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Highly selective formal [4 + 2]-cycloaddition of vinyldiazoacetates with azoalkenes from α-halohydrazones, as well as with cyclopentadiene and furan, occurs with light irradiation at room temperature, producing highly functionalized heterocyclic and bicyclic compounds in good yields and excellent diastereoseletivity. Under blue light these vinyldiazoacetate reagents selectively form unstable cyclopropenes that undergo intermolecular cycloaddition reactions at a faster rate than their competitive ene dimerization. [4 + 2]-cycloaddition of vinyldiazoacetates with in situ formed azoalkenes produces bicyclo[4.1.0]tetrahydropyridazine derivatives and, together with their cycloaddition using cyclopentadiene and furan that form tricyclic compounds, they occur with high chemoselectivity and diastereocontrol, good functional group tolerance, and excellent scalability. Subsequent transformations portray the synthetic versatility of these structures.
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The development of the human neocortex is a highly dynamic process and involves complex cellular trajectories controlled by cell-type-specific gene regulation1. Here, we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence. In parallel, we performed spatial transcriptomic analysis on a subset of the samples to illustrate spatial organization and intercellular communication. This atlas enables us to catalog cell type-, age-, and area-specific gene regulatory networks underlying neural differentiation. Moreover, combining single-cell profiling, progenitor purification, and lineage-tracing experiments, we have untangled the complex lineage relationships among progenitor subtypes during the transition from neurogenesis to gliogenesis in the human neocortex. We identified a tripotential intermediate progenitor subtype, termed Tri-IPC, responsible for the local production of GABAergic neurons, oligodendrocyte precursor cells, and astrocytes. Remarkably, most glioblastoma cells resemble Tri-IPCs at the transcriptomic level, suggesting that cancer cells hijack developmental processes to enhance growth and heterogeneity. Furthermore, by integrating our atlas data with large-scale GWAS data, we created a disease-risk map highlighting enriched ASD risk in second-trimester intratelencephalic projection neurons. Our study sheds light on the gene regulatory landscape and cellular dynamics of the developing human neocortex.
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The nuclear genome is spatially organized into a three-dimensional (3D) architecture by physical association of large chromosomal domains with subnuclear compartments including the nuclear lamina at the radial periphery and nuclear speckles within the nucleoplasm1-5. However, how spatial genome architecture regulates human brain development has been overlooked owing to technical limitations. Here, we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from midgestational human cortex, uncovering an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, spatial genome organization is extensively remodeled, relocating hundreds of neuronal genes from the lamina to speckles including key neurodevelopmental genes bivalent for H3K27me3 and H3K4me3. At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 and increases transcription >7-fold. We further demonstrate that proximity to the nuclear periphery - not the presence of H3K27me3 - is the dominant factor in maintaining the lowly expressed, poised state of bivalent genes embedded in the lamina. In addition to uncovering a critical role of subnuclear genome compartmentalization in neurogenic transcriptional regulation, our results establish a new paradigm in which knowing the spatial location of a gene is necessary to understanding its epigenomic regulation.
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The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.
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African Americans and Hispanic Americans experience a higher incidence and prevalence of dementia than white Americans while also experiencing more environmental, metabolic, and nutritional factors potentially promoting such disparities. Greater exposure to air, water, and soil pollutants, including toxic metals associated with neurodegeneration, accrues in both minorities, as does worse dental care than Whites exposing them to periodontitis, raising dementia risk. Hispanic Americans experience greater occupational exposure to herbicides and pesticides, and have a higher rate of developing non-alcoholic fatty liver disease (NAFLD), predisposing to dementia. African Americans have a greater likelihood of both vitamin D deficiency and magnesium deficiency, increasing neuroinflammation and dementia risk. Both have greater air pollution exposure, a known dementia risk. Nutritional changes, including greater nut consumption and reduced sugar drink consumption, improved dental care, and reduced toxicant exposure, may help reduce this higher risk of dementia among African Americans and Hispanic Americans.
