A Narrative Review on the Pathophysiology of Preeclampsia.

Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, posing significant risks to both maternal and fetal health. Despite extensive research, its complex pathophysiology remains incompletely understood. This narrative review aims to elucidate the intricate mechanisms contributing to PE, focusing on abnormal placentation, maternal systemic response, oxidative stress, inflammation, and genetic and epigenetic factors. This review synthesizes findings from recent studies, clinical trials, and meta-analyses, highlighting key molecular and cellular pathways involved in PE. The review integrates data on oxidative stress biomarkers, angiogenic factors, immune interactions, and mitochondrial dysfunction. PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia. This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation. Oxidative stress, mitochondrial abnormalities, and immune dysregulation further exacerbate the condition. Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles. Emerging therapeutic strategies targeting oxidative stress, inflammation, angiogenesis, and specific molecular pathways like the heme oxygenase-1/carbon monoxide (HO-1/CO) and cystathionine gamma-lyase/hydrogen sulfide (CSE/H2S) pathways show promise in mitigating preeclampsia's effects. PE is a complex disorder with multifactorial origins involving abnormal placentation, endothelial dysfunction, systemic inflammation, and oxidative stress. Despite advances in understanding its pathophysiology, effective prevention and treatment strategies remain limited. Continued research is essential to develop targeted therapies that can improve outcomes for both mothers and their babies.

S100B actions on glial and neuronal cells in the developing brain: an overview.

The S100B is a member of the S100 family of "E" helix-loop- "F" helix structure (EF) hand calcium-binding proteins expressed in diverse glial, selected neuronal, and various peripheral cells, exerting differential effects. In particular, this review compiles descriptions of the detection of S100B in different brain cells localized in specific regions during the development of humans, mice, and rats. Then, it summarizes S100B's actions on the differentiation, growth, and maturation of glial and neuronal cells in humans and rodents. Particular emphasis is placed on S100B regulation of the differentiation and maturation of astrocytes, oligodendrocytes (OL), and the stimulation of dendritic development in serotoninergic and cerebellar neurons during embryogenesis. We also summarized reports that associate morphological alterations (impaired neurite outgrowth, neuronal migration, altered radial glial cell morphology) of specific neural cell groups during neurodevelopment and functional disturbances (slower rate of weight gain, impaired spatial learning) with changes in the expression of S100B caused by different conditions and stimuli as exposure to stress, ethanol, cocaine and congenital conditions such as Down's Syndrome. Taken together, this evidence highlights the impact of the expression and early actions of S100B in astrocytes, OL, and neurons during brain development, which is reflected in the alterations in differentiation, growth, and maturation of these cells. This allows the integration of a spatiotemporal panorama of S100B actions in glial and neuronal cells in the developing brain.

Metabolism-Disrupting Chemical Mixtures during Pregnancy, Folic Acid Supplementation, and Liver Injury in Mother-Child Pairs.

Background and Aims: Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on liver injury limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver injury and effect modification by folic acid (FA) supplementation in mother-child pairs. Methods: We studied ∼200 mother-child pairs from the Mexican PROGRESS cohort, with measured 43 MDCs during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide [OP] metabolites), and serum liver enzymes (ALT, AST) at ∼9 years post-parturition. We defined liver injury as elevated liver enzymes in children, and using established clinical scores for steatosis and fibrosis in mothers (i.e., AST:ALT, FLI, HSI, FIB-4). Bayesian Weighted Quantile Sum regression assessed MDC-mixture associations with liver injury outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. Results: In children, many MDC-mixtures were associated with liver injury outcomes. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95%CI: 1.67%, 19.4%) and AST by 5.27% (95% CI: 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations ( p -interactions<0.05). In mothers, only the LMWP-mixture was associated with liver injury [OR=1.53 (95%CI: 1.01, 2.28) for HSI>36, and OR=1.62 (95%CI: 1.05, 2.49) for AST:ALT<1]. In mothers and children, most associations were attenuated (null) at FA supplementation≥600mcg/day ( p -interactions<0.05). Conclusions: Pregnancy MDC exposures may increase liver injury risk, particularly in children. These associations may be attenuated by higher FA supplementation and maternal cobalt levels.

