A controversial question: Can morphometry and clinical history be enough to diagnose hippocampal dysplasia?

The presence of dysmorphic neurons with strong cytoplasmatic accumulation of heavy non-phosphorylated neurofilament is crucial for the diagnostics of focal cortical dysplasia type II (FCDII). While ILAE's classification describes neocortical dysplasias, some groups have reported patients with mesial t abnormal neurons in the hippocampus of mesial temporal lobe epilepsy. Here we report a patient with such abnormal neurons in the hippocampus and compared it with previous reports of hippocampal dysplasia. Finally, we discuss the need for diagnostic criteria of hippocampal dysplasia.

Explainable artificial intelligence (xAI) in neuromarketing/consumer neuroscience: an fMRI study on brand perception.

Introduction: The research in consumer neuroscience has identified computational methods, particularly artificial intelligence (AI) and machine learning, as a significant frontier for advancement. Previously, we utilized functional magnetic resonance imaging (fMRI) and artificial neural networks (ANNs) to model brain processes related to brand preferences in a paradigm exempted from motor actions. In the current study, we revisit this data, introducing recent advancements in explainable artificial intelligence (xAI) to gain insights into this domain. By integrating fMRI data analysis, machine learning, and xAI, our study aims to search for functional brain networks that support brand perception and, ultimately, search for brain networks that disentangle between preferred and indifferent brands, focusing on the early processing stages. Methods: We applied independent component analysis (ICA) to overcome the expected fMRI data's high dimensionality, which raises hurdles in AI applications. We extracted pertinent features from the returned ICs. An ANN is then trained on this data, followed by pruning and retraining processes. We then apply explanation techniques, based on path-weights and Shapley values, to make the network more transparent, explainable, and interpretable, and to obtain insights into the underlying brain processes. Results: The fully connected ANN model obtained an accuracy of 54.6%, which dropped to 50.4% after pruning. However, the retraining process allowed it to surpass the fully connected network, achieving an accuracy of 55.9%. The path-weights and Shapley-based analysis concludes that, regarding brand perception, the expected initial participation of the primary visual system is followed. Other brain areas participate in early processing and discriminate between preferred and indifferent brands, such as the cuneal and the lateral occipital cortices. Discussion: The most important finding is that a split between processing brands|preferred from brands|indifferent may occur during early processing stages, still in the visual system. However, we found no evidence of a "decision pipeline" that would yield if a brand is preferred or indifferent. The results suggest the existence of a "tagging"-like process in parallel flows in the extrastriate. Network training dynamics aggregate specific processes within the hidden nodes by analyzing the model's hidden layer. This yielded that some nodes contribute to both global brand appraisal and specific brand category classification, shedding light on the neural substrates of decision-making in response to brand stimuli.

Association between oral health-related quality of life and symptoms of temporomandibular disorder among older adults: A cross-sectional study.

OBJECTIVE: Evaluate the association between oral health-related quality of life (OHRQoL) and self-reported symptoms of TMD. METHODS: Representative samples of older adults (≥60 years) were included (n = 569). Both TMD symptoms and OHRQoL were assessed by Fonseca Anamnestic Index (FAI) and Oral Health Impact Profile-14 (OHIP-14), respectively. Prevalence (those answering "frequently" or "always" in at least one question), severity (total means scores), and extent (number of questions answered as "frequently" or "always") of OHRQoL were estimated. RESULTS: Overall, 33.4% and 9.5% had mild or moderate/severe TMD symptoms. Those with any symptom of TMD had a prevalence ratio (PR) 38% higher for the worst OHRQoL (95% confidence interval [95%CI]:1.04-1.82) compared to those without TMD symptoms. Worst OHRQoL were observed for those with mild (PR:1.35; 95%CI:1.01-1.81) and moderate/severe TMD (PR:1.53; 95%CI:1.04-2.26). Similar results were detected in the severity and extent of OHRQoL. CONCLUSION: Severity TMD was associated with worse ORHQoL.

Comprehensive Genome-Wide Natural Variation and Expression Analysis of Tubby-like Proteins Gene Family in Brachypodium distachyon.

