Redefining Molecular Chaperones as Chaotropes

Molecular chaperones are the key instruments of bacterial protein homeostasis. Chaperones not only facilitate folding of client proteins, but also transport them, prevent their aggregation, dissolve aggregates and resolve misfolded states. Despite this seemingly large variety, single chaperones can perform several of these functions even on multiple different clients, thus suggesting a single biophysical mechanism underlying. Numerous recently elucidated structures of bacterial chaperone-client complexes show that dynamic interactions between chaperones and their client proteins stabilize conformationally flexible non-native client states, which results in client protein denaturation. Based on these findings, we propose chaotropicity as a suitable biophysical concept to rationalize the generic activity of chaperones. We discuss the consequences of applying this concept in the context of ATP-dependent and -independent chaperones and their functional regulation

Reactions to synthetic membranes dialyzers: Is there an increase in incidence?

Background: Reactions to dialyzers used in dialysis have been reported more frequently in recent years. Evidence, however, shows that the reaction rate has remained stable for years. Summary: One explanation for the apparent increase in publication frequency could be the lack of knowledge that dialyzer reactions may well occur with biocompatible membranes. Studies showed that the cause of these reactions is very diverse and varied, involving multiple materials. However, polyvinylpyrrolidone continues to be the main suspect, but without conclusive results. There are no differences between the different fibers, and although polysulfone is the most described, it is also the most used. Key Messages: The change to cellulose triacetate continues to be the most appropriate form of treatment. The classification of these reactions into type A and B complicates the diagnosis, and its true usefulness is in doubtThe research presented in this article is supported by the grants from the Spanish Ministry of Economy and Competitiveness and European Regional Development Funds (ERDF/FEDER) through ISCIII/FIS grants PI16/01298, PI17/01495, CIBERDEM and REDINREN RD016/0019 and through the Madrid Renal Society (SOMANE) grant

Regulation of chaperone function by coupled folding and oligomerization

The homotrimeric molecular chaperone Skp of Gram-negative bacteria facilitates the transport of outer membrane proteins across the periplasm. It has been unclear how its activity is modulated during its functional cycle. Here, we report an atomic-resolution characterization of the; Escherichia coli; Skp monomer-trimer transition. We find that the monomeric state of Skp is intrinsically disordered and that formation of the oligomerization interface initiates folding of the α-helical coiled-coil arms via a unique "stapling" mechanism, resulting in the formation of active trimeric Skp. Native client proteins contact all three Skp subunits simultaneously, and accordingly, their binding shifts the Skp population toward the active trimer. This activation mechanism is shown to be essential for; Salmonella; fitness in a mouse infection model. The coupled mechanism is a unique example of how an ATP-independent chaperone can modulate its activity as a function of the presence of client proteins

Bisfenol (A) una toxina a tener en cuenta en el enfermo renal en hemodiálisis

Introduction: Most uremic toxins are by-products of protein metabolism by action of intestinal flora. The metabolism of aromatic amino acids originates phenolic type residues. The most studied is p-cresol that is associated with renal function and vascular damage. Bisphenol A (BPA) is an exogenous molecule with characteristics similar to these aromatic uremic toxins. BPA is an estrogenic endocrine disruptor, found in tin cans, plastic bottles, epoxy resins and in some dialyzers. This molecule accumulates in patients who have impaired renal function. Observational studies have shown that exposure of BPA is linked to renal and cardiovascular injury, among many others in humans, and in animal studies a causal link has been described. Kidneys with normal renal function rapidly excrete BPA, but insufficient excretion in patients with CKD results in accumulation of BPA in the body.Muchas toxinas urémicas son originadas como consecuencia del catabolismo proteico por la flora intestinal. El metabolismo de aminoácidos aromáticos origina residuos de tipo fenólico. De estas toxinas, la más estudiada es el p-cresol, que se asocia a la función renal y daño vascular. El Bisfenol A (BPA) es una molécula exógena de características semejantes a estas toxinas urémicas aromáticas. El BPA es un disruptor endocrino estrogénico que se encuentra en latas de conserva, botellas de plástico, resinas epoxi y en algunos dializadores. Esta molécula se acumula en pacientes que tienen deteriorada la función renal. Estudios observacionales han demostrado que una exposición a BPA está vinculada, entre otras muchas, a lesión renal y cardiovascular en los seres humanos; en estudios en animales se ha descrito un vínculo causal. Los riñones con función renal normal excretan rápidamente BPA, pero una excreción insuficiente en pacientes con ERC da lugar a la acumulación del BPA en el organismo

Estudio de modelos de redes de abastecimiento de agua para el AAHH El Trébol, San Juan de Miraflores

