The seismic retrofitting of essential facilities is a typical problem of public administrations. Due to the large amount of existing and/or historic buildings with a high seismic vulnerability and ...the limited economic resources, it is necessary to provide efficient solutions for the structural reinforcement of these structures on a national, regional, and urban level. This paper proposes an innovative and multidisciplinary framework to choose massive interventions on a large territorial scale according to the potential benefits of the intervention in terms of reduction in expected economic losses associated with retrofitting intervention and other important aspects usually neglected in intervention strategies. The proposed framework is based on Multi-Criteria Decision-Making (MCDM) analysis. It is applied to a very complex urban area: the case study is the school buildings stock (4458 buildings) in the Lima Metropolitan area, Peru. The goal of the study is arisk analysis aimed at selecting the optimal retrofitting strategy in a huge urban area. The results of this work can be considered the base for decision-makers. They could use them as a decision support tool in the seismic risk mitigation on a large territorial scale.
Objective
Irisin is a novel myokine that seems to mediate the beneficial effects of exercise. Levels of circulating irisin before and after an 8‐month physical activity program (PAP) in school‐age ...children were evaluated.
Methods
Irisin and leptin were measured at baseline and at follow‐up among 85 children with different BMI.
Results
Of the 85 children (mean age 8.9; 47% female), 25 children had normal weight, 23 were overweight, and 37 had obesity. We observed no significant difference in irisin serum levels between boys and girls. Irisin was positively associated with BMI before and after the PAP (rbefore = 0.42; rafter = 0.37, P < 0.001), with the highest levels in children with obesity. There was a slight decrease of circulating irisin after PAP, but this decrease was not of statistical significance. We observed a high and positive association between irisin and leptin levels before and after the PAP (rbefore = 0.78; rafter = 0.82, P < 0.001). Moreover, changes in leptin correlated with changes in irisin (r = 0.72, P < 0.001).
Conclusions
Circulating irisin is positively linked to BMI and leptin in school‐age children, supporting the notion that that irisin is produced by adipose tissue. As in previous reports, this study failed to observe changes in irisin levels after exercise, likely because higher irisin levels are produced only during exercise.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
NK cells are key mediators of immune cell-mediated cytotoxicity toward infected and transformed cells, being one of the main executors of cell death in the immune system. NK cells recognize target ...cells through an array of inhibitory and activating receptors for endogenous or exogenous pathogen-derived ligands, which together with adhesion molecules form a structure known as immunological synapse that regulates NK cell effector functions. The main and best characterized mechanisms involved in NK cell-mediated cytotoxicity are the granule exocytosis pathway (perforin/granzymes) and the expression of death ligands. These pathways are recognized as activators of different cell death programmes on the target cells leading to their destruction. However, most studies analyzing these pathways have used pure recombinant or native proteins instead of intact NK cells and, thus, extrapolation of the results to NK cell-mediated cell death might be difficult. Specially, since the activation of granule exocytosis and/or death ligands during NK cell-mediated elimination of target cells might be influenced by the stimulus received from target cells and other microenvironment components, which might affect the cell death pathways activated on target cells. Here we will review and discuss the available experimental evidence on how NK cells kill target cells, with a special focus on the different cell death modalities that have been found to be activated during NK cell-mediated cytotoxicity; including apoptosis and more inflammatory pathways like necroptosis and pyroptosis. In light of this new evidence, we will develop the new concept of cell death induced by NK cells as a new regulatory mechanism linking innate immune response with the activation of tumour adaptive T cell responses, which might be the initiating stimulus that trigger the cancer-immunity cycle. The use of the different cell death pathways and the modulation of the tumour cell molecular machinery regulating them might affect not only tumour cell elimination by NK cells but, in addition, the generation of T cell responses against the tumour that would contribute to efficient tumour elimination and generate cancer immune memory preventing potential recurrences.
