Integrated multimodal cell atlas of Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years. We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin+ inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb+ and Vip+ inhibitory neuron subtypes. These findings were replicated in other major AD studies.

A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.

The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties1-3. Here we report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions-in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain.

Transcriptomic cytoarchitecture reveals principles of human neocortex organization.

Variation in cytoarchitecture is the basis for the histological definition of cortical areas. We used single cell transcriptomics and performed cellular characterization of the human cortex to better understand cortical areal specialization. Single-nucleus RNA-sequencing of 8 areas spanning cortical structural variation showed a highly consistent cellular makeup for 24 cell subclasses. However, proportions of excitatory neuron subclasses varied substantially, likely reflecting differences in connectivity across primary sensorimotor and association cortices. Laminar organization of astrocytes and oligodendrocytes also differed across areas. Primary visual cortex showed characteristic organization with major changes in the excitatory to inhibitory neuron ratio, expansion of layer 4 excitatory neurons, and specialized inhibitory neurons. These results lay the groundwork for a refined cellular and molecular characterization of human cortical cytoarchitecture and areal specialization.

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species.

Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and our astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

Cuidado preventivo y recuperativo en salud oral de mujeres embarazadas en el Perú / Preventive and recuperative oral health care for pregnant women in Peru / Cuidados de saúde oral preventivos e recuperativos em mulheres grávidas no Peru

RESUMEN Durante el embarazo, los cambios fisiológicos incrementan el riesgo de patologías orales, como periodontitis, gingivitis, lesiones de caries, erosión dentaria y granulomas piógenos. Por lo tanto, es fundamental realizar una atención oportuna para mantener la salud bucal de las mujeres en estado de gestación. Objetivo: Describir las características de las atenciones preventivas y de recuperación de la salud bucal en mujeres embarazadas de los centros de salud públicos del Perú. Material y métodos: Estudio observacional, descriptivo y transversal, basado en datos secundarios de atención en odontoestomatología durante el año 2017. Se analizaron las variables trimestre de embarazo, rango de edad materna, tipo de procedimiento preventivo y recuperativo, región y condición del tratamiento. Los datos fueron analizados en el programa RStudio y los resultados se presentaron en tablas con frecuencias relativas y absolutas. Resultados: Fueron realizados 35 523 procedimientos preventivos, de los cuales 37,3 % se dieron en el segundo trimestre; 21,8 % corresponden a examen estomatológico; y 21,7 %, a instrucción de higiene oral; 69,8 %, al grupo de 18-29 años; y 15,5 %, a la región Junín. Se desarrollaron 4265 procedimientos recuperativos, de los cuales 39,0 % se dieron en el segundo trimestre; 53,1 % corresponden a destartraje; y 18,9 %, a consulta estomatológica; 61,7 %, al grupo de 18-29 años; y 16,25 %, a la región Huánuco. Conclusión: Un mayor número de mujeres embarazadas accedieron a cuidados preventivos en comparación con el acceso a procedimientos recuperativos de la salud bucal; y la tasa de abandono fue predominante en los dos casos. Ambos procedimientos se realizaron con mayor frecuencia durante el segundo trimestre, en regiones altoandinas y en madres adultas jóvenes.

ABSTRACT During pregnancy, physiological changes increase the risk of oral pathologies, such as periodontitis, gingivitis, caries lesions, dental erosion and pyogenic granulomas. Therefore, it is essential to provide timely care to maintain the oral health of pregnant women. Objective: To describe the characteristics of preventive and recovery oral health care in pregnant women in public health centers in Peru. Materials and methods: Observational, descriptive, cross-sectional study based on secondary data on odontostomatology care during 2017. The variables trimester of pregnancy, maternal age range, preventive and recuperative procedure, region, and treatment condition were analyzed. The data were analyzed in the RStudio program, and the results were presented in tables with relative and absolute frequencies. Results: 35,523 preventive procedures were performed, 37.3% in the second trimester; 21.8% corresponded to stomatological examination; and 21.7% to oral hygiene instruction; 69.8% in the 18-29-year age group; and 15.5% in the Junin region. There were 4265 recovery procedures, 39.0 % in the second trimester; 53.1 % corresponded to dental scaling and 18.9 % to stomatological consultation, 61.7 % in the 18-29-year age group, and 16.25 % in the Huánuco region. Conclusion: A more significant number of pregnant women accessed preventive care compared to access to oral health recovery procedures, and the dropout rate was predominant in both cases. Both procedures were performed more frequently in high Andean regions and young adult mothers during the second trimester.

