In silico analysis of endocrine-disrupting potential of triclosan, bisphenol A, and their analogs and derivatives.

Owning to the increasing body of evidence about the ubiquitous exposure to endocrine disruptors (EDCs), particularly bisphenol A (BPA), and associated health effects, BPA has been gradually substituted with insufficiently tested structural analogs. The unmanaged excessive use of antimicrobial agents such as triclosan (TCS) during the COVID-19 outbreak has also raised concerns about its possible interferences with hormonal functions. The similarity of BPA and estradiol, as well as TCS and non-steroidal estrogens, imply that endocrine-disrupting properties of their analogs could be predicted based on the chemical structure. Hence, this study aimed to evaluate the endocrine-disrupting potential of BPA substitutes as well as TCS derivatives and degradation/biotransformation metabolites, in comparison to BPA and TCS based on their molecular properties, computational predictions of pharmacokinetics and binding affinities to nuclear receptors. Based on the obtained results several under-researched BPA analogs exhibited higher binding affinities for nuclear receptors than BPA. Notable analogs included compounds detected in receipts (DD-70, BTUM-70, TGSA, and BisOPP-A), along with a flame retardant, BDP. The possible health hazards linked to exposure to TCS and its mono-hydroxylated metabolites were also found. Further research is needed in order to elucidate the health impacts of these compounds and promote better regulation practices.

Morphological and Molecular Characteristics of Perineuronal Nets in the Human Prefrontal Cortex-A Possible Link to Microcircuitry Specialization.

Perineuronal nets (PNNs) are a type of extracellular matrix (ECM) that play a significant role in synaptic activity and plasticity of interneurons in health and disease. We researched PNNs' regional and laminar representation and molecular composition using immunohistochemistry and transcriptome analysis of Brodmann areas (BA) 9, 14r, and 24 in 25 human postmortem brains aged 13-82 years. The numbers of VCAN- and NCAN-expressing PNNs, relative to the total number of neurons, were highest in cortical layers I and VI while WFA-binding (WFA+) PNNs were most abundant in layers III-V. The ECM glycosylation pattern was the most pronounced regional difference, shown by a significantly lower proportion of WFA+ PNNs in BA24 (3.27 ± 0.69%) compared to BA9 (6.32 ± 1.73%; P = 0.0449) and BA14 (5.64 ± 0.71%; P = 0.0278). The transcriptome of late developmental and mature stages revealed a relatively stable expression of PNN-related transcripts (log2-transformed expression values: 6.5-8.5 for VCAN and 8.0-9.5 for NCAN). Finally, we propose a classification of PNNs that envelop GABAergic neurons in the human cortex. The significant differences in PNNs' morphology, distribution, and molecular composition strongly suggest an involvement of PNNs in specifying distinct microcircuits in particular cortical regions and layers.

Biomonitoring Study of Toxic Metal(loid)s: Levels in Lung Adenocarcinoma Patients.

Lung cancer is a leading cause of cancer deaths worldwide. The aim of this study was to investigate heavy metal(loid)s (Cd, Pb, Hg, Cr, Mn, Mo, Ni, and As) in lung cancer patients in order to elucidate their role as lung cancer environmental risk factors. Sixty-three patients of both sexes with adenocarcinoma stage IIIB or IV were enrolled in this research. The heavy metal(loid) urine concentrations were measured using ICP-MS. Arsenic was quantified above 10 µg/L in 44.44% of the samples. Nickel urinary concentrations above the ToxGuide reference levels were found in 50.79% of the samples, while lead was quantified in 9.52% of the urine samples. The urinary chromium levels were above the mean ToxGuide levels in 41.27% of the patients and were significantly higher in men in comparison with women (p = 0.035). The chromium urinary concentrations were positively associated with the CRP serum levels (p = 0.037). Cadmium was quantified in 61.90% of the samples with levels significantly higher in females than in males (p = 0.023), which was associated with smoking habits. Mercury was measured above the limit of quantification in 63.49% of the samples and was not associated with amalgam dental fillings. However, the Hg urinary concentrations were correlated positively with the ALT (p = 0.02), AST (p < 0.001), and GGT (p < 0.001) serum levels. In 46.03% of the samples, the Mo concentrations were above 32 µg/L, the mean value for healthy adults according to the ToxGuide, and 9.52% of the patients had Mn levels higher than 8 µg/L, the reference value for healthy adults based on ToxGuide data. The obtained results are preliminary, and further studies are needed to have a deeper insight into metal(loid) exposure's association with lung cancer development, progression, and survival prediction.