The Tubby-like proteins (TLPs) gene family is a group of transcription factors found in both animals and plants. In this study, we identified twelve B. distachyon TLPs, divided into six groups based on conserved domains and evolutionary relationships. We predicted cis-regulatory elements involved in light, hormone, and biotic and abiotic stresses. The expression patterns in response to light and hormones revealed that BdTLP3, 4, 7, and 14 are involved in light responses, and BdTLP1 is involved in ABA responses. Furthermore, BdTLP2, 7, 9, and 13 are expressed throughout vegetative and reproductive stages, whereas BdTLP1, 3, 5, and 14 are expressed at germinating grains and early vegetative development, and BdTLP4, 6, 8, and 10 are expressed at the early reproduction stage. The natural variation in the eleven most diverged B. distachyon lines revealed high conservation levels of BdTLP1-6 to high variation in BdTLP7-14 proteins. Based on diversifying selection, we identified amino acids in BdTLP1, 3, 8, and 13, potentially substantially affecting protein functions. This analysis provided valuable information for further functional studies to understand the regulation, pathways involved, and mechanism of BdTLPs.

Influence of Titanium Surface Residual Stresses on Osteoblastic Response and Bacteria Colonization.

Grit basting is the most common process applied to titanium dental implants to give them a roughness that favors bone colonization. There are numerous studies on the influence of roughness on osseointegration, but the influence of the compressive residual stress associated with this treatment on biological behavior has not been determined. For this purpose, four types of surfaces have been studied using 60 titanium discs: smooth, smooth with residual stress, rough without stress, and rough with residual stress. Roughness was studied by optic interferometry; wettability and surface energy (polar and dispersive components) by contact angle equipment using three solvents; and residual stresses by Bragg-Bentano X-ray diffraction. The adhesion and alkaline phosphatase (ALP) levels on the different surfaces were studied using Saos-2 osteoblastic cultures. The bacterial strains Streptococcus sanguinis and Lactobacillus salivarius were cultured on different surfaces, determining the adhesion. The results showed that residual stresses lead to increased hydrophilicity on the surfaces, as well as an increase in surface energy, especially on the polar component. From the culture results, higher adhesion and higher ALP levels were observed in the discs with residual stresses when compared between smooth and roughened discs. It was also found that roughness was the property that mostly influenced osteoblasts' response. Bacteria colonize rough surfaces better than smooth surfaces, but no changes are observed due to residual surface tension.

Rumen-Protected Choline Improves Metabolism and Lactation Performance in Dairy Cows.

Choline is required for the synthesis of phosphatidylcholine, an important constituent of lipoproteins. Early lactation cows presumably synthesize insufficient phosphatidylcholine, and choline supplementation in a rumen-protected form might benefit metabolism and lactation. The objectives of this study were to determine the effects of feeding rumen-protected choline (RPC) on lactation and metabolism in dairy cows. In experiment 1, 369 nulliparous and parous Holstein cows housed in four pens per treatment were fed 12.9 g/day of choline as RPC from 25 days prepartum until 80 days postpartum. In experiment 2, 578 nulliparous cows housed in five pens/treatment were fed 12.9 g/day of choline as RPC in the last 22 days of gestation only. In both experiments, blood was sampled and analyzed for concentrations of nonesterified fatty acids (NEFAs) and glucose at 1, 14, and 21 days postpartum and of choline at 1 and 14 days postpartum. Blood from all cows was sampled and analyzed for concentrations of ß-OH butyrate (BHB) at 1 and 14 days postpartum. Cows with BHB > 1.2 mmol/L were classified as having hyperketonemia. Hepatic tissue was collected from 46 cows from the eight pens in experiment 1 at 9 days postpartum and analyzed for concentrations of glycogen and triacylglycerol. Milk yield and components were measured for 80 days postpartum in experiment 1, whereas only milk yield was measured in experiment 2. The pen was the experimental unit of analysis. Supplementing RPC tended to increase dry matter intake (DMI) prepartum in experiments 1 and 2 and postpartum in experiment 1. Feeding cows with RPC increased yields of 3.5% fat-corrected milk (42.8 vs. 44.8 kg/day), energy-corrected milk (38.5 vs. 40.3 kg/day), milk fat (1.52 vs. 1.61 kg/day), and true protein (1.16 vs. 1.21 kg/day) in experiment 1. Milk yield tended to be greater with RPC (26.4 vs. 27.4 kg/day) in experiment 2. Supplementing RPC increased plasma choline concentrations on day 14 postpartum in experiment 1 (3.32 ± 0.27 vs. 4.34 ± 0.28 µM) and on day 1 in experiment 2 (3.35 ± 0.16 and 13.73 ± 0.15 µM). Treatment did not affect the concentrations of glucose, NEFAs, or BHB in plasma, but the incidence of hyperketonemia was less in multiparous cows fed RPC than those fed the control in experiment 1. Feeding cows with RPC reduced hepatic triacylglycerol content and tended to reduce the ratio of triacylglycerol to glycogen and the risk of hepatic lipidosis in cows in experiment 1. The concentrations of hepatic triacylglycerol on day 9 postpartum were inversely related to those of choline in plasma on day 1 postpartum. Feeding cows with RPC improved lactation and metabolism, but more benefits were noted when it was fed before and after calving.