Nighttime eating during pregnancy and infant adiposity at 6 months of life.

Introduction: Chrononutrition studies the relation between diet, circadian rhythms and metabolism, which may alter the metabolic intrauterine environment, influencing infant fat-mass (FM) development and possibly increasing obesity risk. Aim: To evaluate the association of chrononutrition in pregnancy and infant FM at 6 months. Methods: Healthy pregnant women and term-babies (n = 100pairs) from the OBESO cohort (2017-2023) were studied. Maternal registries included pregestational body-mass-index (BMI), gestational complications/medications, weight gain. Diet (three 24 h-recalls, 1 each trimester) and sleep-schedule (first and third trimesters) were evaluated computing fasting (hours from last-first meal), breakfast and dinner latencies (minutes between wake up-breakfast and dinner-sleep, respectively), number of main meals/day, meal skipping (≥1 main meal/d on three recalls) and nighttime eating (from 9:00 pm-5:59 am on three recalls). Neonatal weight, length, BMI/age were assessed. At 6 months, infant FM (kg, %; air-displacement plethysmography) was measured, and FM index (FMI-kgFM/length2) computed. Exclusive breastfeeding (EBF) was recorded. Multiple linear regression models evaluated the association between chrononutrition and 6 month infant FM. Results: Mean fasting was 11.7 ± 1.3 h; breakfast, dinner latency were 87.3 ± 75.2, 99.6 ± 65.6 min, respectively. Average meals/day were 3.0 ± 0.5. Meal skipping was reported in 3% (n = 3) of women and nighttime eating in 35% (n = 35). Most neonates had normal BMI/age (88%, n = 88). Compared to those who did not, mothers engaged in nighttime-eating had infants with higher %FM (p = 0.019). Regression models (R 2 ≥ 0.308, p ≤ 0.001) showed that nighttime eating was positively associated with %FM (B: 2.7, 95%CI: 0.32-5.16). When analyzing women without complications/medications (n = 80), nighttime eating was associated with higher FM [%FM, B: 3.24 (95%CI: 0.59-5.88); kgFM, B: 0.20 (95%CI: 0.003-0.40); FMI, B: 0.54 (95%CI: 0.03-1.05)]. Infant sex and weight (6 months) were significant, while maternal obesity, pregnancy complications/medications, parity, energy intake, birth-BMI/age, and EBF were not. Conclusion: Maternal nighttime eating is associated with higher adiposity in 6 month infants.

Earlier detection of gestational diabetes impacts on medication requirements, neonatal and maternal outcomes.

AIM: Gestational diabetes (GD) is a global health concern with significant implications for maternal and neonatal outcomes. This study investigates the association between early GD (eGD) diagnosis (<24 weeks), pharmacotherapy requirements and adverse neonatal outcomes. MATERIALS AND METHODS: A cohort of 369 pregnant women underwent a 75-g oral glucose tolerance test. Maternal variables, pharmacotherapy prescriptions and neonatal outcomes were analysed employing t-tests, χ2 tests, and logistic regression. A p < .05 was considered significant. RESULTS: Early GD increased the odds of neonatal hypoglycaemia [odds ratio (OR): 18.57, p = .013] and respiratory distress syndrome (OR: 4.75, p = .034). Nutritional therapy prescription by an accredited nutritionist was the most common treatment in women diagnosed after 24 weeks, but those with eGD required more frequently specialized nutritional consulting + metformin to achieve glycaemic control (p = .027). eGD was associated with a higher requirement of nutritional therapy prescription + metformin (OR: 2.26, 95% confidence interval: 1.25-4.09, p = .007) and with maternal hyperglycaemia during the post-partum period at 2 h of the oral glucose tolerance test (OR: 1.03, 95% confidence interval: 1.02-1.13, p = .024). CONCLUSION: Timely diagnosis and personalized treatment of GD are desirable because an earlier presentation is related to a higher risk of adverse neonatal and maternal outcomes.

