Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.

Synovial expression of glucocorticoid receptor parallels fibroblast activation in patients with rheumatoid arthritis.

BACKGROUND: Hypocortisolemia is associated with increased expression of NR3C1 (glucocorticoid receptor, GR) in blood cells. As endogenous cortisol production is decreased in some RA patients, we tested the hypothesis that GR may be aberrantly expressed in rheumatoid synovium. METHODS: We defined the cellular pattern of NR3C1 synovial expression using human and mouse single-cell RNA-sequencing data. Bulk synovial RNA-sequencing data from early (n = 57) or established (n = 94) RA were compared to osteoarthritis (n = 22) and healthy synovium (n = 28). RESULTS: GR was expressed in all synovial cell types in both human and experimental arthritis. GR synovial expression, as well as 11ß-HSD1/11ß-HSD2 enzyme ratio, were higher in RA than healthy and osteoarthritic tissue, regardless of disease duration or treatment. Given that GR expression varied across samples, we searched for differences between RA patients with higher versus lower GR expression. Indeed, the synovial transcriptome of RA patients with high versus low GR expression (1st quartile, 30,517 ± 4876 vs. 4th quartile, 19,382 ± 2523 normalized counts) was enriched for proinflammatory gene-sets, including 'inflammatory response', 'IFN-γ response' and 'IL6/JAK/STAT3 signalling'. High synovial GR expression was also associated with increased JAK2 and PTPRK expression, denoting activation of the proinflammatory sublining fibroblasts. In contrast, low GR expression was associated with increased COMP and COL6A2 expression, denoting a resting synovial state. CONCLUSIONS: GR is overexpressed in the synovium of some RA patients in association with proinflammatory gene expression and activated sublining fibroblast status. Further studies should examine whether GR overexpression may act as a compensatory mechanism sensitizing synovial tissue to glucocorticoid action in RA.

The impact of HLA-DRB1 alleles in a Hellenic, Pediatric-Onset Multiple Sclerosis cohort: Implications on clinical and neuroimaging profile.

BACKGROUND: Pediatric-Onset Multiple Sclerosis (POMS) is considered a complex disease entity and several genetic, hormonal, and environmental factors have been associated with disease pathogenesis. Linkage studies in Caucasians have consistently suggested the human leukocyte antigen (HLA) polymorphisms, as the genetic locus most strongly linked to MS, with the HLA-DRB1*15:01 allele, being associated with both adult and pediatric MS patients. Here we aim to investigate the prevalence of the HLA-DRB1 alleles among a Hellenic POMS cohort and any possible associations with clinical and imaging disease features. MATERIALS AND METHODS: 100 POMS patients fulfilling the IPMSSG criteria, 168 Adult-Onset MS (AOMS) patients, and 246 Healthy Controls (HCs) have been enrolled. HLA genotyping was performed with a standard low-resolution sequence-specific oligonucleotide (SSO) technique. RESULTS: POMS patients display a significantly increased HLA-DRB1*03 frequency compared to both HCs [24% vs. 12.6%, OR [95%CI]: 2.19 (1.21-3.97), p=0.016) and AOMS (24% vs. 13.1%, OR [95%CI]: 2.1 (1.1-3.98), p=0.034] respectively. HLA-DRB1*03-carriers display reduced risk for brainstem lesion development (OR [CI 95%]:0.19 (0.06-0.65), p=0.011). A significantly lower frequency of HLA-DRB1*07 (4% vs 13.4%, OR (95% CI): 0.27 (0.09-0.78), p= 0.017) and HLA-DRB1*11 (37% vs 52%, OR [95% CI]: 0.54 (0.34-0.87), p= 0.016) was observed in POMS compared to HCs. CONCLUSION: The HLA-DRB1*03 allele was associated with a higher risk for POMS, replicating our previous findings, and with a lower risk for brainstem lesion development, a common clinical and neuroimaging feature in POMS, while HLA-DRB1*07 and HLA-DRB1*11 display a protective role. These findings expand the existing knowledge of HLA associations and POMS.