RESUMO Durante a gravidez, as alterações fisiológicas aumentam o risco de patologias orais, como a periodontite, a gengivite, as lesões de cárie, a erosão dentária e os granulomas piogênicos. Portanto, o atendimento oportuno é essencial para a manutenção da saúde bucal das gestantes. Objetivo: Descrever as características dos cuidados de saúde oral preventivos e curativos para mulheres grávidas em centros de saúde pública no Peru. Material e métodos: Estudo observacional, descritivo e transversal, baseado em dados secundários sobre o atendimento odontostomatológico durante o ano de 2017. Foram analisadas as seguintes variáveis: trimestre da gravidez, faixa etária materna, tipo de procedimento preventivo e restaurador, região e condição do tratamento. Os dados foram analisados no programa RStudio e os resultados foram apresentados em tabelas com frequências relativas e absolutas. Resultado: Foram realizados 35.523 procedimentos preventivos, 37,3 % no segundo trimestre; 21,8 % corresponderam a exame estomatológico; e 21,7 % a instrução de higiene bucal; 69,8 % na faixa etária de 18 a 29 anos; e 15,5 % na região de Junín. Foram realizados 4.265 procedimentos de recuperação, 39,0 % no segundo trimestre; 53,1 % corresponderam a raspagem; e 18,9 % a consulta odontológica; 61,7 % na faixa etária de 18-29 anos; e 16,25 % na região de Huánuco. Conclusão: Um maior número de gestantes acessou o atendimento preventivo em comparação com o acesso a procedimentos restauradores de saúde bucal; e a taxa de desistência foi predominante em ambos os casos. Ambos os procedimentos foram realizados com mais frequência durante o segundo trimestre, nas regiões andinas altas e em mães adultas jovens.

A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.

The mammalian brain is composed of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. An essential step towards understanding brain function is to obtain a parts list, i.e., a catalog of cell types, of the brain. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain. The cell type atlas was created based on the combination of two single-cell-level, whole-brain-scale datasets: a single-cell RNA-sequencing (scRNA-seq) dataset of ~7 million cells profiled, and a spatially resolved transcriptomic dataset of ~4.3 million cells using MERFISH. The atlas is hierarchically organized into five nested levels of classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes and 5,200 clusters. We systematically analyzed the neuronal, non-neuronal, and immature neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain: the dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. We also systematically characterized cell-type specific expression of neurotransmitters, neuropeptides, and transcription factors. The study uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types across the brain, suggesting they mediate a myriad of modes of intercellular communications. Finally, we found that transcription factors are major determinants of cell type classification in the adult mouse brain and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole-mouse-brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of the mammalian brain.

VE-cadherin endocytosis controls vascular integrity and patterning during development.

Tissue morphogenesis requires dynamic intercellular contacts that are subsequently stabilized as tissues mature. The mechanisms governing these competing adhesive properties are not fully understood. Using gain- and loss-of-function approaches, we tested the role of p120-catenin (p120) and VE-cadherin (VE-cad) endocytosis in vascular development using mouse mutants that exhibit increased (VE-cadGGG/GGG) or decreased (VE-cadDEE/DEE) internalization. VE-cadGGG/GGG mutant mice exhibited reduced VE-cad-p120 binding, reduced VE-cad levels, microvascular hemorrhaging, and decreased survival. By contrast, VE-cadDEE/DEE mutants exhibited normal vascular permeability but displayed microvascular patterning defects. Interestingly, VE-cadDEE/DEE mutant mice did not require endothelial p120, demonstrating that p120 is dispensable in the context of a stabilized cadherin. In vitro, VE-cadDEE mutant cells displayed defects in polarization and cell migration that were rescued by uncoupling VE-cadDEE from actin. These results indicate that cadherin endocytosis coordinates cell polarity and migration cues through actin remodeling. Collectively, our results indicate that regulated cadherin endocytosis is essential for both dynamic cell movements and establishment of stable tissue architecture.

Efectos cardiovasculares en usuarios de cocaína / Cardiovascular effects in cocaine users

Resumen La cocaína es una sustancia psicoactiva ampliamente utilizada de forma recreativa. El uso indiscriminado de esta sustancia genera múltiples consultas a los servicios de emergencias, principalmente debido a sus efectos cardiovasculares. Los mecanismos fisiopatológicos actúan principalmente en sistema nervioso simpático, cardiomiocito, plaquetas, canales de sodio y potasio, entre otros. El objetivo principal de esta revisión es demostrar los efectos cardiovasculares asociados al uso de la cocaína.

Abstract Cocaine is a psychoactive substance widely used recreationally. The indiscriminate use of this substance generates multiple consultations to the emergency services, mainly due to its cardiovascular effects. The physio pathological mechanisms act mainly in sympathetic nervous system, cardiomyocyte, platelets, sodium and potassium channels, among others. The main objective of this review is to demonstrate the cardiovascular effects associated with the use of cocaine.

