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Background LIPA, situated on chromosome 10q23.2‐q23.3, encodes the enzyme lysosomal acid lipase (LAL) (EC 3.1.1.13). Genetic alterations in LIPA lead to lysosomal acid lipase deficiency (LALD), an inborn error causing lipid metabolism anomalies and impairing cholesterol and triacylglyceride degradation. Over 40 LIPA variants have been documented, yet this study focuses on just two. The rs1051338 variant (NM_000235:c.46A>C) affects the signal peptide in Exon 2, whereas rs116928232, located in Exon 8, alters the splice site (NM_000235:c.894G>A), impacting lysosomal acid lipase activity. Considering the diverse clinical manifestations of LALD and the rising hepatic steatosis prevalence in Mexican population, mainly due to diet, these variants were investigated within this demographic to uncover potential contributing factors. This study aimed to reveal the frequency of rs1051338 and rs116928232 among healthy mestizo individuals in Northwest Mexico, marking a significant genetic exploration in this demographic. Methods Three hundred ten healthy mestizo individuals underwent PCR‐RFLP analysis for both variants, and Sanger sequencing was performed for variant rs116928232. Bioinformatic analysis was also performed to predict protein changes. Results Allele frequencies for rs1051338 (FA = 0.39, p value = 0.15) and rs116928232 (FA = 0.0016, p value = 0.49) aligned with reported data, while bioinformatic analysis allowed us to identify the protein alteration observed in both variants; finally, the variants showed no linkage between them (normalized D′ = 1.03, p value = 0.56). Conclusions Allelic frequencies closely matched reported data, and protein structure analysis confirmed variant impacts on LAL enzyme function. Notably, this study marks the first analysis of rs1051338 and rs116928232 in a healthy Mexican mestizo population. This study examines the frequency of two specific LIPA variants, rs1051338 and rs116928232, in 310 healthy Mexican mestizo individuals and the effects of these on protein structure by bioinformatic analysis. The results confirm the effects of this variants on LAL function and are consistent with existing data, underscoring the significance of this genetic investigation within this demographic.

The 22q11.2 deletion syndrome (22q11.2DS) is mostly caused by deletions of 3 and 1.5 Mb, referred to as typical deletions, although atypical deletions have also been reported. The commonest features are congenital heart disease, immunodeficiency, facial dysmorphism, and developmental delay. However, phenotypic variability is remarkable, and the underlying mechanisms remain poorly understood. To determine copy number variations (CNVs) in the 22q11.2 region and their association with clinical manifestations in Mexican patients with suspected 22q11.2DS. Fluorescence in situ Hybridization (FISH) and Multiplex Ligation-dependent Probe Amplification (MLPA) assays were performed in 80 patients with suspected 22q11.2DS. Clinical characterization was carried out according to the criteria used by the 22q11.2 Consortium. FISH detected deletions in 51%, while MLPA detected CNVs in 54%. Typical deletions were observed in 86% of patients, whereas atypical deletions were found in 14%, including CNVs involving single genes (TBX1, TOP3B, and PRODH). Three families were identified with the 3 Mb deletion and exhibited a heterogeneous phenotype that cannot be explained by the microdeletion alone. 22q11.2DS is a complex disorder for which MLPA is recommended to detect atypical deletions in FISH-negative patients, and to define deletion size, breakpoints, and genes in FISH-positive ones.

Tumor immune escape is associated with the loss of tumor HLA class I (HLA-I) expression commonly found in malignant cells. Accumulating evidence suggests that the efficacy of immunotherapy depends on the expression levels of HLA class I molecules on tumors cells. It also depends on the molecular mechanism underlying the loss of HLA expression, which could be reversible/“soft” or irreversible/“hard” due to genetic alterations in HLA, β2-microglobulin or IFN genes. Immune selection of HLA-I negative tumor cells harboring structural/irreversible alterations has been demonstrated after immunotherapy in cancer patients and in experimental cancer models. Here, we summarize recent findings indicating that tumor HLA-I loss also correlates with a reduced intra-tumor T cell infiltration and with a specific reorganization of tumor tissue. T cell immune selection of HLA-I negative tumors results in a clear separation between the stroma and the tumor parenchyma with leucocytes, macrophages and other mononuclear cells restrained outside the tumor mass. Better understanding of the structural and functional changes taking place in the tumor microenvironment may help to overcome cancer immune escape and improve the efficacy of different immunotherapeutic strategies. We also underline the urgent need for designing strategies to enhance tumor HLA class I expression that could improve tumor rejection by cytotoxic T-lymphocytes (CTL).

Gastric cancer (GC) is the fourth most deadly cancer globally. The adducin 1 (ADD1) protein is involved in oncogenic signal transduction pathways in several types of cancer, and the rs4961 variant (c.1378 G>T, p.Gly460Trp) of the ADD1 gene is associated with salt-sensitive hypertension, renal cell cancer and breast cancer susceptibility; however, it has not been investigated in GC. The aim of the present study was to evaluate the association between the rs4961 variant and the development of GC and preneoplastic gastric lesions (PGLs) in a population from western Mexico. A total of 225 individuals who underwent an endoscopy were evaluated, of which 71 patients had histopathologically diagnosed GC and 53 patients had PGLs, with 101 patients used as controls. The rs4961 variant was genotyped by using PCR and DNA sequencing. The frequency of the mutated homozygous genotype (TT) of the rs4961 variant was <10% in the three evaluated groups, and the frequency of the minor allele (T) was <21% in the GC, PGL and control groups. Genotypic and allelic frequencies were similarly distributed in all of the studied groups (P>0.05). In summary, in the study population, the rs4961 variant was not associated with GC risk; however, its role in other populations and in other types of cancer is worthy of future research.

BackgroundLoss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy. However, there is no data on perioperative chemoimmunotherapy (ChIO) efficacy or response mechanisms in the context of HLA class I defects.MethodsBaseline HLA class I tumor status (HLA-deficient (HLA-DEF) or HLA-proficient (HLA-PRO)) was determined by DNA LOH combined with immunohistochemistry for protein levels in tissue of 24 patients with NSCLC treated with perioperative nivolumab plus chemotherapy from NADIM trial (NCT03081689). We integrated HLA tumor status with molecular data (programmed death-ligand 1 (PD-L1), TMB, TCR repertoire, TILs populations, bulk RNA-seq, and spatial transcriptomics (ST)) and clinical outcomes (pathological response and survival data) to study the activity of perioperative ChIO considering HLA class I defects.ResultsHLA-DEF tumors comprised 41.7% of analyzed tumors and showed a desert-like microenvironment at baseline, with lower PD-L1 levels and reduced immune infiltrate. However, perioperative ChIO induced similar complete pathological response (CPR) rates in both HLA-DEF and PRO tumors (50% and 60% respectively, p=0.670), as well as 3-year survival rates: Progression-free survival (PFS) and overall survival (OS) of 70% (95% CI 32.9% to 89.2%) for HLA-DEF, and PFS 71.4% (95% CI 40.6% to 88.2%) and OS 92.9% (95% CI 59.1% to 99.0%) for HLA-PRO (log-rank PFS p=0.909, OS p=0.137). Proof-of-concept ST analysis of a CPR HLA-DEF tumor after ChIO showed a strong immune response with tertiary lymphoid structures (TLS), CD4+T cells with HLA class II colocalization, and activated CD8+T cells.ConclusionsOur findings highlight the activity of perioperative ChIO, and the potential role of TLS and T-cell immune response, in NSCLC HLA-DEF tumors.

Citrus fruits are crucial globally, impacting economies and livelihoods. However, climate change is affecting water availability and usage, posing challenges for managing water in citrus crops. This paper introduces CARP-flux, a new model designed to assess water needs in citrus orchards, specifically addressing the limitations of traditional methods under changing climates. The study was conducted in El Hundido, an irrigation village located in the Vega del Guadalquivir Valley near Cantillana, Seville (Spain), acknowledged as a significant citrus trade area at both the European and national levels. To adjust the model to contemporary climate conditions, time-series data from the Sentinel-1 Interferometric Wide (IW) satellite (VV and VH polarizations) from 2021 and 2022 were employed. Employing genetic algorithms and the Weibull distribution, the study incorporated 3D radiation models from backscatter data, a spatial interpretation of water and radiation dynamics, which, in turn, validated CARP-flux's performance. This model proved effective in identifying land-use changes and evaluating radiation intensity, which are critical factors for understanding crop water needs in climate change scenarios. CARP-flux offers a precise alternative to the conventional Hargreaves technique for citrus groves, which underestimates water requirements in irrigated and humid regions with ample soil moisture, such as the Vega del Guadalquivir.