Identification of Stage-Specific microRNAs that Govern the Early Stages of Sequential Oral Oncogenesis by Strategically Bridging Human Genetics with Epigenetics and Utilizing an Animal Model.

Oral squamous cell carcinoma (OSCC) is a highly prevalent and aggressive malignancy, with mortality rates reaching 60%, mainly due to its excessive diagnostic delay. MiRNAs, a class of crucial epigenetic gene-expression regulators, have emerged as potential diagnostic biomarkers, with >200 molecules exhibiting expressional dysregulation in OSCC. We had previously established an in silico methodology for the identification of the most disease-specific molecules by bridging genetics and epigenetics. Here, we identified the stage-specific miRNAs that govern the asymptomatic early stages of oral tumorigenesis by exploiting seed-matching and the reverse interplay between miRNA levels and their target genes' expression. Incorporating gene-expression data from our group's experimental hamster model of sequential oral oncogenesis, we bioinformatically detected the miRNAs that simultaneously target/regulate >75% of the genes that are characteristically upregulated or downregulated in the consecutive stages of hyperplasia, dysplasia, and early invasion, while exhibiting the opposite expressional dysregulation in OSCC-derived tissue and/or saliva specimens. We found that all stages share the downregulation of miR-34a-5p, miR124-3p, and miR-125b-5p, while miR-1-3p is under-expressed in dysplasia and early invasion. The malignant early-invasion stage is distinguished by the downregulation of miR-147a and the overexpression of miR-155-5p, miR-423-3p, and miR-34a-5p. The identification of stage-specific miRNAs may facilitate their utilization as biomarkers for presymptomatic OSCC diagnosis.

Stress-Related Roles of Exosomes and Exosomal miRNAs in Common Neuropsychiatric Disorders.

Exosomes, natural nanovesicles that contain a cargo of biologically active molecules such as lipids, proteins, and nucleic acids, are released from cells to the extracellular environment. They then act as autocrine, paracrine, or endocrine mediators of communication between cells by delivering their cargo into recipient cells and causing downstream effects. Exosomes are greatly enriched in miRNAs, which are small non-coding RNAs that act both as cytoplasmic post-transcriptional repression agents, modulating the translation of mRNAs into proteins, as well as nuclear transcriptional gene activators. Neuronal exosomal miRNAs have important physiologic functions in the central nervous system (CNS), including cell-to-cell communication, synaptic plasticity, and neurogenesis, as well as modulating stress and inflammatory responses. Stress-induced changes in exosomal functions include effects on neurogenesis and neuroinflammation, which can lead to the appearance of various neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder, and Alzheimer's and Huntington's diseases. The current knowledge regarding the roles of exosomes in the pathophysiology of common mental disorders is discussed in this review.

Non-Hereditary Obesity Type Networks and New Drug Targets: An In Silico Approach.

Obesity, a chronic, preventable disease, has significant comorbidities that are associated with a great human and financial cost for society. The aim of the present work is to reconstruct the interactomes of non-hereditary obesity to highlight recent advances of its pathogenesis, and discover potential therapeutic targets. Obesity and biological-clock-related genes and/or gene products were extracted from the biomedical literature databases PubMed, GeneCards and OMIM. Their interactions were investigated using STRING v11.0 (a database of known and predicted physical and indirect associations among genes/proteins), and a high confidence interaction score of >0.7 was set. We also applied virtual screening to discover natural compounds targeting obesity- and circadian-clock-associated proteins. Two updated and comprehensive interactomes, the (a) stress- and (b) inflammation-induced obesidomes involving 85 and 93 gene/gene products of known and/or predicted interactions with an average node degree of 9.41 and 10.8, respectively, were produced. Moreover, 15 of these were common between the two non-hereditary entities, namely, ADIPOQ, ADRB2/3, CCK, CRH, CXCL8, FOS, GCG, GNRH1, IGF1, INS, LEP, MC4R, NPY and POMC, while phelligridin E, a natural product, may function as a potent FOX1-DBD interaction blocker. Molecular networks may contribute to the understanding of the integrated regulation of energy balance/obesity pathogenesis and may associate chronopharmacology schemes with natural products.