Prenatal assessment of brain malformations on neuroimaging: an expert panel review.

Brain malformations represent a heterogeneous group of abnormalities of neural morphogenesis, often associated with aberrations of neuronal connectivity and brain volume. Prenatal detection of brain malformations requires a clear understanding of embryology and developmental morphology through the various stages of gestation. This expert panel review is written with the central aim of providing an easy-to-understand roadmap to improve prenatal detection and characterization of structural malformations based on the current understanding of normal and aberrant brain development. The utility of each available neuroimaging modality including prenatal multiplanar neurosonography, anatomical magnetic resonance imaging (MRI), and advanced MRI techniques, as well as further insights from post-mortem imaging have been highlighted for every developmental stage.

Onion Polyphenols as Multi-Target-Directed Ligands in MASLD: A Preliminary Molecular Docking Study.

A sedentary lifestyle associated with unregulated diets rich in high-calorie foods have contributed to the great prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) latterly, with up to 60% in the high-risk population and 25% in the general population. The absence of specific pharmacological strategies for this syndrome represents one of the major problems in the management of MASLD patients. Lifestyle interventions and adherence to a healthy diet are the main cornerstones of current therapies. The identification of nutraceuticals useful in the treatment of MASLD appears to be one of the most promising strategies for the development of new effective and safe treatments for this disease. The onion, one of the most widely studied foods in the field of nutraceuticals, serves as an inexhaustible reservoir of potent compounds with various beneficial effects. The following preliminary study analyzes, mediating in silico studies, the iteration of a library of typical onion compounds with 3-hydroxy-3-methylglutaryl-coenzyme A reductase, liver receptors X α and ß, as well as peroxisome proliferator-activated receptors α and γ. In this study, for the first time promising smart molecules from the onion that could have a beneficial action in MASLD patients were identified.

Fetal indusium griseum is a possible biomarker of the regularity of brain midline development in 3T MR imaging: A retrospective observational study.

INTRODUCTION: This study aimed to assess the visibility of the indusium griseum (IG) in magnetic resonance (MR) scans of the human fetal brain and to evaluate its reliability as an imaging biomarker of the normality of brain midline development. MATERIAL AND METHODS: The retrospective observational study encompassed T2-w 3T MR images from 90 post-mortem fetal brains and immunohistochemical sections from 41 fetal brains (16-40 gestational weeks) without cerebral pathology. Three raters independently inspected and evaluated the visibility of IG in post-mortem and in vivo MR scans. Weighted kappa statistics and regression analysis were used to determine inter- and intra-rater agreement and the type and strength of the association of IG visibility with gestational age. RESULTS: The visibility of the IG was the highest between the 25 and 30 gestational week period, with a very good inter-rater variability (kappa 0.623-0.709) and excellent intra-rater variability (kappa 0.81-0.93). The immunochemical analysis of the histoarchitecture of IG discloses the expression of highly hydrated extracellular molecules in IG as the substrate of higher signal intensity and best visibility of IG during the mid-fetal period. CONCLUSIONS: The knowledge of developmental brain histology and fetal age allows us to predict the IG-visibility in magnetic resonance imaging (MRI) and use it as a biomarker to evaluate the morphogenesis of the brain midline. As a biomarker, IG is significant for post-mortem pathological examination by MRI. Therefore, in the clinical in vivo imaging examination, IG should be anticipated when an assessment of the brain midline structures is needed in mid-gestation, including corpus callosum thickness measurements.

Supercritical fluid technology as a strategy for nifedipine solid dispersions formulation: In vitro and in vivo evaluation.

Supercritical fluid technology (SFT) is an insufficiently investigated approach for the production of solid dispersions, it is environmentally acceptable and has a high potential for application in the pharmaceutical industry. The aim of this work was to formulate and characterize nifedipine solid dispersions (SDs) produced by the SFT and compare the results with ones obtained by the classical solvent based kneading method. The following in vitro tests were conducted: assay and yield, solvent residues, solid state characterization (FTIR, DSC, XRD), flowability, hygroscopicity, solubility, dissolution and stability. Additionally, bioavailability was examined on an animal model (Wistar rats). The formulation selection for in vivo study was performed using the multilevel categoric experimental design and the health risk assessment. Solid state characterization revealed that formulation obtained by the SFT method and higher ratio of polymer (1:5) have had nifedipine in completely amorphous form. Polymer ratio and method of SDs preparation do influence the investigation characteristics. Dissolution rate was fastest in SDs prepared by the SFT and higher polymer ration (1:5). In vivo data of selected SDs prepared by the kneading (ratio 1:1) and the SFT (ratio 1:5) showed alteration in pharmacokinetic profile after i.v. and p.o. application.

T1-weighted fast fluid-attenuated inversion-recovery sequence (T1-FFLAIR) enables the visualization and quantification of fetal brain myelination in utero.

OBJECTIVES: To investigate the advantage of T1-weighted fast fluid-attenuated inversion-recovery MRI sequence without (T1-FFLAIR) and with compressed sensing technology (T1-FFLAIR-CS), which shows improved T1-weighted contrast, over standard used T1-weighted fast field echo (T1-FFE) sequence for the assessment of fetal myelination. MATERIALS AND METHODS: This retrospective single-center study included 115 consecutive fetal brain MRI examinations (63 axial and 76 coronal, mean gestational age (GA) 28.56 ± 5.23 weeks, range 19-39 weeks). Two raters, blinded to GA, qualitatively assessed a fetal myelin total score (MTS) on each T1-weighted sequence at five brain regions (medulla oblongata, pons, mesencephalon, thalamus, central region). One rater performed region-of-interest quantitative analysis (n = 61) at the same five brain regions. Pearson correlation analysis was applied for correlation of MTS and of the signal intensity ratios (relative to muscle) with GA on each T1-weighted sequence. Fetal MRI-based results were compared with myelination patterns of postmortem fetal human brains (n = 46; GA 18 to 42), processed by histological and immunohistochemical analysis. RESULTS: MTS positively correlated with GA on all three sequences (all r between 0.802 and 0.908). The signal intensity ratios measured at the five brain regions correlated best with GA on T1-FFLAIR (r between 0.583 and 0.785). T1-FFLAIR demonstrated significantly better correlations with GA than T1-FFE for both qualitative and quantitative analysis (all p < 0.05). Furthermore, T1-FFLAIR enabled the best visualization of myelinated brain structures when compared to histology. CONCLUSION: T1-FFLAIR outperforms the standard T1-FFE sequence in the visualization of fetal brain myelination, as demonstrated by qualitative and quantitative methods. CLINICAL RELEVANCE STATEMENT: T1-weighted fast fluid-attenuated inversion-recovery sequence (T1-FFLAIR) provided best visualization and quantification of myelination in utero that, in addition to the relatively short acquisition time, makes feasible its routine application in fetal MRI for the assessment of brain myelination. KEY POINTS: • So far, the assessment of fetal myelination in utero was limited due to the insufficient contrast. • T1-weighted fast fluid-attenuated inversion-recovery sequence allows a qualitative and quantitative assessment of fetal brain myelination. • T1-weighted fast fluid-attenuated inversion-recovery sequence outperforms the standard used T1-weighted sequence for visualization and quantification of myelination in utero.

Food contaminants and potential risk of diabetes development: A narrative review.

The number of people diagnosed with diabetes continues to increase, especially among younger populations. Apart from genetic predisposition and lifestyle, there is increasing scientific and public concern that environmental agents may also contribute to diabetes. Food contamination by chemical substances that originate from packaging materials, or are the result of chemical reactions during food processing, is generally recognized as a worldwide problem with potential health hazards. Phthalates, bisphenol A (BPA) and acrylamide (AA) have been the focus of attention in recent years, due to the numerous adverse health effects associated with their exposure. This paper summarizes the available data about the association between phthalates, BPA and AA exposure and diabetes. Although their mechanism of action has not been fully clarified, in vitro, in vivo and epidemiological studies have made significant progress toward identifying the potential roles of phthalates, BPA and AA in diabetes development and progression. These chemicals interfere with multiple signaling pathways involved in glucose and lipid homeostasis and can aggravate the symptoms of diabetes. Especially concerning are the effects of exposure during early stages and the gestational period. Well-designed prospective studies are needed in order to better establish prevention strategies against the harmful effects of these food contaminants.

Compounding of Liquid and Solid Dose Adjustable Formulations with Pantoprazole: Comparison of Stability, Applicability and Suitability.

Pantoprazole is a model substance that requires dosage form adjustments to meet the needs of all patients. Pediatric pantoprazole formulations in Serbia are mostly compounded as capsules (divided powders), while in Western Europe liquid formulations are more common. The aim of this work was to examine and compare the characteristics of compounded liquid and solid dosage forms of pantoprazole. Three syrup bases were used: a sugar-free vehicle for oral solution (according to USP43-NF38), a vehicle with glucose and hydroxypropyl cellulose (according to the DAC/NRF2018) and a commercially available SyrSpend Alka base. Lactose monohydrate, microcrystalline cellulose and a commercially available capsule filler (excipient II, composition: pregelatinized corn starch, magnesium stearate, micronized silicon dioxide, micronized talc) were used as diluents in the capsule formulations. Pantoprazole concentration was determined by the usage of the HPLC method. Pharmaceutical technological procedures and microbiological stability measurements were performed according to the recommendations of the EP10. Although dose appropriate compounding with pantoprazole is suitable using both liquid vehicles as well as solid formulations, chemical stability is enhanced in solid formulation. Nevertheless, according to our results, if liquid formulation is a pH adjusted syrup, it could be safely kept in a refrigerator for up to 4 weeks. Additionally, liquid formulations could be readily applied, while solid formulation should be mixed with appropriate vehicles with higher pH values.

When the microbiome helps the brain-current evidence.

The gut microbiota-brain axis has been recognized as a network of connections that provides communication between the gut microflora and both central and autonomic nervous system. The gut microbiota alteration has been targeted for therapy in various neurodegenerative and psychiatric disbalances. Psychobiotics are probiotics that contribute beneficially to the brain function and the host mental health as a result of an interaction with the commensal gut bacteria, although their mechanism of action has not been completely revealed. In this state-of-art review, the findings about the potential therapeutic effects of the psychobiotics alone or in combination with conventional medicine in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as in some psychiatric diseases like depression, schizophrenia, and bipolar disorder, have been summarized. The evidence of the psychobiotics therapeutic outcomes obtained in preclinical and clinical trials have been given respectively for the observed neurodegenerative and psychiatric disorders.

The effects of phthalate exposure on metabolic parameters in polycystic ovary syndrome.