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The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain.
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Cerebelo , Neuronas , Retina , Animales , Femenino , Masculino , Ratones , Cerebelo/metabolismo , Cerebelo/irrigación sanguínea , Cerebelo/citología , Canales Iónicos/metabolismo , Ratones Endogámicos C57BL , Neuronas/metabolismo , Retina/citología , Retina/metabolismo , Células Ganglionares de la Retina/metabolismo , Vasos Retinianos/metabolismoRESUMEN
OBJECTIVES: Complementing the well-established evidence base on health inequalities experienced by migrants, refugees and asylum seekers in the UK; we examined the extent to which their right to equal non-discriminatory access to health services (promotive, preventive, curative) was upheld during the COVID-19 pandemic. STUDY DESIGN: Arksey and O'Malley's scoping review framework. METHODS: A comprehensive search was conducted on Medline, PubMed, and CINAHL using detailed MESH terms, for literature published between 01 January 2020 and 01 January 2024. The process was supported by a ten-page Google search and hand searching of reference lists. 42 records meeting the inclusion criteria were charted, coded inductively and analysed thematically in an integrated team-based approach. RESULTS: Dissonance between immigration regulation and health governance is illustrated in four themes: Health systems leveraged to (re)enforce the hostile environment; Dissonance between health rights on paper and in practice; Structural failures to overcome communication and digital exclusion; and COVID-19 vaccine (in)equity exacerbated fear, mistrust and exclusion. Migrants, refugees and asylum seekers encountered substantial individual, structural and policy-level barriers to accessing healthcare in the UK during COVID-19. Insecure immigration status, institutional mistrust, data-sharing and charging fears, communication challenges and digital exclusion impacted heavily on their ability to access healthcare in an equitable non-discriminatory manner. CONCLUSIONS: An inclusive and innovative health equity and rights-based responses reaching all migrants, refugees and asylum seekers are warranted if the National Health Service is to live up to its promise of 'leaving no one behind' in post-pandemic and future responses.
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COVID-19 , Accesibilidad a los Servicios de Salud , Refugiados , Migrantes , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Refugiados/psicología , Refugiados/estadística & datos numéricos , Reino Unido , Migrantes/psicología , Migrantes/estadística & datos numéricos , Emigración e Inmigración/legislación & jurisprudencia , SARS-CoV-2RESUMEN
Scleroglucan (SG) is resistant to harsh reservoir conditions such as high temperature, high shear stresses, and the presence of chemical substances. However, it is susceptible to biological degradation because bacteria use SG as a source of energy and carbon. All degradation effects lead to viscosity loss of the SG solutions, affecting their performance as an enhanced oil recovery (EOR) polymer. Recent studies have shown that nanoparticles (NPs) can mitigate these degradative effects. For this reason, the EOR performance of two new nanohybrids (NH-A and NH-B) based on carboxymethyl-scleroglucan and amino-functionalized silica nanoparticles was studied. The susceptibility of these products to chemical, mechanical, and thermal degradation was evaluated following standard procedures (API RP 63), and the microbial degradation was assessed under reservoir-relevant conditions (1311 ppm and 100 °C) using a bottle test system. The results showed that the chemical reactions for the nanohybrids obtained modified the SG triple helix configuration, impacting its viscosifying power. However, the nanohybrid solutions retained their viscosity during thermal, mechanical, and chemical degradation experiments due to the formation of a tridimensional network between the nanoparticles (NPs) and the SG. Also, NH-A and NH-B solutions exhibited bacterial control because of steric hindrances caused by nanoparticle modifications to SG. This prevents extracellular glucanases from recognizing the site of catalysis, limiting free glucose availability and generating cell death due to substrate depletion. This study provides insights into the performance of these nanohybrids and promotes their application in reservoirs with harsh conditions.
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In this study, two new nanohybrids (NH-A and NH-B) were synthesized through carbodiimide-assisted coupling. The reaction was performed between carboxymethyl-scleroglucans (CMS-A and CMS-B) with different degrees of substitution and commercial amino-functionalized silica nanoparticles using 4-(dimethylamino)-pyridine (DMAP) and N,N'-dicyclohexylcarbodiimide (DCC) as catalysts. The morphology and properties of the nanohybrids were investigated by using transmission (TEM) and scanning electron microscopy (SEM), electron-dispersive scanning (EDS), attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FT-IR), X-ray photoelectron spectroscopy (XPS), powder X-ray diffraction (XRD), inductively coupled plasma atomic emission spectroscopy (ICP-OES), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic light scattering (DLS). The nanohybrids exhibited differences in structure due to the incorporation of polyhedral oligomeric silsesquioxane (POSS) materials. The results reveal that hybrid nanomaterials exhibit similar thermal properties but differ in morphology, chemical structure, and crystallinity properties. Finally, a viscosity study was performed on the newly obtained nanohybrid materials; viscosities of nanohybrids increased significantly in comparison to the carboxymethyl-scleroglucans, with a viscosity difference of 7.2% for NH-A and up to 32.6% for NH-B.
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INTRODUCTION: Baseline sarcopenia and postoperative changes in muscle mass are independently associated with overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy (CN). Here we examine the relationships between preoperative (baseline), postoperative changes in muscle quantity, and survival outcomes following CN as determined by linear segmentation, a clinic-friendly tool that rapidly estimates muscle mass. MATERIALS AND METHODS: Our nephrectomy database was reviewed for patients with metastatic disease who underwent CN for RCC. Linear segmentation of the bilateral psoas/paraspinal muscles was completed for baseline imaging within 60 days of surgery and imaging 30 to 365 days postoperatively. Kruskal-Wallis for numerical and Fisher's exact test for categorical variables were used to test for differences between groups according to percent change in linear muscle index (LMI, cm2/m2). Multivariable Cox proportional hazards models evaluated associations between LMI percent change and cancer-specific (CSM) and all-cause mortality (ACM). Kaplan Meier curves estimated cancer-specific (CSS) and overall survival (OS). RESULTS: From 2004-2020, 205 patients were included of whom 52 demonstrated stable LMI (25.4%; LMI change < 5% [0Δ]), 60 increase (29.3%; LMI +5% [+Δ]), and 92 decrease (44.9%; LMI -5% [-Δ]). Median time from baseline imaging to surgery was 18 days, and time from surgery to postoperative imaging was 133 days. Median CSS and OS were highest among patients with 0Δ LMI (CSS: 133.6 [0Δ] vs. 61.9 [+Δ] vs. 37.4 [-Δ] months; P = .0018 || OS: 67.2 [0Δ] vs. 54.8 [+Δ] vs. 29.5 [-Δ] months; P = .0007). Stable LMI was a protective factor for CSM (HR 0.48; P = .024) and ACM (HR 0.59; P = .040) on multivariable analysis. DISCUSSION: Change in muscle mass after CN, as measured by the linear muscle segmentation technique, is independently associated with OS and CSS in patients following CN. Of note, lack of change was associated with longer survival.
