Platelets and endothelial dysfunction in gestational diabetes mellitus.

The prevalence of gestational diabetes mellitus (GDM) has increased in recent years, along with the higher prevalence of obesity in women of reproductive age. GDM is a pathology associated with vascular dysfunction in the fetoplacental unit. GDM-associated endothelial dysfunction alters the transfer of nutrients to the foetus affecting newborns and pregnant women. Various mechanisms for this vascular dysfunction have been proposed, of which the most studied are metabolic alterations of the vascular endothelium. However, different cell types are involved in GDM-associated endothelial dysfunction, including platelets. Platelets are small, enucleated cell fragments that actively take part in blood haemostasis and thrombus formation. Thus, they play crucial roles in pathologies coursing with endothelial dysfunction, such as atherosclerosis, cardiovascular diseases, and diabetes mellitus. Nevertheless, platelet function in GDM is understudied. Several reports show a potential relationship between platelet volume and mass with GDM; however, platelet roles and signaling mechanisms in GDM-associated endothelial dysfunction are unclear. This review summarizes the reported findings and proposes a link among altered amount, volume, mass, reactivity, and function of platelets and placenta development, resulting in fetoplacental vascular dysfunction in GDM.

Worldwide Selection Footprints for Drought and Heat in Bread Wheat (Triticum aestivum L.).

Genome-environment Associations (GEA) or Environmental Genome-Wide Association scans (EnvGWAS) have been poorly applied for studying the genomics of adaptive traits in bread wheat landraces (Triticum aestivum L.). We analyzed 990 landraces and seven climatic variables (mean temperature, maximum temperature, precipitation, precipitation seasonality, heat index of mean temperature, heat index of maximum temperature, and drought index) in GEA using the FarmCPU approach with GAPIT. Historical temperature and precipitation values were obtained as monthly averages from 1970 to 2000. Based on 26,064 high-quality SNP loci, landraces were classified into ten subpopulations exhibiting high genetic differentiation. The GEA identified 59 SNPs and nearly 89 protein-encoding genes involved in the response processes to abiotic stress. Genes related to biosynthesis and signaling are mainly mediated by auxins, abscisic acid (ABA), ethylene (ET), salicylic acid (SA), and jasmonates (JA), which are known to operate together in modulation responses to heat stress and drought in plants. In addition, we identified some proteins associated with the response and tolerance to stress by high temperatures, water deficit, and cell wall functions. The results provide candidate regions for selection aimed to improve drought and heat tolerance in bread wheat and provide insights into the genetic mechanisms involved in adaptation to extreme environments.

Gestational diabesity and foetoplacental vascular dysfunction.

Gestational diabetes mellitus (GDM) shows a deficiency in the metabolism of D-glucose and other nutrients, thereby negatively affecting the foetoplacental vascular endothelium. Maternal hyperglycaemia and hyperinsulinemia play an important role in the aetiology of GDM. A combination of these and other factors predisposes women to developing GDM with pre-pregnancy normal weight, viz. classic GDM. However, women with GDM and prepregnancy obesity (gestational diabesity, GDty) or overweight (GDMow) show a different metabolic status than women with classic GDM. GDty and GDMow are associated with altered l-arginine/nitric oxide and insulin/adenosine axis signalling in the human foetoplacental microvascular and macrovascular endothelium. These alterations differ from those observed in classic GDM. Here, we have reviewed the consequences of GDty and GDMow in the modulation of foetoplacental endothelial cell function, highlighting studies describing the modulation of intracellular pH homeostasis and the potential implications of NO generation and adenosine signalling in GDty-associated foetal vascular insulin resistance. Moreover, with an increase in the rate of obesity in women of childbearing age worldwide, the prevalence of GDty is expected to increase in the next decades. Therefore, we emphasize that women with GDty and GDMow should be characterized with a different metabolic state from that of women with classic GDM to develop a more specific therapeutic approach for protecting the mother and foetus.

Application of multi-trait Bayesian decision theory for parental genomic selection.

