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CONTEXT: The proportion of the elderly population is on the rise across the globe, and with it the prevalence of age-related neurodegenerative diseases. The gut microbiota, whose composition is highly regulated by dietary intake, has emerged as an exciting research field in neurology due to its pivotal role in modulating brain functions via the gut-brain axis. OBJECTIVES: We aimed at conducting a systematic review of preclinical and clinical studies investigating the effects of dietary interventions on cognitive ageing in conjunction with changes in gut microbiota composition and functionality. METHODS: PubMed and Scopus were searched using terms related to ageing, cognition, gut microbiota and dietary interventions. Studies were screened, selected based on previously determined inclusion and exclusion criteria, and evaluated for methodological quality using recommended risk of bias assessment tools. RESULTS: A total of 32 studies (18 preclinical and 14 clinical) were selected for inclusion. We found that most of the animal studies showed significant positive intervention effects on cognitive behavior, while outcomes on cognition, microbiome features, and health parameters in humans were less pronounced. The effectiveness of dietary interventions depended markedly on the age, gender, degree of cognitive decline and baseline microbiome composition of participants. CONCLUSION: To harness the full potential of microbiome-inspired nutrition for cognitive health, one of the main challenges remains to better understand the interplay between host, his microbiome, dietary exposures, whilst also taking into account environmental influences. Future research should aim toward making use of host-specific microbiome data to guide the development of personalized therapies.
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Disfunción Cognitiva , Microbioma Gastrointestinal , Humanos , Disfunción Cognitiva/prevención & control , Animales , Dieta , Envejecimiento/fisiología , Cognición , Eje Cerebro-Intestino/fisiología , Envejecimiento CognitivoRESUMEN
Morphological remodeling of dendritic spines is critically involved in memory formation and depends on adhesion molecules. Serotonin receptors are also implicated in this remodeling, though the underlying mechanisms remain enigmatic. Here, we uncovered a signaling pathway involving the adhesion molecule L1CAM (L1) and serotonin receptor 5-HT4 (5-HT4R, encoded by HTR4). Using Förster resonance energy transfer (FRET) imaging, we demonstrated a physical interaction between 5-HT4R and L1, and found that 5-HT4R-L1 heterodimerization facilitates mitogen-activated protein kinase activation in a Gs-dependent manner. We also found that 5-HT4R-L1-mediated signaling is involved in G13-dependent modulation of cofilin-1 activity. In hippocampal neurons in vitro, the 5-HT4R-L1 pathway triggers maturation of dendritic spines. Thus, the 5-HT4R-L1 signaling module represents a previously unknown molecular pathway regulating synaptic remodeling.
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Molécula L1 de Adhesión de Célula Nerviosa , Hipocampo , Molécula L1 de Adhesión de Célula Nerviosa/genética , Neuronas , Serotonina , Transducción de SeñalRESUMEN
Polyacrylonitrile (PAN) is widely used as a raw material for the production of high-modulus carbon fibers, the internal structure of which is directly affected by the spinning of the precursor. Although PAN fibers have been studied for a long time, the formation of their internal structure has not been sufficiently investigated theoretically. This is due to the large number of stages in the process and the parameters controlling them. In this study, we present a mesoscale model describing the evolution of nascent PAN fibers during the coagulation. It is constructed within the framework of a mesoscale dynamic density functional theory. We use the model to study the influence of a combined solvent of dimethyl sulfoxide (DMSO, a good solvent) and water (a non-solvent) on the microstructure of the fibers. A porous structure of PAN is formed as a result of the microphase separation of the polymer and the residual combined solvent at a high water content in the system. The model shows that one of the possible ways to obtain the homogeneous fiber structure is to slow down the coagulation by increasing the amount of good solvent in the system. This result is in agreement with the existing experimental data and confirms the efficiency of the presented model.