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Carcinoma de Células Renales , Procedimientos Quirúrgicos de Citorreducción , Neoplasias Renales , Nefrectomía , Sarcopenia , Humanos , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/secundario , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Nefrectomía/métodos , Femenino , Masculino , Procedimientos Quirúrgicos de Citorreducción/métodos , Persona de Mediana Edad , Anciano , Sarcopenia/diagnóstico por imagen , Estudios Retrospectivos , Pronóstico , Músculos Psoas/diagnóstico por imagen , Músculos Psoas/patologíaRESUMEN
Objective: To determine the frequency with which suspected pathogenic factors, including metals and metabolites that might contribute to Alzheimer's disease (AD), may be found in patients with cognitive impairment through commonly available blood tests. Methods: A variety of serum studies, including metals, ammonia, homocysteine, vitamin B12, folate, thyroid tests, metabolic products, and inflammatory markers, were measured in two cohorts: one meeting mild cognitive impairment (MCI) criteria and the other meeting mild-to-moderate dementia (DE) criteria. Medications these patients received were reviewed. Results: Metal abnormalities were detected in over half the subjects, including evidence of mercury, lead, and arsenic elevation as well as instances of excessive essential metals, iron (Fe), and copper. Some metal aberration was detected in 64% of the DE group and 66% of the MCI group. Females were more likely to have elevated copper, consistent with hormonal effects on copper excretion. Homocysteinemia was the most common abnormality, detected in 71% with DE and 67% with MCI, while methylmalonic acid was not elevated. Slight hyperammonemia was moderately common (38%) suggesting a hepatic factor in this subset. Findings of moderate insulin resistance were present in nearly half (44% DE, 52% MCI). Sixty of 65 (92%) had at least one abnormal biomarker and 60% had two or more. The most common drug taken by the total cohort was proton pump inhibitors at 22% DE and 38% MCI. Conclusions: This study suggests that both toxic metals and excessive vital metals such as copper and iron, as well as common metabolic and hepatic factors are detectable at both stages of MCI and DE. There appears to be a multiplicity of provocative factors leading to DE. Individualized interventions based on these parameters may be a means to reduce cognitive decline leading to DE. A more comprehensive prospective study of these environmental and metabolic factors with corrective early interventions appears warranted.
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Biomarcadores , Disfunción Cognitiva , Demencia , Humanos , Femenino , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/metabolismo , Masculino , Anciano , Biomarcadores/sangre , Demencia/sangre , Demencia/diagnóstico , Anciano de 80 o más Años , Persona de Mediana Edad , Homocisteína/sangre , Metales/sangre , Metales/metabolismo , Vitamina B 12/sangreRESUMEN
This paper presents the methodology for synthesizing and characterizing two carboxymethyl EOR-grade Scleroglucans (CMS-A and CMS-B). An O-Alkylation reaction was used to insert a hydrophilic group (monochloroacetic acid-MCAA) into the biopolymer's anhydroglucose subunits (AGUs). The effect of the degree of the carboxymethyl substitution on the rheology and thermal stability of the Scleroglucan (SG) was also evaluated. Simultaneous thermal analysis (STA/TGA-DSC), differential scanning calorimetry (DSC), X-ray Diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, Scanning Electron Microscopy, and Energy Dispersive Spectroscopy (SEM/EDS) were employed to characterize both CMS products. FTIR analysis revealed characteristic peaks corresponding to the carboxymethyl functional groups, confirming the modification. Also, SEM analysis provided insights into the structural changes in the polysaccharide after the O-Alkylation reaction. TGA results showed that the carboxymethylation of SG lowered its dehydroxylation temperature but increased its thermal stability above 300 °C. The CMS products and SG exhibited a pseudoplastic behavior; however, lower shear viscosities and relaxation times were observed for the CMS products due to the breakage of the SG triple helix for the chemical modification. Despite the viscosity results, the modified Scleroglucans are promising candidates for developing new engineering materials for EOR processes.
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Biopolymers emerge as promising candidates for enhanced oil recovery (EOR) applications due to their molecular structures, which exhibit better stability than polyacrylamides under harsh conditions. Nonetheless, biopolymers are susceptible to oxidation and biological degradation. Biopolymers reinforced with nanoparticles could be a potential solution to the issue. The nanofluids' stability and performance depend on the nanoparticles' properties and the preparation method. The primary objective of this study was to evaluate the effect of the preparation method and the nanoparticle type (SiO2, Al2O3, and TiO2) on the viscosity and stability of the scleroglucan (SG). The thickening effect of the SG solution was improved by adding all NPs due to the formation of three-dimensional structures between the NPs and the SG chains. The stability test showed that the SG + Al2O3 and SG + TiO2 nanofluids are highly unstable, but the SG + SiO2 nanofluids are highly stable (regardless of the preparation method). According to the ANOVA results, the preparation method and standing time influence the nanofluid viscosity with a statistical significance of 95%. On the contrary, the heating temperature and NP type are insignificant. Finally, the nanofluid with the best performance was 1000 ppm of SG + 100 ppm of SiO2_120 NPs prepared by method II.
