Mini-Review: The Contribution of Intermediate Phenotypes to GxE Effects on Disorders of Body Composition in the New OMICS Era

Abstract: Studies of gene-environment (GxE) interactions describe how genetic and environmental factors influence the risk of developing disease. Intermediate (molecular or clinical) phenotypes (IPs) are traits or metabolic biomarkers that mediate the effects of gene-environment influences on risk behaviors. Functional systems genomics discovery offers mechanistic insights into how DNA variations affect IPs in order to detect genetic causality for a given disease. Disorders of body compositionincludeobesity(OB),Type2diabetes(T2D),andosteoporosis(OSTP).Thesepathologies are examples of how a GxE interaction contributes to their development. IPs as surrogates for inherited genotypes play a key role in models of genetic and environmental interactions in health outcomes. Such predictive models may unravel relevant genomic and molecular pathways for preventive and therapeutic interventions for OB, T2D, and OSTP. Annotation strategies for genomes, in contrast to phenomes, are well advanced. They generally do not measure specific aspects of the environment. Therefore, the concepts of deep phenotyping and the exposome generate new avenues to exploit with high-resolution technologies for analyzing this sophisticated phenome. With the successful characterization of phenomes, exposomes, and genomes, environmental and geneticdeterminantsofchronicdiseasescanbeunitedwithmulti-OMICSstudiesthatbetterexamine GxE interactions. Keywords: GxE interactions; intermediate phenotypes; OMICS; diabetes; obesity; osteoporosis; phenome; exposom

Reconstrucción del ligamento cruzado anterior con doble haz de U-Dos y haz único de aloinjerto: Un estudio comparativo

Las lesiones del ligamento cruzado anterior (LCA) son muy frecuentes entre los deportistas. Si estas lesiones no se reparan, se producen daños en el menisco y el cartílago, con graves consecuencias en la articulación. Se han descrito diferentes opciones para la reconstrucción del LCA, con el objetivo de conseguir estabilidad anteroposterior, lateral y rotacional. El uso de injertos de uno o dos haces ha sido uno de los temas más debatidos, con el objetivo de mejorar la estabilidad rotacional. Realizamos un estudio prospectivo aleatorizado para evaluar los resultados de la reconstrucción del LCA utilizando injertos de doble o único haz en 72 pacientes con lesiones agudas del LCA. Los pacientes fueron aleatorizados a ciegas en 2 grupos de 36 rodillas antes de la cirugía mediante un sobre ciego que contenía la técnica que se iba a utilizar: técnica U-Dos de doble haz (grupo DB) o técnica de haz único (grupo SB). Todos los pacientes se sometieron a una evaluación preoperatoria y postoperatoria y fueron seguidos con los mismos parámetros a los 2, 4, 6, 12 y 24 meses. Tanto la estabilidad anteroposterior como la rotacional se evaluaron mediante un artrómetro KT-1000 (MEDmetric) y un dispositivo experimental Pivot-Shift Meter (ORMEDS). Los resultados funcionales se midieron mediante la escala de Tegner-Lysholm. El grupo DB tuvo menos rectificaciones del LCA, menos lesiones meniscales y mejores puntuaciones de Tegner-Lysholm y del Comité Internacional de Documentación de la Rodilla. Este grupo también tuvo mejores valores de KT-1000 y Pivot-Shift Meter. Tras un seguimiento de 2 años, el grupo DB obtuvo resultados significativamente mejores que el grupo SB.Anterior cruciate ligament (ACL) injuries are very common among athletes. If these injuries are not repaired, meniscus and cartilage damage will arise, with serious consequences in the joint. Different options for ACL reconstruction have been described, aiming for anteroposterior, lateral, and rotational stability. Using single- or double-bundle grafts has been one of the most discussed topics, aiming for better rotational stability. We performed a prospective randomized study to evaluate the outcomes of ACL reconstruction using double- or single-bundle grafts for 72 patients with acute ACL injuries. Patients were blindly randomized into 2 groups of 36 knees before surgery using a blind envelope that contained the technique to be used: double-bundle U-Dos technique (DB group) or single-bundle technique (SB group). All patients had a preoperative and postoperative evaluation and were followed with the same parameters at 2, 4, 6, 12, and 24 months. Both anteroposterior and rotational stability were evaluated using a KT-1000 arthrometer (MEDmetric) and an experimental Pivot-Shift Meter (ORMEDS) device. Functional outcomes were measured using the Tegner-Lysholm scale. The DB group had fewer ACL re-tears, fewer meniscal injuries, and better Tegner-Lysholm and International Knee Documentation Committee scores. This group also had better KT-1000 and Pivot-Shift Meter values. After 2-year follow-up, the DB group had significantly better results than the SB group