BACKGROUND-AIM: Phthalates are known as endocrine disrupting chemicals which are present in wide-range of products. The objective of the study was to investigate whether phthalate exposure may attribute to the metabolic syndrome development in women with polycystic ovary syndrome (PCOS). METHOD: The cross-sectional study involved 60 women in reproductive age with confirmed PCOS. Anthropometric and biochemical measurements were examined together with detected levels of ten phthalate metabolites measured by GC-MS in morning urine samples. RESULTS: In this study at least one phthalate metabolite was detected in 51.7% of samples. Total phthalate metabolites urine concentrations were positively associated with BMI, waist circumference, waist-to-height-ratio (WtHR), leptin serum levels as well as lipid accumulation product (LAP) and visceral adiposity index (VAI). Mono-methyl-phthalate (MMP) levels was significantly correlated with WtHR, LAP and VAI. Additionally, total phthalate metabolites levels were significantly linked with fasting plasma glucose and HOMA index, whereas MMP concentrations were associated with fasting plasma glucose and insulin levels. Total cholesterol (TC) level was statistically significantly higher among PCOS women with detected phthalate metabolites compared to those without phthalates. The sum of all phthalates was correlated with LDL and triglyceride levels as well as TC/HDL. MMP concentrations were linked positively with TC, LDL and triglyceride levels as well as with TC/HDL. It is noteworthy that MMP concentrations were positively associated with testosterone serum levels while the total phthalate metabolites concentrations were also linked but with moderate significance. CONCLUSIONS: The increased phthalate metabolites concentrations may interfere with obesity, glucose and lipid impairment in PCOS women. Additionally, testosterone serum levels can be disrupted by MMP.

Comprehensive insight into triclosan-from widespread occurrence to health outcomes.

Humans are exposed to the variety of emerging environmental pollutant in everyday life. The special concern is paid to endocrine disrupting chemicals especially to triclosan which could interfere with normal hormonal functions. Triclosan could be found in numerous commercial products such as mouthwashes, toothpastes and disinfectants due to its antibacterial and antifungal effects. Considering the excessive use and disposal, wastewaters are recognized as the main source of triclosan in the aquatic environment. As a result of the incomplete removal, triclosan residues reach surface water and even groundwater. Triclosan has potential to accumulate in sediment and aquatic organisms. Therefore, the detectable concentrations of triclosan in various environmental and biological matrices emerged concerns about the potential toxicity. Triclosan impairs thyroid homeostasis and could be associated with neurodevelopment impairment, metabolic disorders, cardiotoxicity and the increased cancer risk. The growing resistance of the vast groups of bacteria, the evidenced toxicity on different aquatic organisms, its adverse health effects observed in vitro, in vivo as well as the available epidemiological studies suggest that further efforts to monitor triclosan toxicity at environmental levels are necessary. The safety precaution measures and full commitment to proper legislation in compliance with the environmental protection are needed in order to obtain triclosan good ecological status. This paper is an overview of the possible negative triclosan effects on human health. Sources of exposure to triclosan, methods and levels of detection in aquatic environment are also discussed.

Lasting mesothalamic dopamine imbalance and altered exploratory behavior in rats after a mild neonatal hypoxic event.

Introduction: Adversities during the perinatal period can decrease oxygen supply to the fetal brain, leading to various hypoxic brain injuries, which can compromise the regularity of brain development in different aspects. To examine the catecholaminergic contribution to the link between an early-life hypoxic insult and adolescent behavioral aberrations, we used a previously established rat model of perinatal hypoxia but altered the hypobaric to normobaric conditions. Methods: Exploratory and social behavior and learning abilities were tested in 70 rats of both sexes at adolescent age. Inherent vertical locomotion, sensory-motor functions and spatial learning abilities were explored in a subset of animals to clarify the background of altered exploratory behavior. Finally, the concentrations of dopamine (DA) and noradrenaline in midbrain and pons, and the relative expression of genes for DA receptors D1 and D2, and their down-stream targets (DA- and cAMP-regulated phosphoprotein, Mr 32 kDa, the regulatory subunit of protein kinase A, and inhibitor-5 of protein phosphatase 1) in the hippocampus and thalamus were investigated in 31 rats. Results: A lesser extent of alterations in exploratory and cognitive aspects of behavior in the present study suggests that normobaric conditions mitigate the hypoxic injury compared to the one obtained under hypobaric conditions. Increased exploratory rearing was the most prominent consequence, with impaired spatial learning in the background. In affected rats, increased midbrain/pons DA content, as well as mRNA levels for DA receptors and their down-stream elements in the thalamus, but not the hippocampus, were found. Conclusion: We can conclude that a mild hypoxic event induced long-lasting disbalances in mesothalamic DA signaling, contributing to the observed behavioral alterations. The thalamus was thereby indicated as another structure, besides the well-established striatum, involved in mediating hypoxic effects on behavior through DA signaling.

