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Aging is a universal and progressive process involving the deterioration of physiological functions and the accumulation of cellular damage. Gene regulation programs influence how phenotypes respond to environmental and intrinsic changes during aging. Although several factors, including sex, are known to impact this process, the underlying mechanisms remain incompletely understood. Here, we investigate the functional organization patterns of skeletal muscle genes across different sexes and ages using gene co-expression networks (GCNs) to explore their influence on aging. We constructed GCNs for three different age groups for male and female samples, analyzed topological similarities and differences, inferred significant associated processes for each network, and constructed null models to provide statistically robust results. We found that each network is topologically and functionally distinct, with young women having the most associated processes, likely due to reproductive tasks. The functional organization and modularity of genes decline with age, starting from middle age, potentially leading to age-related deterioration. Women maintain better gene functional organization throughout life compared to men, especially in processes like macroautophagy and sarcomere organization. The study suggests that the loss of gene co-expression could be a universal aging marker. This research offers insights into how gene organization changes with age and sex, providing a complementary method to analyze aging.

The availability of pure individual betalains in sufficient quantities which permit deeper understanding is still a challenge. This study investigates the high-yielding semisynthesis of betaxanthins using betalamic acid from a natural source (Opuntia dillenii), followed by condensation with ʟ−amino acids and further purification. Moreover, the color stability of the four synthesized individual betaxanthins, namely proline (ʟ−ProBX), alanine (ʟ−AlaBX), leucine (ʟ−LeuBX), and phenylalanine (ʟ−PheBX) betaxanthins, was investigated at different pHs. Their relative contribution to free radical scavenging was also scrutinized by TEAC and DPPH. ʟ−AlaBX and ʟ−LeuBx showed a significantly (p < 0.05) higher antioxidant activity, whereas ʟ−ProBX was the most resistant to the hydrolysis of betaxanthin and hence the least susceptible to color change. The color stability was strongly influenced by pH, with the color of ʟ−ProBX, ʟ−LeuBX, and ʟ−AlaBX at pH 6 being more stable, probably due to the easier hydrolysis under acid conditions. The semisynthesis and purification allowed us to have available remarkable quantities of pure individual betaxanthins of Opuntia dillenii for the first time, and to establish their color properties and antioxidant capacity. This study could be a step forward in the development of the best natural food colorant formulation, based on the betalain structure, which is of special interest in food technology.

Retinoblastoma (Rb) is a rare intraocular tumour in early childhood, with an approximate incidence of 1 in 18 000 live births. Experimental studies for Rb are complex due to the challenges associated with obtaining a normal retina to contrast with diseased tissue. In this work, we reanalyse a dataset that contains normal retina samples. We identified the individual genes whose expression is different in Rb in contrast with normal tissue, determined the pathways whose global expression pattern is more distant from the global expression observed in normal tissue, and finally, we identified which transcription factors regulate the highest number of differentially expressed genes (DEGs) and proposed as transcriptional master regulators (TMRs). The enrichment of DEGs in the phototransduction and retrograde endocannabinoid signalling pathways could be associated with abnormal behaviour of the processes leading to cellular differentiation and cellular proliferation. On the other hand, the TMRs nuclear receptor subfamily 5 group A member 2 and hepatocyte nuclear factor 4 gamma are involved in hepatocyte differentiation. Therefore, the enrichment of aberrant expression in these transcription factors could suggest an abnormal retina development that could be involved in Rb origin and progression.

Abstract Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10–6). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10–10). Class II HLA alleles HLA-DQB1*03:01, -DRB1*08:02, -DRB1*16:02, -DRB1*14:06 and -DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America.