Factores de riesgo para enfermedades metabólicas en adolescentes de tres etnias de Chihuahua, México

This study carried out in adolescents of the Mennonite, Tarahumara and Mestizo ethnic groups of the state of Chihuahua, Mexico, aims to make a description of the risk components for metabolic syndrome (MS) that our population has in current life, and that predispose to a large number of metabolic diseases. The following variables were reviewed: age, sex, BMI, waist circumference, fasting glucose, total cholesterol, triglycerides, HDL-C and blood pressure. The variables were compared according to the various criterion to determine the metabolic syndrome: IDF, NCEP-ATP III (Cook and de Ferranti) and WHO. The prevalence of MS in the sample was higher in Tarahumara adolescents (12.65%) compared to mestizos (11.95%) and Mennonites (7.15%), according to the ATP III criterion (De Ferranti). Conclusions. There is a significant statistical difference in the prevalence of MS in adolescents from different ethnic groups in Chihuahua.Este estudio realizado en adolescentes de las etnias Menonita, Tarahumara y Mestiza del estado de Chihuahua, pretende hacer una descripción de los componentes de riesgo para síndrome metabólico (SM) que en la vida actual tiene nuestra población, y que predisponen a un gran número de enfermedades metabólicas. Se revisaron las variables: edad, sexo, IMC, circunferencia de cintura, glucosa en ayunas, colesterol total, triglicéridos, c-HDL y presión arterial. Las variables fueron comparadas de acuerdo con los diversos criterios para determinar el síndrome metabólico: IDF, NCEP-ATP III (Cook y de Ferranti) y OMS. La prevalencia de SM en la muestra fue mayor en adolescentes tarahumaras (12.65%) en comparación con mestizos (11.95%) y menonitas (7.15%), de acuerdo con los criterios de la ATP III (De Ferranti). Conclusiones. Existe una diferencia estadística significante en la prevalencia de SM en adolescentes de los diferentes grupos étnicos de Chihuahua

Establecimiento de una plataforma molecular in vitro para desarrollar oocitos a partir de células madre embrionarias

Las células madre embrionarias (CME) son derivadas de la masa celular interna de blastocitos de mamíferos y debido a su pluripotencia in vitro e in vivo son capaces de generar los 200 tipos celulares identificados en el organismo. El uso de medios selectivos suplementados con determinados factores y la expresión artificial de genes que regulan vías de diferenciación específicas, ha permitido dirigir in vitro la diferenciación de las CME hacia tipos celulares especializados somáticos como células neuronales, cardiacas, etc. Recientes estudios han demostrado que la diferenciación espontánea de las CME, también puede dar origen in vitro a células de tipo germinal que posteriormente se desarrollan hacia células similares a gametos, como son los espermatozoides y óvulos. Lo anterior plantea la interesante idea de generar sistemas in vitro, que permitan dirigir la diferenciación de las CME hacia la formación in vitro de gametos. El desarrollo de estos sistemas tendrá un impacto directo en el entendimiento molecular de la programación genética, que interviene en los procesos de la oogénesis y espermatogénesis, así como el desarrollo de protocolos más eficientes para la clonación animal, clonación terapéutica, fertilización in vitro y transferencia de embriones. En relación a lo anterior, nuestro grupo de trabajo se ha enfocado al estudio de genes denominados ̈maestros ̈, cuya expresión además de darse en etapas muy tempranas de la determinación de la línea germinal, está en relación directa con el correcto desarrollo de las células germinales en los ovarios y testículos, características que los hace candidatos a ser utilizados para dirigir la diferenciación de las CME hacia células de linaje germinal. DOI: https://doi.org/10.54167/tecnociencia.v2i1.6

Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic lowgrade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders

Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis

<p>Abstract</p> <p>Background</p> <p>Although mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls.</p> <p>Methods</p> <p>Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF (20 lung regions; 5 patients), IPF (21 regions; 7 patients) and controls (16 regions; 8 subjects). In each compartment the densities and distribution of MC_Tand MC_TCmast cell populations were studied as well as the mast cell expression of IL-6 and TGF-β.</p> <p>Results</p> <p>In the alveolar parenchyma in lungs from patients with CF, MC_TCnumbers increased in areas showing cellular inflammation or fibrosis compared to controls. Apart from an altered balance between MC_TCand MC_Tcells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MC_TCdensity was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-β. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MC_TCcorrelated positively with the degree of fibrosis. The increased density of MC_TC, as well as MC_TCexpression of TGF-β, correlated negatively with patient lung function.</p> <p>Conclusions</p> <p>The present study reveals that altered mast cell populations, with increased numbers of MC_TCin diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.</p

Mast Cells in Allergic Asthma and Beyond

Mast cells have been regarded for a long time as effector cells in IgE mediated type I reactions and in host defence against parasites. However, they are resident in all environmental exposed tissues and express a wide variety of receptors, suggesting that these cells can also function as sentinels in innate immune responses. Indeed, studies have demonstrated an important role of mast cells during the induction of life-saving antibacterial responses. Furthermore, recent findings have shown that mast cells promote and modulate the development of adaptive immune responses, making them an important hinge of innate and acquired immunity. In addition, mast cells and several mast cell-produced mediators have been shown to be important during the development of allergic airway diseases. In the present review, we will summarize findings on the role of mast cells during the development of adaptive immune responses and highlight their function, especially during the development of allergic asthma

Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders

Amplified Genes May Be Overexpressed, Unchanged, or Downregulated in Cervical Cancer Cell Lines

Several copy number-altered regions (CNAs) have been identified in the genome of cervical cancer, notably, amplifications of 3q and 5p. However, the contribution of copy-number alterations to cervical carcinogenesis is unresolved because genome-wide there exists a lack of correlation between copy-number alterations and gene expression. In this study, we investigated whether CNAs in the cell lines CaLo, CaSki, HeLa, and SiHa were associated with changes in gene expression. On average, 19.2% of the cell-line genomes had CNAs. However, only 2.4% comprised minimal recurrent regions (MRRs) common to all the cell lines. Whereas 3q had limited common gains (13%), 5p was entirely duplicated recurrently. Genome-wide, only 15.6% of genes located in CNAs changed gene expression; in contrast, the rate in MRRs was up to 3 times this. Chr 5p was confirmed entirely amplified by FISH; however, maximum 33.5% of the explored genes in 5p were deregulated. In 3q, this rate was 13.4%. Even in 3q26, which had 5 MRRs and 38.7% recurrently gained SNPs, the rate was only 15.1%. Interestingly, up to 19% of deregulated genes in 5p and 73% in 3q26 were downregulated, suggesting additional factors were involved in gene repression. The deregulated genes in 3q and 5p occurred in clusters, suggesting local chromatin factors may also influence gene expression. In regions amplified discontinuously, downregulated genes increased steadily as the number of amplified SNPs increased (p<0.01, Spearman's correlation). Therefore, partial gene amplification may function in silencing gene expression. Additional genes in 1q, 3q and 5p could be involved in cervical carcinogenesis, specifically in apoptosis. These include PARP1 in 1q, TNFSF10 and ECT2 in 3q and CLPTM1L, AHRR, PDCD6, and DAP in 5p. Overall, gene expression and copy-number profiles reveal factors other than gene dosage, like epigenetic or chromatin domains, may influence gene expression within the entirely amplified genome segments