Dysfunctional hippocampal-prefrontal network underlies a multidimensional neuropsychiatric phenotype following early-life seizure.

Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status epilepticus in male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.

Green Enzymatic Synthesis of Geranyl Butyrate: Process Optimization and Mechanistic Insights.

Flavor esters are organic compounds widely used in the food industry to enhance the aroma and taste of products. However, most chemical processes for the production of these flavoring compounds use toxic organic solvents. Some organic solvents derived from petroleum can leave behind residual traces in food products, which may raise concerns about potential health risks and contamination. In this study, we employ Eversa Transform 2.0, a commercial lipase derived from the lipase from Thermomyces lanuginosus, to produce geranyl butyrate in aqueous media. The chemical process was optimized using the Taguchi method, and a conversion of 93% was obtained at the optimal reaction conditions of: 1:5 molar ratio (v/v), 15% biocatalyst load (w/w), at 50 °C, in 6 h. Classic (molecular dynamics) and quantum (density functional theory) simulations unveiled amino acid residues involved in the stabilization of the enzyme-substrate complex. Detailed QM/MM mechanistic studies identified the nucleophilic attack of the deacylation reaction as the rate-limiting step of the entire mechanism, which has a free energy barrier of 14.0 kcal/mol.

Developing a hetero-intelligence methodological framework for sustainable policy-making based on the assessment of large language models.

This work delves into the increasing relevance of Large Language Models (LLMs) in the realm of sustainable policy-making, proposing an innovative hetero-intelligence framework that blends human and artificial intelligence (AI) for tackling modern sustainability challenges. The research methodology includes a hetero-intelligence performance test, which juxtaposes human intelligence with AI in the formulation and implementation of sustainable policies. After testing this hetero-intelligence methodology, seven steps are rigorously described so that it can be replicated in any sustainability planning related context. The results underscore the capabilities and limitations of LLMs, underscoring the critical role of human intelligence in enhancing the efficacy of hetero-intelligence systems. This work fulfils the need of a rigorous methodological framework based on empirical steps that can provide unbiased outcomes to be integrated into sustainable planning and decision-making processes.•Assesses LLMs' limitations and capabilities regarding sustainable planning issues•A replicable methodology is proposed based on the combination of both human and artificial intelligence•It proposes and systematises the integration of a hetero-intelligent approach into the formulation of sustainability policies to be more efficient and effective.

Vasodilation and Blood Pressure-Lowering Effect of 3-Demethyl-2-Geranyl-4-Prenylbellidifoline, a Xanthone Obtained from Garcinia achachairu, in Hypertensive Rats.

3-demethyl-2-geranyl-4-prenylbellidifoline (DGP), a natural xanthone isolated from Garcinia achachairu, has previously demonstrated remarkable diuretic and renal protective actions. The present study expands its actions on the cardiovascular system by evaluating its vasorelaxant and blood pressure-lowering effects in spontaneously hypertensive rats (SHRs). Aortic endothelium-intact (E+) preparations of SHRs pre-contracted by phenylephrine and exposed to cumulative concentrations of G. achachairu extract, fractions, and DGP exhibited a significant relaxation compared to vehicle-only exposed rings. The non-selective muscarinic receptor antagonist (atropine), the non-selective inhibitor of nitric oxide synthase (L-NAME), as well as the inhibitor of soluble guanylate cyclase (ODQ) altogether avoided DGP-induced relaxation. Tetraethylammonium (small conductance Ca2+-activated K+ channel blocker), 4-aminopyridine (a voltage-dependent K+ channel blocker), and barium chloride (an influx-rectifying K+ channel blocker) significantly reduced DGP capacity to induce relaxation without the interference of glibenclamide (an ATP-sensitive inward rectifier 6.1 and 6.2 K+ channel blocker). Additionally, administration of DGP, 1 mg/kg i.v., decreased the mean, systolic, and diastolic arterial pressures, and the heart rate of SHRs. The natural xanthone DGP showed promising potential as an endothelium-dependent vasorelaxant, operating through the nitric oxide pathway and potassium channels, ultimately significantly reducing blood pressure in hypertensive rats.