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Resinas Acrílicas , Dimetilsulfóxido , Solventes , AguaRESUMEN
Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton, eyes, kidneys, and face and caused by pathogenic variants in the JAG1 or NOTCH2 gene. The variable expressivity of the clinical phenotype and the lack of genotype-phenotype correlations lead to significant diagnostic difficulties. Here we present an analysis of 18 patients with cholestasis who were diagnosed with ALGS. We used an NGS panel targeting coding exons of 52 genes, including the JAG1 and NOTCH2 genes. Sanger sequencing was used to verify the mutation in the affected individuals and family members. The specific facial phenotype was seen in 16/18 (88.9%). Heart defects were seen in 8/18 (44.4%) patients (pulmonary stenosis in 7/8). Butterfly vertebrae were seen in 5/14 (35.7%) patients. Renal involvement was detected in 2/18 (11.1%) cases-one patient had renal cysts, and one had obstructive hydronephrosis. An ophthalmology examination was performed on 12 children, and only one had posterior embryotoxon (8.3%). A percutaneous liver biopsy was performed in nine cases. Bile duct paucity was detected in six/nine cases (66.7%). Two patients required liver transplantation because of cirrhosis. We identified nine novel variants in the JAG1 gene-eight frameshift variants (c.1619_1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168_3169delAG (p.R1056Sfs*51), c.2688delG (p.896CysfsTer49), c.164dupG (p.Cys55fs)) and one missense variant, c.2806T > G (p.Cys936Gly). None of the patients presented with NOTCH2 variants. In accordance with the classical criteria, only six patients could meet the diagnostic criteria in our cohort without genetic analysis. Genetic testing is important in the diagnosis of ALGS and can help differentiate it from other types of cholestasis.
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Síndrome de Alagille , Colestasis , Humanos , Síndrome de Alagille/complicaciones , Síndrome de Alagille/genética , Colestasis/genética , Mutación , Mutación Missense , Fenotipo , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismoRESUMEN
A new de novo frameshift variant has been identified in the CASZ1 gene leading to severe dilated cardiomyopathy. METHODS: The proband was analyzed with WES NGS, post-mortem, using dried blood spots on filters. The variant was verified with Sanger sequencing for the proband and her parents. RESULTS: We reported a proband with a new de novo frameshift mutation, c.3781del (p.(Trp1261GlyfsTer29)), in the CASZ1 gene. The clinical presentation was similar to the severe phenotype described in previous studies. CONCLUSIONS: In this study, we described a new case with a frameshift mutation in CASZ1 causing a severe phenotype of dilated cardiomyopathy.
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Cardiomiopatía Dilatada , Femenino , Humanos , Cardiomiopatía Dilatada/genética , Mutación del Sistema de Lectura , Fenotipo , Mutación , Linaje , Proteínas de Unión al ADN/genética , Factores de Transcripción/genéticaRESUMEN
Hearing loss is one of the most genetically heterogeneous disorders known. Over 120 genes are reportedly associated with non-syndromic hearing loss (NSHL). To date, in Russia, there have been relatively few studies that apply massive parallel sequencing (MPS) methods to elucidate the genetic factors underlying non-GJB2-related hearing loss cases. The current study is intended to provide an understanding of the mutation spectrum in non-GJB2-related hearing loss in a cohort of Russian sensorineural NSHL patients and establish the best diagnostic algorithm. Genetic testing using an MPS panel, which included 33 NSHL and syndromic hearing loss (SHL) genes that might be misdiagnosed as NSHL genes, was completed on 226 sequentially accrued and unrelated patients. As a result, the molecular basis of deafness was found in 21% of the non-GJB2 NSHL cases. The total contribution pathogenic, and likely pathogenic, variants in the genes studied among all hereditary NSHL Russian patients was 12%. STRC pathogenic and likely pathogenic, variants accounted for 30% of diagnoses in GJB2-negative patients, providing the most common diagnosis. The majority of causative mutations in STRC involved large copy number variants (CNVs) (80%). Among the point mutations, the most common were c.11864G>A (p.Trp3955*) in the USH2A gene, c.2171_2174delTTTG (p.Val724Glyfs*6) in the STRC gene, and c.107A>C (p.His36Pro) and c.1001G>T (p.Gly334Val) in the SLC26A4 gene. Pathogenic variants in genes involved in SHL accounted for almost half of the cases with an established molecular genetic diagnosis, which were 10% of the total cohort of patients with non-GJB2-related hearing loss.