Optimizing perinatal wellbeing in pregnancy with obesity: a clinical trial with a multi-component nutrition intervention for prevention of gestational diabetes and infant growth and neurodevelopment impairment.

Pregnancy complicated by obesity represents an increased risk of unfavorable perinatal outcomes such as gestational diabetes mellitus (GDM), hypertensive disorders in pregnancy, preterm birth, and impaired fetal growth, among others. Obesity is associated with deficiencies of micronutrients, and pregnant women with obesity may have higher needs. The intrauterine environment in pregnancies complicated with obesity is characterized by inflammation and oxidative stress, where maternal nutrition and metabolic status have significant influence and are critical in maternal health and in fetal programming of health in the offspring later in life. Comprehensive lifestyle interventions, including intensive nutrition care, are associated with a lower risk of adverse perinatal outcomes. Routine supplementation during pregnancy includes folic acid and iron; other nutrient supplementation is recommended for high-risk women or women in low-middle income countries. This study is an open label randomized clinical trial of parallel groups (UMIN Clinical Trials Registry: UMIN000052753, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000060194) to evaluate the effect of an intensive nutrition therapy and nutrient supplementation intervention (folic acid, iron, vitamin D, omega 3 fatty acids, myo-inositol and micronutrients) in pregnant women with obesity on the prevention of GDM, other perinatal outcomes, maternal and newborn nutritional status, and infant growth, adiposity, and neurodevelopment compared to usual care. Given the absence of established nutritional guidelines for managing obesity during pregnancy, there is a pressing need to develop and implement new nutritional programs to enhance perinatal outcomes.

Isolation of Primary Human Decidual Cells from the Fetal Membranes of Term Placentae.

The maternal decidua is a transient and dynamic tissue that functions as an immunoprivileged matrix related to nutritional and endocrine processes. The function of decidual cells is key to the success of embryo implantation and the maintenance of pregnancy with a positive maternal-fetal outcome. Therefore, establishing a method to optimize the isolation of primary decidual cells is essential. Our protocol described here provides a good yield of decidual cells in an optimized time.

Analysis of the GFP-labelled ß-dystroglycan interactome in HEK-293 transfected cells reveals novel intracellular networks.

Dystroglycan (DG) is a cell adhesion complex that is widely expressed in tissues. It is composed by two subunits, α-DG, a highly glycosylated protein that interacts with several extracellular matrix proteins, and transmembrane ß-DG whose, cytodomain binds to the actin cytoskeleton. Glycosylation of α-DG is crucial for functioning as a receptor for its multiple extracellular binding partners. Perturbation of α-DG glycosylation is the central event in the pathogenesis of severe pathologies such as muscular dystrophy and cancer. ß-DG acts as a scaffold for several cytoskeletal and nuclear proteins and very little is known about the fine regulation of some of these intracellular interactions and how they are perturbed in diseases. To start filling this gap by identifying uncharacterized intracellular networks preferentially associated with ß-DG, HEK-293 cells were transiently transfected with a plasmid carrying the ß-DG subunit with GFP fused at its C-terminus. With this strategy, we aimed at forcing ß-DG to occupy multiple intracellular locations instead of sitting tightly at its canonical plasma membrane milieu, where it is commonly found in association with α-DG. Immunoprecipitation by anti-GFP antibodies followed by shotgun proteomic analysis led to the identification of an interactome formed by 313 exclusive protein matches for ß-DG binding. A series of already known ß-DG interactors have been found, including ezrin and emerin, whilst significant new matches, which include potential novel ß-DG interactors and their related networks, were identified in diverse subcellular compartments, such as cytoskeleton, endoplasmic reticulum/Golgi, mitochondria, nuclear membrane and the nucleus itself. Of particular interest amongst the novel identified matches, Lamina-Associated Polypeptide-1B (LAP1B), an inner nuclear membrane protein, whose mutations are known to cause nuclear envelopathies characterized by muscular dystrophy, was found to interact with ß-DG in HEK-293 cells. This evidence was confirmed by immunoprecipitation, Western blotting and immunofluorescence experiments. We also found by immunofluorescence experiments that LAP1B looses its nuclear envelope localization in C2C12 DG-knock-out cells, suggesting that LAP1B requires ß-DG for a proper nuclear localization. These results expand the role of ß-DG as a nuclear scaffolding protein and provide novel evidence of a possible link between dystroglycanopathies and nuclear envelopathies displaying with muscular dystrophy.