The Effect of Humidity on the Dissolution Kinetics and Tablet Properties of Immediate-Release Tablet Formulation Containing Lamotrigine.

This study aims to find the effects of high (75%) and low (30%) humidity conditions and its correlation with formulation composition on dissolution kinetics of lamotrigine (LMT) from prepared immediate-release tablets during one- and four-week periods. Two types of fillers microcrystalline cellulose (MCC) or anhydrous lactose (LAC), disintegrant sodium starch glycolate (NaSG, 0.5% or 4%), and lubricant magnesium stearate (MgST, 0.25% or 5%) were used. A three-factor two-stage complete factorial design (23) was used to assess the influence of the composition of the tested formulations. The tablets were produced by direct compression and characterized using a disintegration test, a resistance to crushing test, and dissolution tests (pH 1.2 and pH 6.8). Using Design Expert software, it was concluded that in addition to the effect of fillers on pH 6.8, NaSG has a significant impact after exposure to high and low humidity, as well as its interaction with LAC and MCC. In the dissolution medium pH 1.2, under conditions of high humidity, the content of MgST and NaSG and their interaction show a significant influence. The release rate of LMT was affected by humidity as well as type of excipients and their interactions.

Reorganization of the Brain Extracellular Matrix in Hippocampal Sclerosis.

The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less intense diffuse WFA staining in Cornu Ammonis (CA) fields. Our findings suggest that PNN reduction, changed ECM protein, and glycosylation expression pattern in HS1 might be involved in the pathogenesis and persistence of drug-resistant MTLE by contributing to the increase of CA pyramidal neurons' excitability. This research corroborates the validity of ECM molecules and their modulators as a potential target for the development of new therapeutic approaches to drug-resistant epilepsy.

In silico-in vitro estimation of lipophilicity and permeability association for succinimide derivatives using chromatographic anisotropic systems and parallel artificial membrane permeability assay.

Passive permeability is one of the key features that determine absorbability and one of the most studied properties in the early phases of drug development. Newly synthesized succinimide derivatives from two different series (1-aryl-3-methylsuccinimides and 1-aryl-3-ethyl-3-methylsuccinimides) with high biological potential have been subjected to estimation of their passive permeability and their association with (a) experimentally obtained anisotropic lipophilicity, (b) in silico-calculated lipophilicity and (c) in silico-predicted permeability and absorbability. Non-cellular-based parallel artificial membrane permeability assay was applied for quantifying their passive permeation, expressed as logPapp . Passive permeation was governed by the lipophilicity of the analysed compounds, and anisotropic lipophilicity was related with statistically significant passive transcellular diffusion (r2 = 0.614, P < 0.001). Moreover, experimentally determined passive permeability, logPapp , was statistically significantly associated with both in silico-predicted absorption constant, ka (r2 = 0.7886, P < 0.001), and human intestinal absorption (HIA) in percentage (r2 = 0.484, P < 0.001), respectively. However, there was no statistically significant relationship between experimentally obtained permeability on non-cellular-based model and in silico-predicted Caco-2 permeability based on the predictions conducted on two different software. Based on the obtained results, anisotropic systems are promising surrogates for determining lipophilicity, except for compounds with acidic functional groups that are completely ionized under (pH = 7.4).

The Signature of Moderate Perinatal Hypoxia on Cortical Organization and Behavior: Altered PNN-Parvalbumin Interneuron Connectivity of the Cingulate Circuitries.

