RESUMEN
Experiment was conducted to study the effects of Mulberry Leaf (ML) powder on reproductive performance, serum and milk amino acid composition in sows. Fifty sows (D 85 at gestation) with parity 3 or 4 were randomly divided into 5 groups: C, M100, M200, M300 and M400, receiving 0, 100, 200, 300 and 400 g ML powder per sow per day. Blood and milk of sows at Days 1 and 21 of lactation were collected. Results showed that average daily feed intake (ADFI) during lactation was higher in groups supplemented ML compared with control group (p < 0.01). Litter weight gain during lactation was higher in M400 than in groups M200 and C (p < 0.05), with no significant difference compared with M100 and M300. Serum glucose concentration in groups M400 and M300 was higher than those in the other groups (p < 0.01). Serum HDL-C concentration in group M400 was significantly greater than those in groups M100 and M200 (p < 0.05), with no significant difference between group M400 and groups M300, control. Milk amino acid concentrations such as isoleucine, leucine, lysine and valine were all lower in group M400 than in control (p < 0.01). Serum methionine (Met) concentration was higher in M300 than in other groups (p < 0.01). Milk Met concentration in group C was higher than those of the sows in the group M400, with no significant difference compared with groups M100, M200 and M300 (p < 0.05). Serum Lys and Met concentrations were lower in M400 than in control group (p < 0.05). In summary, our results have revealed the ML supplementation at a high dose such as 300 g/day during later gestation and lactation showed benefit in regulating lipid and amino acid metabolism in sows and then improved growth performance of their offspring.
Asunto(s)
Leche , Morus , Porcinos , Animales , Femenino , Embarazo , Leche/química , Lactancia/fisiología , Aminoácidos/metabolismo , Polvos/farmacología , Tamaño de la Camada , Dieta/veterinaria , Lisina/farmacología , Hojas de la Planta/metabolismo , Alimentación Animal/análisisRESUMEN
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by intracellular α-synuclein (α-Syn) deposition. Alternation of the α-Syn expression level in plasma or erythrocytes may be used as a potential PD biomarker. However, no studies have compared their prognostic value directly with the same cohort. METHODS: The levels of α-Syn in plasma and erythrocytes, obtained from 45 PD patients and 45 control subjects, were measured with enzyme-linked immunosorbent assay. Then, correlation and receiver operating characteristic curve (ROC) analysis were performed to characterize the predictive power of erythrocytic and plasma α-Syn. RESULTS: Our results showed that α-Syn expression levels in both plasma and erythrocytes were significantly higher in PD patients than in control subjects (823.14 ± 257.79 vs. 297.10 ± 192.82 pg/mL, p < 0.0001 in plasma; 3,104.14 ± 143.03 vs. 2,944.82 ± 200.41 pg/mL, p < 0.001 in erythrocytes, respectively). The results of the ROC analysis suggested that plasma α-Syn exhibited better predictive power than erythrocytic α-Syn with a sensitivity of 80.0%, specificity of 97.7%, and a positive predictive value of 77.8%. The expression level of plasma α-Syn correlated well with the age of patients, H-Y stage, MoCA scale, and UPDRS motor scale. On the contrary, there was no correlation between erythrocytic α-Syn level and clinical parameters in this study. CONCLUSION: Our results suggest that plasma α-Syn could be a specific and sensitive potential diagnostic biomarker for PD.
Asunto(s)
Eritrocitos/metabolismo , Enfermedad de Parkinson/sangre , alfa-Sinucleína/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
Emerging evidence suggests functional regulation of the Hippo pathway by the actin cytoskeleton, although the detailed molecular mechanism remains incomplete. In a genetic screen, we identified a requirement for ß-Spectrin in the posterior follicle cells for the oocyte repolarization process during Drosophila mid-oogenesis. ß-spectrin mutations lead to loss of Hippo signaling activity in the follicle cells. A similar reduction of Hippo signaling activity was observed after ß-Spectrin knockdown in mammalian cells. We further demonstrated that ß-spectrin mutations disrupt the basal actin network in follicle cells. The abnormal stress fiber-like actin structure on the basal side of follicle cells provides a likely link between the ß-spectrin mutations and the loss of the Hippo signaling activity phenotype.