Nonfucosylation of an anti-TIGIT antibody enhances FcγR engagement, driving innate immune activation and antitumor activity.

TIGIT is an immune checkpoint receptor expressed on activated and memory T cells, immunosuppressive T regulatory cells, and natural killer (NK) cells. TIGIT has emerged as an attractive target for antitumor therapies, due to its proposed immunosuppressive effects on lymphocyte function and T cell activation. We generated an anti-TIGIT monoclonal antibody (mAb) that binds with high affinity to human, non-human primate, and murine TIGIT and through multiple experimental methodologies demonstrated that checkpoint blockade alone is insufficient for antitumor activity. Generating anti-TIGIT mAbs with various Fc backbones we show that muting the Fc-Fcγ receptor (FcγR) interaction failed to drive antitumor activity, while mAbs with Fc functional backbones demonstrate substantial antitumor activity, mediated through activation of antigen-presenting cells (APCs), T cell priming, and NK-mediated depletion of suppressive Tregs and exhausted T cells. Further, nonfucosylation of the Fc backbone resulted in enhanced immune responses and antitumor activity relative to the intact IgG1 backbone. The improved activity correlated with the biased FcγR interaction profile of the nonfucosylated anti-TIGIT mAb, which supports that FcγRIIIa binding with decreased FcγRIIb binding favorably activates APCs and enhances tumor-specific CD8+ T cell responses. The anti-TIGIT mAbs with intact FcγR interacting backbones also demonstrated synergistic enhancement of other standard antitumor treatments, including anti-PD-1 treatment and a model monomethyl auristatin E antibody-drug conjugate. These findings highlight the importance of the anti-TIGIT mAb's Fc backbone to its antitumor activity and the extent to which this activity can be enhanced through nonfucosylation of the backbone.

The Molecular Role of Polyamines in Age-Related Diseases: An Update.

Polyamines (Pas) are short molecules that exhibit two or three amine groups that are positively charged at a physiological pH. These small molecules are present in high concentrations in a wide variety of organisms and tissues, suggesting that they play an important role in cellular physiology. Polyamines include spermine, spermidine, and putrescine, which play important roles in age-related diseases that have not been completely elucidated. Aging is a natural process, defined as the time-related deterioration of the physiological functions; it is considered a risk factor for degenerative diseases such as cardiovascular, neurodegenerative, and musculoskeletal diseases; arthritis; and even cancer. In this review, we provide a new perspective on the participation of Pas in the cellular and molecular processes related to age-related diseases, focusing our attention on important degenerative diseases such as Alzheimerߣs disease, Parkinsonߣs disease, osteoarthritis, sarcopenia, and osteoporosis. This new perspective leads us to propose that Pas function as novel biomarkers for age-related diseases, with the main purpose of achieving new molecular alternatives for healthier aging.

AI-Enhanced Analysis Reveals Impact of Maternal Diabetes on Subcutaneous Fat Mass in Fetuses without Growth Alterations.

Pregnant women with diabetes often present impaired fetal growth, which is less common if maternal diabetes is well-controlled. However, developing strategies to estimate fetal body composition beyond fetal growth that could better predict metabolic complications later in life is essential. This study aimed to evaluate subcutaneous fat tissue (femur and humerus) in fetuses with normal growth among pregnant women with well-controlled diabetes using a reproducible 3D-ultrasound tool and offline TUI (Tomographic Ultrasound Imaging) analysis. Additionally, three artificial intelligence classifier models were trained and validated to assess the clinical utility of the fetal subcutaneous fat measurement. A significantly larger subcutaneous fat area was found in three-femur and two-humerus selected segments of fetuses from women with diabetes compared to the healthy pregnant control group. The full classifier model that includes subcutaneous fat measure, gestational age, fetal weight, fetal abdominal circumference, maternal body mass index, and fetal weight percentile as variables, showed the best performance, with a detection rate of 70%, considering a false positive rate of 10%, and a positive predictive value of 82%. These findings provide valuable insights into the impact of maternal diabetes on fetal subcutaneous fat tissue as a variable independent of fetal growth.