This study was designed in a rat model to determine the hallmarks of possible permanent behavioral and structural brain alterations after a single moderate hypoxic insult. Eighty-two Wistar Han (RccHan: WIST) rats were randomly subjected to hypoxia (pO2 73 mmHg/2 h) or normoxia at the first postnatal day. The substantially increased blood lactate, a significantly decreased cytochrome-C-oxygenase expression in the brain, and depleted subventricular zone suggested a high vulnerability of subset of cell populations to oxidative stress and consequent tissue response even after a single, moderate, hypoxic event. The results of behavioral tests (open-field, hole-board, social-choice, and T-maze) applied at the 30-45th and 70-85th postnatal days revealed significant hyperactivity and a slower pace of learning in rats subjected to perinatal hypoxia. At 3.5 months after hypoxic insult, the histochemical examination demonstrated a significantly increased number of specific extracellular matrix-perineuronal nets and increased parvalbumin expression in a subpopulation of interneurons in the medial and retrosplenial cingulate cortex of these animals. Conclusively, moderate perinatal hypoxia in rats causes a long-lasting reorganization of the connectivity in the cingulate cortex and consequent alterations of related behavioral and cognitive abilities. This non-invasive hypoxia model in the rat successfully and complementarily models the moderate perinatal hypoxic injury in fetuses and prematurely born human babies and may enhance future research into new diagnostic and therapeutic strategies for perinatal medicine.

Constitutive activation of canonical Wnt signaling disrupts choroid plexus epithelial fate.

The choroid plexus secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the choroid plexus epithelium arises from the Wnt- expressing cortical hem. Canonical Wnt signaling pathway molecules such as nuclear ß-CATENIN are expressed in the mouse and human embryonic choroid plexus epithelium indicating that this pathway is active. Point mutations in human ß-CATENIN are known to result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of choroid plexus epithelial identity and an apparent transformation of this tissue to a neuronal identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell derived organoids. The choroid plexus is also disrupted when ß-Catenin is conditionally inactivated. Together, our results indicate that canonical Wnt signaling is required in a precise and regulated manner for normal choroid plexus development in the mammalian brain.

Association of Dietary Patterns with MRI Markers of Hepatic Inflammation and Fibrosis in the MAST4HEALTH Study.

Whereas the etiology of non-alcoholic fatty liver disease (NAFLD) is complex, the role of nutrition as a causing and preventive factor is not fully explored. The aim of this study is to associate dietary patterns with magnetic resonance imaging (MRI) parameters in a European population (Greece, Italy, and Serbia) affected by NAFLD. For the first time, iron-corrected T1 (cT1), proton density fat fraction (PDFF), and the liver inflammation fibrosis score (LIF) were examined in relation to diet. A total of 97 obese patients with NAFLD from the MAST4HEALTH study were included in the analysis. A validated semi-quantitative food frequency questionnaire (FFQ) was used to assess the quality of diet and food combinations. Other variables investigated include anthropometric measurements, total type 2 diabetes risk, physical activity level (PAL), and smoking status. Principal component analysis (PCA) was performed to identify dietary patterns. Six dietary patterns were identified, namely "High-Sugar", "Prudent", "Western", "High-Fat and Salt", "Plant-Based", and "Low-Fat Dairy and Poultry". The "Western" pattern was positively associated with cT1 in the unadjusted model (beta: 0.020, p-value: 0.025) and even after adjusting for age, sex, body mass index (BMI), PAL, smoking, the center of the study, and the other five dietary patterns (beta: 0.024, p-value: 0.020). On the contrary, compared with low-intake patients, those with medium intake of the "Low-Fat Dairy and Poultry" pattern were associated with lower values of cT1, PDFF, and LIF. However, patients with a "Low-Fat Dairy and Poultry" dietary pattern were negatively associated with MRI parameters (cT1: beta: -0.052, p-value: 0.046, PDFF: beta: -0.448, p-value: 0.030, LIF: beta: -0.408, p-value: 0.025). Our findings indicate several associations between MRI parameters and dietary patterns in NAFLD patients, highlighting the importance of diet in NAFLD.