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Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Conexinas/genética , Conexina 26/genética , Sordera/genética , Pérdida Auditiva/genética , Mutación , Pérdida Auditiva Sensorineural/genética , Péptidos y Proteínas de Señalización Intercelular/genéticaRESUMEN
Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7-/- mice. Although palmitoylation of barttin in kidneys of Zdhhc7-/- animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7-/- mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension.
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Aciltransferasas/metabolismo , Canales de Cloruro/metabolismo , Ácido Palmítico/metabolismo , Procesamiento Proteico-Postraduccional , Aciltransferasas/deficiencia , Aciltransferasas/genética , Animales , Perros , Técnicas de Inactivación de Genes , Células HEK293 , Humanos , Riñón/citología , Riñón/metabolismo , Células de Riñón Canino Madin Darby , Ratones , Mutación , FenotipoRESUMEN
The gut barrier has been recognized as being of relevance in the pathogenesis of multiple different diseases ranging from inflammatory bowel disease, irritable bowel syndrome, inflammatory joint disease, fatty liver disease, and cardiometabolic disorders. The regulation of the gut barrier is, however, poorly understood. Especially, the role of food components such as sugars and complex carbohydrates has been discussed controversially in this respect. More recently, the intestinal microbiota has been proposed as an important regulator of the gut barrier. Whether the microbiota affects the barrier by its own, or whether food components such as carbohydrates mediate their effects through alterations of the microbiota composition or its metabolites, is still not clear. In this review, we will summarize the current knowledge on this topic derived from both animal and human studies and discuss data for possible clinical impact.
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Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Microbiota , Animales , Carbohidratos , Dieta , HumanosRESUMEN
We report the results of an experimental and theoretical study of structure formation in mixtures of phenyl-C71-butyric acid methyl ester (PC71BM) with high boiling octane based solvent additives 1,8-octanedithiol (ODT), 1,8-dibromooctane, and 1,8-diiodooctane obtained by evaporation of a host-solvent (chlorobenzene). Experimental studies by DSC, SAXS and WAXS methods found evidence of crystallization of fullerenes in the presence of the high boiling additives in the mixtures. A molecular dynamics simulation of a PC71BM/ODT mixture revealed the self-assembly of fullerenes into sponge-like network structures.
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BACKGROUND: Pruritus is a major symptom of atopic dermatitis (AD) and is transmitted by a subpopulation of non-myelinated C-type free nerve endings in the epidermis and upper dermis. Stimulation of these nerve terminals is affected by histamine, neurotrophins and physical factors. Eosinophils of patients with AD are a source of neurotrophins, including brain-derived neurotrophic factor (BDNF), levels of which correlate with disease severity. OBJECTIVE: The purpose of this study was to determine the anatomical localization of eosinophils in the skin of patients with AD with regard to peripheral nerves and to investigate whether eosinophils induce sprouting and neurite outgrowth in murine sensory neurons. METHODS: Cryosections of skin derived from AD and control (NA) patients were subjected to immunofluorescence analysis with markers for eosinophils, BDNF and neuronal cells. Stimulated eosinophil supernatants were used for the treatment of cultured peripheral mouse dorsal root ganglia (DRG) neurons followed by morphometric analysis. RESULTS: Dermal axon density and the proximity of eosinophils to nerve fibres were significantly higher in AD patients vs NA. Both neuronal projections and eosinophils expressed BDNF. Furthermore, activated eosinophil supernatants induced BDNF-dependent mouse DRG neuron branching. CONCLUSIONS AND CLINICAL RELEVANCE: Our results indicate that BDNF-positive eosinophils are also localized in close proximity with nerve fibres in AD, suggesting a functional relationship between BDNF-expressing eosinophils and neuronal projections. These observations suggest that eosinophils may have considerable impact on pruritus by supporting sensory nerve branching.
