viral-mediated-labeling-transplantation-medial-ganglionic-eminence

Viral-mediated Labeling and Transplantation of Medial Ganglionic Eminence (MGE) Cells for <em>In Vivo</em> Studies

GABAergic cortical interneurons, derived from the embryonic medial and caudal ganglionic eminences (MGE and CGE), are functionally and morphologically ...

University of California San Francisco

Cysteine string proteins (CSPs) are conserved secretory vesicle proteins involved in regulating neurotransmitter and peptide release. While the function of the J-domain has been studied in detail, little is known about other conserved regions. We have constructed mutant genes coding for proteins with modified cysteine string, linker region or C terminus and transformed them into Csp null-mutant Drosophila: In the living animal, mutated CSP lacking all cysteines fails to associate with membranes, does not concentrate in synaptic terminals, and cannot rescue adult temperature-sensitive paralysis and short life span, both prominent null mutant phenotypes. A mutant protein with 5 instead of 11 string cysteines appears to be normally targeted but cannot rescue paralysis at 37 degrees C. We propose that the cysteine string, in addition to its role in targeting, may be essential for a function of CSP that is dependent on the number of cysteines in the string. A deletion in the linker region or the C terminus does not affect CSP targeting, and function in adults is only marginally impaired.

Structure-function analysis of the cysteine string protein in Drosophila: cysteine string, linker and C terminus.

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The transgenic arteriovenous fistula model, surgically constructed with transgenic mouse aorta interposed in common carotid artery-to-external jugular vein fistulae in nude rats, has a 4-month experimental window because patency and transgenic phenotype are lost over time. We adapted this model to investigate occlusive arteriopathy in brain arteriovenous malformations after radiosurgery by radiating grafted aorta before insertion in the fistula. We hypothesized that high-dose radiation would reproduce the arteriopathy observed clinically within the experimental time window and that deletions of endoglin (ENG) and endothelial nitric oxide synthase (eNOS) genes would modify the radiation response.

Radiation arteriopathy in the transgenic arteriovenous fistula model.

Le mod&egrave;le transg&eacute;nique Fistule art&eacute;rio-veineuse, chirurgicalement construit avec l&#39;aorte de souris transg&eacute;niques interpos&eacute; en commun carotide veine jugulaire de l&#39;art&egrave;re-&agrave;-external fistules chez le rat nu, a une fen&ecirc;tre exp&eacute;rimentale de 4 mois car la perm&eacute;abilit&eacute; et le ph&eacute;notype transg&eacute;nique sont perdus au fil du temps. Nous avons adapt&eacute; ce mod&egrave;le pour &eacute;tudier l&#39;art&eacute;riopathie occlusive dans les malformations art&eacute;rio-veineuses c&eacute;r&eacute;brales apr&egrave;s que radiochirurgie par rayonnant greff&eacute;s aorte avant insertion dans la fistule. Nous avons &eacute;mis l&#39;hypoth&egrave;se que les irradiations &agrave; hautes doses reproduirait l&#39;art&eacute;riopathie observ&eacute;e cliniquement dans la fen&ecirc;tre de temps exp&eacute;rimental et que les destructions de l&#39;endogline (ENG) et endothelial nitric oxide synthase (eNOS) g&egrave;nes modifierait les r&eacute;ponses &agrave; la radiation.

Art&eacute;riopathie de rayonnement dans le mod&egrave;le de la Fistule art&eacute;rio-veineuse transg&eacute;niques.

Modell das transgenen arterioven&ouml;se Fistel chirurgisch mit transgenen Maus ascendens konstruiert zwischengeschaltet gemeinsame Halsschlagader Arteria-zu-External Vena jugularis Fisteln in nackte Ratten, hat ein experimentelles 4-Monats-Fenster weil Durchg&auml;ngigkeit und transgenen Ph&auml;notyp im Laufe der Zeit verloren gehen. Wir angepasst dieses Modell zur Untersuchung okklusive Arteriopathie im Gehirn Arterioven&ouml;se Fehlbildungen nach Radiochirurgie durch die Ausstrahlung ascendens vor dem Einf&uuml;gen in die Fistel veredelt. Wir die Hypothese, dass hoch dosierte Strahlung die Arteriopathie innerhalb der experimentellen Zeitfenster klinisch beobachteten reproduzieren w&uuml;rde und L&ouml;schungen von Endoglin (ENG) und endotheliale Stickstoffmonoxid-Synthase (eNOS) Gene w&uuml;rde die Strahlung-Antwort zu &auml;ndern.

Strahlung Arteriopathie im transgenen arterioven&ouml;se Fistel Modell.