In all breeding programs, the decision about which individuals to select and intermate to form the next selection cycle is crucial. The improvement of genetic stocks requires considering multiple traits simultaneously, given that economic value and net genetic merits depend on many traits; therefore, with the advance of computational and statistical tools and genomic selection (GS), researchers are focusing on multi-trait selection. Selection of the best individuals is difficult, especially in traits that are antagonistically correlated, where improvement in one trait might imply a reduction in other(s). There are approaches that facilitate multi-trait selection, and recently a Bayesian decision theory (BDT) has been proposed. Parental selection using BDT has the potential to be effective in multi-trait selection given that it summarizes all relevant quantitative genetic concepts such as heritability, response to selection and the structure of dependence between traits (correlation). In this study, we applied BDT to provide a treatment for the complexity of multi-trait parental selection using three multivariate loss functions (LF), Kullback-Leibler (KL), Energy Score, and Multivariate Asymmetric Loss (MALF), to select the best-performing parents for the next breeding cycle in two extensive real wheat data sets. Results show that the high ranking lines in genomic estimated breeding value (GEBV) for certain traits did not always have low values for the posterior expected loss (PEL). For both data sets, the KL LF gave similar importance to all traits including grain yield. In contrast, the Energy Score and MALF gave a better performance in three of four traits that were different than grain yield. The BDT approach should help breeders to decide based not only on the GEBV per se of the parent to be selected, but also on the level of uncertainty according to the Bayesian paradigm.

On Hadamard and Kronecker products in covariance structures for genotype × environment interaction.

When including genotype × environment interactions (G × E) in genomic prediction models, Hadamard or Kronecker products have been used to model the covariance structure of interactions. The relation between these two types of modeling has not been made clear in genomic prediction literature. Here, we demonstrate that a certain model based on a Hadamard formulation and another using the Kronecker product lead to exactly the same statistical model. Moreover, we illustrate how a multiplication of entries of covariance matrices is related to modeling locus × environmental-variable interactions explicitly. Finally, we use a wheat and a maize data set to illustrate that the environmental covariance E can be specified easily, also if no information on environmental variables - such as temperature or precipitation - is available. Given that lines have been tested in different environments, the corresponding environmental covariance can simply be estimated from the training set as phenotypic covariance between environments. To achieve a high level of increase in predictive ability, the environmental covariance has to be defined appropriately and records on the performance of the lines of the test set under different environmental conditions have to be included in the training set.

Retrospective Quantitative Genetic Analysis and Genomic Prediction of Global Wheat Yields.

Breeding for grain yield (GY) in bread wheat at the International Maize and Wheat Improvement Center (CIMMYT) involves three-stage testing at Obregon, Mexico in different selection environments (SEs). To understand the efficiency of selection in the SEs, we performed a large retrospective quantitative genetics study using CIMMYT's yield trials evaluated in the SEs (2013-2014 to 2017-2018), the South Asia Bread Wheat Genomic Prediction Yield Trials (SABWGPYTs) evaluated in India, Pakistan, and Bangladesh (2014-2015 to 2017-2018), and the Elite Spring Wheat Yield Trials (ESWYTs) evaluated in several sites globally (2003-2004 to 2016-2017). First, we compared the narrow-sense heritabilities in the Obregon SEs and target sites and observed that the mean heritability in the SEs was 44.2 and 92.3% higher than the mean heritabilities in the SABWGPYT and ESWYT sites, respectively. Second, we observed significant genetic correlations between a SE in Obregon and all the five SABWGPYT sites and 65.1% of the ESWYT sites. Third, we observed high ratios of response to indirect selection in the SEs of Obregon with a mean of 0.80 ± 0.21 and 2.6 ± 5.4 in the SABWGPYT and ESWYT sites, respectively. Furthermore, our results also indicated that for all the SABWGPYT sites and 82% of the ESWYT sites, a response greater than 0.5 can be achieved by indirect selection for GY in Obregon. We also performed genomic prediction for GY in the target sites using the performance of the same lines in the SEs of Obregon and observed moderate mean prediction accuracies of 0.24 ± 0.08 and 0.28 ± 0.08 in the SABWGPYT and ESWYT sites, respectively using the genotype x environment (GxE) model. However, we observed similar accuracies using the baseline model with environment and line effects and no advantage of modeling GxE interactions. Overall, this study provides important insights into the suitability of the Obregon SEs in breeding for GY, while the variable genomic predictabilities of GY and the high year-to-year GY fluctuations reported, highlight the importance of multi-environment testing across time and space to stave off GxE induced uncertainties in varietal yields.