Asunto(s)
Proteínas de Drosophila/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Oogénesis/genética , Folículo Ovárico/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Espectrina/genética , Actinas/genética , Animales , Citoesqueleto/genética , Citoesqueleto/metabolismo , Drosophila , Proteínas de Drosophila/genética , Células Epiteliales/metabolismo , Femenino , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Oocitos/crecimiento & desarrollo , Oocitos/metabolismo , Folículo Ovárico/crecimiento & desarrollo , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/genéticaRESUMEN
The primary treatment for early esophageal cancer and precancerous lesions is endoscopic submucosal dissection (ESD). However, this approach leads to a high incidence of postoperative esophageal stenosis, which can significantly impact a patient's quality of life. While various methods are available to prevent post-ESD esophageal stenosis, their effectiveness varies. Therefore, this study aims to provide an overview of the currently employed methods for preventing post-ESD esophageal stenosis in clinical practice in view of assisting clinical practitioners.
Asunto(s)
Resección Endoscópica de la Mucosa , Neoplasias Esofágicas , Estenosis Esofágica , Humanos , Estenosis Esofágica/etiología , Estenosis Esofágica/prevención & control , Resección Endoscópica de la Mucosa/efectos adversos , Resección Endoscópica de la Mucosa/métodos , Calidad de Vida , Neoplasias Esofágicas/patología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiologíaRESUMEN
Circular RNAs (circRNAs) are noncoding RNAs abundant in brain tissue, and many are derived from activity-dependent, linear mRNAs encoding for synaptic proteins, suggesting that circRNAs may directly or indirectly play a role in regulating synaptic development, plasticity, and function. However, it is unclear if the circular forms of these RNAs are similarly regulated by activity and what role these circRNAs play in developmental plasticity. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent linear forms of the Homer1 gene, circHomer1 and Homer1a respectively, were of interest as their expression changed in opposite directions: circHomer1 expression increased while the expression of Homer1a decreased following MD. Knockdown of circHomer1 prevented the depression of closed-eye responses normally observed after 3-day MD. circHomer1-knockdown led to a reduction in average dendritic spine size prior to MD, but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity. circHomer1-knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller in circHomer1-knockdown neurons, suggesting that circHomer1 regulates plasticity through mechanisms of activity-dependent AMPA receptor endocytosis. Thus, activity-dependent circRNAs regulate developmental synaptic plasticity, and our findings highlight the essential role of circHomer1 in V1 plasticity induced by short-term MD.
RESUMEN
Astragalosides are the main active constituents of traditional Chinese medicine Huang-Qi, of which cycloastragenol-type glycosides are the most typical and major bioactive compounds. This kind of compounds exhibit various biological functions including cardiovascular protective, neuroprotective, etc. Owing to the limitations of natural sources and the difficulties encountered in chemical synthesis, re-engineering of biosynthetic machinery will offer an alternative and promising approach to producing astragalosides. However, the biosynthetic pathway for astragalosides remains elusive due to their complex structures and numerous reaction types and steps. Herein, guided by transcriptome and phylogenetic analyses, a cycloartenol synthase and four glycosyltransferases catalyzing the committed steps in the biosynthesis of such bioactive astragalosides were functionally characterized from Astragalus membranaceus. AmCAS1, the first reported cycloartenol synthase from Astragalus genus, is capable of catalyzing the formation of cycloartenol; AmUGT15, AmUGT14, AmUGT13, and AmUGT7 are four glycosyltransferases biochemically characterized to catalyze 3-O-xylosylation, 3-O-glucosylation, 25-O-glucosylation/O-xylosylation and 2'-O-glucosylation of cycloastragenol glycosides, respectively. These findings not only clarified the crucial enzymes for the biosynthesis and the molecular basis for the structural diversity of astragalosides in Astragalus plants, also paved the way for further completely deciphering the biosynthetic pathway and constructing an artificial pathway for their efficient production.