Suboptimal vaccine response is a significant concern in patients with Inflammatory Bowel Disease (IBD) receiving biologic drugs. This single-center observational study involved 754 patients with IBD. ...In Phase I (October 2020-April 2021), 754 IBD participants who had not previously received the SARS-CoV-2 vaccine, underwent blood extraction to assess the seroprevalence of SARS-CoV-2 infection and IBD-related factors. Phase II (May 2021-October 2021) included a subgroup of 52 IBD participants with confirmed previous SARS-CoV-2 infection, who were studied for humoral and cellular response to the SARS-CoV-2 vaccine. In Phase I, treatment with anti-TNF was associated with lower rates of seroconversion (aOR 0.25 95% CI 0.10-0.61). In Phase II, a significant increase in post-vaccination IgG levels was observed regardless of biologic treatment. However, patients treated with anti-TNF exhibited significantly lower IgG levels compared to those without IBD therapy (5.32 ± 2.47 vs. 7.99 ± 2.59 U/ml, p = 0.042). Following vaccination, a lymphocyte, monocyte, and NK cell activation pattern was observed, with no significant differences between patients receiving biologic drugs and those without IBD treatment. Despite lower seroprevalence and humoral response to the SARS-CoV-2 vaccine in patients treated with anti-TNF, the cellular response to the vaccine did not differ significantly from that patients without IBD therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The design of new polymeric systems for antimicrobial drug release focused on medical/surgical procedures is of great interest in the biomedical area due to the high prevalence of bacterial ...infections in patients with wounds or burns. For this reason, in this work, we present a new design of pH-sensitive hydrogels copolymerized by a graft polymerization method (gamma rays), intended for localized prophylactic release of ciprofloxacin and silver nanoparticles (AgNPs) for potential topical bacterial infections. The synthesized hydrogels were copolymerized from acrylic acid (AAc) and agar. Cross-linked hydrogel film formation depended on monomer concentrations and the degree of radiation used (Cobalt-60). The obtained hydrogel films were characterized by attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and mechanical testing. The swelling of the hydrogels was evidenced by the influence of their pH-sensitiveness. The hydrogel was loaded with antimicrobial agents (AgNPs or ciprofloxacin), and their related activity was evaluated. Finally, the antimicrobial activity of biocidal-loaded hydrogel was tested against Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) on in vitro conditions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. ...While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC.
Methods
NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed
in vitro
and
in vivo
and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity.
Results
HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression.
In vivo
experiments confirmed the efficacy of the therapy against both HLA
+
and HLA
−
CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control.
Conclusions
Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.
The contribution of the T cell-related inhibitory checkpoint PD-1 to the regulation of NK cell activity is still not clear with contradictory results concerning its expression and role in the ...modulation of NK cell cytotoxicity. We provide novel key findings on the mechanism involved in the regulation of PD-1 expression on NK cell membrane and its functional consequences for the elimination of cancer cells. In contrast to freshly isolated NK cells from cancer patients, those from healthy donors did not express PD-1 on the cell membrane. However, when healthy NK cells were incubated with tumor target cells, membrane PD-1 expression increased, concurrent with the CD107a surface mobilization. This finding suggested that PD-1 was translocated to the cell membrane during NK cell degranulation after contact with target cells. Indeed, cytosolic PD-1 was expressed in freshly-isolated-NK cells and partly co-localized with CD107a and GzmB, confirming that membrane PD-1 corresponded to a pool of preformed PD-1. Moreover, NK cells that had mobilized PD-1 to the cell membrane presented a significantly reduced anti-tumor activity on PD-L1-expressing-tumor cells in vitro and in vivo, which was partly reversed by using anti-PD-1 blocking antibodies. Our results indicate that NK cells from healthy individuals express cytotoxic granule-associated PD-1, which is rapidly mobilized to the cell membrane after interaction with tumor target cells. This novel finding helps to understand how PD-1 expression is regulated on NK cell membrane and the functional consequences of this expression during the elimination of tumor cells, which will help to design more efficient NK cell-based cancer immunotherapies.
Background
Dilated cardiomyopathy (DCM) is a major cause of nonischemic heart failure and death in young adults. Next generation sequencing (NGS) has become part of the diagnostic workup in ...idiopathic and familial DCM. More than 50 DCM genes have been identified, revealing great molecular heterogeneity and variable diagnostic yield. Interpretation of variant pathogenicity is challenging particularly in underrepresented populations, as pathogenic variant databases include studies mainly from European/Caucasian populations. To date, no studies on genomic diagnosis of DCM have been conducted in Mexico.
Methods
We recruited 55 unrelated DCM patients, 22 familial (F‐DCM), and 33 idiopathic (I‐DCM), and performed site‐directed NGS seeking causal mutations. Diagnostic yield was defined as the proportion of individuals with at least one pathogenic (P) or likely pathogenic (LP) variant in DCM genes.