A mild and transient form of autosomal recessive pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene.

We investigate the genetic etiology in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of a mild and transient form of pseudohypoaldosteronism type 1 (PHA1). Twelve patients with PHA1 from four different families with clinical and biochemical data were analyzed. The coding regions of NR3C2 and SCNN1A genes were sequenced. Human α-epithelial sodium channel (ENaC) wild-type (wt), αPhe226Cys and αPhe226Ser ENaC variants were expressed in Xenopus laevis oocytes to evaluate ENaC activity. The protein expression of α-ENaC wt and mutants was determined by Western blot. All patients were homozygotes for the p.Phe226Cys mutation of the α subunit of ENaC. In functional studies in X. laevis oocytes, p.Phe226Cys caused a significant reduction of ENaC activity (83% reduction), reduced the number of active ENαC mutant channels, and reduced the basal open probability compared with wt. Quantitative Western blot analysis revealed that the reduced activity of ENαC mutant channels was due to a reduced ENaC protein expression for the αPhe226Cys compared with wt. We present 12 patients from four different families with a mild and transient autosomal recessive PHA1 due to a novel homozygous missense mutation in the SCNN1A gene. Functional studies showed that the p.Phe226Cys substitution mutation in ENaC leads to a partial loss of function resulting mainly from both a decrease in the intrinsic ENaC activity and a reduction in channel expression at the protein level. The partial loss of ENaC function could explain the mild phenotype, variable expressivity, and the transient course of the disorder in these patients.NEW & NOTEWORTHY This paper demonstrates that mild autosomal recessive pseudohypoaldosteronism type 1 (PHA1) due to p.Phe226Cys missense mutation in the extracellular domain of ENαC α subunit can be transient, with phenotypic variability even with the normal sweat test, and incomplete penetrance. Functional studies explain the phenotype and denote the importance of the location on the extracellular domain of the SCNN1A p.Phe226Cys mutation for the intrinsic ENaC activity and the channel expression at the protein level.

The neuroendocrinology of stress: the stress-related continuum of chronic disease development.

Stress is defined as a state of threatened homeodynamic balance by a wide range of intrinsic or extrinsic, real or perceived challenges or stimuli, defined as stressors. To preserve this optimal homeodynamic state within a physiologic range, organisms have developed a highly sophisticated system, the stress system, which serves self-regulation and adaptability of the organism by energy redirection according to the current needs. Repeated, ephemeral, and motivating stress states lead to adaptive responses and response habituations, being fairly beneficial; in contrast, inadequate, aversive, excessive, or prolonged stress may surpass the regulatory capacity and adjustive resources of the organism and produce maladaptive responses and a chronically altered homeodynamic state associated with compromised mental and physical health and life expectancy. Neuroendocrine responses to stress depend on developmental timing, duration, time of day and nature of stressors leading to a vulnerable phenotype with disrupted stress reactivity (i.e., hyper- or hypoactivation of the stress system), impaired glucocorticoid signaling, and accumulated cacostatic load with cumulatively elevated long-term risk of mental and physical morbidity. This article offers a brief overview on the organization and physiology of the human stress system and its (re)activity, refreshes the plethora of somatic effects of acute and chronic stress and discusses a conceptual model of acute and chronic stress pathophysiology as a continuum in chronic disease development.

Extracellular Vesicles and the Stress System.

Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that contain various biomolecules, including nucleic acids, proteins and lipids, and are manufactured and released by virtually all cell types. There is evidence that EVs are involved in intercellular communication, acting in an autocrine, paracrine or/and endocrine manner. EVs are released by the cells of the central nervous system (CNS), including neurons, astrocytes, oligodendrocytes and microglia, and have the ability to cross the blood-brain barrier (BBB) and enter the systemic circulation. Neuroendocrine cells are specialized neurons that secrete hormones directly into blood vessels, such as the hypophyseal portal system or the systemic circulation, a process that allows neuroendocrine integration to take place. In mammals, neuroendocrine cells are widely distributed throughout various anatomic compartments, with the hypothalamus being a central neuroendocrine integrator. The hypothalamus is a key part of the stress system (SS), a highly conserved neuronal/neuroendocrine system aiming at maintaining systemic homeostasis when the latter is threatened by various stressors. The central parts of the SS are the interconnected hypothalamic corticotropin-releasing hormone (CRH) and the brainstem locus caeruleus-norepinephrine (LC-NE) systems, while their peripheral parts are, respectively, the pituitary-adrenal axis and the sympathetic nervous/sympatho-adrenomedullary systems (SNS-SAM) as well as components of the parasympathetic nervous system (PSNS). During stress, multiple CNS loci show plasticity and undergo remodeling, partly mediated by increased glutamatergic and noradrenergic activity, and the actions of cytokines and glucocorticoids, all regulated by the interaction of the hypothalamic-pituitary-adrenal (HPA) axis and the LC-NE/SNS-SAM systems. In addition, there are peripheral changes due to the increased secretion of stress hormones and pro-inflammatory cytokines in the context of stress-related systemic (para)inflammation. We speculate that during stress, central and peripheral, cellular and molecular alterations take place, with some of them generated, communicated, and spread via the release of stress-induced neural/neuroendocrine cell-derived EVs.

Thyroid Diseases and Intestinal Microbiome.

The human microbiome plays an integral role in health. In particular, it is important for the development, differentiation, and maturation of the immune system, 70% of which resides in the intestinal mucosa. Microbiome studies conducted to date have revealed an association between disturbances in the microbiota (dysbiosis) and various pathological disorders, including changes in host immune status. Autoimmune thyroid diseases are one of the most common organ-specific autoimmune disorders, with a worldwide prevalence higher than 5%. The predominant autoimmune thyroid diseases are Hashimoto's thyroiditis and Grave's disease. Several factors, such as genetic and environmental ones, have been studied. In accordance with recent studies, it is assumed that the gut microbiome might play a significant role in triggering autoimmune diseases of the thyroid gland. However, the exact etiology has not yet been elucidated. The present review aims to describe the work carried out so far regarding the role of gut microflora in the pathogenesis of autoimmune thyroid diseases and its involvement in the appearance of benign nodules and papillary thyroid cancer. It appears that future work is needed to elucidate more precisely the mechanism for gut microbiota involvement in the development of autoimmune thyroid diseases.

Association of fructose consumption with prevalence of functional gastrointestinal disorders manifestations: results from Hellenic National Nutrition and Health Survey (HNNHS).

The study aimed to assess the total prevalence of functional gastrointestinal disorders (FGID), and separately, irritable bowel syndrome (IBS) among adults and to determine their potential association with fructose consumption. Data from the Hellenic National Nutrition and Health Survey were included (3798 adults; 58·9 % females). Information regarding FGID symptomatology was assessed using self-reported physician diagnosis questionnaires the reliability of which were screened using the ROME III, in a sample of the population. Fructose intake was estimated from 24 h recalls, and the MedDiet score was used to assess adherence to the Mediterranean diet. The prevalence of FGID symptomatology was 20·2 %, while 8·2 % had IBS (representing 40·2 % of total FGID). The likelihood of FGID was 28 % higher (95 %CI: 1·03-1·6) and of IBS 49 % (95 %CI: 1·08-2·05) in individuals with higher fructose intake than with lower intake (3rd tertile compared with 1st). When area of residence was accounted for, individuals residing in the Greek islands had a significantly lower probability of FGID and IBS compared with those residing in Mainland and the main Metropolitan areas, with Islanders also achieving a higher MedDiet score and lower added sugar intake, comparatively to inhabitants of the main metropolitan areas. FGID and IBS symptomatology was most prominent among individuals with higher fructose consumption, and this was most conspicuous in areas with a lower Mediterranean diet adherence, suggesting that the dietary source of fructose rather than total fructose should be examined in relation to FGID.