RESUMEN
Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system. The safety and efficacy of gene therapies rely upon expressing a transgene in affected cells while minimizing off-target expression. Here we show organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery, which we achieved by employing a Cre-transgenic-based screening platform and sequential engineering of AAV-PHP.eB between the surface-exposed AA452 and AA460 of VP3. From this selection, we identified capsid variants that were enriched in the brain and targeted away from the liver in C57BL/6J mice. This tropism extends to marmoset (Callithrix jacchus), enabling robust, non-invasive gene delivery to the marmoset brain after intravenous administration. Notably, the capsids identified result in distinct transgene expression profiles within the brain, with one exhibiting high specificity to neurons. The ability to cross the blood-brain barrier with neuronal specificity in rodents and non-human primates enables new avenues for basic research and therapeutic possibilities unattainable with naturally occurring serotypes.
Asunto(s)
Cápside , Dependovirus , Administración Intravenosa , Animales , Encéfalo/metabolismo , Callithrix/genética , Dependovirus/genética , Vectores Genéticos , Hígado , Ratones , Ratones Endogámicos C57BL , Transducción Genética , TransgenesRESUMEN
The pathology of familial Alzheimer's disease, which is caused by dominant mutations in the gene that encodes amyloid-beta precursor protein (APP) and in those that encode presenilin 1 and presenilin 2, is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles in multiple brain regions. Here we show that the brain-wide selective disruption of a mutated APP allele in transgenic mouse models carrying the human APP Swedish mutation alleviates amyloid-beta-associated pathologies for at least six months after a single intrahippocampal administration of an adeno-associated virus that encodes both Cas9 and a single-guide RNA that targets the mutation. We also show that the deposition of amyloid-beta, as well as microgliosis, neurite dystrophy and the impairment of cognitive performance, can all be ameliorated when the CRISPR-Cas9 construct is delivered intravenously via a modified adeno-associated virus that can cross the blood-brain barrier. Brain-wide disease-modifying genome editing could represent a viable strategy for the treatment of familial Alzheimer's disease and other monogenic diseases that affect multiple brain regions.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Sistemas CRISPR-Cas , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: Assess the efficiency and cost-effectiveness of infliximab, cyclosporine and tacrolimus for the treatment of ulcerative colitis (UC). METHODS: A literature search identified studies that investigated infliximab, cyclosporine or tacrolimus compared with placebo in UC patients. Short-term, long-term remission rates and response rates were employed to assess efficacy. Odds ratios with 95% confidence intervals were analyzed. A Markov model was constructed to simulate the progression in a cohort of patients with UC, with an over 10 years of time horizon, with a discount rate of 3%, and established threshold of 30,000/quality-adjusted life-year (QALY) or ¥82442/QALY. RESULTS: Results of network meta-analysis showed that the order was cyclosporine, tacrolimus, infliximab and placebo from high rate to low with regard to short-term clinical response. The comparison between infliximab versus cyclosporine achieved an incremental cost effectiveness ratio (ICER) of 184435/QALY and ¥531607/QALY, with a 0.34893 QALYs difference of efficacy, and an incremental cost of 64355 and ¥185494. Tacrolimus versus cyclosporine reached an ICER of 44236/QALY and ¥57494/QALY, with a difference of 0.40963 QALYs in efficacy, and a raising cost to 18120 and ¥23551. The probabilistic sensitivity analysis shows that cyclosporine would be cost-effective in the 75.8% of the simulations, tacrolimus in the 24.2%, and infliximab for the 0%. CONCLUSION: Infliximab, cyclosporine and tacrolimus as salvage therapies are efficacious. For long-term of clinical remission, the order of pharmacological agents was tacrolimus, infliximab and cyclosporine from high efficacy to low while no significant difference is seen. In cost-effectiveness analysis, the cyclosporine versus infliximab or tacrolimus is expected to be at best.