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Factor Neurotrófico Derivado del Encéfalo/inmunología , Dermatitis Atópica , Dermis , Eosinófilos , Epidermis , Células Receptoras Sensoriales , Adolescente , Adulto , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Dermis/inmunología , Dermis/inervación , Dermis/patología , Eosinófilos/inmunología , Eosinófilos/patología , Epidermis/inmunología , Epidermis/inervación , Epidermis/patología , Femenino , Humanos , Masculino , Células Receptoras Sensoriales/inmunología , Células Receptoras Sensoriales/patologíaRESUMEN
Precise control of dendritic spine density and synapse formation is critical for normal and pathological brain functions. Therefore, signaling pathways influencing dendrite outgrowth and remodeling remain a subject of extensive investigations. Here, we report that prolonged activation of the serotonin 5-HT7 receptor (5-HT7R) with selective agonist LP-211 promotes formation of dendritic spines and facilitates synaptogenesis in postnatal cortical and striatal neurons. Critical role of 5-HT7R in neuronal morphogenesis was confirmed by analysis of neurons isolated from 5-HT7R-deficient mice and by pharmacological inactivation of the receptor. Acute activation of 5-HT7R results in pronounced neurite elongation in postnatal striatal and cortical neurons, thus extending previous data on the morphogenic role of 5-HT7R in embryonic and hippocampal neurons. We also observed decreased number of spines in neurons with either genetically (i.e. 5-HT7R-knock-out) or pharmacologically (i.e. antagonist treatment) blocked 5-HT7R, suggesting that constitutive 5-HT7R activity is critically involved in the spinogenesis. Moreover, cyclin-dependent kinase 5 and small GTPase Cdc42 were identified as important downstream effectors mediating morphogenic effects of 5-HT7R in neurons. Altogether, our data suggest that the 5-HT7R-mediated structural reorganization during the postnatal development might have a crucial role for the development and plasticity of forebrain areas such as cortex and striatum, and thereby can be implicated in regulation of the higher cognitive functions. Read the Editorial Highlight for this article on page 644.
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Corteza Cerebral/citología , Cuerpo Estriado/citología , Espinas Dendríticas/metabolismo , Neurogénesis/genética , Neuronas/citología , Receptores de Serotonina/metabolismo , Sinapsis/genética , Animales , Animales Recién Nacidos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células Cultivadas , Espinas Dendríticas/efectos de los fármacos , Diterpenos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Serotonina/genética , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sinapsis/efectos de los fármacos , Factores de TiempoRESUMEN
Dendritic cells are potent antigen-presenting cells endowed with the unique ability to initiate adaptive immune responses upon inflammation. Inflammatory processes are often associated with an increased production of serotonin, which operates by activating specific receptors. However, the functional role of serotonin receptors in regulation of dendritic cell functions is poorly understood. Here, we demonstrate that expression of serotonin receptor 5-HT7 (5-HT7R) as well as its downstream effector Cdc42 is upregulated in dendritic cells upon maturation. Although dendritic cell maturation was independent of 5-HT7R, receptor stimulation affected dendritic cell morphology through Cdc42-mediated signaling. In addition, basal activity of 5-HT7R was required for the proper expression of the chemokine receptor CCR7, which is a key factor that controls dendritic cell migration. Consistent with this, we observed that 5-HT7R enhances chemotactic motility of dendritic cells in vitro by modulating their directionality and migration velocity. Accordingly, migration of dendritic cells in murine colon explants was abolished after pharmacological receptor inhibition. Our results indicate that there is a crucial role for 5-HT7R-Cdc42-mediated signaling in the regulation of dendritic cell morphology and motility, suggesting that 5-HT7R could be a new target for treatment of a variety of inflammatory and immune disorders.