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OBJECTIVE: To examine the performance of the Palacios et al [Aguilar Palacios D, Wilson B, Ascha M, et al. New baseline renal function after radical or partial nephrectomy: a simple and accurate predictive model. J Urol. 2021;205:1310-1320] post-nephrectomy future glomerular function rate (fGFR) equation in a diverse cohort using both the Chronic Kidney Disease Epidemiology (CKD-EPI) 2009 equation with race, used in the creation of the formula, as well as the CKD-EPI 2021 equation without race. METHODS: Patients who underwent partial or radical nephrectomy for renal cell carcinoma from 2005-2021 were identified in our institutional database. Patients with creatinine values preoperatively and 3-12â¯months postoperatively were included. Correlation/bias/accuracy/precision of the fGFR equation (fGFRâ¯=â¯35+ [preoperative eGFRâ¯×â¯0.65]â¯-â¯18 [if radical]â¯-â¯[ageâ¯×â¯0.25]â¯+â¯3 [if tumor >7â¯cm]â¯-â¯2 [if diabetes]) with observed postoperative eGFR was determined by both the CKD-EPI-2021 and CKD-EPI 2009 equations. RESULTS: A total of 1443 patients were analyzed. Seventy-one percent (1024) were White and 22.9% (331) were Black. Most underwent radical nephrectomy (60.3%). 40% T3-T4 renal cell carcinoma (RCC), with 14.8% of patients having M1 disease. Median observed vs predicted fGFR was 58.0 vs 58.7â¯mL/min/1.73â¯m2 for CKD-EPI 2021 and 56.0 vs 57.5 for CKD-EPI 2009. For the total cohort, the correlation/bias/accuracy/precision of the fGFR equation was 0.805/-0.5/81.7/7.9-9.0 for CKD-EPI 2021 and 0.809/-0.8/81.3/-8.1 to 8 for CKD-EPI 2009. In Black patients, fGFR equation demonstrated >75% accuracy with both CKD-EPI equations; however, accuracy was lower in black patients with the CKD-EPI2021 equation (76.1% vs 83.4%, Pâ¯=â¯.003). CONCLUSION: The fGFR equation performed well in our large, diverse cohort, though accuracy was relatively lower when using CKD-EPI 2021 compared to CKD-EPI 2009.