In acute lymphoblastic leukaemia (ALL), elevated foetal haemoglobin (HbF) levels have been associated with the prognosis of patients. Genetic variants in HbF regulatory genes: BAF chromatin remodelling complex subunit ( BCL11A ), HBS1L-MYB transcriptional GTPase intergenic region ( HBS1L-MYB ), Krüppel-like factor 1 ( KLF1 ), haemoglobin gamma subunit 2 ( HBG2 ), haemoglobin gamma subunit 1 ( HBG1 ), and haemoglobin subunit beta pseudogene 1 ( HBBP1 ) are often associated with elevated HbF concentration. This study investigated the association of genetic variants in HbF regulatory genes with HbF concentration, unfavourable prognosis, and outcome in children with ALL. We quantified HbF concentration and genotyped 17 genetic variants in 48 patients with ALL and 64 children without ALL as a reference group. HbF concentration was higher in patients than in the reference group (4.4% vs 1.4%), and 75% ( n  = 36) of the patients had HbF > 2.5%. Unfavourable prognosis ALL was established in 68.8% ( n  = 33) of the patients. Variant HBG2 rs7482144 was associated with high HbF concentration ( P  = 0.015); while HBS1L - MYB rs9399137 ( P  = 0.001), HBG2 rs7482144 ( P  = 0.001) and the β-globin genes HBG2 , HBG1 , and HBPP1 haplotype TGC ( P  = 0.017) with unfavourable prognosis ALL. Additionally, variant BCL11A rs4671393 showed a protective role ( P  = 0.0001). In conclusion, variants HBG2 rs7482144, HBS1L - MYB rs9399137 and BCL11A rs4671393 may play a significant role in ALL.

Esta obra surge de la iniciativa del Grupo de Investigación IDEA-TEXT (HUM-060), de la Universidad de Córdoba. Quiere cumplir dos objetivos: analizar las complejas y múltiples relaciones entre las lenguas y el pensamiento a través de su manifestación en los textos y estudiar cómo las ideas sobre el mundo se concretan en diversos códigos lingüísticos y se difunden a través de textos de diferentes estructuras y funcionamiento.En la primera parte de la obra, encontramos dos tradiciones que son relevantes en la interrelación entre el pensamiento y el lenguaje a través de los textos: el discurso gramatical y el de la didáctica de las lenguas. La motivación lingüística es tratada desde la lingüística cognitiva por parte de Iraide Ibarretxe; Gerda Haßler trata la categoría funcional de la evidencialidad y Estrella Ramírez revisa la forma en que se incorporó la fonología en la Real Academia Española. Respecto a la didáctica de las lenguas, Laura Arroyo trata los resultados que produce el aprendizaje inductivo, Antonio Jesús Tinedo indaga en la perspectiva de género y la competencia multicultural, y Adamantía Zerva realiza un análisis crítico y contrastivo de manuales de turismo de español y francés.En la segunda parte, el foco se dirige a la religión, la política y la literatura en dos capítulos en los que se aborda el pensamiento escatológico romano, de la mano de Rafael A. Barroso, y las ideas de mesianismo y milenarismo, por parte de Salvador Rubio. María del Carmen López se acerca al discurso político. Y Virginia Díaz y Tomás Vouilloz muestran el discurso literario como un poderoso vehículo de manifestación de la ideología y las representaciones sociales.

Abstract Objective To identify the TMPRSS6 gene variants in Mexican patients with iron treatment refractoriness, to describe hematological and iron profile parameters, and to use bioinformatic prediction and protein modeling tools to assess a possible biological impact for the detected missense variants. Methods Nineteen patients referred with iron treatment refractoriness were studied. Peripheral blood was collected to determine hematic cytometry, iron profile, hemoglobin electrophoresis, and quantification. Molecular screening was carried out for exons 15 through 18 of the TMPRSS6 gene by Sanger sequencing and for frequent thalassemia variants by amplification-refractory mutation system-polymerase chain reaction (PCR) and gap-PCR. The biological impact of the detected missense variants was assessed using bioinformatic prediction and protein modeling tools. Results We found 5 genetic variants in the matriptase-2 catalytic domain: 1 at intron-15/exon-16 junction (rs60484081) and 4 exonic, 3 missense (rs377054987, p.Gly626Asp; rs1384127820, p.Ser672Thr; rs855791, p.Val727Ala) and 1 synonymous (rs2235321, p.Tyr730=), with frequencies ranging from 0.18 to 0.53. No significant differences were observed in the hematological parameters or iron profile, considering type and number of variants. Bioinformatic predictions suggested a possible biological impact only for rs377054987. Conclusions The TMPRSS6 variants observed in Mexican patients with oral iron treatment refractoriness have high frequencies; nevertheless, their relationship with hematological and iron profile parameters needs further research. The possible biological impact for rs377054987 is due to size and amino acid hydrophobicity changes and hydrogen bond modifications.