Abstract Here we studied HLA blocks and haplotypes in a group of 218 Lacandon Maya Native American using a high-resolution next generation sequencing (NGS) method. We assessed the genetic diversity of HLA class I and class II in this population, and determined the most probable ancestry of Lacandon Maya HLA class I and class II haplotypes. Importantly, this Native American group showed a high degree of both HLA homozygosity and linkage disequilibrium across the HLA region and also lower class II HLA allelic diversity than most previously reported populations (including other Native American groups). Distinctive alleles present in the Lacandon population include HLA-A*24:14 and HLA-B*40:08. Furthermore, in Lacandons we observed a high frequency of haplotypes containing the allele HLA-DRB1*04:11, a relatively frequent allele in comparison with other neighboring indigenous groups. The specific demographic history of the Lacandon population including inbreeding, as well as pathogen selection, may have elevated the frequencies of a small number of HLA class II alleles and DNA blocks. To assess the possible role of different selective pressures in determining Native American HLA diversity, we evaluated the relationship between genetic diversity at HLA-A, HLA-B and HLA-DRB1 and pathogen richness for a global dataset and for Native American populations alone. In keeping with previous studies of such relationships we included distance from Africa as a covariate. After correction for multiple comparisons we did not find any significant relationship between pathogen diversity and HLA genetic diversity (as measured by polymorphism information content) in either our global dataset or the Native American subset of the dataset. We found the expected negative relationship between genetic diversity and distance from Africa in the global dataset, but no relationship between HLA genetic diversity and distance from Africa when Native American populations were considered alone.

[This corrects the article DOI: 10.1371/journal.pone.0245772.].

Genome-wide association studies (GWAS) have allowed the identification of different loci associated with primary root (PR) growth, and Arabidopsis is an excellent model for these studies. The PR length is controlled by cell proliferation, elongation, and differentiation; however, the specific contribution of proliferation and differentiation in the control of PR growth is still poorly studied. To this end, we analyzed 124 accessions and used a GWAS approach to identify potential causal genomic regions related to four traits: PR length, growth rate, cell proliferation and cell differentiation. Twenty-three genes and five statistically significant SNPs were identified. The SNP with the highest score mapped to the fifth exon of NAC048 and this change makes a missense variant in only 33.3% of the accessions with a large PR, compared with the accessions with a short PR length. Moreover, we detected five more SNPs in this gene and in NAC3 that allow us to discover closely related accessions according to the phylogenetic tree analysis. We also found that the association between genetic variants among the 18 genes with the highest scores in our GWAS and the phenotypic classes into which we divided our accessions are not straightforward and likely follow historical patterns.

Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well identified as risk factors. SLE patients present different clinical phenotypes, which are partly explained by admixture patterns variation among Mexicans. Population genetic has insight into the high genetic variability of Mexicans, mainly described through HLA gene studies with anthropological and biomedical importance. A prospective, case-control study was performed. In this study, we recruited 146 SLE patients, and 234 healthy individuals were included as a control group; both groups were admixed Mexicans from Mexico City. The HLA typing methods were based on Next Generation Sequencing and Sequence-Based Typing (SBT). The data analysis was performed with population genetic programs and statistical packages. The admixture estimations based on HLA-B and -DRB1 revealed that SLE patients have a higher Southwestern European ancestry proportion (48 ± 8%) than healthy individuals (30 ± 7%). In contrast, Mexican Native American components are diminished in SLE patients (44 ± 1%) and augmented in Healthy individuals (63 ± 4%). HLA alleles and haplotypes’ frequency analysis found variants previously described in SLE patients from Mexico City. Moreover, a conserved extended haplotype that confers risk to develop SLE was found, the HLA-A∗29:02∼C∗16:01∼B∗44:03∼DRB1∗07:01∼DQB1∗02:02, pC = 0.02, OR = 1.41. Consistent with the admixture estimations, the origin of all risk alleles and haplotypes found in this study are European, while the protection alleles are Mexican Native American. The analysis of genetic distances supported that the SLE patient group is closer to the Southwestern European parental populace and farthest from Mexican Native Americans than healthy individuals. Heterogeneity of genetic admixture determines SLE susceptibility and protection in Mexicans. HLA sequencing is helpful to determine susceptibility alleles and haplotypes restricted to some populations.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a current public health concern. Rapid diagnosis is crucial, and reverse transcription polymerase chain reaction (RT-PCR) is presently the reference standard for SARS-CoV-2 detection. Objective: Automated RT-PCR analysis (ARPA) is a software designed to analyze RT-PCR data for SARSCoV-2 detection. ARPA loads the RT-PCR data, classifies each sample by assessing its amplification curve behavior, evaluates the experiment’s quality, and generates reports. Methods: ARPA was implemented in the R language and deployed as a Shiny application. We evaluated the performance of ARPA in 140 samples. The samples were manually classified and automatically analyzed using ARPA. Results: ARPA had a true-positive rate = 1, true-negative rate = 0.98, positive-predictive value = 0.95, and negative-predictive value = 1, with 36 samples correctly classified as positive, 100 samples correctly classified as negative, and two samples classified as positive even when labeled as negative by manual inspection. Two samples were labeled as invalid by ARPA and were not considered in the performance metrics calculation. Conclusions: ARPA is a sensitive and specific software that facilitates the analysis of RT-PCR data, and its implementation can reduce the time required in the diagnostic pipeline.