Asunto(s)
Colitis Ulcerosa , Humanos , Infliximab/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Ciclosporina/uso terapéutico , Tacrolimus/uso terapéutico , Análisis de Costo-Efectividad , Metaanálisis en Red , Análisis Costo-Beneficio , Años de Vida Ajustados por Calidad de Vida , Resultado del TratamientoRESUMEN
A self-strengthening coating with silver nanoparticles (Ag NPs) doped chitosan (CHI) and sodium alginate (SA) polyelectrolytes was constructed on the surface of polydopamine (PDA) coated Ti substrate by a layer-by-layer assembly method. The PDA coating exhibited an excellent bond with Ti substrate, and also can uniformly deposit Ag NPs via a mild method without introducing any exogenous reductant. The CHI coating was assembled through a spin-coating method for controlling Ag+ release. The SA was introduced to enhance the anticorrosion performance by forming calcium alginate (CA) in a corrosive medium. The corrosion protection was investigated with electrochemical impedance spectroscopy and polarization curves tests in fluorine-containing artificial saliva. During immersion, the charge-transfer resistance and the protection efficiency (Å) presented a continuous increase with the immersion time, demonstrating that this coating possessed a remarkable self-strengthening capability, and the compositions of the outermost film changed from SA to CA with the Ca2+ cations of the corrosive medium as a crosslinker by SEM and EDS analysis. Furthermore, the Å remained up to 96.8% after immersion of 30 days, and then the coating also displayed a distinct inhibition zone on S. mutans. These results prove this coating possesses an excellent anticorrosion performance and antibacterial property.
Asunto(s)
Alginatos/química , Antibacterianos/farmacología , Quitosano/química , Materiales Biocompatibles Revestidos/química , Titanio/farmacología , Animales , Antibacterianos/química , Línea Celular , Corrosión , Indoles/química , Ensayo de Materiales , Nanopartículas del Metal , Ratones , Polielectrolitos/química , Polímeros/química , Saliva Artificial , Streptococcus mutans/efectos de los fármacos , Propiedades de Superficie , Titanio/químicaRESUMEN
Parkinson's disease (PD) is a common neurodegenerative disease in the middle-aged and elderly populations. The purpose of this study was to investigate the clinical value of lncRNA TUG1 in PD and its effect on the microglial inflammatory response. A total of 181 subjects were recruited for the study, including 97 patients with PD (male/female 50/47) and 84 healthy individuals (male/female 41/43). There was no significant difference for gender and age distribution between the groups. The expression of serum TUG1 was determined by qRT-PCR. The receiver operating curve (ROC) was applied for diagnostic value analysis. CCK-8 was used to detect the effect of TUG1 on the proliferation of BV2 cells. The motor coordination ability of mice was tested by the rotarod and pole tests. ELISA was used to detect serum pro-inflammatory factors. TUG1 was highly expressed in the serum of PD patients. Serum TUG1 can distinguish PD patients to form healthy controls with the AUC of 0.902. Serum TUG1 was positively correlated with the levels of UPDRS, IL-6, IL-1ß, and TNF-α in PD patients. Cell experiment results showed that the downregulation of TUG1 significantly inhibited cell proliferation and the release of TNF-α, IL-6, and IL-1ß. Besides, animal experiments suggested that the downregulation of TUG1 significantly improved the motor coordination ability of the PD mice and inhibited the expression of inflammatory factors. lncRNA TUG1 is a latent biomarker of PD patients. TUG1 downregulation may inhibit the inflammatory response in the progression of PD. These findings provide a possible target for the early diagnosis and therapeutic intervention of PD.
Asunto(s)
Inflamación/genética , Microglía/patología , Enfermedad de Parkinson/genética , ARN Largo no Codificante/genética , Anciano , Animales , Área Bajo la Curva , Biomarcadores , División Celular , Línea Celular , Citocinas/sangre , Femenino , Humanos , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Persona de Mediana Edad , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/patología , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , ARN/genética , ARN Largo no Codificante/antagonistas & inhibidores , ARN Largo no Codificante/sangre , Curva ROC , Prueba de Desempeño de Rotación con Aceleración Constante , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , TransfecciónRESUMEN
Spinal cord microcirculation plays an important role in maintaining the function of spinal cord neurons and other cells. Previous studies have largely focused on the ability of microtubule stabilization to inhibit the fibroblast migration and promote axon regeneration after spinal cord injury (SCI). However, the effect of microtubule stabilization treatment on microcirculation reconstruction after SCI remains unclear. By using immunofluorescence, we found that microtubule stabilization treatment improved microcirculation reconstruction via increasing the number of microvessels, pericytes, and the perfused microvessels after SCI. To clarify the underlying mechanisms, rat brain microvascular endothelial cells and pericytes were subjected to glucose oxygen deprivation. By using flow cytometry and western blotting, we found that microtubule stabilization treatment inhibited apoptosis and migration of endothelial cells and pericytes but promoted proliferation and survival of endothelial cells and pericytes through upregulated expression of vascular endothelial growth factor A (VEGFA), VEGF receptor 2, platelet-derived growth factor-B (PDGFB), PDGF receptor ß, and angiopoietin-1 after SCI. Taken together, this study provides evidence for the mechanisms underlying the promotion of microcirculation reconstruction after SCI by microtubule stabilization treatment. Importantly, this study suggests the potential of microtubule stabilization as a therapeutic target to reduce microcirculation dysfunction after SCI in the clinic.
Asunto(s)
Epotilonas/farmacología , Microcirculación , Microtúbulos/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Moduladores de Tubulina/farmacología , Animales , Apoptosis , Hipoxia de la Célula , Movimiento Celular , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Epotilonas/uso terapéutico , Femenino , Glucosa/deficiencia , Microtúbulos/efectos de los fármacos , Pericitos/efectos de los fármacos , Pericitos/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Médula Espinal/irrigación sanguínea , Médula Espinal/metabolismo , Moduladores de Tubulina/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Freezing of gait (FOG) is a disabling paroxysmal gait disorder that prevents starting or resuming walking, which seriously negatively affects patients' quality of life (QOL). The diagnosis and treatment of FOG remain a huge medical challenge. The purpose of this study was to explore the clinical characteristics and related factors of FOG in patients with Parkinson's disease (PD). METHODS: The motor and nonmotor symptoms of a total number of 77 PD patients were evaluated. Patients with or without FOG were defined as a score ≥1 in the new freezing of gait questionnaire (NFOG-Q). A comparative study between patients with and without FOG was conducted. RESULTS: In this investigation, the prevalence of FOG was 48%. The patients with FOG had longer disease duration, higher Hoehn-Yahr stage (H-Y stage), higher dose of dopaminergic agents, and higher nonmotor and motor symptom scores. A significant positive correlation was found between the NFOG-Q score and the H-Y stage, PIGD subscore, PDQ-39, and the attention/memory in the nonmotor symptoms assessment scale (NMSS) subitem (r > 0.5, p < .05). The binary logistic regression analysis showed that the higher H-Y stage, higher rigidity subscore and Unified Parkinson's Disease Rating Scale II (UPDRS II) score, and UPDRS III score were significantly correlated with the occurrence of FOG (p < .05). In the analysis of the frequency of FOG, the prevalence of FOG in H-Y stage was higher in the middle and late stages, and the prevalence of FOG increased with the increase in PDQ-39 scores. CONCLUSION: The severity of FOG was significantly positively correlated with the H-Y stage, PIGD subscore, PDQ-39 score, and attention/memory score. Based on our findings, we conclude that the clinical characteristics of rigidity can be used as a potential predictor of FOG.
Asunto(s)
Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Marcha , Trastornos Neurológicos de la Marcha/epidemiología , Trastornos Neurológicos de la Marcha/etiología , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Calidad de Vida , Índice de Severidad de la EnfermedadRESUMEN
The dysregulation of gene dosage due to duplication or haploinsufficiency is a major cause of autosomal dominant diseases such as Alzheimer's disease. However, there is currently no rapid and efficient method for manipulating gene dosage in a human model system such as human induced pluripotent stem cells (iPSCs). Here, we demonstrate a simple and precise method to simultaneously generate iPSC lines with different gene dosages using paired Cas9 nickases. We first generate a Cas9 nickase variant with broader protospacer-adjacent motif specificity to expand the targetability of double-nicking-mediated genome editing. As a proof-of-concept study, we examine the gene dosage effects on an Alzheimer's disease patient-derived iPSC line that carries three copies of APP (amyloid precursor protein). This method enables the rapid and simultaneous generation of iPSC lines with monoallelic, biallelic, or triallelic knockout of APP. The cortical neurons generated from isogenically corrected iPSCs exhibit gene dosage-dependent correction of disease-associated phenotypes of amyloid-beta secretion and Tau hyperphosphorylation. Thus, the rapid generation of iPSCs with different gene dosages using our method described herein can be a useful model system for investigating disease mechanisms and therapeutic development.
Asunto(s)
Proteína 9 Asociada a CRISPR/genética , Sistemas CRISPR-Cas , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Variaciones en el Número de Copia de ADN , Dosificación de Gen , Edición Génica , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Apoptosis , Proteína 9 Asociada a CRISPR/metabolismo , Línea Celular , Regulación de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/patología , Neurogénesis , Neuronas/patología , Fosforilación , Prueba de Estudio Conceptual , Proteínas tau/metabolismoRESUMEN
Specification of the progenitors' regional identity is a pivotal step during development of the cerebral cortex and basal ganglia. The molecular mechanisms underlying progenitor regionalization, however, are poorly understood. Here we showed that the transcription factor Vax1 was highly expressed in the developing subpallium. In its absence, the RNA-Seq analysis, in situ RNA hybridization, and immunofluorescence staining results showed that the cell proliferation was increased in the subpallium, but the neuronal differentiation was blocked. Moreover, the dLGE expands ventrally, and the vLGE, MGE, and septum get smaller. Finally, overexpressed VAX1 in the LGE progenitors strongly inhibits Gsx2 expression. Taken together, our findings show that Vax1 is crucial for subpallium regionalization by repressing Gsx2.
Asunto(s)
Cuerpo Estriado/embriología , Cuerpo Estriado/metabolismo , Globo Pálido/embriología , Globo Pálido/metabolismo , Proteínas de Homeodominio/biosíntesis , Neuropéptidos/biosíntesis , Animales , Cuerpo Estriado/citología , Globo Pálido/citología , Proteínas de Homeodominio/antagonistas & inhibidores , Proteínas de Homeodominio/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células-Madre Neurales/metabolismo , Neurogénesis/fisiología , Neuropéptidos/genéticaRESUMEN
Mouse cortical radial glial cells (RGCs) are primary neural stem cells that give rise to cortical oligodendrocytes, astrocytes, and olfactory bulb (OB) GABAergic interneurons in late embryogenesis. There are fundamental gaps in understanding how these diverse cell subtypes are generated. Here, by combining single-cell RNA-Seq with intersectional lineage analyses, we show that beginning at around E16.5, neocortical RGCs start to generate ASCL1+EGFR+ apical multipotent intermediate progenitors (MIPCs), which then differentiate into basal MIPCs that express ASCL1, EGFR, OLIG2, and MKI67. These basal MIPCs undergo several rounds of divisions to generate most of the cortical oligodendrocytes and astrocytes and a subpopulation of OB interneurons. Finally, single-cell ATAC-Seq supported our model for the genetic logic underlying the specification and differentiation of cortical glial cells and OB interneurons. Taken together, this work reveals the process of cortical radial glial cell lineage progression and the developmental origins of cortical astrocytes and oligodendrocytes.
Asunto(s)
Células-Madre Neurales , Neurogénesis , Animales , Diferenciación Celular , Ratones , Neuroglía , OligodendroglíaRESUMEN
An electrochemical aptasensor for the lipopolysaccharide (LPS) detection was constructed by using copper-based metal-organic framework (Cu-MOF) as a label and the LPS aptamer of specific single-stranded DNA as a probe. The carboxyl-functionalized polypyrrole nanowires (PPy NWs) were synthesized by electrochemical polymerization method, and the amino-terminated aptamer covalently coupling with the carboxyl group of the PPy NWs was immobilized onto the modified electrode. The aptamer can specifically combine with the target LPS molecules, and Cu-MOF was labeled by adsorption based on specific interactions of LPS carbohydrate portions with anionic groups. The fabrication processes of the aptasensor were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and electrochemical impedance spectroscopy (EIS). Differential pulse voltammetry (DPV) was used to measure electrochemical performance of the aptasensor, and the electrochemical signal can be directly measured by the electrochemical redox reaction of Cu(II)/Cu(I) existed in the Cu-MOF. The electrochemical aptasensor exhibited a high sensitivity toward LPS ranging from 1.0 pg/mL to 1.0 ng/mL with a detection limit of 0.29 pg/mL. Moreover, the developed sensor was found to have good selectivity, stability and regeneration properties, and the sensor also successfully detected LPS in real tap water samples.
