Haptoglobin genotype and risk of diabetic nephropathy in patients with type 1 diabetes mellitus: a study on a Spanish population

[en] BACKGROUND: Few reports have studied the possible association between the haptoglobin (Hp) genotype and the risk of diabetic nephropathy (DN) in type 1 diabetes (T1D), with conflicting results to date. AIMS: To study whether the 2-2 Hp genotype is associated with an increased risk of overt DN in a Spanish population with T1D. METHODS: We performed a case-control study in a Spanish population. CASES: T1D patients with end-stage renal disease (stage 5 of NKF-KDOQI), awaiting reno-pancreatic transplantation or having already been transplanted (reno-pancreatic or renal alone). CONTROLS: T1D patients, matched for sex and time of diabetes evolution, with preserved renal function and normal urinary albumin excretion. Hp genotyping was done using polymerase chain reaction and electrophoresis. RESULTS: We included 57 cases and 57 controls in the study. There were no statistically significant differences in gender (70% vs. 61% males, p=1.0) or the duration of diabetes (23.0 ± 6.7 vs. 20.8 ± 9.3 years; p=0.1), although the age of onset of diabetes was lower in the cases (14.1 ± 6.8 vs. 17.7 ± 10.1 years, p=0.03). The frequency of genotypes 1-1, 1-2 and 2-2 was 19.3%, 42.1% and 38.6% in cases and 17.5%, 49.1% and 33.4% in controls, respectively, with no statistically significant differences between groups (p=0.8). Conditional logistic regression analysis showed no significant association between genotype 2-2 of Hp and the development of DN (OR 1.14, CI 0.52-2.52). CONCLUSIONS: In our sample of a Spanish population with T1D, no association was found between the Hp genotype and risk of overt DN. [spa] Antecedentes: Pocos trabajos han estudiado la asociación entre el genotipo de la haptoglobina (Hp) y el riesgo de nefropatía diabética (ND) en pacientes con diabetes tipo 1 (DM1), con resultados contradictorios hasta ahora. Objetivos: Estudiar si el genotipo 2-2 de Hp se asocia a un incremento del riesgo de ND en población española con DM1. Métodos: Se diseñó un estudio de casos y controles. CASOS: pacientes con DM1 y enfermedad renal crónica estadio 5 de la NKF-KDOQI, en espera de trasplante reno-pancreático o que han sido trasplantados (reno-pancreático o renal aislado). CONTROLES: pacientes con DM1, apareados por sexo y tiempo de evolución de la diabetes, con función renal y excreción urinaria de albúmina normales. El genotipo de Hp se realizó mediante reacción en cadena de la polimerasa y electroforesis. Resultados: Incluimos 57 casos y 57 controles, sin diferencias estadísticamente significativas en el sexo (70 % frente a 61 % varones, p = 1,0) o duración de la diabetes (23,0 ± 6,7 frente a 20,8 ± 9,3 años; p = 0,1), aunque la edad de inicio de la diabetes fue menor en los casos (14,1 ± 6,8 frente a 17,7 ± 10,1 años, p = 0,03). La frecuencia de genotipos 1-1, 1-2 y 2-2 fue de 19,3 %, 42,1 % y 38,6 % en los casos y de 17,5 %, 49,1 % y 33,4 % en los controles, respectivamente, sin diferencias significativas (p = 0,8). El análisis de regresión logística condicional no mostró asociación entre el genotipo 2-2 de Hp y el desarrollo de ND (OR 1,14, IC 0,52-2,52). Conclusiones: En nuestra muestra de población española con DM1, no se ha hallado asociación entre el genotipo de Hp y el riesgo de ND

Decay of linkage disequilibrium within genes across HGDP-CEPH human samples: most population isolates do not show increased LD