The radiation of nodulated Chamaecrista species from the rainforest into more diverse habitats has been accompanied by a reduction in growth form and a shift from fixation threads to symbiosomes.

All non-mimosoid nodulated genera in the legume subfamily Caesalpinioideae confine their rhizobial symbionts within cell wall-bound "fixation threads" (FTs). The exception is the large genus Chamaecrista in which shrubs and subshrubs house their rhizobial bacteroids more intimately within symbiosomes, whereas large trees have FTs. This study aimed to unravel the evolutionary relationships between Chamaecrista growth habit, habitat, nodule bacteroid type, and rhizobial genotype. The growth habit, bacteroid anatomy, and rhizobial symbionts of 30 nodulated Chamaecrista species native to different biomes in the Brazilian state of Bahia, a major centre of diversity for the genus, was plotted onto an ITS-TrnL-F-derived phylogeny of Chamaecrista. The bacteroids from most of the Chamaecrista species examined were enclosed in symbiosomes (SYM-type nodules), but those in arborescent species in the section Apoucouita, at the base of the genus, were enclosed in cell wall material containing homogalacturonan (HG) and cellulose (FT-type nodules). Most symbionts were Bradyrhizobium genotypes grouped according to the growth habits of their hosts, but the tree, C. eitenorum, was nodulated by Paraburkholderia. Chamaecrista has a range of growth habits that allow it to occupy several different biomes and to co-evolve with a wide range of (mainly) bradyrhizobial symbionts. FTs represent a less intimate symbiosis linked with nodulation losses, so the evolution of SYM-type nodules by most Chamaecrista species may have (a) aided the genus-wide retention of nodulation, and (b) assisted in its rapid speciation and radiation out of the rainforest into more diverse and challenging habitats.

The Performance of Using the Parasympathetic Tone Activity (PTA) Index to Assess Intraoperative Nociception in Cats.

BACKGROUND: The monitoring of nociception/antinociception poses a significant challenge during anesthesia, making the incorporation of new tools like the Parasympathetic Tone Activity (PTA) monitor an added value in feline anesthesia. OBJECTIVES: To compare the effectiveness and speed of PTA monitoring when compared to heart rate (HR) in detecting surgical stimuli (SS) during the intraoperative period in 49 female cats undergoing ovariectomy (OV). METHODS: Instantaneous Parasympathetic Tone Activity (PTAi) values, HR, fR, and non-invasive SAP and MAP were continuously monitored and systematically assessed. The time required for HR (HR time) and PTAi (PTAi time) to reach their minimum peak values following each surgical stimulus was collected at five points for each anaesthetized cat. Each collected surgical stimulus was categorized into 3 groups for statistical analysis: no nociception detection, no hemodynamic reaction and a PTAi > 50 (Nhre); no hemodynamic reaction and a PTAi < 50 (Nhre < 50); and hemodynamic reaction and PTAi < 50 (Hre < 50). RESULTS: PTAi response demonstrated effectiveness in detecting nociception compared to HR. The SS were categorized as 36.1% in the Nhre group, 50% in the Nhre < 50 group, and only 13.9% in the Hre < 50 group. In the Hre < 50 group, PTAi time and HR time had similar speeds in detecting the SS (p = 0.821); however, PTA time was significantly slower in the Nhre < 50 group when compared to the Hre < 50 group (p = 0.001). CONCLUSIONS: PTA monitoring may be a useful tool to complement HR monitoring for detecting nociception. PTA monitoring demonstrated a superior diagnostic value compared to HR for detecting nociception in cats undergoing OV and a similar speed to HR in detecting SS when HR increases above 20%. Future studies are needed to understand in a clinical setting the meaning of sympathetic activation/nociception detected using the PTA monitor when the HR increase is not clinically relevant.

Relation between Body Composition Trajectories from Childhood to Adolescence and Nonalcoholic Fatty Liver Disease Risk.

NAFLD has become the leading cause of chronic liver disease in children, as a direct consequence of the high prevalence of childhood obesity. This study aimed to characterize body composition trajectories from childhood to adolescence and their association with the risk of developing nonalcoholic fatty liver disease (NAFLD) during adolescence. The participants were part of the 'Chilean Growth and Obesity Cohort Study', comprising 784 children who were followed prospectively from age 3 years. Annual assessments of nutritional status and body composition were conducted, with ultrasound screening for NAFLD during adolescence revealing a 9.8% prevalence. Higher waist circumference measures were associated with NAFLD from age 3 years (p = 0.03), all skin folds from age 4 years (p < 0.01), and DXA body fat measurements from age 12 years (p = 0.01). The fat-free mass index was higher in females (p = 0.006) but not in males (p = 0.211). The second and third tertiles of the fat mass index (FMI) had odds ratios for NAFLD during adolescence of 2.19 (1.48-3.25, 95% CI) and 6.94 (4.79-10.04, 95% CI), respectively. Elevated waist circumference, skin folds, and total body fat were identified as risk factors for future NAFLD development. A higher FMI during childhood was associated with an increased risk of NAFLD during adolescence.

The neurobiological effects of senescence on dopaminergic system: A comprehensive review.

Over time, the body undergoes a natural, multifactorial, and ongoing process named senescence, which induces changes at the molecular, cellular, and micro-anatomical levels in many body systems. The brain, being a highly complex organ, is particularly affected by this process, potentially impairing its numerous functions. The brain relies on chemical messengers known as neurotransmitters to function properly, with dopamine being one of the most crucial. This catecholamine is responsible for a broad range of critical roles in the central nervous system, including movement, learning, cognition, motivation, emotion, reward, hormonal release, memory consolidation, visual performance, sexual drive, modulation of circadian rhythms, and brain development. In the present review, we thoroughly examine the impact of senescence on the dopaminergic system, with a primary focus on the classic delimitations of the dopaminergic nuclei from A8 to A17. We provide in-depth information about their anatomy and function, particularly addressing how senescence affects each of these nuclei.

Enhancing biocatalyst performance through immobilization of lipase (Eversa® Transform 2.0) on hybrid amine-epoxy core-shell magnetic nanoparticles.

Magnetic nanoparticles were functionalized with polyethylenimine (PEI) and activated with epoxy. This support was used to immobilize Lipase (Eversa® Transform 2.0) (EVS), optimization using the Taguchi method. XRF, SEM, TEM, XRD, FTIR, TGA, and VSM performed the characterizations. The optimal conditions were immobilization yield (I.Y.) of 95.04 ± 0.79 %, time of 15 h, ionic load of 95 mM, protein load of 5 mg/g, and temperature of 25 °C. The maximum loading capacity was 25 mg/g, and its stability in 60 days of storage showed a negligible loss of only 9.53 % of its activity. The biocatalyst demonstrated better stability at varying temperatures than free EVS, maintaining 28 % of its activity at 70 °C. It was feasible to esterify free fatty acids (FFA) from babassu oil with the best reaction of 97.91 % and ten cycles having an efficiency above 50 %. The esterification of produced biolubricant was confirmed by NMR, and it displayed kinematic viscosity and density of 6.052 mm2/s and 0.832 g/cm3, respectively, at 40 °C. The in-silico study showed a binding affinity of -5.8 kcal/mol between EVS and oleic acid, suggesting a stable substrate-lipase combination suitable for esterification.

A comprehensive review on enzyme-based biosensors: Advanced analysis and emerging applications in nanomaterial-enzyme linkage.

Biosensors with nanomaterials and enzymes detect and quantify specific targets in samples, converting recognition into measurable signals. The study explores the intrinsic synergy between these elements for detecting and quantifying particular targets in biological and environmental samples, with results demonstrated through bibliometric analysis and a comprehensive review of enzyme-based biosensors. Using WoS, 57,331 articles were analyzed and refined to 880. Key journals, countries, institutions, and relevant authors were identified. The main areas highlighted the multidisciplinary nature of the field, and critical keywords identified five thematic clusters, revealing the primary nanoparticles used (CNTs, graphene, AuNPs), major application fields, basic application themes, and niche topics such as sensitive detection, peroxidase activity, and quantum dot utilization. The biosensor overview covered nanomaterials and their primary applications, addressing recent advances and inherent challenges. Patent analysis emphasized the U.S. leadership in the industrial sector, contrasting with China's academic prominence. Future studies should focus on enhancing biosensor portability and analysis speed, with challenges encompassing efficient integration with recent technologies and improving stability and reproducibility in the nanomaterial-enzyme interaction.