Polyamines modulate mouse sperm motility.

Polyamines are polycationic molecules which contains two or more amino groups (-NH3+) highly charged at physiological pH, and among them we found spermine, spermidine, putrescine, and cadaverine. They interact with proteins, nucleic acids, modulate Ca2+, K+, and Na+ channels, and protect sperm from oxidative stress. In this work, we evaluate the effect of spermine, spermidine, and putrescine on the total, progressive and kinematic parameters of motility, capacitation, acrosome reaction, also in presence and absence of the dbcAMP, an analogue of the cAMP, and the IBMX, a phosphodiesterase inhibitor. In addition, we evaluated the intracellular concentrations of cAMP [cAMP]i, and performed an in silico analysis between polyamines and the sAC from mouse to predict the possible interaction among them. Our results showed that all polyamines decrease drastically the total, progressive and the kinetic parameters of sperm motility, decrease the capacitation, and only spermidine and putrescine impeded the acquisition of acrosome reaction. Moreover, the effect of polyamines was attenuated but not countered by the addition of db-cAMP and IBMX, suggesting a possible inhibition of the sAC. Also, the presence of polyamines induced a decrease of the [cAMP]i, and the in silico analysis predicted a strong interaction among polyamines and the sAC. Overall, the evidence suggests that probably the polyamines interact and inhibit the activity of the sAC.

Excessive Pregestational Weight and Maternal Obstetric Complications: The Role of Adipokines.

There is a high frequency of overweight and obesity in women of reproductive age. Women who start pregnancy with overweight or obesity have an increased risk of developing maternal obstetric complications such as gestational hypertension, pre-eclampsia, gestational diabetes mellitus, postpartum hemorrhage, and requiring C-section to resolve the pregnancy with a higher risk of C-section surgical site infection. Excessive weight in pregnancy is characterized by dysregulation of adipokines, the functions of which partly explain the predisposition of pregnant women with overweight or obesity to these maternal obstetric complications. This review compiles, organizes, and analyzes the most recent studies on adipokines in pregnant women with excess weight and the potential pathophysiological mechanisms favoring the development of maternal pregnancy complications.

A Novel Predictive Machine Learning Model Integrating Cytokines in Cervical-Vaginal Mucus Increases the Prediction Rate for Preterm Birth.

Preterm birth (PB) is a leading cause of perinatal morbidity and mortality. PB prediction is performed by measuring cervical length, with a detection rate of around 70%. Although it is known that a cytokine-mediated inflammatory process is involved in the pathophysiology of PB, none screening method implemented in clinical practice includes cytokine levels as a predictor variable. Here, we quantified cytokines in cervical-vaginal mucus of pregnant women (18-23.6 weeks of gestation) with high or low risk for PB determined by cervical length, also collecting relevant obstetric information. IL-2, IL-6, IFN-γ, IL-4, and IL-10 were significantly higher in the high-risk group, while IL-1ra was lower. Two different models for PB prediction were created using the Random Forest machine-learning algorithm: a full model with 12 clinical variables and cytokine values and the adjusted model, including the most relevant variables-maternal age, IL-2, and cervical length- (detection rate 66 vs. 87%, false positive rate 12 vs. 3.33%, false negative rate 28 vs. 6.66%, and area under the curve 0.722 vs. 0.875, respectively). The adjusted model that incorporate cytokines showed a detection rate eight points higher than the gold standard calculator, which may allow us to identify the risk PB risk more accurately and implement strategies for preventive interventions.

Influential Serum Kinases (Non-sFlt-1) and Phosphatases in Preeclampsia-Systemic Review and Metanalysis.