Il modello transgenico fistola artero-venosa, costruito chirurgicamente con aorta mouse transgenici interposto in comune carotide arteria-esterno giugulare vena fistole nel ratto nudo, ha una finestra sperimentale 4-mese perch&eacute; perviet&agrave; e fenotipo transgenico sono persi nel tempo. Abbiamo adattato questo modello per indagare arteriopatia occlusiva in malformazioni artero-venose cerebrali dopo radiochirurgia emanando innestate aorta prima dell&#39;inserimento nella fistola. Abbiamo ipotizzato che alte dosi di radiazioni vuoi riprodurre l&#39;arteriopatia clinicamente osservato all&#39;interno della finestra di tempo sperimentale e che delezioni di endoglin (ENG) ed endoteliali di ossido nitrico sintasi (eNOS) geni sarebbero modificare la risposta di radiazione.

Radiazione arteriopatia nel modello transgenico fistola artero-venosa.

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&#xC720;&#xC804;&#xC790; &#xBCC0;&#xD615; &#xB9C8;&#xC6B0;&#xC2A4; &#xB300;&#xB3D9;&#xB9E5; &#xC218;&#xC220;&#xB85C; &#xAD6C;&#xC131; &#xD558;&#xB294; &#xC720;&#xC804;&#xC790; &#xBCC0;&#xD615; arteriovenous &#xB204; &#xBAA8;&#xB378; &#xB204;&#xB4DC; &#xC950;&#xC5D0;&#xC11C; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xACBD; &#xB3D9;&#xB9E5; &#xC678;&#xBD80; &#xACBD; &#xC815; &#xB9E5; fistulae interposed, 4 &#xAC1C;&#xC6D4; &#xC2E4;&#xD5D8; &#xCC3D; patency &#xBC0F; &#xC720;&#xC804;&#xC790; &#xBCC0;&#xD615; &#xD615; &#xC2DC;&#xAC04;&#xC774; &#xC9C0;&#xB0A8;&#xC5D0; &#xC190;&#xC2E4; &#xB429;&#xB2C8;&#xB2E4; &#xB54C;&#xBB38;&#xC5D0;. &#xC6B0;&#xB9AC; radiosurgery &#xBC1C;&#xC0B0; &#xD558; &#xC5EC; &#xB300;&#xB3D9;&#xB9E5;&#xC740; &#xB204; &#xAD00;&#xC5D0; &#xC0BD;&#xC785; &#xD558;&#xAE30; &#xC804;&#xC5D0; &#xD22C;&#xC785; &#xD55C; &#xD6C4; &#xB1CC; arteriovenous &#xAE30;&#xD615; occlusive arteriopathy&#xB97C; &#xC870;&#xC0AC; &#xD558;&#xAE30; &#xC704;&#xD574;&#xC774; &#xBAA8;&#xB378;&#xC5D0; &#xC801;&#xC751;. &#xC6B0;&#xB9AC;&#xB294; &#xB192;&#xC740; &#xC120; &#xB7C9; &#xBC29;&#xC0AC;&#xC120; &#xC2E4;&#xD5D8; &#xC2DC;&#xAC04; &#xCC3D; &#xB0B4;&#xC5D0;&#xC11C; &#xC784;&#xC0C1; &#xAD00;&#xCC30; arteriopathy &#xC7AC;&#xD604;&#xD560; &#xAC83; &#xC774;&#xB2E4; endoglin (&#xC789;&#xAE00;&#xB79C;&#xB4DC;)&#xC640; &#xB0B4; &#xD53C; &#xC0B0;&#xD654; &#xC9C8;&#xC18C; synthase (eNOS) &#xC720;&#xC804;&#xC790;&#xC758; &#xC0AD;&#xC81C; &#xBC29;&#xC0AC;&#xC120; &#xC751;&#xB2F5;&#xC744; &#xC218;&#xC815;&#xD560; &#xAC83; &#xC774;&#xB77C;&#xACE0; &#xAC00;&#xC124;&#xC744; &#xC138;&#xC6E0;&#xB2E4;.

&#xC720;&#xC804;&#xC790; &#xBCC0;&#xD615; arteriovenous &#xB204; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xBC29;&#xC0AC;&#xC120; arteriopathy&#xC785;&#xB2C8;&#xB2E4;.

El modelo transg&eacute;nico f&iacute;stula arteriovenosa, quir&uacute;rgicamente construido con aorta de rat&oacute;n transg&eacute;nico interpuesto f&iacute;stulas car&oacute;tida com&uacute;n en vena yugular de arteria-a-externo en ratas desnudas, tiene una ventana experimental de cuatro meses debido a la permeabilidad y fenotipo transg&eacute;nico se pierden en el tiempo. Adaptamos este modelo para investigar la Arteriopat&iacute;a oclusiva en malformaciones arteriovenosas cerebrales despu&eacute;s de radiocirug&iacute;a irradiando injertado aorta antes de la inserci&oacute;n en la f&iacute;stula. Presumimos que altas dosis de radiaci&oacute;n reproducir&iacute;a la arteriopat&iacute;a observado cl&iacute;nicamente dentro de la ventana del tiempo experimental y que eliminaciones de endoglina (ENG) y endotelial de &oacute;xido n&iacute;trico sintasa (eNOS) genes modificar&iacute;a la respuesta de la radiaci&oacute;n.