Neuroprotective effects of platinum nanoparticle-based microreactors in bicuculline-induced seizures.

Epilepsy designates a group of chronic brain disorders, characterized by the recurrence of hypersynchronous, repetitive activity, of neuronal clusters. Epileptic seizures are the hallmark of epilepsy. The primary goal of epilepsy treatment is to eliminate seizures with minimal side effects. Nevertheless, approximately 30% of patients do not respond to the available drugs. An imbalance between excitatory/inhibitory neurotransmission, that leads to excitotoxicity, seizures, and cell death, has been proposed as an important mechanism regarding epileptogenesis. Recently, it has been shown that microreactors composed of platinum nanoparticles (Pt-NP) and glutamate dehydrogenase possess in vitro and in vivo activity against excitotoxicity. This study investigates the in vivo effects of these microreactors in an animal model of epilepsy induced by the administration of the GABAergic antagonist bicuculline. Male Wistar rats were administered intracerebroventricularly (i.c.v.) with the microreactors or saline and, five days later, injected with bicuculline or saline. Seizure severity was evaluated in an open field. Thirty min after behavioral measurements, animals were euthanized, and their brains processed for neurodegeneration evaluation and for neurogenesis. Treatment with the microreactors significantly increased the time taken for the onset of seizures and for the first tonic-clonic seizure, when compared to the bicuculline group that did not receive the microreactor. The administration of the microreactors also increased the time spent in total exploration and grooming. Treatment with the microreactors decreased bicuculline-induced neurodegeneration and increased neurogenesis in the dorsal and ventral hippocampus. These observations suggest that treatment with Pt-NP-based microreactors attenuates the behavioral and neurobiological consequences of epileptiform seizure activity.

Ferritin heavy chain supports stability and function of the regulatory T cell lineage.

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

Functional polymorphisms of NOS3 and GUCY1A3 affect both nitric oxide formation and association with hypertensive disorders of pregnancy.

Impaired nitric oxide (NO) formation may be associated with endothelial dysfunction and increased cardiovascular disease risk in preeclampsia (PE). Functional single-nucleotide polymorphisms (SNPs) of nitric oxide synthase 3 (NOS3) (rs3918226) and guanylate cyclase 1, soluble, alpha 3 (GUCY1A3) (rs7692387) increase susceptibility to the adverse consequences due to inadequate generation of NO by the endothelium. However, no previous study has examined whether these SNPs affect NO formation in healthy pregnancy and in gestational hypertension (GH) and PE. Here, we compared the alleles and genotypes of NOS3 (rs3918226) and GUCY1A3 (rs7692387) SNPs in normotensive pregnant women (NP, n = 153), in GH (n = 96) and PE (n = 163), and examined whether these SNPs affect plasma nitrite concentrations (a marker of NO formation) in these groups. We further examined whether the interaction among SNP genotypes is associated with GH and PE. Genotypes were determined using TaqMan allele discrimination assays, and plasma nitrite concentrations were determined by an ozone-based chemiluminescence assay. Multifactor dimensionality reduction was used to examine the interactions among SNP genotypes. Regarding NOS3 rs3918226, the CT genotype (p = 0.046) and T allele (p = 0.020) were more frequent in NP than in GH, and GH patients carrying the CT+TT genotypes showed lower nitrite concentrations than NP carrying the CT+TT genotypes (p < 0.05). Regarding GUCY1A3 rs7692387, the GA genotype (p = 0.013) and A allele (p = 0.016) were more frequent in PE than in NP, and NP women carrying the GG genotype showed higher nitrite concentrations than GH or PE patients carrying the GG genotype (p < 0.05). However, we found no significant interactions among genotypes for these functional SNPs to be associated with GH or PE. Our novel findings suggest that NOS3 rs3918226 and GUCY1A3 rs7692387 may affect NO formation and association with hypertensive disorders of pregnancy.