The early identification of women with an increased risk of preeclampsia (PE) is desirable, but apart from soluble fms-like tyrosine kinase-1 (sFlt-1), few biomarkers have previously been identified as relevant for predicting preeclampsia. Since kinases and phosphatases regulate critical biological processes and previous evidence suggests a potential role of these molecules in preeclampsia, we performed this systematic review and metanalysis. The objective was to determine if there are kinases and phosphatases whose serum levels are different between women with and without PE, being relevant biomarkers of PE. We followed the recommendations of Cochrane and the Preferred Reported Items for Systematic Reviews and Metanalysis (PRISMA) to perform this study. The MESH terms preeclampsia, kinases, phosphatases, angiopoietins, soluble tyrosine protein kinase receptor (sTIE2), and cellular-mesenchymal-epithelial transition factor (c-MET) were combined to find relevant articles in the PubMed, PROSPERO, and Cochrane databases. Then, a qualitative and quantitative analysis was performed in R Studio software. From 580 abstracts identified, 37 were included in the final analysis, which comprised 24,211 pregnant women (2879 with PE and 21,332 women without PE [HP]. The pooled analysis showed that serum creatine kinase (CK) (SMD: 2.43, CI 95% 0.25-4.62) was significantly higher in PE, whereas sTIE2 and anti-angiogenic factor soluble c-Met (sMet)were significantly lower in PE than in HP (SMD: -0.23, CI95% -0.37 to -0.09; and SMD:0.24, CI95% 0.01-0.47, respectively). Adenosine monophosphate-activated protein kinase (AMPK), angiopoietin-1 (ANG-1), angiopoietin-2 (ANG-2), the ratio angiopoietin-1/angiopoietin-2, acid phosphatase, and alkaline phosphatase were not different between women with PE and HP. In summary CK, sTIE2, and c-MET are relevant biomarkers of PE. It is desirable to incorporate them into current models for PE prediction to evaluate their utility as biomarkers.

Gestational diabetes mellitus and size at birth modify early adiposity accretion. Evidence from the OBESO cohort.

AIM: To evaluate the association between maternal obesity, gestational diabetes (GDM), and birth size with infant fat-mass (FM) accretion from 1 to 6 months (M). METHODS: Healthy pregnant women and their term babies from the OBESO cohort were studied (1 M-3 M, n = 122; 1 M-6 M, n = 90). Registered maternal data was: pregestational body-mass-index (preBMI), GDM (2hOGTT), medications, gestational weight gain. Macrosomia (>4000 g), large/small for gestational age (LGA/SGA)(weight/age > 90° and < 90°, respectively-WHO) were recorded at birth. Infant FM (air-displacement plethysmography) was measured (1 M, 3 M, 6 M) and FM accretion computed (ΔkgFM from 1 M-3 M and 1 M-6 M). Exclusive breastfeeding (EBF) was assessed. Adjusted-multiple linear regression models were performed. RESULTS: PreBMI was 27.4 ± 5.2 kg/m2. GDM was present in9%(n = 11) of women; 12.3%(n = 15) of them received metformin/insulin. One newborn was LGA; 20.7%(n = 25) were SGA. From 1 M-3 M, SGA was a predictor of higher FM accretion (B:0.28, 95%CI:0.14-0.43); GDM was not associated. From 1 M-6 M, higher FM accretion was observed in SGA newborns (B:0.43, 95%CI:0.19-0.67) and GDM infants (B:0.48, 95%CI:0.06-0.89). In all models (R2 ≥ 0.48, p < 0.001), infant weight and being female were positively associated, while maternal obesity, metformin/insulin, and EBF were not. CONCLUSIONS: GDM appears to program early higher adiposity accretion, independently of excessive fetal growth. SGA was associated with higher FM accretion in early infancy.

Single-cell analysis reveals transcriptomic and epigenomic impacts on the maternal-fetal interface following SARS-CoV-2 infection.