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Movimiento Celular/inmunología , Células Dendríticas/inmunología , Receptores de Serotonina/metabolismo , Transducción de Señal/inmunología , Proteína de Unión al GTP cdc42/biosíntesis , Células 3T3 , Animales , Línea Celular , Quimiocina CCL19/metabolismo , Colon/citología , Colon/inmunología , Células Dendríticas/citología , Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/biosíntesis , Receptores CCR7/biosíntesis , Receptores de Serotonina/biosíntesis , Receptores de Serotonina/genética , Regulación hacia ArribaRESUMEN
CLC-K/barttin chloride channels are essential for NaCl re-absorption in Henle's loop and for potassium secretion by the stria vascularis in the inner ear. Here, we studied the posttranslational modification of such channels by palmitoylation of their accessory subunit barttin. We found that barttin is palmitoylated in vivo and in vitro and identified two conserved cysteine residues at positions 54 and 56 as palmitoylation sites. Point mutations at these two residues reduce the macroscopic current amplitudes in cells expressing CLC-K/barttin channels proportionally to the relative reduction in palmitoylated barttin. CLC-K/barttin expression, plasma membrane insertion, and single channel properties remain unaffected, indicating that these mutations decrease the number of active channels. R8W and G47R, two naturally occurring barttin mutations identified in patients with Bartter syndrome type IV, reduce barttin palmitoylation and CLC-K/barttin channel activity. Palmitoylation of the accessory subunit barttin might thus play a role in chloride channel dysfunction in certain variants of Bartter syndrome. We did not observe pronounced alteration of barttin palmitoylation upon increased salt and water intake or water deprivation, indicating that this posttranslational modification does not contribute to long term adaptation to variable water intake. Our results identify barttin palmitoylation as a novel posttranslational modification of CLC-K/barttin chloride channels.
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Canales de Cloruro/química , Canales de Cloruro/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Síndrome de Bartter/genética , Síndrome de Bartter/metabolismo , Canales de Cloruro/genética , Cisteína/química , Perros , Células HEK293 , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/metabolismo , Humanos , Lipoilación , Células de Riñón Canino Madin Darby , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación Puntual , Subunidades de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de AminoácidoRESUMEN
Serotonin receptors 5-HT(1A) and 5-HT(7) are highly coexpressed in brain regions implicated in depression. However, their functional interaction has not been established. In the present study we show that 5-HT(1A) and 5-HT(7) receptors form heterodimers both in vitro and in vivo. Foerster resonance energy transfer-based assays revealed that, in addition to heterodimers, homodimers composed either of 5-HT(1A) or 5-HT(7) receptors together with monomers coexist in cells. The highest affinity for complex formation was obtained for the 5-HT(7)-5-HT(7) homodimers, followed by the 5-HT(7)-5-HT(1A) heterodimers and 5-HT(1A)-5-HT(1A) homodimers. Functionally, heterodimerization decreases 5-HT(1A)-receptor-mediated activation of G(i) protein without affecting 5-HT(7)-receptor-mediated signalling. Moreover, heterodimerization markedly decreases the ability of the 5-HT(1A) receptor to activate G-protein-gated inwardly rectifying potassium channels in a heterologous system. The inhibitory effect on such channels was also preserved in hippocampal neurons, demonstrating a physiological relevance of heteromerization in vivo. In addition, heterodimerization is crucially involved in initiation of the serotonin-mediated 5-HT(1A) receptor internalization and also enhances the ability of the 5-HT(1A) receptor to activate the mitogen-activated protein kinases. Finally, we found that production of 5-HT(7) receptors in the hippocampus continuously decreases during postnatal development, indicating that the relative concentration of 5-HT(1A)-5-HT(7) heterodimers and, consequently, their functional importance undergoes pronounced developmental changes.
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Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Serotonina/metabolismo , Transducción de Señal , Animales , Encéfalo/metabolismo , Línea Celular Tumoral , Dimerización , Ratones , Neuronas/metabolismo , Unión Proteica , Transporte de Proteínas , Receptor de Serotonina 5-HT1A/química , Receptor de Serotonina 5-HT1A/genética , Receptores de Serotonina/química , Receptores de Serotonina/genéticaRESUMEN
Gene and cell-based therapies comprise innovative aspects of regenerative medicine. Even though stem cells represent a highly potential therapeutic strategy, their wide-spread exploitation is marred by ethical concerns, potential for malignant transformation and a plethora of other technical issues, largely restricting their use to experimental studies. Utilizing genetically modified human umbilical cord blood mono-nuclear cells (hUCB-MCs), this communication reports enhanced differentiation of transplants in a mouse model of amyotrophic lateral sclerosis (ALS). Over-expressing Oct4 and Sox2 induced production of neural marker PGP9.5, as well as transformation of hUCB-MCs into micro-glial and endothelial lines in ALS spinal cords. In addition to producing new nerve cells, providing degenerated areas with trophic factors and neo-vascularisation might prevent and even reverse progressive loss of moto-neurons and skeletal muscle paralysis.
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Sangre Fetal/citología , Factor 3 de Transcripción de Unión a Octámeros/biosíntesis , Factores de Transcripción SOXB1/biosíntesis , Esclerosis Amiotrófica Lateral/genética , Animales , Desdiferenciación Celular , Diferenciación Celular , Modelos Animales de Enfermedad , Humanos , Ratones , Células Madre Pluripotentes/metabolismo , Medicina Regenerativa , TransfecciónRESUMEN
Noonan syndrome is a group of diseases with a similar clinical picture, consisting of 16 diseases caused by mutations in 15 genes. According to the literature, approximately half of all cases are attributed to Noonan syndrome type 1, NSML, caused by mutations in the PTPN11 gene. We analyzed 456 unrelated probands using a gene panel NGS, and in 206 cases, the cause of the disease was identified. Approximately half of the cases (107) were caused by variants in the PTPN11 gene, including three previously undescribed variants, one of which was classified as VOUS, and the other two as LP causative complex alleles. Frequent variants of the PTPN11 gene characteristics for Russian patients were identified, accounting for more than 38% (c.922A>G p.Asn308Asp, c.417G>C p.Glu139Asp, c.1403C>T p.Thr468Met) of all cases with mutations in the PTPN11 gene. A comparative characterization of frequent variants of the PTPN11 gene in different populations is shown. The most common features of Noonan syndrome in the studied sample were facial dysmorphisms and cardiovascular system abnormalities. A lower representation of patients with growth delay was observed compared to previously described samples.
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Síndrome de Noonan , Humanos , Síndrome de Noonan/genética , Mutación , Alelos , Federación de Rusia , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genéticaRESUMEN
The common neurotransmitter serotonin controls different aspects of early neuronal differentiation, although the underlying mechanisms are poorly understood. Here we report that activation of the serotonin 5-HT(7) receptor promotes synaptogenesis and enhances synaptic activity in hippocampal neurons at early postnatal stages. An analysis of Gα(12)-deficient mice reveals a critical role of G(12)-protein for 5-HT(7) receptor-mediated effects in neurons. In organotypic preparations from the hippocampus of juvenile mice, stimulation of 5-HT(7)R/G(12) signaling potentiates formation of dendritic spines, increases neuronal excitability, and modulates synaptic plasticity. In contrast, in older neuronal preparations, morphogenetic and synaptogenic effects of 5-HT(7)/G(12) signaling are abolished. Moreover, inhibition of 5-HT(7) receptor had no effect on synaptic plasticity in hippocampus of adult animals. Expression analysis reveals that the production of 5-HT(7) and Gα(12)-proteins in the hippocampus undergoes strong regulation with a pronounced transient increase during early postnatal stages. Thus, regulated expression of 5-HT(7) receptor and Gα(12)-protein may represent a molecular mechanism by which serotonin specifically modulates formation of initial neuronal networks during early postnatal development.
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Envejecimiento/genética , Subunidades alfa de la Proteína de Unión al GTP G12-G13/fisiología , Hipocampo/citología , Hipocampo/fisiología , Neurogénesis/genética , Neuronas/fisiología , Receptores de Serotonina/fisiología , Transducción de Señal/genética , Animales , Animales Recién Nacidos , Subunidades alfa de la Proteína de Unión al GTP G12-G13/biosíntesis , Subunidades alfa de la Proteína de Unión al GTP G12-G13/genética , Hipocampo/crecimiento & desarrollo , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Receptores de Serotonina/biosíntesis , Receptores de Serotonina/genética , Sinapsis/genéticaRESUMEN
BACKGROUND: Intestinal barrier dysfunctions have been associated with liver steatosis and metabolic diseases. Besides nutritional factors, like a Western-style diet (WSD), serotonin has been linked with leaky gut. Therefore, we aimed to evaluate the role of serotonin in the pathogenesis of intestinal barrier dysfunctions and liver steatosis in mice fed high-fat and high-sugar diets. METHODS: 6-8 weeks old male serotonin reuptake transporter knockout mice (SERT-/- ) and wild-type controls (SERT+/+ ) were fed either a WSD or a control diet (CD) ad libitum with or without fructose 30% (F) added to the drinking water for 12 weeks. Markers of liver steatosis and intestinal barrier function were assessed. KEY RESULTS: SERT-/- mice showed increased weight gain compared with SERT+/+ mice when fed a WSD ± F for 12 weeks (p < 0.05), whereby SERT-/- mice exhibited reduced energy (-21%) intake. Furthermore, SERT knockout resulted in a more pronounced liver steatosis (p < 0.05), enhanced levels of endotoxin in portal vein plasma (p < 0.05), and increased liver expression of Tnf and Myd88 (p < 0.05), when mice were fed a WSD ± F. Finally, SERT-/- mice, when compared with SERT+/+ mice, had a decreased mRNA expression of Muc2 (p < 0.01), Ocln (p < 0.05), Cldn5 (p = 0.054) and 7 (p < 0.01), Defa5 (p < 0.05) and other antimicrobial peptides in the ileum. On the protein level, ZO-1 (p < 0.01) and DEFA5 protein (p < 0.0001) were decreased. CONCLUSION AND INFERENCES: Our data demonstrate that SERT knockout causes weight gain, liver steatosis, and leaky gut, especially in mice fed a WSD. Therefore, SERT induction could be a novel therapeutic approach to improve metabolic diseases associated with intestinal barrier dysfunction.
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Hígado Graso , Serotonina , Masculino , Animales , Ratones , Ratones Obesos , Defecación , FatigaRESUMEN
Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute to neuroplasticity regulation and are implicated in numerous neuronal disorders. Here, we demonstrate a physical interaction between 5-HT2A and TrkB in vitro and in vivo using co-immunoprecipitation and biophysical and biochemical approaches. Heterodimerization decreased TrkB autophosphorylation, preventing its activation with agonist 7,8-DHF, even with low 5-HT2A receptor expression. A blockade of 5-HT2A receptor with the preferential antagonist ketanserin prevented the receptor-mediated downregulation of TrkB phosphorylation without restoring the TrkB response to its agonist 7,8-DHF in vitro. In adult mice, intraperitoneal ketanserin injection increased basal TrkB phosphorylation in the frontal cortex and hippocampus, which is in accordance with our findings demonstrating the prevalence of 5-HT2A-TrkB heteroreceptor complexes in these brain regions. An expression analysis revealed strong developmental regulation of 5-HT2A and TrkB expressions in the cortex, hippocampus, and especially the striatum, demonstrating that the balance between TrkB and 5-HT2A may shift in certain brain regions during postnatal development. Our data reveal the functional role of 5-HT2A-TrkB receptor heterodimerization and suggest that the regulated expression of 5-HT2A and TrkB is a molecular mechanism for the brain-region-specific modulation of TrkB functions during development and under pathophysiological conditions.
Asunto(s)
Receptor de Serotonina 5-HT2A/metabolismo , Receptor trkB/metabolismo , Serotonina , Animales , Ketanserina , Ratones , Receptores de Serotonina , Serotonina/metabolismo , Serotonina/farmacología , TropomiosinaRESUMEN
The influence of polydispersity on the interfacial kinetics of end-coupling and microstructure formation in the melt of immiscible polymers was studied using dissipative particle dynamics simulations. The irreversible reaction started at a flat interface between two layers, each of which contained polymer chains of two different lengths with functionalized or unreactive end groups. As in the case of fully functionalized monodisperse reactants [A. V. Berezkin and Y. V. Kudryavtsev, Macromolecules 44, 112 (2011)], four kinetic regimes were observed: linear (mean field coupling at the initial interface), saturation (decreasing the reaction rate due to the copolymer brush formation or reactant depletion near the interface), autocatalytic (loss of the initial interface stability and formation of a lamellar microstructure), and terminal (microstructure ripening under diffusion control). The interfacial instability is caused by overcrowding the interface with the reaction product, and it can be kinetically suppressed by increasing chain length of the reactants. Main effects of polydispersity are as follows: (i) the overall end-coupling rate is dominated by the shortest reactive chains; (ii) the copolymer concentration at the interface causing its instability can be not the same as in the lamellas formed afterwards; (iii) mean length of the copolymer product considerably changes with conversion passing through a minimum when a microstructure is just formed.