En el presente trabajo se realiza un diseño de red de distribución de agua al asentamiento humano El Trébol, ubicado en Pamplona Alta Para esto, se analizó la zona y se propusieron 3 distintos modelos utilizando el programa de análisis hidráulico Epanet 2 0 uno con red cerrada y dos de red abierta para observar cómo se desenvuelven estos sistemas El modelo 2 y 3 de redes abiertas, tuvieron resultados favorables al evidenciarse una distribución uniforme de caudales, velocidades y presiones a lo largo de la red, sin embargo, al no contar con bomba, el modelo 3 resulta una mejor opción

Increased 1-year mortality in haemodialysis patients with COVID-19: A prospective, observational study

Background: Dialysis confers the highest risk of coronavirus disease 2019 (COVID-19) death among comorbidities predisposing to severe COVID-19. However, reports of COVID-19-associated mortality frequently refer to mortality during the initial hospitalization or first month after diagnosis. Methods: In a prospective, observational study, we analysed the long-term (1-year follow-up) serological and clinical outcomes of 56 haemodialysis (HD) patients who were infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first pandemic wave. COVID-19 was diagnosed by a positive polymerase chain reaction (PCR) test (n = 37) or by the development of anti-SARS-CoV-2 antibodies (n = 19). Results: After >1 year of follow-up, 35.7% of HD patients infected by SARS-CoV-2 during the first pandemic wave had died, 6 (11%) during the initial admission and 14 (25%) in the following months, mainly within the first 3 months after diagnosis. Overall, 30% of patients died from vascular causes and 40% from respiratory causes. In adjusted analysis, a positive SARS-CoV-2 PCR test for diagnosis {hazard ratio [HR] 5.18 [interquartile range (IQR) 1.30-20.65], P = 0.020}, higher baseline C-reactive protein levels [HR 1.10 (IQR 1.03-1.16), P = 0.002] and lower haemoglobin levels [HR 0.62 (IQR 0.45-0.86), P = 0.005] were associated with higher 1-year mortality. Mortality in the 144 patients who did not have COVID-19 was 21 (14.6%) over 12 months [HR of death for COVID-19 patients 3.00 (IQR 1.62-5.53), log-rank P = 0.00023]. Over the first year, the percentage of patients having anti-SARS-CoV-2 immunoglobulin G (IgG) decreased from 36/49 (73.4%) initially to 27/44 (61.3%) at 6 months and 14/36 (38.8%) at 12 months. Conclusions: The high mortality of HD patients with COVID-19 is not limited to the initial hospitalization. Defining COVID-19 deaths as those occurring within 3 months of a COVID-19 diagnosis may better represent the burden of COVID-19. In HD patients, the anti-SARS-CoV-2 IgG response was suboptimal and short-livedThis research received no external funding. The research groups of E.G.-P., S.M. and A.O. are funded by the Ministerio de Economia, Industria y competitividad: FIS/Fondos FEDER (PI16/01298, PI17/00257, PI18/01386, PI19/00588, PI19/00815, PI20/00487, PI21/01430), ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/-0009) and Sociedad Española de Nefrología, Comunidad de Madrid en Biomedicina (B2017/BMD-3686 CIFRA2-CM

The spectrum of clinical and serological features of COVID-19 in urban hemodialysis patients

The inherent immunosuppression of uremia increases the susceptibility of hemodialysis patients to infection. There is still limited evidence on hemodialysis patients and COVID-19. The clinical and analytical spectrum and treatment responses and mortality are poorly characterized. Material and Methods: Clinical and analytical features, chest X-ray, polymerase chain reaction (PCR) and antibodies for SARS-CoV-2, treatment and outcomes were analyzed in 48 patients diagnosed with COVID-19 during March and April 2020 in two coordinated Spanish hemodialysis units. Results: In 200 haemodialysis patients, COVID-19 was diagnosed in 48, of whom 22 were PCR positive, eight PCR negative but seroconverted and two were diagnosed on typical clinical grounds. Despite a mean age of 72.6 years, the overall mortality rate was 5/48 (10%). Among the PCR positive patients, 21 (55%) required admission and five (13%) died. PCR positive patients were more often symptomatic and hospitalized and had higher troponin I levels than PCR negative patients, but did not differ in lymphocyte counts, D-dimer or interleukin-6 (IL-6) levels. Among PCR negative COVID-19 patients, three out of 10 (30%) required admission, and none died. The most frequent symptom among the 48 patients was fever (31%), followed by asymptomatic patients (23%). A low number of lymphocytes was the only parameter significantly different between hospitalized and ambulatory COVID-19 patients, independently of PCR status. Conclusions: COVID-19 hemodialysis patients are frequently asymptomatic, and mortality may be lower than previously reported. Diagnosis may be retrospective, based on seroconversion, as PCR may be negative. This information should guide preventive and patient isolation strategiesResearch support from FIS ISCIII FEDER funds PI16/01298, PI15/00298, PI16/02057, PI16/01900, PI19/00815, DTS18/00032 ISCIII-RETIC REDinREN RD16/0009, CYTED IBERERC and Sociedad Madrileña de Nefrologia, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071), Comunidad de Madrid CIFRA2 B2017/BMD-3686. to A