During pregnancy the maternal-fetal interface plays vital roles in fetal development. Its disruption is frequently found in pregnancy complications. Recent studies show increased incidences of adverse pregnancy outcomes in patients with COVID-19; however, the mechanism remains unclear. Here we analysed the molecular impacts of SARS-CoV-2 infection on the maternal-fetal interface. Generating bulk and single-nucleus transcriptomic and epigenomic profiles from patients with COVID-19 and control samples, we discovered aberrant immune activation and angiogenesis patterns in distinct cells from patients. Surprisingly, retrotransposons were also dysregulated in specific cell types. Notably, reduced enhancer activities of LTR8B elements were functionally linked to the downregulation of pregnancy-specific glycoprotein genes in syncytiotrophoblasts. Our findings revealed that SARS-CoV-2 infection induced substantial changes to the epigenome and transcriptome at the maternal-fetal interface, which may be associated with pregnancy complications.

Implication of myddosome complex genetic variants in outcome severity of COVID-19 patients.

BACKGROUND/PURPOSE(S): During a viral infection, the immune response is mediated by the toll-like receptors and myeloid differentiation Factor 88 (MyD88) that play an important role sensing infections such as SARS-CoV-2 which has claimed the lives of more than 6.8 million people around the world. METHODS: We carried out a cross-sectional with a population of 618 SARS-CoV-2-positive unvaccinated subjects and further classified based on severity: 22% were mild, 34% were severe, 26% were critical, and 18% were deceased. Toll Like Receptor 7 (TLR7) single-nucleotide polymorphisms (rs3853839, rs179008, rs179009, and rs2302267) and MyD88 (rs7744) were genotyped using TaqMan OpenArray. The association of polymorphisms with disease outcomes was performed by logistic regression analysis adjusted by covariates. RESULTS: A significant association of rs3853839 and rs7744 of the TLR7 and MyD88 genes, respectively, was found with COVID-19 severity. The G/G genotype of the rs3853839 TLR7 was associated with the critical outcome showing an Odd Ratio = 1.98 (95% IC = 1.04-3.77). The results highlighted an association of the G allele of MyD88 gene with severe, critical and deceased outcomes. Furthermore, in the dominant model (AG + GG vs. AA), we observed an Odd Ratio = 1.70 (95% CI = 1.02-2.86) with severe, Odd Ratio = 1.82 (95% CI = 1.04-3.21) with critical, and Odd Ratio = 2.44 (95% CI = 1.21-4.9) with deceased outcomes. CONCLUSION: To our knowledge this work represents an innovative report that highlights the significant association of TLR7 and MyD88 gene polymorphisms with COVID-19 outcomes and the possible implication of the MyD88 variant with D-dimer and IFN-α concentrations.

Programming Mechanism of Adipose Tissue Expansion in the Rat Offspring of Obese Mothers Occurs in a Sex-Specific Manner.

We investigated whether excessive retroperitoneal adipose tissue (AT) expansion programmed by maternal obesity (MO) affects adipocyte size distribution and gene expression in relation to adipocyte proliferation and differentiation in male and female offspring (F1) from control (F1C) and obese (F1MO) mothers. Female Wistar rats (F0) ate a control or high-fat diet from weaning through pregnancy and lactation. F1 were weaned onto a control diet and euthanized at 110 postnatal days. Fat depots were weighed to estimate the total AT. Serum glucose, triglyceride, leptin, insulin, and the insulin resistance index (HOMA-IR) were determined. Adipocyte size and adipogenic gene expression were examined in retroperitoneal fat. Body weight, retroperitoneal AT and adipogenesis differed between male and female F1Cs. Retroperitoneal AT, glucose, triglyceride, insulin, HOMA-IR and leptin were higher in male and female F1MO vs. F1C. Small adipocytes were reduced in F1MO females and absent in F1MO males; large adipocytes were increased in F1MO males and females vs. F1C. Wnt, PI3K-Akt, and insulin signaling pathways in F1MO males and Egr2 in F1MO females were downregulated vs. F1C. MO induced metabolic dysfunction in F1 through different sex dimorphism mechanisms, including the decreased expression of pro-adipogenic genes and reduced insulin signaling in males and lipid mobilization-related genes in females.