Results
Overall diagnostic yield was 47.3%, and higher in F‐DCM (63.6%) than in I‐DCM (36.4%, p = 0.047). Overall, NGS disclosed 41 variants of clinical interest (61.0% novel), 27 were classified as P/LP and 14 of unknown clinical significance. Of P/LP variants, 10 were A‐band region TTN truncating variants, five were found in DSP (18.5%), five in MYH7 (18.5%), two in LMNA (7.4%), and one in RBM20, ABCC9, FKTN, ACTA1, and TNNT2. NGS findings suggested autosomal recessive inheritance in three families, two with DSP loss of function mutations in affected individuals. The increasing number of mutation reports in DCM, increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of DCM‐related proteins, the recent refinement ACMG/ClinGen Guidelines, and co‐segregation analysis in DCM families helped increase the diagnostic yield.
Conclusion
This is the first NGS study performed in a group of Mexican DCM patients, contributing to understand the mutational spectrum and complexity of DCM molecular diagnosis.
Molecular diagnosis in dilated cardiomyopathy (DCM) is challenging, particularly in underrepresented populations. We obtained a relatively high diagnostic yield in familial DCM (63.6%) and in idiopathic DCM (47.3%) in a group of Mexican patients. The increasing number of reports of mutations in DCM patients, the increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of some DCM‐related proteins, the refinement ACMG/ClinGen Guidelines and co‐segregation analysis helped achieve this higher diagnostic yield.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The clinical phenotype of LMNA-associated dilated cardiomyopathy (DCM) varies even among individuals who share the same mutation. LMNA encodes lamin AC, which interacts with the lamin-associated ...protein 2 alpha (LAP2α) encoded by the TMPO gene. The LAP2α/Arg690Cys polymorphism is frequent in Latin America and was previously found to disrupt LAP2α-Lamin AC interactions in vitro. We identified a DCM patient heterozygous for both a lamin AC truncating mutation (Ser431*) and the LAP2α/Arg690Cys polymorphism. We performed protein modeling and docking experiments, and used confocal microscopy to compare leukocyte nuclear morphology among family members with different genotype combinations (wild type, LAP2α Arg690Cys heterozygous, lamin AC/Ser431* heterozygous, and LAP2α Arg690Cys/lamin AC Ser431* double heterozygous). Protein modeling predicted that 690Cys destabilizes the LAP2α homodimer and impairs lamin AC-LAP2α docking. Lamin AC-deficient nuclei (Ser431* heterozygous) showed characteristic blebs and invaginations, significantly decreased nuclear area, and increased elongation, while LAP2α/Arg690Cys heterozygous nuclei showed a lower perimeter and higher circularity than wild-type nuclei. LAP2α Arg690Cys apparently attenuated the effect of LMNA Ser431* on the nuclear area and fully compensated for its effect on nuclear circularity. Altogether, the data suggest that LAP2α/Arg690Cys may be one of the many factors contributing to phenotype variation of LMNA-associated DCM.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Several studies have identified multiple obesity-associated loci mainly in European populations. However, their contribution to obesity in other ethnicities such as Mexicans is largely unknown. The ...aim of this study was to examine 26 obesity-associated single-nucleotide polymorphisms (SNP) in a sample of Mexican mestizos.
9 SNPs in biological candidate genes showing replications (PPARG, ADRB3, ADRB2, LEPR, GNB3, UCP3, ADIPOQ, UCP2, and NR3C1), and 17 SNPs in or near genes associated with obesity in first, second and third wave GWAS (INSIG2, FTO, MC4R, TMEM18, FAIM2/BCDIN3, BDNF, SH2B1, GNPDA2, NEGR1, KCTD15, SEC16B/RASAL2, NPC1, SFRF10/ETV5, MAF, PRL, MTCH2, and PTER) were genotyped in 1,156 unrelated Mexican-Mestizos including 683 cases (441 obese class I/II and 242 obese class III) and 473 normal-weight controls. In a second stage we selected 12 of the SNPs showing nominal associations with obesity, to seek associations with quantitative obesity-related traits in 3 cohorts including 1,218 Mexican Mestizo children, 945 Mexican Mestizo adults, and 543 Indigenous Mexican adults.
After adjusting for age, sex and admixture, significant associations with obesity were found for 6 genes in the case-control study (ADIPOQ, FTO, TMEM18, INSIG2, FAIM2/BCDIN3 and BDNF). In addition, SH2B1 was associated only with class I/II obesity and MC4R only with class III obesity. SNPs located at or near FAIM2/BCDIN3, TMEM18, INSIG2, GNPDA2 and SEC16B/RASAL2 were significantly associated with BMI and/or WC in the combined analysis of Mexican-mestizo children and adults, and FTO locus was significantly associated with increased BMI in Indigenous Mexican populations.
Our findings replicate the association of 8 obesity-related SNPs with obesity risk in Mexican adults, and confirm the role of some of these SNPs in BMI in Mexican adults and children.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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