Characteristics of Café-au-lait Macules and their Association with the Neurofibromatosis type I Genotype in a Cohort of Greek Children.

Cafe-au-lait macules are the most distinctive clinical finding in neurofibromatosis type I. The aim of this prospective study of Greek children diagnosed with neurofibromatosis type I was to describe the dermatological phenotype and to analyse the characteristics of cafe-au-lait macules and their association with genotype. Pigment intensity and melatonin content of cafe-au-lait macules were measured with a narrowband spectrophotometer. A total of 63 children aged 6 months to 16 years old were studied. Mean melanin content varied, both among patients, and within each patient (p < 0.001). Females had a higher number of cafe-au-lait macules than did males (p = 0.025), and the melanin content of cafe-au-lait macules was lower in females than males (p < 0.001). Patients with protein-truncating variants in the neurofibromatosis type I gene had higher melanin content of cafe-au-lait macules than other types of genetic variants t (55) = 2.196, p = 0.032. Plexiform neurofibromas were also detected in the majority of patients with protein- truncating variants, while juvenile xanthogranulomas were detected equally in patients with protein-truncating and non-protein-truncating variants. In conclusion, cafe-au-lait macules with high melatonin content are associated with patients carrying non-protein-truncating variants. Therefore, measurement of cafe-au-lait macule pigment intensity might provide useful information for initial assessment of patients with neurofibromatosis type I and the severity of their future phenotype.

First-line disease modifying treatments in pediatric-onset multiple sclerosis in Greece: therapy initiation at more advanced age is the main cause of treatment failure, in a retrospective observational study, with a cohort from a single Multiple Sclerosis Center.

OBJECTIVES: Long-term immunomodulatory therapy of pediatric onset-multiple sclerosis (POMS) is based mainly on published case series and internationally agreed guidelines. Relevant studies in the Greek population are absent from the literature. The purpose of this study is to present data on the efficacy and safety of the 1st line immunomodulatory drugs in the treatment of POMS patients. MATERIALS AND METHODS: The present study included 27 patients meeting the IPMSSG criteria for POMS and who are monitored at the outpatient clinic of the Multiple Sclerosis and Demyelinating Diseases Unit (MSDDU), of the 1st Neurological Department, University Hospital of Aeginition. All patients received 1st line immunomodulatory drugs as initial therapy. Clinical, laboratory, and imaging parameters of the disease were recorded before and after treatment. RESULTS: Post-treatment, a significant reduction of the relapse number (mean ± SD: 2.0 ± 1.0 vs 1.2 ± 1.6, p = 0.002), EDSS progression (mean ± SD: 1.5 ± 0.8 vs 0.9 ± 0.7, p = 0.005) and ARR (mean ± SD: 1.5 ± 0.7 vs 0.4 ± 0.5, p = 0.0001) was observed, while no changes were observed in the EDSS score, (mean ± SD: 1.8 ± 0.6 vs 1.9. 0.6, p = 0.60). Advanced age at treatment initiation increased the risk for drug discontinuation before 24 months of therapy (HR = 0.6, 95% CI (0.35-0.99), p = 0.04). CONCLUSIONS: Most pediatric patients are forced to switch to either more efficacious 1st line or 2nd line drugs. Additionally, our study suggests that older age at the time of the 1st line treatment initiation, contributes to earlier drug discontinuation.

Mindfulness and Academic Performance of College and University Students: A Systematic Review.

Higher education's expectations place demands on students' attainment, leading them to experience stress and anxiety, which negatively affect their academic improvement and life satisfaction. The aim of this systematic review was to investigate (a) if mindfulness as an inner ability is related to academic attainment, through dependent variables, including compassion, engagement, stress or anxiety state, depression, self-efficacy, mindfulness's facets (non-reactivity, acting with awareness) and (b) if mindfulness-based interventions positively affect the academic performance of college and university students. The systematic review was conducted in accordance with the PRISMA statement. PubMed, Web of Science, and Cochrane Library Wiley were screened to identify studies published relevant to the topic. In total, 568 papers were retrieved in the initial search. Five papers met the eligibility criteria and were included in the systematic review: a randomized controlled trial, a non-randomized controlled trial, a quasi-experimental study, a quantitative exploratory pilot study, and a longitudinal randomized controlled study. Most interventional studies revealed a non-significant direct effect of practicing mindfulness technique on academic attainment. Further research, especially randomized controlled trials are necessary to clarify the effect of mindfulness on academic performance of college and university students.

How Does Meditation Affect the Default Mode Network: A Systematic Review.

This article provides a systematic review of studies evaluating the effect of meditation on the Default Mode Network (DMN). The review was conducted according to PRISMA guidelines. A literature search of PubMed, Scopus, and Embase was conducted up to June 2020. Search terms included default mode network or DMN and meditation.A total of 306 articles were identified, of which 16 controlled trials with a total of 853 experienced (in Mindfulness, Samatha, Raja Yoga, Transcendental Meditation, Vipassana, Insight meditation Theravada tradition) and non-experienced mediators were finally included in this systematic review. The results showed that meditative interventions affect the operation of DMN and there are differences in functional connectivity between networks. Further research should be undertaken to establish meditation as an effective intervention strategy for well-being.

Clinical and Molecular Genetic Analysis of Cases with Ectodermal Dysplasia.

INTRODUCTION: Ectodermal dysplasias are a group of >200 clinically and congenitally heterogeneous disorders characterized by abnormal development in the ectodermal structures, such as hair, nails, teeth, and sweat glands. We report here the clinical and molecular genetic analysis of five Greek families with different types of ectodermal dysplasia (ED). SUBJECTS: The study involved 15 individuals from 5 Greek families that included 8 ED patients, 5 carriers of recessive X-linked or autosomal ED, and 2 healthy relatives. After genetic counseling, the parents signed an informed consent form before subsequent genetic testing. METHODS: Genomic DNA was isolated from white blood cells of all studied individuals. The search for mutations was realized in patients' DNA samples using next-generation sequencing (NGS) gene panel, whole exome sequencing (WES), chromosomal microarray analysis (CMA), and multiplex ligation-dependent probe amplification (MLPA) technique. RESULTS: The clinical diagnosis of common X-linked recessive hypohidrotic ectodermal dysplasia (HED) was suspected in five male patients with partial anodontia of baby and permanent teeth, hypohidrosis, and thin hair from three families. All HED patients were hemizygous for deletions in the EDA1 gene (Xq13.1): three related patients had a 20 bp deletion, one had a 19 bp deletion, and one had a 180 bp deletion. A female patient had the rare autosomal dominant syndrome of ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) caused by heterozygous missense mutation in the TP63 gene (3q28) that appeared de novo. Two siblings with hypotrichosis and hypodontia, a female and a male, had two pathogenic mutations in compound heterozygosity in the TSPEAR gene (21q22.3); therefore they presented with ectodermal dysplasia type 14 (ECTD14). CONCLUSION: Clinical and molecular genetic analysis may set an accurate diagnosis of different types of ED. In the reported families, genetic diagnosis and genetic counselling assisted the parents to view their children's condition realistically and to cooperate with the specialists who will contribute to the best possible treatment for their children.

The Impact of Genetic Variability of TGF-Beta Signaling Biomarkers in Major Craniofacial Syndromes.