9 pages, 2 figures, 4 additional files.[Background] It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, particularly in isolated populations where it is assumed to be higher. Here, we explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing particularly on the populations defined as isolates. Within each gene region and population we use r2 between all possible single nucleotide polymorphism (SNP) pairs as a measure of linkage disequilibrium and focus on the proportion of SNP pairs with r2 greater than 0.8.[Results] Although the average r2 was found to be significantly different both between and within continental regions, a much higher proportion of r2 variance could be attributed to differences between continental regions (2.8% vs. 0.5%, respectively). Similarly, while the proportion of SNP pairs with r2 > 0.8 was significantly different across continents for all distance classes, it was generally much more homogenous within continents, except in the case of Africa and the Americas. The only isolated populations with consistently higher LD in all distance classes with respect to their continent are the Kalash (Central South Asia) and the Surui (America). Moreover, isolated populations showed only slightly higher proportions of SNP pairs with r2 > 0.8 per gene region than non-isolated populations in the same continent. Thus, the number of SNPs in isolated populations that need to be genotyped may be only slightly less than in non-isolates.[Conclusion] The "isolated population" label by itself does not guarantee a greater genotyping efficiency in association studies, and properties other than increased linkage disequilibrium may make these populations interesting in genetic epidemiology.This research was supported by "Fundación Genoma España" (proyectos piloto CEGEN 2004–2005), Dirección General de Investigación, Ministerio de Educación y Ciencia of Spain (grants BFU2005-00243, BFU2006-01235, BFU2006-15413-CO2-01, SEJ2006-13537) and Direcció General de Recerca, Generalitat de Catalunya (2005SGR00608). SNP genotyping services were provided by the Spanish "Centro Nacional de Genotipado"Peer reviewe

The UBA-UIM Domains of the USP25 Regulate the Enzyme Ubiquitination State and Modulate Substrate Recognition

USP25m is the muscle isoform of the deubiquitinating (DUB) enzyme USP25. Similarly to most DUBs, data on USP25 regulation and substrate recognition is scarce. In silico analysis predicted three ubiquitin binding domains (UBDs) at the N-terminus: one ubiquitin-associated domain (UBA) and two ubiquitin-interacting motifs (UIMs), whereas no clear structural homology at the extended C-terminal region outside the catalytic domains were detected. In order to asses the contribution of the UBDs and the C-terminus to the regulation of USP25m catalytic activity, ubiquitination state and substrate interaction, serial and combinatorial deletions were generated. Our results showed that USP25m catalytic activity did not strictly depend on the UBDs, but required a coiled-coil stretch between amino acids 679 to 769. USP25 oligomerized but this interaction did not require either the UBDs or the C-terminus. Besides, USP25 was monoubiquitinated and able to autodeubiquitinate in a possible loop of autoregulation. UBDs favored the monoubiquitination of USP25m at the preferential site lysine 99 (K99). This residue had been previously shown to be a target for SUMO and this modification inhibited USP25 activity. We showed that mutation of K99 clearly diminished USP25-dependent rescue of the specific substrate MyBPC1 from proteasome degradation, thereby supporting a new mechanistic model, in which USP25m is regulated through alternative conjugation of ubiquitin (activating) or SUMO (inhibiting) to the same lysine residue (K99), which may promote the interaction with distinct intramolecular regulatory domains

Diversity of Y-chromosomal and mtDNA Markers Included in Mediscope Chip within Two Albanian Subpopulations from Croatia and Kosovo: Preliminary Data

The aim of this preliminary study is to analyze genetic specificity of Kosovo Albanians comparing with neighboring populations using new genetic tool - MEDISCOPE gene chip, to investigate the feasibility of this approach. We collected 37 DNA samples (9 Croats, 17 Albanians from Croatia and 11 Albanians from Kosovo) from unrelated males born in Croatia and Kosovo. Additionally, samples were expanded with female individuals and mtDNA analysis included a total of 61 samples (15 Croats, 23 Albanians from Croatia and 23 Albanians from Kosovo). This pilot study suggests that the usage of the MEDISCOPE chip could be recognized as an efficient tool within recognition of the population genetic specificity even within extremely small sample size

Detection of norovirus in saliva samples from acute gastroenteritis cases and asymptomatic subjects : Association with age and higher shedding in stool