Asunto(s)
Cobre/química , Técnicas Electroquímicas/instrumentación , Lipopolisacáridos/análisis , Estructuras Metalorgánicas/química , Adsorción , Aptámeros de Nucleótidos/química , Técnicas Biosensibles , Espectroscopía Dieléctrica , Electrodos , Límite de Detección , Microscopía Electrónica de Rastreo , Nanocables/química , Oxidación-ReducciónRESUMEN
Six new Diels-Alder type adducts, morusalisins A-F (1-6), were isolated from Morus alba cell cultures. The structures of 1-6 were determined by extensive spectroscopic data analysis, including HRESIMS, NMR, and ECD experiments. Furthermore, compounds 1-6 exhibited potent protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC50 values ranging from 1.14 to 2.24 µM, making them promising as bioactive compounds for anti-diabetic drug discovery.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Morus/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Técnicas de Cultivo de Célula , Inhibidores Enzimáticos/aislamiento & purificación , Humanos , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacologíaRESUMEN
OBJECTIVE: This study aims to identify effective gene networks and biomarkers to predict response and prognosis for HER2-negative breast cancer patients who received sequential taxane-anthracycline neoadjuvant chemotherapy. MATERIALS AND METHODS: Transcriptome data of training dataset including 310 HER2-negative breast cancer who received taxane-anthracycline treatment and an independent validation set with 198 samples were analyzed by weighted gene co-expression network analysis (WGCNA) approach in R language. Gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were performed for the selected genes. Module-clinical trait relationships were analyzed to explore the genes and pathways that associated with clinicopathological parameters. Log-rank tests and COX regression were used to identify the prognosis-related genes. RESULTS: We found a significant correlation of an expression module with distant relapse-free survival (HR = 0.213, 95% CI [0.131-0.347], P = 4.80E-9). This blue module contained genes enriched in biological process of hormone levels regulation, reproductive system, response to estradiol, cell growth and mammary gland development as well as pathways including estrogen, apelin, cAMP, the PPAR signaling pathway and fatty acid metabolism. From this module, we further screened and validated six hub genes (CA12, FOXA1, MLPH, XBP1, GATA3 and MAGED2), the expression of which were significantly associated with both better chemotherapeutic response and favorable survival for BC patients. CONCLUSION: We used WGCNA approach to reveal a gene network that regulate HER2-negative breast cancer treatment with taxane-anthracycline neoadjuvant chemotherapy, which enriched in pathways of estrogen signaling, apelin signaling, cAMP signaling, the PPAR signaling pathway and fatty acid metabolism. In addition, genes of CA12, FOXA1, MLPH, XBP1, GATA3 and MAGED2 might serve as novel biomarkers predicting chemotherapeutic response and prognosis for HER2-negative breast cancer.
RESUMEN
AIMS: TL1A was reported to contribute to the susceptibility to ulcerative colitis (UC). However, the molecular mechanisms of TL1A in UC development are poorly understood. We aimed to investigate the role of TL1A in colitis, and reveal the regulatory mechanism of TL1A in chronic colitis development. MAIN METHODS: Wild-type mice and transgenic mice with overexpressing TL1A in lymphocytes were used to construct chronic DSS colitis models. To investigate the molecular mechanism in vitro, CD4+ T cells were sorted from spleens and mesenteric lymph node cells to induce Th9 cells. Biopsy specimens from ulcerative colitis patients were collected for in vivo validation. KEY FINDINGS: The elevated TL1A expression in chronic DSS colitis models exacerbated intestinal inflammation. The differentiation of Th9 cells, IL-9 secretion and production of TGF-ß, IL-4 and PU.1 was significantly enhanced in transgenic mice with TL1A overexpression. In vitro results showed that TL1A enhanced the Th9 cells, IL-9 and PU.1 production, while TL1A antibodies inhibited their production. In human translational studies, patients with ulcerative colitis with elevated TL1A expression also exhibited more serious inflammation with higher levels of Th9 cells, IL-9 and PU.1 expression. SIGNIFICANCE: We presented a possible mechanism of TL1A in UC development that TL1A may promote the differentiation of Th9 cells and enhanced IL-9 secretion by up-regulating the expression of TGF-ß, IL-4 and PU.1, which provided a novel perspective to study the UC pathogenesis, and indicated that targeting of TL1A signal pathway may by a likely strategy for the treatment of chronic colitis.