and interest-relative invariantists deny this, claiming that even when the factors that have traditionally been taken to constitute or be necessary for knowledge are held fixed, stakes continue to play a role in ordinary knowledge ascriptions (e.g., DeRose, 2009; Lawlor, 2013). So we see a dispute over what best explains the role of stakes in ordinary knowledge ascriptions. It is thus extremely surprising that a wide range of empirical evidence suggests that ordinary knowledge ascriptions fail to display any sensitivity to stakes (e.g., Buckwalter, 2010; Buckwalter and Schaffer, 2015; Feltz and Zarpentine, 2010; May, Sinnott-Armstrong, Hull, and Zimmerman, 2010; Turri, forthcoming; though see e.g., Pinillos, 2012; Pinillos and Simpson, 2014; Sripada and Stanley, 2012). If stakes really do not play any role in ordinary knowledge ascriptions, one of the main motivations for epistemic contextualism and interest relative invariantism would be undermined. Perhaps these different explanations of the role of stakes in ordinary knowledge ascription are born out of nothing more than a myth (Schaffer and Knobe, 2009). If so, classical invariantism about knowledge might be best supported—not because it provides the best explanation of the role of stakes in ordinary knowledge ascriptions, but rather because the failure of stakes to play a role in ordinary knowledge ascription would undercut an important motivation for its two competitors, epistemic contextualism and interest-relative invariantism. These radical alternatives to classical invariantism, lacking evidence in support of one of their important motivations, should perhaps then fall. Classical invariantism would stand. In the remainder of this article, we’ll disarm an important motivation for epistemic contextualism and interest-relative invariantism. We’ll accomplish this by presenting a stringent test of whether there is a stakes effect on ordinary knowledge ascription. Having shown that, even on a stringent way of testing, stakes fail to impact ordinary knowledge ascription, we will conclude that we should take another look at classical invariantism. Here is how we will proceed. Section 1 lays out some limitations of previous research on stakes. Section 2 presents our study and concludes that there is little evidence for a substantial stakes effect. Section 3 responds to objections. The conclusion clears the way for classical invariantism

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality