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1.
Ambio ; 53(1): 126-137, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37707687

RESUMEN

Biological recording is a prominent and widely practised form of citizen science, but few studies explore long-term demographic trends in participation and knowledge production. We studied long-term demographic trends of age and gender of participants reporting to a large online citizen science multi-taxon biodiversity platform ( www.artportalen.se ). Adoption by user communities and continually developing Information and Communications Technologies (ICTs) greatly increased the number of participants reporting data, but profound long-term imbalances in gender contribution across species groups persisted over time. Reporters identifying as male dominated in numbers, spent more days in the field reporting and reported more species on each field day. Moreover, an age imbalance towards older participants amplified over time. As the first long-term study of citizen participation by age and gender, our results show that it is important for citizen science project developers to account for cultural and social developments that might exclude participants, and to engage with underrepresented and younger participants. This could facilitate the breadth of engagement and learning across a larger societal landscape, ensure project longevity and biodiversity data representation (e.g. mitigate gender bias influence on the number of reports of different species groups).


Asunto(s)
Ciencia Ciudadana , Femenino , Masculino , Humanos , Sexismo , Aprendizaje , Biodiversidad
2.
Ann Med Surg (Lond) ; 85(12): 6057-6066, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38098605

RESUMEN

Stroke is a leading cause of long-term disability worldwide, and cognitive impairment is a common consequence of stroke. Understanding the connection between stroke and cognitive impairment is crucial for effectively managing symptoms and improving patients' quality of life. This abstract provides an overview of the relationship between stroke and cognitive impairment and explores strategies for managing cognitive symptoms in stroke survivors. A comprehensive review of relevant literature was conducted to examine the association between stroke and cognitive impairment. Various factors contributing to cognitive impairment after stroke were explored, including the location and severity of the stroke, vascular risk factors, and underlying mechanisms. Evidence-based strategies for managing cognitive symptoms in stroke survivors were also analyzed, such as cognitive rehabilitation, pharmacological interventions, and lifestyle modifications. The review revealed a strong link between stroke and cognitive impairment. The location and severity of the stroke play a significant role in determining the specific cognitive deficits experienced by individuals. Vascular risk factors, including hypertension, diabetes, and atrial fibrillation, contribute to cognitive decline after stroke. Mechanisms such as cerebral hypoperfusion, white matter damage, and neuroinflammation also play a role. Cognitive rehabilitation programs have shown promising results in improving cognitive function, while certain medications may help manage specific cognitive symptoms. Lifestyle modifications like physical exercise and a healthy diet have been associated with better cognitive outcomes in stroke survivors.

3.
Development ; 150(24)2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37997696

RESUMEN

Toll-like receptors (TLRs) in mammalian systems are well known for their role in innate immunity. In addition, TLRs also fulfil crucial functions outside immunity, including the dorsoventral patterning function of the original Toll receptor in Drosophila and neurogenesis in mice. Recent discoveries in flies suggested key roles for TLRs in epithelial cells in patterning of junctional cytoskeletal activity. Here, we address the function of TLRs and the downstream key signal transduction component IRAK4 in human epithelial cells. Using differentiated human Caco-2 cells as a model for the intestinal epithelium, we show that these cells exhibit baseline TLR signalling, as revealed by p-IRAK4, and that blocking IRAK4 function leads to a loss of epithelial tightness involving key changes at tight and adherens junctions, such as a loss of epithelial tension and changes in junctional actomyosin. Changes upon IRAK-4 inhibition are conserved in human bronchial epithelial cells. Knockdown of IRAK4 and certain TLRs phenocopies the inhibitor treatment. These data suggest a model whereby TLR receptors near epithelial junctions might be involved in a continuous sensing of the epithelial state to promote epithelial tightness and integrity.


Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1 , Receptores Toll-Like , Humanos , Células CACO-2 , Inmunidad Innata , Quinasas Asociadas a Receptores de Interleucina-1/genética , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Transducción de Señal
4.
Medicine (Baltimore) ; 102(43): e35652, 2023 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-37904369

RESUMEN

HIV-related neurocognitive disorders (HAND) have emerged as a significant concern in the context of HIV infection. This article provides a comprehensive overview of the diagnosis, treatment, and mental health implications associated with HAND. Diagnosis of HAND involves a multifaceted approach, combining clinical assessments, neurocognitive testing, and neuroimaging techniques. Various screening tools and standardized assessments have been developed to aid in the early detection and monitoring of HAND. Timely diagnosis allows for appropriate interventions and personalized treatment strategies. Treatment for HAND encompasses a multidisciplinary approach targeting different aspects of cognitive impairment. Antiretroviral therapy (ART) remains the cornerstone of treatment, effectively reducing viral load and preventing further neurocognitive decline. Adjunctive therapies, including cognitive rehabilitation, pharmacological interventions, and psychosocial support, play crucial roles in managing cognitive symptoms and enhancing overall quality of life. Mental health implications associated with HAND are profound and require special attention. Individuals with HAND are at higher risk of experiencing psychological distress, depression, anxiety, and reduced social functioning. Integrated care models that address physical and mental health aspects are vital in optimizing treatment outcomes and promoting mental well-being in this population. Furthermore, this paper highlights the need for ongoing research to unravel the underlying mechanisms of HAND and develop targeted interventions. Identifying risk factors, understanding the impact of HIV on the brain, and exploring novel treatment modalities are essential areas of focus. Additionally, living with HAND social and cultural aspects must be considered to ensure equitable access to care and support for all affected individuals.


Asunto(s)
Infecciones por VIH , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Salud Mental , VIH , Calidad de Vida/psicología , Trastornos Neurocognitivos/diagnóstico , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/terapia
5.
Stem Cell Reports ; 12(4): 680-695, 2019 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-30930245

RESUMEN

The olfactory epithelium (OE) regenerates after injury via two types of tissue stem cells: active globose cells (GBCs) and dormant horizontal basal cells (HBCs). HBCs are roused to activated status by OE injury when P63 levels fall. However, an in-depth understanding of activation requires a system for culturing them that maintains both their self-renewal and multipotency while preventing spontaneous differentiation. Here, we demonstrate that mouse, rat, and human HBCs can be cultured and passaged as P63+ multipotent cells. HBCs in vitro closely resemble HBCs in vivo based on immunocytochemical and transcriptomic comparisons. Genetic lineage analysis demonstrates that HBCs in culture arise from both tissue-derived HBCs and multipotent GBCs. Treatment with retinoic acid induces neuronal and non-neuronal differentiation and primes cultured HBCs for transplantation into the lesioned OE. Engrafted HBCs generate all OE cell types, including olfactory sensory neurons, confirming that HBC multipotency and neurocompetency are maintained in culture.


Asunto(s)
Diferenciación Celular , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Trasplante de Células Madre , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Proliferación Celular , Células Cultivadas , Ratones , Células-Madre Neurales/efectos de los fármacos , Neurogénesis , Mucosa Olfatoria/citología , Mucosa Olfatoria/metabolismo , Neuronas Receptoras Olfatorias/citología , Neuronas Receptoras Olfatorias/metabolismo , Regeneración , Transactivadores/genética , Transactivadores/metabolismo , Tretinoina/metabolismo , Tretinoina/farmacología
6.
J Neurosci ; 39(5): 814-832, 2019 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-30530861

RESUMEN

Neurons in the murine olfactory epithelium (OE) differ by the olfactory receptor they express as well as other molecular phenotypes that are regionally restricted. These patterns can be precisely regenerated following epithelial injury, suggesting that spatial cues within the tissue can direct neuronal diversification. Nonetheless, the permanency and mechanism of this spatial patterning remain subject to debate. Via transplantation of stem and progenitor cells from dorsal OE into ventral OE, we demonstrate that, in mice of both sexes, nonautonomous spatial cues can direct the spatially circumscribed differentiation of olfactory sensory neurons. The vast majority of dorsal transplant-derived neurons express the ventral marker OCAM (NCAM2) and lose expression of NQO1 to match their new location. Single-cell analysis also demonstrates that OSNs adopt a fate defined by their new position following progenitor cell transplant, such that a ventral olfactory receptor is expressed after stem and progenitor cell engraftment. Thus, spatially constrained differentiation of olfactory sensory neurons is plastic, and any bias toward an epigenetic memory of place can be overcome.SIGNIFICANCE STATEMENT Spatially restricted differentiation of olfactory sensory neurons is both key to normal olfactory function and a challenging example of biological specificity. That the stem cells of the olfactory epithelium reproduce the organization of the olfactory periphery to a very close approximation during lesion-induced regeneration begs the question of whether stem cell-autonomous genomic architecture or environmental cues are responsible. The plasticity demonstrated after transfer to a novel location suggests that cues external to the transplanted stem and progenitor cells confer neuronal identity. Thus, a necessary prerequisite is satisfied for using engraftment of olfactory stem and progenitor cells as a cellular therapeutic intervention to reinvigorate neurogenesis whose exhaustion contributes to the waning of olfaction with age.


Asunto(s)
Mucosa Olfatoria/citología , Neuronas Receptoras Olfatorias/fisiología , Animales , Diferenciación Celular/fisiología , Señales (Psicología) , Epigénesis Genética , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Moléculas de Adhesión de Célula Nerviosa/biosíntesis , Moléculas de Adhesión de Célula Nerviosa/genética , Células-Madre Neurales , Neurogénesis/fisiología , Plasticidad Neuronal , Trasplante de Células Madre
7.
J Manag Care Spec Pharm ; 23(12): 1255-1259, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29172981

RESUMEN

Biosimilars have the potential to greatly reduce medication costs in the United States. As of July 1, 2017, 5 biosimilars have been approved by the FDA, but only 2 are available for purchase. This commentary outlines the efforts of an integrated health system to ensure biosimilar accessibility and discusses the current challenges and future implications. We highlight the implementation of a health plan policy and how a health system's formulary committee can encourage use while considering provider perceptions and operational challenges. In addition, we provide our perspective on potential implications for pricing, site of care, and pharmacy dispensing practices based on our experience with regulatory hurdles and market trends. Overall, we believe biosimilars are a good thing for the health care system, but their expected benefit may not be realized for years to come. DISCLOSURES: No outside funding supported this work. Affeldt reports advisory board membership with Janssen, and Skiermont reports membership with Amgen and McKesson. The other authors have nothing to disclose. Peterson and Budlong contributed the study concept and design and wrote the manuscript. Affeldt, Skiermont, Kyllo, and Heaton reviewed and revised the manuscript.


Asunto(s)
Biosimilares Farmacéuticos/administración & dosificación , Prestación Integrada de Atención de Salud/organización & administración , Aprobación de Drogas , Biosimilares Farmacéuticos/economía , Prestación Integrada de Atención de Salud/economía , Costos de los Medicamentos , Formularios Farmacéuticos como Asunto , Accesibilidad a los Servicios de Salud , Humanos , Servicios Farmacéuticos/organización & administración , Comité Farmacéutico y Terapéutico , Estados Unidos , United States Food and Drug Administration
8.
Cell Stem Cell ; 21(6): 761-774.e5, 2017 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-29174332

RESUMEN

Adult neurogenesis in the olfactory epithelium is often depicted as a unidirectional pathway during homeostasis and repair. We challenge the unidirectionality of this model by showing that epithelial injury unlocks the potential for Ascl1+ progenitors and Neurog1+ specified neuronal precursors to dedifferentiate into multipotent stem/progenitor cells that contribute significantly to tissue regeneration in the murine olfactory epithelium (OE). We characterize these dedifferentiating cells using several lineage-tracing strains and single-cell mRNA-seq, and we show that Sox2 is required for initiating dedifferentiation and that inhibition of Ezh2 promotes multipotent progenitor expansion. These results suggest that the apparent hierarchy of neuronal differentiation is not irreversible and that lineage commitment can be overridden following severe tissue injury. We elucidate a previously unappreciated pathway for endogenous tissue repair by a highly regenerative neuroepithelium and introduce a system to study the mechanisms underlying plasticity in the OE that can be adapted for other tissues.


Asunto(s)
Desdiferenciación Celular , Reprogramación Celular , Células Madre Multipotentes/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Animales , Ratones , Ratones Endogámicos , Células Madre Multipotentes/metabolismo , Células Madre Multipotentes/patología , Mucosa Olfatoria/metabolismo , Mucosa Olfatoria/patología
9.
J Virol ; 91(20)2017 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-28768870

RESUMEN

Progressive multifocal leukoencephalopathy (PML) is an often-fatal demyelinating disease of the central nervous system. PML results when oligodendrocytes within immunocompromised individuals are infected with the human JC virus (JCV). We have identified an oligodendrocyte precursor cell line, termed G144, that supports robust levels of JCV DNA replication, a central part of the JCV life cycle. In addition, we have determined that JC virus readily infects G144 cells. Furthermore, we have determined that JCV DNA replication in G144 cells is stimulated by myristoylated (i.e., constitutively active) Akt and reduced by the Akt-specific inhibitor MK2206. Thus, this oligodendrocyte-based model system will be useful for a number of purposes, such as studies of JCV infection, establishing key pathways needed for the regulation of JCV DNA replication, and identifying inhibitors of this process.IMPORTANCE The disease progressive multifocal leukoencephalopathy (PML) is caused by the infection of particular brain cells, termed oligodendrocytes, by the JC virus. Studies of PML, however, have been hampered by the lack of an immortalized human cell line derived from oligodendrocytes. Here, we report that the G144 oligodendrocyte cell line supports both infection by JC virus and robust levels of JCV DNA replication. Moreover, we have established that the Akt pathway regulates JCV DNA replication and that JCV DNA replication can be inhibited by MK2206, a compound that is specific for Akt. These and related findings suggest that we have established a powerful oligodendrocyte-based model system for studies of JCV-dependent PML.


Asunto(s)
Virus JC/fisiología , Oligodendroglía/virología , Proteína Oncogénica v-akt/metabolismo , Replicación Viral , Línea Celular , Replicación del ADN , ADN Viral , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Virus JC/genética , Leucoencefalopatía Multifocal Progresiva/virología , Oligodendroglía/efectos de los fármacos , Proteína Oncogénica v-akt/antagonistas & inhibidores , Proteína Oncogénica v-akt/química
10.
Proc Natl Acad Sci U S A ; 114(28): E5589-E5598, 2017 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-28637720

RESUMEN

The remarkable capacity of the adult olfactory epithelium (OE) to regenerate fully both neurosensory and nonneuronal cell types after severe epithelial injury depends on life-long persistence of two stem cell populations: the horizontal basal cells (HBCs), which are quiescent and held in reserve, and mitotically active globose basal cells. It has recently been demonstrated that down-regulation of the ΔN form of the transcription factor p63 is both necessary and sufficient to release HBCs from dormancy. However, the mechanisms by which p63 is down-regulated after acute OE injury remain unknown. To identify the cellular source of potential signaling mechanisms, we assessed HBC activation after neuron-only and sustentacular cell death. We found that ablation of sustentacular cells is sufficient for HBC activation to multipotency. By expression analysis, next-generation sequencing, and immunohistochemical examination, down-regulation of Notch pathway signaling is coincident with HBC activation. Therefore, using HBC-specific conditional knockout of Notch receptors and overexpression of N1ICD, we show that Notch signaling maintains p63 levels and HBC dormancy, in contrast to its suppression of p63 expression in other tissues. Additionally, Notch1, but not Notch2, is required to maintain HBC dormancy after selective neuronal degeneration. Taken together, our data indicate that the activation of HBCs observed after tissue injury or sustentacular cell ablation is caused by the reduction/elimination of Notch signaling on HBCs; elimination of Jagged1 expressed by sustentacular cells may be the ligand responsible.


Asunto(s)
Células-Madre Neurales/citología , Mucosa Olfatoria/citología , Fosfoproteínas/metabolismo , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Transactivadores/metabolismo , Animales , Muerte Celular , Biología Computacional , Genotipo , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células 3T3 NIH , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Neuronas Receptoras Olfatorias/citología , Neuronas Receptoras Olfatorias/metabolismo , Análisis de Secuencia de ARN , Transducción de Señal , Transcriptoma
11.
J Comp Neurol ; 525(4): 1034-1054, 2017 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-27560601

RESUMEN

The capacity of the olfactory epithelium (OE) for lifelong neurogenesis and regeneration depends on the persistence of neurocompetent stem cells, which self-renew as well as generating all of the cell types found within the nasal epithelium. This Review focuses on the types of stem and progenitor cells in the epithelium and their regulation. Both horizontal basal cells (HBCs) and some among the population of globose basal cells (GBCs) are stem cells, but the two types plays vastly different roles. The GBC population includes the basal cells that proliferate in the uninjured OE and is heterogeneous with respect to transcription factor expression. From upstream in the hierarchy to downstream, GBCs encompass 1) Sox2+ /Pax6+ stem-like cells that are totipotent and self-renew over the long term, 2) Ascl1+ transit-amplifying progenitors with a limited capacity for expansive proliferation, and 3) Neurog1+ /NeuroD1+ immediate precursor cells that make neurons directly. In contrast, the normally quiescent HBCs are activated to multipotency and proliferate when sustentacular cells are killed, but not when only OSNs die, indicating that HBCs are reserve stem cells that respond to severe epithelial injury. The master regulator of HBC activation is the ΔN isoform of the transcription factor p63; eliminating ΔNp63 unleashes HBC multipotency. Notch signaling, via Jagged1 ligand on Sus cells and Notch1 and Notch2 receptors on HBCs, is likely to play a major role in setting the level of p63 expression. Thus, ΔNp63 becomes a potential therapeutic target for reversing the neurogenic exhaustion characteristic of the aged OE. J. Comp. Neurol. 525:1034-1054, 2017. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Células-Madre Neurales/citología , Mucosa Olfatoria/citología , Animales , Humanos
12.
Proc Natl Acad Sci U S A ; 112(36): E5068-77, 2015 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-26305958

RESUMEN

Adult tissue stem cells can serve two broad functions: to participate actively in the maintenance and regeneration of a tissue or to wait in reserve and participate only when activated from a dormant state. The adult olfactory epithelium, a site for ongoing, life-long, robust neurogenesis, contains both of these functional stem cell types. Globose basal cells (GBCs) act as the active stem cell population and can give rise to all the differentiated cells found in the normal tissue. Horizontal basal cells (HBCs) act as reserve stem cells and remain dormant unless activated by tissue injury. Here we show that HBC activation following injury by the olfactotoxic gas methyl bromide is coincident with the down-regulation of protein 63 (p63) but anticipates HBC proliferation. Gain- and loss-of-function studies show that this down-regulation of p63 is necessary and sufficient for HBC activation. Moreover, activated HBCs give rise to GBCs that persist for months and continue to act as bona fide stem cells by participating in tissue maintenance and regeneration over the long term. Our analysis provides mechanistic insight into the dynamics between tissue stem cell subtypes and demonstrates that p63 regulates the reserve state but not the stem cell status of HBCs.


Asunto(s)
Mucosa Olfatoria/metabolismo , Neuronas Receptoras Olfatorias/metabolismo , Fosfoproteínas/metabolismo , Células Madre/metabolismo , Transactivadores/metabolismo , Animales , Western Blotting , Diferenciación Celular/genética , Proliferación Celular/genética , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Confocal , Neurogénesis/genética , Mucosa Olfatoria/citología , Neuronas Receptoras Olfatorias/citología , Neuronas Receptoras Olfatorias/trasplante , Fosfoproteínas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Madre/citología , Transactivadores/genética
13.
J Biol Chem ; 288(48): 34384-93, 2013 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-24133213

RESUMEN

During the biosynthesis of heparan sulfate (HS), glucuronyl C5-epimerase (Hsepi) catalyzes C5-epimerization of glucuronic acid (GlcA), converting it to iduronic acid (IdoA). Because HS 2-O-sulfotransferase (Hs2st) shows a strong substrate preference for IdoA over GlcA, C5-epimerization is required for normal HS sulfation. However, the physiological significance of C5-epimerization remains elusive. To understand the role of Hsepi in development, we isolated Drosophila Hsepi mutants. Homozygous mutants are viable and fertile with only minor morphological defects, including the formation of an ectopic crossvein in the wing, but they have a short lifespan. We propose that two mechanisms contribute to the mild phenotypes of Hsepi mutants: HS sulfation compensation and possible developmental roles of 2-O-sulfated GlcA (GlcA2S). HS disaccharide analysis showed that loss of Hsepi resulted in a significant impairment of 2-O-sulfation and induced compensatory increases in N- and 6-O-sulfation. Simultaneous block of Hsepi and HS 6-O-sulfotransferase (Hs6st) activity disrupted tracheoblast formation, a well established FGF-dependent process. This result suggests that the increase in 6-O-sulfation in Hsepi mutants is critical for the rescue of FGF signaling. We also found that the ectopic crossvein phenotype can be induced by expression of a mutant form of Hs2st with a strong substrate preference for GlcA-containing units, suggesting that this phenotype is associated with abnormal GlcA 2-O-sulfation. Finally, we show that Hsepi formed a complex with Hs2st and Hs6st in S2 cells, raising the possibility that this complex formation contributes to the close functional relationships between these enzymes.


Asunto(s)
Carbohidrato Epimerasas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/crecimiento & desarrollo , Glucuronatos/metabolismo , Heparitina Sulfato/biosíntesis , Sulfotransferasas/metabolismo , Animales , Carbohidrato Epimerasas/genética , Drosophila/enzimología , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Ácido Glucurónico/metabolismo , Ácido Idurónico/metabolismo , Longevidad/genética , Mutagénesis Sitio-Dirigida , Mutación , Transducción de Señal , Sulfotransferasas/genética
14.
Stem Cells Int ; 2011: 586586, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22190964

RESUMEN

Bone marrow-derived mesenchymal stromal cells (MSCs) hold promise for autologous treatment of neuropathologies. Intranasal delivery is relatively noninvasive and has recently been reported to result in transport of MSCs to the brain. However, the ability of MSCs to migrate from nasal passages to sites of neuropathology and ultimately survive has not been fully examined. In this paper, we harvested MSCs from transgenic mice expressing enhanced green fluorescent protein (cells hereafter referred to as MSC-EGFP) and delivered them intranasally to wild-type mice sustaining mechanical lesions in the striatum. Using fluorescent, colorimetric, and ultrastructural detection methods, GFP-expressing cells were undetectable in the brain from 3 hours to 2 months after MSC delivery. However, bright autofluorescence that strongly resembled emission from GFP was observed in the olfactory bulb and striatum of lesioned control and MSC-EGFP-treated mice. In a control experiment, we directly implanted MSC-EGFPs into the mouse striatum and detected robust GFP expression 1 and 7 days after implantation. These findings suggest that-under our conditions-intranasally delivered MSC-EGFPs do not survive or migrate in the brain. Furthermore, our observations highlight the necessity of including appropriate controls when working with GFP as a cellular marker.

15.
Alcohol Clin Exp Res ; 35(11): 1974-84, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21649667

RESUMEN

BACKGROUND: Ethanol consumption during pregnancy can lead to fetal alcohol spectrum disorder (FASD), which consists of the complete spectrum of developmental deficits including neurological dysfunction. FASD is associated with a variety of neurobehavioral disturbances dependent on the age and duration of exposure. Ethanol exposure in neonatal rodents can also induce widespread apoptotic neurodegeneration and long-lasting behavioral abnormalities similar to FASD. The developmental stage of neonatal rodent brains that are at the peak of synaptogenesis is equivalent to the third trimester of human gestation. METHODS: Male and female C57BL/6By mice were injected with ethanol (20%, 2.5 g/kg, 2 s.c. injections) or an equal volume of saline (controls) on postnatal day 7 (P7). Animals were allowed to mature and at 3 months were tested on an olfactory habituation task known to be dependent on piriform cortex function, a hippocampal-dependent object place memory task, and used for electrophysiological testing of spontaneous and odor-evoked local field potential (LFP) activity in the olfactory bulb, piriform cortex, and dorsal hippocampus. RESULTS: P7 ethanol induced widespread cell death within 1 day of exposure, with highest levels in the neocortex, intermediate levels in the dorsal hippocampus, and relatively low levels in the primary olfactory system. No impairment of odor investigation or odor habituation was detected in P7 ethanol-exposed 3-month-old mice compared to saline controls. However, hippocampal-dependent object place memory was significantly impaired in the P7 ethanol-treated adult mice. Odor-evoked LFP activity was enhanced throughout the olfacto-hippocampal pathway, primarily within the theta frequency band, although the hippocampus also showed elevated evoked delta frequency activity. In addition, functional coherence between the piriform cortex and olfactory bulb and between the piriform cortex and dorsal hippocampus was enhanced in the beta frequency range in P7 ethanol-treated adult mice compared to controls. CONCLUSIONS: P7 ethanol induces an immediate wave of regionally selective cell death followed by long-lasting changes in local circuit and regional network function that are accompanied by changes in neurobehavioral performance. The results suggest that both the activity of local neural circuits within a brain region and the flow of information between brain regions can be modified by early alcohol exposure, which may contribute to long-lasting behavioral abnormalities known to rely on those circuits.


Asunto(s)
Conducta Animal/efectos de los fármacos , Etanol/farmacología , Neocórtex/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , Animales , Animales Recién Nacidos , Conducta Animal/fisiología , Fenómenos Electrofisiológicos , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Neocórtex/fisiología , Red Nerviosa/fisiología , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/fisiología
16.
Neurobiol Aging ; 30(9): 1453-65, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18180075

RESUMEN

In vivo quantitative magnetic resonance imaging (MRI) was employed to detect brain pathology and map its distribution within control, disomic mice (2N) and in Ts65Dn and Ts1Cje trisomy mice with features of human Down syndrome (DS). In Ts65Dn, but not Ts1Cje mice, transverse proton spin-spin (T(2)) relaxation time was selectively reduced in the medial septal nucleus (MSN) and in brain regions that receive cholinergic innervation from the MSN, including the hippocampus, cingulate cortex, and retrosplenial cortex. Basal forebrain cholinergic neurons (BFCNs) in the MSN, identified by choline acetyltransferase (ChAT) and nerve growth factor receptors p75(NTR) and TrkA immunolabeling were reduced in Ts65Dn brains and in situ acetylcholinesterase (AChE) activity was depleted distally along projecting cholinergic fibers, and selectively on pre- and postsynaptic profiles in these target areas. T(2) effects were negligible in Ts1Cje mice that are diploid for App and lack BFCN neuropathology, consistent with the suspected relationship of this pathology to increased App dosage. These results establish the utility of quantitative MRI in vivo for identifying Alzheimer's disease-relevant cholinergic changes in animal models of DS and characterizing the selective vulnerability of cholinergic neuron subpopulations.


Asunto(s)
Acetilcolina/metabolismo , Corteza Cerebral/patología , Fibras Colinérgicas/metabolismo , Síndrome de Down/patología , Núcleos Septales/patología , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Colina O-Acetiltransferasa/metabolismo , Modelos Animales de Enfermedad , Síndrome de Down/metabolismo , Síndrome de Down/fisiopatología , Vías Eferentes/metabolismo , Vías Eferentes/patología , Vías Eferentes/fisiopatología , Dosificación de Gen/genética , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Imagen por Resonancia Magnética/métodos , Ratones , Valor Predictivo de las Pruebas , Receptor de Factor de Crecimiento Nervioso/metabolismo , Receptor trkA/metabolismo , Sensibilidad y Especificidad , Núcleos Septales/metabolismo , Núcleos Septales/fisiopatología , Sinapsis/metabolismo , Sinapsis/ultraestructura , Trisomía/genética
17.
Am J Pathol ; 173(3): 665-81, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18688038

RESUMEN

Mechanisms of neuronal loss in Alzheimer's disease (AD) are poorly understood. Here we show that apoptosis is a major form of neuronal cell death in PS/APP mice modeling AD-like neurodegeneration. Pyknotic neurons in adult PS/APP mice exhibited apoptotic changes, including DNA fragmentation, caspase-3 activation, and caspase-cleaved alpha-spectrin generation, identical to developmental neuronal apoptosis in wild-type mice. Ultrastructural examination using immunogold cytochemistry confirmed that activated caspase-3-positive neurons also exhibited chromatin margination and condensation, chromatin balls, and nuclear membrane fragmentation. Numbers of apoptotic profiles in both cortex and hippocampus of PS/APP mice compared with age-matched controls were twofold to threefold higher at 6 months of age and eightfold higher at 21 to 26 months of age. Additional neurons undergoing dark cell degeneration exhibited none of these apoptotic features. Activated caspase-3 and caspase-3-cleaved spectrin were abundant in autophagic vacuoles, accumulating in dystrophic neurites of PS/APP mice similar to AD brains. Administration of the cysteine protease inhibitor, leupeptin, promoted accumulation of autophagic vacuoles containing activated caspase-3 in axons of PS/APP mice and, to a lesser extent, in those of wild-type mice, implying that this pro-apoptotic factor is degraded by autophagy. Leupeptin-induced autophagic impairment increased the number of apoptotic neurons in PS/APP mice. Our findings establish apoptosis as a mode of neuronal cell death in aging PS/APP mice and identify the cross talk between autophagy and apoptosis, which influences neuronal survival in AD-related neurodegeneration.


Asunto(s)
Enfermedad de Alzheimer/patología , Apoptosis/fisiología , Autofagia/fisiología , Encéfalo/patología , Neuronas/ultraestructura , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Encéfalo/efectos de los fármacos , Caspasa 3/metabolismo , Inhibidores de Cisteína Proteinasa/administración & dosificación , Modelos Animales de Enfermedad , Activación Enzimática/fisiología , Femenino , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Inyecciones Intraventriculares , Leupeptinas/administración & dosificación , Masculino , Ratones , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Neuronas/efectos de los fármacos , Receptor Cross-Talk
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