There has been limited study of Native American whole genome diversity to date, which impairs effective implementation of personalized medicine and a detailed description of its demographic history. Here we report high coverage whole genome sequencing of 76 unrelated individuals, from 27 indigenous groups across Mexico, with more than 97% average Native American ancestry. On average, each individual has 3.26 million Single Nucleotide Variants and short indels, that together comprise a catalog of 9,737,152 variants, 44,118 of which are novel. We report 497 common Single Nucleotide Variants (with allele frequency > 5%) mapped to drug responses and 316,577 in enhancer or promoter elements; interestingly we found some of these enhancer variants in PPARG, a nuclear receptor involved in highly prevalent health problems in Mexican population, such as obesity, diabetes, and insulin resistance. By detecting signals of positive selection we report 24 enriched key pathways under selection, most of them related to immune mechanisms. No missense variants in ACE2, the receptor responsible for the entry of the SARS CoV-2 virus, were found in any individual. Population genomics and phylogenetic analyses demonstrated stratification in a Northern-Central-Southern axis, with major substructure in the Central region. The Seri, a northern group with the most genetic divergence in our study, showed a distinctive genomic context with the most novel variants, and the most population specific genotypes. Genome-wide analysis showed that the average haplotype blocks are longer in Native Mexicans than in other world populations. With this dataset we describe previously undetected population level variation in Native Mexicans, helping to reduce the gap in genomic data representation of such groups.

BackgroundAs the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has remained in Latin America, Mexico has become the third country with the highest death rate worldwide. Data regarding in-hospital mortality and its risk factors, as well as the impact of hospital overcrowding in Latin America has not been thoroughly explored.Methods and findingsIn this prospective cohort study, we enrolled consecutive adult patients hospitalized with severe confirmed COVID-19 pneumonia at a SARS-CoV-2 referral center in Mexico City from February 26th, 2020, to June 5th, 2020. A total of 800 patients were admitted with confirmed diagnosis, mean age was 51.9 ± 13.9 years, 61% were males, 85% were either obese or overweight, 30% had hypertension and 26% type 2 diabetes. From those 800, 559 recovered (69.9%) and 241 died (30.1%). Among survivors, 101 (18%) received invasive mechanical ventilation (IMV) and 458 (82%) were managed outside the intensive care unit (ICU); mortality in the ICU was 49%. From the non-survivors, 45.6% (n = 110) did not receive full support due to lack of ICU bed availability. Within this subgroup the main cause of death was acute respiratory distress syndrome (ARDS) in 95% of the cases, whereas among the non-survivors who received full (n = 105) support the main cause of death was septic shock (45%) followed by ARDS (29%). The main risk factors associated with in-hospital death were male sex (RR 2.05, 95% CI 1.34-3.12), obesity (RR 1.62, 95% CI 1.14-2.32)-in particular morbid obesity (RR 3.38, 95%CI 1.63-7.00)-and oxygen saturation < 80% on admission (RR 4.8, 95%CI 3.26-7.31).ConclusionsIn this study we found similar in-hospital and ICU mortality, as well as risk factors for mortality, compared to previous reports. However, 45% of the patients who did not survive justified admission to ICU but did not receive IMV / ICU care due to the unavailability of ICU beds. Furthermore, mortality rate over time was mainly due to the availability of ICU beds, indirectly suggesting that overcrowding was one of the main factors that contributed to hospital mortality.

Studies have suggested a potential role of somatic mitochondrial mutations in cancer development. To analyze the landscape of somatic mitochondrial mutation in breast cancer and to determine whether mitochondrial DNA (mtDNA) mutational burden is correlated with overall survival (OS), we sequenced whole mtDNA from 92 matched-paired primary breast tumors and peripheral blood. A total of 324 germline variants and 173 somatic mutations were found in the tumors. The most common germline allele was 663G (12S), showing lower heteroplasmy levels in peripheral blood lymphocytes than in their matched tumors, even reaching homoplasmic status in several cases. The heteroplasmy load was higher in tumors than in their paired normal tissues. Somatic mtDNA mutations were found in 73.9% of breast tumors; 59% of these mutations were located in the coding region (66.7% non-synonymous and 33.3% synonymous). Although the CO1 gene presented the highest number of mutations, tRNA genes (T,C, and W), rRNA 12S, and CO1 and ATP6 exhibited the highest mutation rates. No specific mtDNA mutational profile was associated with molecular subtypes of breast cancer, and we found no correlation between mtDNA mutational burden and OS. Future investigations will provide insight into the molecular mechanisms through which mtDNA mutations and heteroplasmy shifting contribute to breast cancer development.