The activity of IKCa and BKCa channels contributes to insulin-mediated NO synthesis and vascular tone regulation in human umbilical vein.

Insulin regulates the l-arginine/nitric oxide (NO) pathway in human umbilical vein endothelial cells (HUVECs), increasing the plasma membrane expression of the l-arginine transporter hCAT-1 and inducing vasodilation in umbilical and placental veins. Placental vascular relaxation induced by insulin is dependent of large conductance calcium-activated potassium channels (BKCa), but the role of KCa channels on l-arginine transport and NO synthesis is still unknown. The aim of this study was to determine the contribution of KCa channels in both insulin-induced l-arginine transport and NO synthesis, and its relationship with placental vascular relaxation. HUVECs, human placental vein endothelial cells (HPVECs) and placental veins were freshly isolated from umbilical cords and placenta from normal pregnancies. Cells or tissue were incubated in absence or presence of insulin and/or tetraethylammonium, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole, iberiotoxin or NG-nitro-l-arginine methyl ester. l-Arginine uptake, plasma membrane polarity, NO levels, hCAT-1 expression and placenta vascular reactivity were analyzed. The inhibition of intermediate-conductance KCa (IKCa) and BKCa increases l-arginine uptake, which was related with protein abundance of hCAT-1 in HUVECs. IKCa and BKCa activities contribute to NO-synthesis induced by insulin but are not directly involved in insulin-stimulated l-arginine uptake. Long term incubation (8 h) with insulin increases the plasma membrane hyperpolarization and hCAT-1 expression in HUVECs and HPVECs. Insulin-induced relaxation in placental vasculature was reversed by KCa inhibition. The results show that the activity of IKCa and BKCa channels are relevant for both physiological regulations of NO synthesis and vascular tone regulation in the human placenta, acting as a part of negative feedback mechanism for autoregulation of l-arginine transport in HUVECs.

Oxidative stress: Normal pregnancy versus preeclampsia.

The role of oxidative stress in the physiopathology of human pregnancy is of particular interest. Pregnancy is well-known to increase the oxidative stress, mainly produced by a normal systemic inflammatory response, which results in high amounts of circulating reactive oxygen species (ROS) and reactive nitrogen species (RNS). Both ROS and RNS play an important role as secondary messengers in many intracellular signalling cascades. However, they can also exert critical effects on pathological processes involving the pregnant woman. ROS, RNS and antioxidants establish a balance that determines the oxidation status of animals and humans. This review focuses on the mechanism of oxidative stress in pregnancy as well as its involvement and consequences on the human pregnancy-specific clinical syndrome preeclampsia.

DNA methylation changes in genes coding for leptin and insulin receptors during metabolic-altered pregnancies.

The overwhelming rates of obesity worldwide are a major concern due to the elevated medical costs associated and the poor quality of life of obese patients. In the recent years, it has become evident that the intrauterine milieu can have a long-term impact on the foetus health. The placenta is a highly dynamic organ; whose primary function is to carry nutrients from the mother to the foetus and to remove waste products from the foetus. Any alteration in maternal circulating metabolites elicits a response in order to ensure the developing foetus an adequate growth environment. This response can be translated into epigenetic modifications in coding genes for metabolic-related receptors located in the placenta and foetal tissues. The most studied receptors involved in the metabolic sensing are the leptin and the insulin receptors. A maternal metabolic disease-like state can alter the expression of these receptors in different organs, including placenta. There is evidence that these alterations not only affect the expression level of these receptors, but there are also differences in epigenetic marks in regulatory elements of these genes that may become permanent despite the mother's treatment. This review provides evidence about possible mechanisms involved in the foetal programming of metabolic diseases originated from the pre-natal environment that could contributive to increasing levels of obesity in the world.

Placental structure in gestational diabetes mellitus.