Alteraciones electrofisiológicas y/o bioquímicas del trauma cardíaco / Electrophysiological and/or biochemical alterations of cardiac trauma

Resumen El trauma cardíaco constituye una de las primeras causas de mortalidad en la población general. La gran mayoría son causados por accidentes automovilísticos. Su diagnóstico es difícil y requiere alto índice de sospecha en trauma cerrado. Posee un índice de mortalidad muy elevado, cercano al 76%. Existen varios métodos diagnósticos disponibles para facilitar su detección pero ninguno logra alcanzar una sensibilidad cercana al 100%. El trauma cardíaco contuso puede variar desde lesión cardíaca asintomática hasta ruptura cardíaca y muerte. Actualmente se utilizan marcadores bioquímicos como enzimas cardíacas, siendo la Troponina I la más específica; y electrofisiológicos como hallazgos en el electrocardiograma sugestivos de bloqueo de rama y taquicardia sinusal, siendo estos los más frecuentemente encontrados.

Abstract Heart trauma is one of the leading causes of mortality in the general population. The vast majority are caused by automobile accidents. Its diagnosis is difficult and requires a high index of suspicion in closed trauma. It has a very high mortality rate, close to 76%. There are several diagnostic methods available to facilitate its detection, but none can reach a sensitivity close to 100%. Contusive heart trauma can range from asymptomatic cardiac injury to cardiac rupture and death. Currently, biochemical markers are used as cardiac enzymes, with Troponin I being the most specific; and electrophysiological findings in the electrocardiogram suggestive of branch block and sinus tachycardia, these being the most frequently found.

Malformaciones cardíacas causantes de muerte súbita en adulto / Cardiac malformations causing sudden death in adults

Resumen La muerte súbita cardiaca se define como la muerte que ocurre dentro de una hora después de inicio de síntomas en los casos presenciados y en los no presenciados dentro de las últimas 24 horas de haberse visto con vida. Su incidencia anual en el mundo ronda entre 4-5 millones de casos. Aproximadamente un 90-95% de las víctimas de muerte súbita cardíaca sufren una cardiopatía estructural. Siendo la cardiopatía isquémica la causa principal en mayores de 35 años y las afectaciones congénitas y hereditarias en adultos jóvenes entre 18-35 años. La etiología de la muerte súbita cardíaca se puede clasificar en coronariopatías, miocardiopatías, cardiopatías congénitas, enfermedades eléctricas hereditarias y cardiopatías adquiridas. Siendo la aterosclerosis y la miocardiopatía dilatada las más prevalentes y de las cardiopatías congénitas la que tiene mayor mortalidad por muerte súbita cardíaca es la coartación de aorta. Múltiples mecanismos pueden derivar en muerte súbita cardíaca como fibrilación ventricular, taquicardia ventricular polimorfa y actividad eléctrica sin pulso. Sin embargo, en la actualidad la muerte súbita cardíaca continúa siendo un reto en la salud pública, tanto el diagnóstico como el tratamiento oportuno. Mediante la prevención de factores de riesgo modificables y con el control adecuado de los no modificables, así como la optimización de la terapéutica, se podrá reducir la incidencia de muerte súbita cardíaca.

Abstract Sudden cardiac death is defined as death that occurs within one hour after the onset of symptoms in the presence and not witnessed cases within the last 24 hours of having seen life. Its annual incidence in the world is between 4-5 million cases. Approximately 90-95% of victims of sudden cardiac death suffered from structural heart disease. Ischemic heart disease is the main cause in people older than 35 years and the congenital and hereditary affectations in young adults between 18-35 years. The etiology of sudden cardiac death can be classified as coronary artery disease, cardiomyopathy, congenital heart disease, hereditary diseases and acquired heart disease. Being atherosclerosis and dilated cardiomyopathy the most frequent and congenital cardiopathies, the one with the highest mortality due to sudden cardiac death is the coarctation of the aorta. Multiple mechanisms can lead to sudden cardiac death such as ventricular fibrillation, polymorphic ventricular tachycardia and pulseless electrical activity. However, at the right time. Through the prevention of modifiable risk factors and with the adequate control of the non-modifiable ones, as well as the optimization of therapeutics, the incidence of sudden cardiac death can be reduced.

The Survival of Motor Neuron Protein Acts as a Molecular Chaperone for mRNP Assembly.

Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival of motor neuron (SMN) protein. SMN is part of a multiprotein complex that facilitates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN has also been found to associate with mRNA-binding proteins, but the nature of this association was unknown. Here, we have employed a combination of biochemical and advanced imaging methods to demonstrate that SMN promotes the molecular interaction between IMP1 protein and the 3' UTR zipcode region of ß-actin mRNA, leading to assembly of messenger ribonucleoprotein (mRNP) complexes that associate with the cytoskeleton to facilitate trafficking. We have identified defects in mRNP assembly in cells and tissues from SMA disease models and patients that depend on the SMN Tudor domain and explain the observed deficiency in mRNA localization and local translation, providing insight into SMA pathogenesis as a ribonucleoprotein (RNP)-assembly disorder.