The endocytic pathway is a common strategy that several highly pathogenic viruses use to enter into the cell. To demonstrate the usefulness of this pathway as a common target for the development of ...broad-spectrum antivirals, the inhibitory effect of drug compounds targeting endosomal membrane proteins were investigated. This study entailed direct comparison of drug effectiveness against animal and human pathogenic viruses, namely Ebola (EBOV), African swine fever virus (ASFV), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
A panel of experimental and FDA-approved compounds targeting calcium channels and PIKfyve at the endosomal membrane caused potent reductions of entry up to 90% in SARS-CoV-2 S-protein pseudotyped retrovirus. Similar inhibition was observed against transduced EBOV glycoprotein pseudovirus and ASFV. SARS-CoV-2 infection was potently inhibited by selective estrogen receptor modulators in cells transduced with pseudovirus, among them Raloxifen inhibited ASFV with very low 50% inhibitory concentration. Finally, the mechanism of the inhibition caused by the latter in ASFV infection was analyzed.
Overall, this work shows that cellular proteins related to the endocytic pathway can constitute suitable cellular targets for broad range antiviral compounds.
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•Targeting the endocytic pathway can be a common antiviral strategy against distant animal and human pathogenic viruses.•Compounds targeting endosomal calcium channels and PIKfyve enzyme, inhibited entry of these viruses with similar potency.•SERMS TMX and RLX caused marked infectivity reductions, obtaining for RLX an IC50 of 0.91 inhibiting ASFV.•The mechanism of action of SERMS on ASFV was not due to their action on the estrogen receptor pathway.•SERMS inhibited ASFV infectivity acting at the endosomal flux of calcium and cholesterol.
In an effort to identify rare alleles associated with SLE, we have performed whole exome sequencing of the most distantly related affected individuals from two large Icelandic multicase SLE families ...followed by Ta targeted genotyping of additional relatives. We identified multiple rare likely pathogenic variants in nineteen genes co-segregating with the disease through multiple generations. Gene co-expression and protein-protein interaction analysis identified a network of highly connected genes comprising several loci previously implicated in autoimmune diseases. These genes were significantly enriched for immune system development, lymphocyte activation, DNA repair, and V(D)J gene recombination GO-categories. Furthermore, we found evidence of aggregate association and enrichment of rare variants at the FAM71E1/EMC10 locus in an independent set of 4,254 European SLE-cases and 4,349 controls. Our study presents evidence supporting that multiple rare likely pathogenic variants, in newly identified genes involved in known disease pathogenic pathways, segregate with SLE at the familial and population level.
Since demonstration of the benefit of endovascular treatment (EVT) in acute ischemic stroke patients with proximal arterial occlusion, stroke care systems need to be reorganized to deliver EVT in a ...timely and equitable way. We analyzed differences in the access to EVT by geographical areas in Catalonia, a territory with a highly decentralized stroke model.
We studied 965 patients treated with EVT from a prospective multicenter population-based registry of stroke patients treated with reperfusion therapies in Catalonia, Spain (SONIIA). Three different areas were defined: (A) health areas primarily covered by Comprehensive Stroke Centers, (B) areas primarily covered by local stroke centers located less than hour away from a Comprehensive Stroke Center, and (C) areas primarily covered by local stroke centers located more than hour away from a Comprehensive Stroke Center. We compared the number of EVT×100 000 inhabitants/year and time from stroke onset to groin puncture between groups.
Baseline characteristics were similar between groups. Throughout the study period, there were significant differences in the population rates of EVT across geographical areas. EVT rates by 100 000 in 2015 were 10.5 in A area, 3.7 in B, and 2.7 in C. Time from symptom onset to groin puncture was 82 minutes longer in group B (312 minutes 245-435) and 120 minutes longer in group C (350 minutes 284-408) compared with group A (230 minutes 160-407; P<0.001).
Accessibility to EVT from remote areas is hampered by lower rate and longer time to treatment compared with areas covered directly by Comprehensive Stroke Centers.
Primary graft failure (PGF) is the leading cause of early heart transplantation (HT) mortality. Our aim was to analyze PGF currently and explore the ability of a dedicated score for PGF risk ...stratification.
After applying a dedicated PGF definition, we analyzed its incidence, mortality, and associated factors in a multicenter cohort of 857 HTs performed in 2006 to 2009. We used the following criteria: recipient right (R) atrial pressure ≥ 10 mm Hg; age (A) ≥ 60 years; diabetes (D) mellitus, and inotrope (I) dependence; donor age (A) ≥ 30 years, and length (L) of ischemia ≥ 240 minutes to calculate the RADIAL score for PGF risk prediction.