The placenta is a transitory organ, located between the mother and the foetus, which supports intrauterine life. This organ has nutritional, endocrine and immunologic functions to support foetal development. Several factors are related to the correct functioning of the placenta including foetal and maternal blood flow, appropriate nutrients, expression and function of receptors and transporters, and the morphology of the placenta itself. Placental morphology is crucial for understanding the pathophysiology of the organ as represents the physical structure where nutrient exchange occurs. In pathologies of pregnancy such as diabetes mellitus in humans and animal models, several changes in the placental morphology occur, related mainly with placental size, hypervascularization, higher branching capillaries of the villi and increased glycogen deposits among others. Gestational diabetes mellitus is associated with modifications in the structure of the human placenta including changes in the surface area and volume, as well as histological changes including an increased volume of intervillous space and terminal villi, syncytiotrophoblast number, fibrinoid areas, and glycogen deposits. These modifications may result in functional changes in this organ thus limiting the wellbeing of the developing foetus. This review gives an overview of recurrent morphological changes at macroscopic and histological levels seen in the placenta from gestational diabetes in humans and animal models. This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia.

Improving grain yield, stress resilience and quality of bread wheat using large-scale genomics.

Bread wheat improvement using genomic tools is essential for accelerating trait genetic gains. Here we report the genomic predictabilities of 35 key traits and demonstrate the potential of genomic selection for wheat end-use quality. We also performed a large genome-wide association study that identified several significant marker-trait associations for 50 traits evaluated in South Asia, Africa and the Americas. Furthermore, we built a reference wheat genotype-phenotype map, explored allele frequency dynamics over time and fingerprinted 44,624 wheat lines for trait-associated markers, generating over 7.6 million data points, which together will provide a valuable resource to the wheat community for enhancing productivity and stress resilience.

Neonates from women with pregestational maternal obesity show reduced umbilical vein endothelial response to insulin.

OBJECTIVE: Pregestational maternal obesity (PGMO) associates with foetoplacental vascular endothelial dysfunction and higher risk for insulin resistance in the neonate. We characterised the PGMO consequences on the insulin response of the human foetoplacental vasculature. METHODS: Umbilical veins were from pregnancies where the mother was with PGMO (body mass index 30-42.3 kg/m2, n = 33) or normal pregestational weight (PGMN) (body mass index 19.5-24.4 kg/m2, n = 21) with total gestational weight gain within the physiological range. Umbilical vein ring segments were mounted in a myograph for isometric force measurements. Primary cultures of human umbilical vein endothelial cells were used in passage 3. Vessel rings and cells were exposed to 1 nmol/L insulin (20 min) in the absence or presence of 100 µmol/L NG-nitro-l-arginine methyl ester (inhibitor of nitric oxide synthase, NOS). RESULTS: Vessel rings from PGMO showed reduced nitric oxide synthase-activity dependent dilation to insulin or calcitonin-gene related peptide compared with PGMN. PGMO associated with higher inhibitor phosphorylation of the insulin receptor substrate 1 (IRS-1) and lower activator phosphorylation of protein kinase B/Akt (Akt). Cells from PGMO also showed lower nitric oxide level and reduced activator serine1177 but increased inhibitor threonine495 phosphorylation of endothelial nitric oxide synthase (eNOS) and saturable transport of l-arginine. HUVECs from PGMO were not responsive to insulin. CONCLUSION: The lack of response to insulin by the foetoplacental endothelium may result from reduced IRS-1/Akt/eNOS signalling in PGMO. These findings may result in higher risk of insulin resistance in neonates to PGMO pregnancies.

Application of Remote Sensing for Phenotyping Tar Spot Complex Resistance in Maize.