Norovirus infections are a leading cause of acute gastroenteritis outbreaks worldwide and across all age groups, with two main genogroups (GI and GII) infecting humans. The aim of our study was to investigate the occurrence of norovirus in saliva samples from individuals involved in outbreaks of acute gastroenteritis in closed and semiclosed institutions, and its relationship with the virus strain, virus shedding in stool, the occurrence of symptoms, age, and the secretor status of the individual. Epidemiological and clinical information was gathered from norovirus outbreaks occurring in Catalonia, Spain during 2017-2018, and stool and saliva samples were collected from affected and exposed resident individuals and workers. A total of 347 saliva specimens from 25 outbreaks were analyzed. Further, 84% of individuals also provided a paired stool sample. For GII infections, norovirus was detected in 17.9% of saliva samples from symptomatic cases and 5.2% of asymptomatic individuals. Positivity in saliva occurred in both secretors and nonsecretors. None of the individuals infected by norovirus GI was positive for the virus in saliva. Saliva positivity did not correlate with any of the studied symptoms but did correlate with age ≥ 65 years old. Individuals who were positive in saliva showed higher levels of virus shedding in stool. Mean viral load in positive saliva was 3.16 ± 1.08 log10 genome copies/mL, and the predominance of encapsidated genomes was confirmed by propidium monoazide (PMA)xx-viability RTqPCR assay. The detection of norovirus in saliva raises the possibility of oral-to-oral norovirus transmission during the symptomatic phase and, although to a lesser extent, even in cases of asymptomatic infections

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant

BACKGROUND: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. METHODS: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. RESULTS: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. CONCLUSIONS: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

L'Enzim deubiqüitinant USP25: cerca de substrats i relació estructura-funció

[cat] La degradació de proteïnes mitjançant el sistema de les ubiquitines i el proteasoma (UPS) és un procés altament regulat, en el qual diverses famílies enzimàtiques s'encarreguen de la correcte conjugació i deconjugació de molècules d'ubiquitina a un determinat substrat. Una d'aquestes famílies és la dels enzims deubiquitinitzants (DUBs), de la qual se n'han descrit, en humans, més de 90 membres. USP25 (21q11.2) codifica per un enzim deubiquitinitzant i produeix tres isoformes per splicing alternatiu. Una d'elles, generada per la inclusió de l'exó 19a entre el 18 i el 19b, presenta una expressió restringida a múscul esquelètic i cor (USP25m). Mitjançant un assaig de dos híbrids en llevat varem determinar que USP25m interacciona amb una proteïna d'unió a la miosina (MyBPC1), amb l'actina 1 (ACTA1) i amb la filamina C (FLNC). Totes aquestes proteïnes són sarcomèriques, regulen la diferenciació i el manteniment de les cèl.lules musculars i han estat implicades en diverses patologies humanes. Assajos bioquímics realitzats per aprofundir en la rellevància funcional d'aquestes interaccions ens mostren que els nivells de MyBPC1 estan regulats pel proteasoma, i que USP25m és capaç d'abolir seva degradació. En canvi, ACTA1 i FLNC són proteïnes estables, suggerint que la seva interacció amb USP25m està relacionada amb mecanismes reguladors de l'estructura i la funció del sarcòmer, i no amb la seva degradació. USP25 conté tres dominis d'unió a ubiqüitina implicats en el reconeixement de substrats i pot ser modificada per diversos tipus de modificació posttraduccional com la ubiqüitinació, la sumoïlació, la fosforilació i l'acetilació. El fet que sigui una proteïna multimodificada suggereix que la seva activitat enzimàtica ha d'estar finament regulada. Per últim, la sobreexpressió d'USP25 és capaç d'induïr una aturada en el cicle cel·lular, per mecanismes encara desconeguts.[eng] USP25 is a deubiquitinating enzyme (DUB) that generates a muscle-specific isoform, USP25m, by alternative splicing. USP25m interacts with several sarcomeric proteins, but similarly to most DUBs, the contribution of different protein domains to enzymatic activity and substrate recognition remains to be ascertained. In silico analysis revealed the position of the catalytic signatures and predicted three ubiquitin binding domains (UBDs): one ubiquitin-associated domain (UBA) and 2 ubiquitin-interacting motifs (UIMs). By generating serial and combinatorial deletions of these domains, we analyzed their contribution to USP25m catalytic activity, substrate recognition, subcellular localization, and post-translational modifications, such as ubiquitination and sumoylation. Our results indicate that ablation of these motifs do not abrogate USP25 deubiquitinating activity, neither promoted any significant alteration in subcellular localization of the enzyme nor ubiquitin. However, USP25 UBDs contribute to specific substrate recognition, as interaction with each substrate requires a different combination or number of UBDs, in an additive or synergistic manner. USP25m is sumoylated in vitro and ubiquitinated, although the UBDs are not required for these post-translational modifications. In addition, USP25m is phosphorylated in Tyr, Ser/Thr residues and acetylated. The physiological relevance of all these modifications remains to be ascertained. USP25 overexpression causes cell cycle arrest, most probably at the G1/S transition