PGF incidence was 22%. The right ventricle was almost always affected, alone (45%) or as part of biventricular failure (47%). Mechanical circulatory support was used in 55%. Mortality attributable to PGF was 53% and extended through the third month after HT, but thereafter, PGF had little influence in long-term outcome. The RADIAL score was higher in PGF patients (2.78 ± 1.1 vs. 2.42 ± 1.1, p = 0.001) and stratified 3 groups with incremental PGF incidence: low risk (12.1%), intermediate risk (19.4%), and high risk (27.5%, p = 0.001).
PGF had a strong impact, with an incidence of 22% and a mortality exceeding 50% that extends through the third post-HT month. The RADIAL score classified patients into 3 groups with incremental risk for PGF and may be useful for its prevention and early therapy.
•PCV13 effectiveness since its inclusion in the Community of Madrid in 2010.•PCV13 implementation led to the almost total disappearance of serotype 19A.•Near-elimination of serotype 19A caused ...disappearance of all related meningitis cases.•Near-elimination of serotype 19A caused a decrease in antibiotic resistance.•PCV13 did not cause replacement by other serotypes not covered by the vaccine.
Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. Using the data from the HERACLES clinical surveillance study (2007–2016), we describe the population impact of the 13-valent pneumococcal conjugate vaccine (PVC13) on invasive pneumococcal disease (IPD) in children <15 years of age in the Community of Madrid, Spain. After six years of the inclusion of PCV13 in the vaccination calendar (2010–2016), and despite changes in the Regional Immunization Programme that limited its availability, the net benefit incidence rate (IR) of IPD fell by 70.1% (IRR 0.3 95% CI: 0.22–0.4; p ≤ 0.001), mainly due to a significant reduction (91%) in the PCV13 serotypes (IRR 0.09 95% CI: 0.05–0.16, p ≤ 0.001). Furthermore, no significant changes were detected in the IR of IPD caused by non-PCV13 serotypes. The IRs of the aggressive, resistant and most prevalent serotype in the analysed population, the 19A serotype, dramatically decreased from the beginning to the end of the study (98%) IRR 0.03 (95% CI: 0.00–0.19), p ≤ 0.001, to its almost total disappearance. Remarkably, this reduction led to a pronounced decline in the percentage of cefotaxime-resistant isolates and the incidence of meningitis cases. Assessment of the clinical impact revealed a reduction in the number of all clinical presentations of IPD, confirming the effectiveness of the PCV13. Finally, PCV13 detected by PCR is predicted to have a stronger impact than the one based on culture methods, which can overlook more than 20% of cases of IPD, mainly pleural empyemas.
Importance: Functional methionine synthase reductase deficiency, also known as cobalamin E disorder, is a rare autosomal recessive inherited disease that results in an impaired remethylation of ...homocysteine to methionine. It presents with macrocytic anemia, hyperhomocysteinemia, and hypomethioninemia, and may also be accompanied with neurological impairment.
Clinical presentation: We describe two new cases of unrelated girls with megaloblastic anemia misclassified at first as congenital dyserythropoietic anemia with development of neurologic dysfunction in one of them.
Intervention: The posterior finding of biochemical features (hyperhomocysteinemia and hypomethioninemia) focused the diagnosis on the inborn errors of intracellular vitamin B12. Subsequent molecular analysis of the methionine synthase reductase (MTRR) gene revealed compound heterozygosity for a transition c.1361C > T (p.Ser454Leu) and another, not yet described in literature, c.1677-1G > A (p.Glu560fs) in one patient, and a single homozygosis mutation, c.1361C > T (p.Ser545Leu) in the other one. These mutations confirmed the diagnosis of cobalamin E deficiency.
Conclusion: Treatment with hydroxocobalamin in combination with betaine appears to be useful for hematological improvement and prevention of brain disabilities in CblE-affected patients. Our study widens the clinical, molecular, metabolic, and cytological knowledge of deficiency MTRR enzyme.
Fermented dairy products have been associated with a better diet quality and cardio-metabolic profile. However, in Mediterranean populations, these associations have not been well characterized.
The ...aim of this study was to assess the diet quality and the associations between the consumption of total fermented dairy products and their subtypes and the prevalence of Metabolic Syndrome (MetS) components in a Mediterranean population at high cardiovascular risk.
Baseline cross-sectional analyses were conducted on 6,572 men and women (mean age: 65 years) with overweight or obesity and MetS recruited into the PREDIMED-Plus cohort. A 143-item Food Frequency Questionnaire (FFQ) was used, and anthropometrical, biochemical, and blood pressure measurements were recorded. Multivariate-adjusted Cox regressions were fitted to analyze the association between quartiles of consumption of fermented dairy products and their subtypes and MetS components to estimate the relative risk (RR) and 95% confidence intervals (95% CIs).