Facilitation by tussocks is common in high-altitude tropical environments. It is thought that facilitation results from stress amelioration, but it is unclear which of the many stressors acting in these environments is ameliorated. We aimed at determining the relative importance of different stressors as drivers of facilitation by the tussock Festuca tolucensis in Mexico. We employed eight experimental treatments to manipulate five stressors in the field: minimum temperatures by using electric radiators that kept plants warm; maximum temperatures by means of reflective sand that precluded temperature build-up during the day; UV radiation by using screens opaque to UV; poor soil properties by comparing soils from beneath tussocks and from bare ground; and low water availability by adding vermiculite to the soil. The performance (survival and growth) of Mexerion sarmentosum (a plant usually associated with Festuca) in these treatments was compared to that recorded under tussocks and in bare ground. Amelioration of extreme temperatures had the largest positive effects on Mexerion survival. UV radiation and increased soil humidity did not affect survival, although humidity increased growth rates. Nevertheless, tussocks reduced the growth of Mexerion, which is consistent with observations of competition between plants and soil microorganisms favoured by tussocks. Our results highlight the importance of the extreme daily fluctuations in temperature that characterise tropical mountains as fundamental drivers of their dynamics.

Analysis of gene regulatory networks allows the identification of master transcriptional factors that control specific groups of genes. In this work, we inferred a gene regulatory network from a large dataset of breast cancer samples to identify the master transcriptional factors that control the genes within signal transduction pathways. The focus in a particular subset of relevant genes constitutes an extension of the original Master Regulator Inference Algorithm (MARINa) analysis. This modified version of MARINa utilizes a restricted molecular signature containing genes from the 25 human pathways in KEGG's signal transduction category. Our breast cancer RNAseq expression dataset consists of 881 samples comprising tumors and normal mammary gland tissue. The top 10 master transcriptional factors found to regulate signal transduction pathways in breast cancer we identified are: TSHZ2, HOXA2, MEIS2, HOXA3, HAND2, HOXA5, TBX18, PEG3, GLI2, and CLOCK. The functional enrichment of the regulons of these master transcriptional factors showed an important proportion of processes related to morphogenesis. Our results suggest that, as part of the aberrant regulation of signaling pathways in breast cancer, pathways similar to the regulation of cell differentiation, cardiovascular system development, and vasculature development may be dysregulated and co-opted in favor of tumor development through the action of these transcription factors.

BACKGROUND Hypertension affects 33% of Americans while type 2 diabetes and Alzheimer's disease (AD) affect 10% of Americans, respectively. Ryanodine receptor 3 gene (RYR3) codes for the RYR which functions to release stored endoplasmic reticulum calcium ions (Ca2+) to increase intracellular Ca2+ concentration. Increasing studies demonstrate that altered levels of intracellular Ca2+ affect cardiac contraction, insulin secretion, and neurodegeneration. In this study, we investigated associations of the RYR3 genetic variants with hypertension, AD, and diabetes. METHODS Family data sets were used to explore association of RYR3 polymorphisms with risk and age at onset (AAO) of hypertension, diabetes, and AD. RESULTS Family-based association tests using generalized estimating equations (FBAT--GEE) showed several unique or shared disease-1 associated variants in the RYR3 gene. Three single nuclear polymorphisms (SNPs; rs2033610, rs2596164, and rs2278317) are significantly associated with risk for hypertension, diabetes, and AD. Two SNPs (rs4780174 and rs7498093) are significantly associated with AAO of the 3 diseases. CONCLUSIONS RYR3 variants are associated with hypertension, diabetes, and AD. Replication of these results of this gene in these 3 complex traits may help to better understand the genetic basis of calcium-signaling gene, RYR3 in association with risk and AAO of these diseases. [ABSTRACT FROM AUTHOR]