Craniofacial development is a complex process involving several signaling pathways, including the one regulated by the TGF-beta (TGF-ß) superfamily of growth factors. Isoforms of TGF-ß play a vital part in embryonic development, notably in craniofacial patterning. Consequently, pathogenic variants in their coding genes may result in a variety of orofacial and craniofacial malformations. Here, we review the impact of genetic variability of TGF-ß signaling biomarkers in major disorders, including palatal and lip clefts, dental anomalies, and craniofacial syndromes, such as the Loeys-Dietz syndrome (LDS) and Camurati-Engelmann disease. Cleft lip and cleft palate are associated with missense mutations in the TGFB1 and TGFB3 genes, while mutations in the LTBP3 gene encoding TGF-ß binding protein 3 may cause selective tooth agenesis. Oligodontia may also be caused by TGFB1-inactivating mutations and/or by variations in the GREM2 gene, which disrupt the activity of gremlin 2, a TGF-ß/bone morphogenetic protein (BMP4) signaling antagonist. CED may be caused by mutations in the TGFB1 gene, while the TGF-ß-related genetic background of LDS consists mostly of TGFBR1 and TGFBR2 mutations, which may also impact the above syndromes' vascular manifestations. The potential utility of the TGF-ß signaling pathway factors as biomarkers that correlate genetics with clinical outcome of craniofacial malformations is discussed.

Human Breast Milk Omics and Neurodevelopment.

Breast milk is the ideal food for the premature and mature babies and has undoubtedly immediate and ultimate benefits. Among other things, it protects against infections, reduces the risk of necrotizing enterocolitis and retinopathy of the premature babies, improves neurodevelopmental outcome, and reduces the risk of obesity and metabolic syndrome later in life. In the present study, breast milk will be studied with all the available omics technologies. More specifically, functional genomics, comparative genomics, transcriptomics, sequencing, proteomics, and metabolomics will be performed. The above results and this multidimensional information will be coordinated under the framework of a holistic approach of systems biology and bioinformatic analysis. Important IncRNAs and protein molecules will be validated as candidate biomarkers in exosomes of a larger group of breast milk and blood/serum samples. Validated ncRNAs/proteins will be analyzed in exudates of breast milk and bovine, goat, and sheep milk to explore new ways to improve milk synthesis. Expression of ncRNAs, unlike mRNAs, is a direct indicator of their functional presence. The information to be generated in this study will be analyzed by mining and data combining techniques and algorithms. After defining breast milk molecular fingerprinting, an attempt will be made to enhance the commercial product. The benefits of breast milk are attributed to its various components, including nutrients, hormones, growth factors, immune cells, antibodies, cytokines, antimicrobial peptides, and extracellular vesicles.

Endosymbiosis in Nature and the Gut-Brain Axis.

Exploring the origin of plastids is an interesting theme for study because it enhances our knowledge of the basis of photosynthesis in flora. Plastids, which are organelles, are actually the major sites of photosynthesis in eukaryotic cells. Plastids are also every chloroplast which contains cytoplasmic organelles, enabling the harvesting and conversion of light and carbon dioxide into food and energy. Plastids can be found in eukaryotic cells, and according to their structure in their membrane, they can be separated in primary (which can be found in most algae and plants) and secondary plastids (which can be found in plankton).

Post-traumatic Stress Disorder as a Risk Factor for the Development of Risky Behavior Among Adolescent Offenders: A Systematic Review.

The purpose of this research study was to obtain greater insight into the associations of post-traumatic stress disorder (PTSD) and trauma-exposed experiences with the development of offending behavior in adolescents. Using the PubMed and Scopus databases, we performed a systematic review of recent cross-sectional studies between 2016 and 2022, investigating the associations of PTSD and trauma with the social and mental behavior of adolescents. Fifty-three articles were initially identified. Due to duplication, eight articles were excluded, leaving 45 remaining articles. In addition, 34 articles were excluded due to year of publication, review, abstract, or irrelevant title. Seven articles were included in this systematic review after excluding the remaining due to different study types or samples. Included studies primarily examined the associations of PTSD symptomatology and expression of externalizing symptoms with risky behavior and the commission of a crime. The strongest outcomes were increased levels of violent behavior, violent delinquency, and total risk in correlation with PTSD symptoms, emotional numbing, use of drugs, and in some cases maltreatment. The results of the systematic review suggest that PTSD symptoms and risky behavior, which can be also fueled by maltreatment activities in the family circle, are associated with criminal behavior. Future research is needed to confirm these findings.