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Carcinoma de Células Renales , Neoplasias Renales , Insuficiencia Renal Crónica , Humanos , Tasa de Filtración Glomerular , Carcinoma de Células Renales/cirugía , Insuficiencia Renal Crónica/epidemiología , Nefrectomía , Creatinina , Neoplasias Renales/cirugíaRESUMEN
OBJECTIVE: In patients with Dravet syndrome (DS), fenfluramine reduced convulsive seizure frequency and provided clinical benefit in nonseizure endpoints (e.g., executive function, survival). In zebrafish mutant scn1 DS models, chronic fenfluramine treatment preserved neuronal cytoarchitecture prior to seizure onset and prevented gliosis; here, we extend these findings to a mammalian model of DS (Scn1a+/- mice) by evaluating the effects of fenfluramine on neuroinflammation (degenerated myelin, activated microglia) and survival. METHODS: Scn1a+/- DS mice were treated subcutaneously once daily with fenfluramine (15 mg/kg) or vehicle from postnatal day (PND) 7 until 35-37. Sagittal brain sections were processed for immunohistochemistry using antibodies to degraded myelin basic protein (D-MBP) for degenerated myelin, or CD11b for activated (inflammatory) microglia; sections were scored semi-quantitatively. Apoptotic nuclei were quantified by TUNEL assay. Statistical significance was evaluated by 1-way ANOVA with post-hoc Dunnett's test (D-MBP, CD11b, and TUNEL) or Logrank Mantel-Cox (survival). RESULTS: Quantitation of D-MBP immunostaining per 0.1 mm2 unit area of the parietal cortex and hippocampus CA3 yielded significantly higher spheroidal and punctate myelin debris counts in vehicle-treated DS mice than in wild-type mice. Fenfluramine treatment in DS mice significantly reduced these counts. Activated CD11b + microglia were more abundant in DS mouse corpus callosum and hippocampus than in wild-type controls. Fenfluramine treatment of DS mice resulted in significantly fewer activated CD11b + microglia than vehicle-treated DS mice in these brain regions. TUNEL staining in corpus callosum was increased in DS mice relative to wild-type controls. Fenfluramine treatment in DS mice lowered TUNEL staining relative to vehicle-treated DS mice. By PND 35-37, 55% of control DS mice had died, compared with 24% of DS mice receiving fenfluramine treatment (P = 0.0291). SIGNIFICANCE: This is the first report of anti-neuroinflammation and pro-survival after fenfluramine treatment in a mammalian DS model. These results corroborate prior data in humans and animal models and suggest important pharmacological activities for fenfluramine beyond seizure reduction. PLAIN LANGUAGE SUMMARY: Dravet syndrome is a severe epilepsy disorder that impairs learning and causes premature death. Clinical studies in patients with Dravet syndrome show that fenfluramine reduces convulsive seizures. Additional studies suggest that fenfluramine may have benefits beyond seizures, including promoting survival and improving control over emotions and behavior. Our study is the first to use a Dravet mouse model to investigate nonseizure outcomes of fenfluramine. Results showed that fenfluramine treatment of Dravet mice reduced neuroinflammation significantly more than saline treatment. Fenfluramine-treated Dravet mice also lived longer than saline-treated mice. These results support clinical observations that fenfluramine may have benefits beyond seizures.
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Epilepsias Mioclónicas , Fenfluramina , Humanos , Animales , Ratones , Fenfluramina/farmacología , Fenfluramina/uso terapéutico , Anticonvulsivantes/uso terapéutico , Pez Cebra , Enfermedades Neuroinflamatorias , Epilepsias Mioclónicas/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Modelos Animales de Enfermedad , Mamíferos , Canal de Sodio Activado por Voltaje NAV1.1RESUMEN
The temporal lobe of the human brain contains the entorhinal cortex (EC). This region of the brain is a highly interconnected integrative hub for sensory and spatial information; it also has a key role in episodic memory formation and is the main source of cortical hippocampal inputs1-4. The human EC continues to develop during childhood5, but neurogenesis and neuronal migration to the EC are widely considered to be complete by birth. Here we show that the human temporal lobe contains many young neurons migrating into the postnatal EC and adjacent regions, with a large tangential stream persisting until the age of around one year and radial dispersal continuing until around two to three years of age. By contrast, we found no equivalent postnatal migration in rhesus macaques (Macaca mulatta). Immunostaining and single-nucleus RNA sequencing of ganglionic eminence germinal zones, the EC stream and the postnatal EC revealed that most migrating cells in the EC stream are derived from the caudal ganglionic eminence and become LAMP5+RELN+ inhibitory interneurons. These late-arriving interneurons could continue to shape the processing of sensory and spatial information well into postnatal life, when children are actively interacting with their environment. The EC is one of the first regions of the brain to be affected in Alzheimer's disease, and previous work has linked cognitive decline to the loss of LAMP5+RELN+ cells6,7. Our investigation reveals that many of these cells arrive in the EC through a major postnatal migratory stream in early childhood.