Tar spot complex (TSC), caused by at least two fungal pathogens, Phyllachora maydis and Monographella maydis, is one of the major foliar diseases of maize in Central and South America. P. maydis was also detected in the United States of America in 2015 and since then the pathogen has spread in the maize growing regions of the country. Although remote sensing (RS) techniques are increasingly being used for plant phenotyping, they have not been applied to phenotyping TSC resistance in maize. In this study, several multispectral vegetation indices (VIs) and thermal imaging of maize plots under disease pressure and disease-free conditions were tested using an unmanned aerial vehicle (UAV) over two crop seasons. A strong relationship between grain yield, a vegetative index (MCARI2), and canopy temperature was observed under disease pressure. A strong relationship was also observed between the area under the disease progress curve of TSC and three vegetative indices (RDVI, MCARI1, and MCARI2). In addition, we demonstrated that TSC could cause up to 58% yield loss in the most susceptible maize hybrids. Our results suggest that the RS techniques tested in this study could be used for high throughput phenotyping of TSC resistance and potentially for other foliar diseases of maize. This may help reduce the cost and time required for the development of improved maize germplasm. Challenges and opportunities in the use of RS technologies for disease resistance phenotyping are discussed.

Glioma progression in diabesity.

Diabetes mellitus, obesity, and cancer are diseases that in recent years have caused a large number of deaths worldwide, so have been in the front line of biomedical research. On the other hand, obesity is a risk factor for several types of cancer and type 2 diabetes mellitus. The metabolic disorder and global inflammatory environment seen in obese patients is also critical for the treatment of both diabetes mellitus and gliomas. Several molecules are increased in patients with obesity and are considered risk factors in the failure of multimodal therapies for diabetes mellitus and gliomas. These molecules include adenosine, insulin, adenosine deaminases, adenosine kinase, lipids, as well as adenosine receptors, adenosine membrane transporters, and the immune response. The role of adenosine will be explained in depth since it is a nucleoside aberrantly increased in patients with these diseases, is one of the main causes of diabetes mellitus progression and the failure of glioma therapies. In addition, the role of type 2 diabetes mellitus/obesity, i.e., diabesity, and its implication in glioma treatment is discussed.

Optimum and Decorrelated Constrained Multistage Linear Phenotypic Selection Indices Theory.

Some authors have evaluated the unconstrained optimum and decorrelated multistage linear phenotypic selection indices (OMLPSI and DMLPSI, respectively) theory. We extended this index theory to the constrained multistage linear phenotypic selection index context, where we denoted OMLPSI and DMLPSI as OCMLPSI and DCMLPSI, respectively. The OCMLPSI (DCMLPSI) is the most general multistage index and includes the OMLPSI (DMLPSI) as a particular case. The OCMLPSI (DCMLPSI) predicts the individual net genetic merit at different individual ages and allows imposing constraints on the genetic gains to make some traits change their mean values based on a predetermined level, while the rest of them remain without restrictions. The OCMLPSI takes into consideration the index correlation values among stages, whereas the DCMLPSI imposes the restriction that the index correlation values among stages be null. The criteria to evaluate OCMLPSI efficiency vs. DCMLPSI efficiency were that the total response of each index must be lower than or equal to the single-stage constrained linear phenotypic selection index response and that the expected genetic gain per trait values should be similar to the constraints imposed by the breeder. We used one real and one simulated dataset to validate the efficiency of the indices. The results indicated that OCMLPSI accuracy when predicting the selection response and expected genetic gain per trait was higher than DCMLPSI accuracy when predicting them. Thus, breeders should use the OCMLPSI when making a phenotypic selection.

Involvement of Intracellular pH in Vascular Insulin Resistance.

The maintenance of the pH homeostasis is maintained by several mechanisms including the efflux of protons (H+) via membrane transporters expressed in almost all mammalian cells. Along these membrane transporters the sodium/H+ exchangers (NHEs), mainly NHE isoform 1 (NHE1), plays a key role in this phenomenon. NHE1 is under modulation by several environmental conditions (e.g. hyperglycaemia, protein kinase C activity) as well as hormones, including insulin. NHE1 activation causes intracellular alkalization in human endothelial cells leading to activation of the endothelial Nitric Oxide Synthase (eNOS) to generate NO. Intracellular alkalization is a phenomenon that also results in upregulation of the glucose transporter GLUT4 in cells that are responsive to insulin. A reduction in the removal of the extracellular D-glucose is seen in states of insulin resistance, such as in diabetes mellitus and obesity. Since insulin is a potent activator of eNOS in human endothelium, therefore causing vasodilation, and its vascular effect is reduced in insulin resistance it is likely that a defective signal to activate NHE1 in insulin target cells is expected. This phenomenon results in lower redistribution and activation of GLUT4 leading to reduced uptake of D-glucose and hyperglycaemia. The general concept of a role for NHE1, and perhaps other NHEs isoforms, in insulin resistance in the human vasculature is proposed.