Experimental Demonstration of ML-Based DWDM System Margin Estimation

SNR margins between partially and fully loaded DWDM systems are estimated without detailed knowledge of the network. The ML model, trained on simulation data, achieves accurate predictions on experimental data with an RMSE of 0.16 dB.Comment: This work has been partially funded by the German Federal Ministry of Education and Research in the CELTIC-NEXT project AI-NET-PROTECT (#16KIS1279K) and in the programme of "Souver\"an. Digital. Vernetzt." joint project 6G-life (#16KISK002). Work was also funded by Science Foundation Ireland projects OpenIreland (18/RI/5721) and 13/RC/2077 p

Animal Models of Cardiovascular Diseases

Cardiovascular diseases are the first leading cause of death and morbidity in developed countries. The use of animal models have contributed to increase our knowledge, providing new approaches focused to improve the diagnostic and the treatment of these pathologies. Several models have been developed to address cardiovascular complications, including atherothrombotic and cardiac diseases, and the same pathology have been successfully recreated in different species, including small and big animal models of disease. However, genetic and environmental factors play a significant role in cardiovascular pathophysiology, making difficult to match a particular disease, with a single experimental model. Therefore, no exclusive method perfectly recreates the human complication, and depending on the model, additional considerations of cost, infrastructure, and the requirement for specialized personnel, should also have in mind. Considering all these facts, and depending on the budgets available, models should be selected that best reproduce the disease being investigated. Here we will describe models of atherothrombotic diseases, including expanding and occlusive animal models, as well as models of heart failure. Given the wide range of models available, today it is possible to devise the best strategy, which may help us to find more efficient and reliable solutions against human cardiovascular diseases

Sarcopenia and mortality in older hemodialysis patients

(1) Sarcopenia is a progressive loss of skeletal muscle mass and strength. The aim of this study was to determine the association of sarcopenia, defined according to the Working Group on Sarcopenia in Older People (EWGSOP2) diagnostic criteria, with mortality at 24 months in very elderly hemodialysis patients. (2) A prospective study was conducted in 60 patients on chronic hemodialysis who were older than 75 years. Sarcopenia was diagnosed according to EWGSOP2 criteria. Additionally, clinical, anthropometric and analytical variables and body composition by bioimpedance were assessed. The date and cause of death were recorded during 2 years of follow-up. (3) Among study participants, 41 (68%) were men, the mean age 81.85 ± 5.58 years and the dialysis vintage was 49.88 ± 40.29 months. The prevalence of probable sarcopenia was 75% to 97%, depending on the criteria employed: confirmed sarcopenia ranged from 37 to 40%, and severe sarcopenia ranged from 18 to 37%. A total of 30 (50%) patients died over 24 months. Sarcopenia probability variables were not related to mortality. In contrast, sarcopenia confirmation (appendicular skeletal muscle mass, ASM) and severity (gait speed, GS) variables were associated with mortality. In multivariate analysis, the hazard ratio (95% confidence interval) for all-cause death was 3.03 (1.14-8.08, p = 0.028) for patients fulfilling ASM sarcopenia criteria and 3.29 (1.04-10.39, p = 0.042) for patients fulfilling GS sarcopenia criteria. (4) The diagnosis of sarcopenia by EWGSOP2 criteria is associated with an increased risk of all-cause death in elderly dialysis patients. Specifically, ASM and GS criteria could be used as mortality risk markers in elderly hemodialysis patients. Future studies should address whether the early diagnosis and treatment of sarcopenia improve outcomes.This research received no external funding. E.G.-P., S.M.-F. and A.O.-A. research groups are funded by Ministerio de Economia, Industria y competitividad: FIS/Fondos FEDER (PI16/01298, PI17/00257, PI18/01386, PI19/00588, PI19/00815, PI20/00487, PI21/01430, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009) and Sociedad Española de Nefrología, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. All authors want to thank Fundación Renal Íñigo Álvarez de Toledo (FRIAT) for its support to renal research in Spain. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Financiadores Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM FRIAT Fundación Renal Íñigo Álvarez de Toledo Ministerio de Economia Sociedad Española de Nefrología Spain Federación Española de Enfermedades Raras Spain PI21/0143