Participants who were high consumers of fermented dairy products reported a higher consumption of fruit, vegetables, fish, nuts, and whole bread and a lower consumption of white bread, alcohol, and cookies. Participants in the higher quartile showed a lower prevalence of the low HDL-cholesterol component of the MetS (RR=0.88; 95% CI: 0.78-0.98) than those in the lowest quartile of cheese consumption. Cheese consumption was inversely associated with the prevalence of hypertriglyceridemia. Total fermented dairy products, yogurt, and its types were not associated with any of the MetS components.
Compared to nonconsumers, participants consuming fermented dairy products reported a better diet quality and, particularly, cheese consumers presented a lower prevalence of hypertriglyceridemia and low HDL-cholesterol plasma levels, which are MetS components.
•The consumption of total fermented dairy products is associated with a better quality diet and a higher adherence to the Mediterranean diet pattern.•Cheese consumption was inversely associated with a low risk of low HDL-cholesterol plasma levels and hypertriglyceridemia, which are components of the metabolic syndrome.•Yogurt consumption and its different subtypes was not associated with any of the metabolic syndrome components.
A diet quality index (DQI) is a tool that provides an overall score of an individual's dietary intake when assessing compliance with food-based dietary guidelines. A number of DQIs have emerged, ...albeit their associations with health-related outcomes are debated. The aim of the present study was to assess whether adherence to dietary intervention, and the overall quality of the diet, can predict body composition changes.
To this purpose, overweight/obese adolescents (n = 117, aged: 13–16 years; 51 males, 66 females) were recruited into a multi-component (diet, physical activity and psychological support) family-based group treatment programme. We measured the adolescents' compliance and body composition at baseline and after 2 months (intensive phase) and 13 months (extensive phase) of follow-up. Also, at baseline, after 6 months, and at the end of follow-up we calculated the DQI.
Global compliance with the dietary intervention was 37.4% during the intensive phase, and 14.3% during the extensive phase. Physical activity compliance was 94.1% at 2-months and 34.7% at 13months and psychological support compliance were growing over the intervention period (10.3% intensive phase and 45.3% during extensive phase). Adolescents complying with the meal frequency criteria at the end of the extensive phase had greater reductions in FMI z-scores than those did not complying (Cohen's d = 0.53). A statistically significant association was observed with the diet quality index. DQI-A variation explained 98.1% of BMI z-score changes and 95.1% of FMI changes.
We conclude that assessment of changes in diet quality could be a useful tool in predicting body composition changes in obese adolescents involved in a diet and physical activity intervention programme backed-up by psychological and family support.
To perform fine mapping of the PXK locus associated with systemic lupus erythematosus (SLE) and study functional effects that lead to susceptibility to the disease.
Linkage disequilibrium (LD) ...mapping was conducted by using 1251 SNPs (single nucleotide polymorphism) covering a 862 kb genomic region on 3p14.3 comprising the PXK locus in 1467 SLE patients and 2377 controls of European origin. Tag SNPs and genotypes imputed with IMPUTE2 were tested for association by using SNPTEST and PLINK. The expression QTLs data included three independent datasets for lymphoblastoid cells of European donors: HapMap3, MuTHER and the cross-platform eQTL catalogue. Correlation analysis of eQTLs was performed using Vassarstats. Alternative splicing for the PXK gene was analysed on mRNA from PBMCs.
Fine mapping revealed long-range LD (>200 kb) extended over the ABHD6, RPP14, PXK, and PDHB genes on 3p14.3. The highly correlated variants tagged an SLE-associated haplotype that was less frequent in the patients compared with the controls (OR=0.89, p=0.00684). A robust correlation between the association with SLE and enhanced expression of ABHD6 gene was revealed, while neither expression, nor splicing alterations associated with SLE susceptibility were detected for PXK. The SNP allele frequencies as well as eQTL pattern analysed in the CEU and CHB HapMap3 populations indicate that the SLE association and the effect on ABHD6 expression are specific to Europeans.
These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants.
This paper proposes the implementation of the SupWald test of Andrews (1993) to detect structural breaks in the loadings of a static factor model. The procedure is illustrated by testing for ...structural breaks in the common factors of GDP growth series for a sample of advanced countries from 1950 until 2006.
► SupWald test of
Andrews (1993) may detect structural breaks in the factor loadings. ► Principal components provide consistent estimations of factors. ► Implementation of the SupWald test depends on the sample size and the error term. ► Application to common factors from GDP growth series locates some breaks.
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