Pre-pregnancy maternal obesity associates with endoplasmic reticulum stress in human umbilical vein endothelium.

Obesity associates with the endoplasmic reticulum (ER) stress-induced endothelial dysfunction. Pregnant women with pre-pregnancy maternal obesity (PGMO) may transfer this potential risk to their offspring; however, whether ER stress occurs and associates with foetoplacental endothelial dysfunction in PGMO is unknown. We studied the l-arginine transport and nitric oxide (NO) synthesis in human umbilical vein endothelial cells (HUVECs) from women with PGMO or with a normal pre-pregnancy weight. We analysed the expression and activation of the ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). PGMO associated with lower endothelial NO synthase activity due to increased Thr495-inhibitor and decreased Ser1177-stimulator phosphorylation. However, higher expression and activity of the human cationic amino acid transporter 1 was found. PGMO caused activation of PERK and its downstream targets eukaryotic initiation factor 2 (eIF2α), C/EBP homologous protein 10 (CHOP), and tribbles-like protein 3 (TRB3). Increased IRE1α protein abundance (but not its phosphorylation or X-box binding protein 1-mRNA splicing) and increased c-Jun N-terminal kinase 1 phosphorylation was seen in PGMO. A preferential nuclear location of the activating transcription factor 6 (ATF6) was found in HUVECs from PGMO. All the changes seen in PGMO were blocked by TUDCA but unaltered by tunicamycin. Thus, PGMO may determine a state of ER stress via upregulation of the PERK-eIF2α-CHOP-TRB3 axis signalling in HUVECs. This phenomenon results in foetoplacental vascular endothelial dysfunction at birth.

Insulin therapy and its consequences for the mother, foetus, and newborn in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a disease characterised by glucose intolerance and first diagnosed in pregnancy. This condition relates to an anomalous placental environment and aberrant placental vascular function. GDM-associated hyperglycaemia changes the placenta structure leading to abnormal development and functionality of this vital organ. Aiming to avoid the GDM-hyperglycaemia and its deleterious consequences in the mother, the foetus and newborn, women with GDM are firstly treated with a controlled diet therapy; however, some of the women fail to reach the recommended glycaemia values and therefore they are passed to the second line of treatment, i.e., insulin therapy. The several protocols available in the literature regarding insulin therapy are variable and not a clear consensus is yet reached. Insulin therapy restores maternal glycaemia, but this beneficial effect is not reflected in the foetus and newborn metabolism, suggesting that other factors than d-glucose may be involved in the pathophysiology of GDM. Worryingly, insulin therapy may cause alterations in the placenta and umbilical vessels as well as the foetus and newborn additional to those seen in pregnant women with GDM treated with diet. In this review, we summarised the variable information regarding indications and protocols for administration of the insulin therapy and the possible outcomes on the function and structure of the foetoplacental unit and the neonate parameters from women with GDM.

Akt/mTOR Role in Human Foetoplacental Vascular Insulin Resistance in Diseases of Pregnancy.

Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature. PE, GDM, and PGMO are abnormal conditions coursing with reduced insulin signalling, but the possibility of the involvement of similar cell signalling mechanisms is not addressed. This review aimed to determine whether reduced insulin signalling in PE, GDM, and PGMO shares a common mechanism in the human foetoplacental vasculature. Insulin resistance in these pathological conditions results from reduced Akt activation mainly due to inhibition of IRS1/2, likely due to the increased activity of the mammalian target of rapamycin (mTOR) resulting from lower activity of adenosine monophosphate kinase. Thus, a defective signalling via Akt/mTOR in response to insulin is a central and common mechanism of insulin resistance in these diseases of pregnancy. In this review, we summarise the cell signalling mechanisms behind the insulin resistance state in PE, GDM, and PGMO focused in the Akt/mTOR signalling pathway in the human foetoplacental endothelium.