Arteriopat&iacute;a de radiaci&oacute;n en el modelo de la f&iacute;stula arteriovenosa transg&eacute;nicos.

The subtemporal approach for a superficial temporal artery-to-superior cerebellar artery bypass requires significant superior retraction that can injure the temporal lobe, compromise veins, and cause edema postoperatively. In contrast, the pretemporal approach requires posterolateral retraction that seems to be less injurious to the temporal lobe and better tolerated clinically. We hypothesized that the pretemporal approach provides ample exposure, more gentle retraction, and better clinical results than the subtemporal approach.

Deep bypasses to the distal posterior circulation: anatomical and clinical comparison of pretemporal and subtemporal approaches.

The anatomy of the perisylvian component of the superior longitudinal fasciculus (SLF) has recently been reviewed by numerous diffusion tensor imaging tractography (DTI) studies. However, little is known about the exact cortical terminations of this tract. The aim of the present work is to isolate the different subcomponents of this tract with fiber dissection and DTI tractography, and to identify the exact cortical connections. Twelve postmortem human hemispheres (6 right and 6 left) were dissected using the cortex-sparing fiber dissection. In addition, three healthy brains were analyzed using DTI-based tractography software. The different components of the perisylvian SLF were isolated and the fibers were followed until the cortical terminations. Three segments of the perisylvian SLF were identified: (1) anterior segment, connecting the supramarginal gyrus and superior temporal gyrus with the precentral gyrus, (2) posterior segment, connecting the posterior portion of the middle temporal gyrus with the angular gyrus, and (3) long segment of the arcuate fasciculus that connects the middle and inferior temporal gyri with the precentral gyrus and posterior portion of the inferior and middle frontal gyri. In the present study, three different components of the perisylvian SLF were identified. For the first time, our dissections revealed that each component was connected to a specific cortical area within the frontal, parietal and temporal lobes. By accurately depicting not only the trajectory but also cortical connections of this bundle, it is possible to develop new insights into the putative functional role of this tract.

Analysis of the subcomponents and cortical terminations of the perisylvian superior longitudinal fasciculus: a fiber dissection and DTI tractography study.

Directed differentiation from human pluripotent stem cells (hPSCs) has seen significant progress in recent years. However, most differentiated populations exhibit immature properties of an early embryonic stage, raising concerns about their ability to model and treat disease. Here, we report the directed differentiation of hPSCs into medial ganglionic eminence (MGE)-like progenitors and their maturation into forebrain type interneurons. We find that early-stage progenitors progress via a radial glial-like stem cell enriched in the human fetal brain. Both in vitro and posttransplantation into the rodent cortex, the MGE-like cells develop into GABAergic interneuron subtypes with mature physiological properties along a prolonged intrinsic timeline of up to 7 months, mimicking endogenous human neural development. MGE-derived cortical interneuron deficiencies are implicated in a broad range of neurodevelopmental and degenerative disorders, highlighting the importance of these results for modeling human neural development and disease.

Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development.

Poor communication among obstetric and pediatric professionals is associated with adverse perinatal events leading to severe disability and neonatal mortality. This study evaluated the effectiveness of an interdisciplinary simulation-based training (SBT) program to improve delivery room communication between obstetric and pediatric teams.

Interdisciplinary simulation-based training to improve delivery room communication.

The prescribing of antibiotics for uncomplicated skin abscesses and diverticulitis has no benefit. Some antibiotics are more at risk of causing a Clostridium difficile infection. The tests used to exclude a history of a penicillin allergy are safe. A threshold of D-dimer adjusted for the age significantly improves the specificity of the test without affecting the sensitivity. The prescription of paraclinics tests is not an effective "treatment" for the patient's anxiety. In the sleep apnea syndrome, treatment with CPAP (Continuous positive airway pressure) appears to have more benefits compared to the mandibular advancement prosthesis. The work of primary care physicians can be supported by the work of advanced practice nurses. The limitation placed on the working hours of doctors in hospitals seems to affect their ability to spend time with their patients.

[2013 literature findings in internal general medicine].

In recent years, Kenya's capital city Nairobi has experienced an influx of international economic migrants, as well as migrants forced to flee their neighboring countries of origin, or coming from UNHCR-managed refugee camps into the city. Urban migrants regularly face challenges integrating with host communities and consequently face health vulnerabilities. The International Organization for Migration in Kenya was concerned about the potential marginalization of urban migrants from mainstream health programming and a lack of data upon which to base their activities. The purpose of this project was to gain a greater understanding of urban migrants' barriers to accessing healthcare in Nairobi compared with barriers faced by Kenyans living in the same locations. Guiding our work was a conceptual framework for assessing access to healthcare, which defines availability, geographic accessibility, financial accessibility and acceptability as the four dimensions of access. We identified key informants in collaboration with The National Organisation for Peer Educators, and these individuals assisted in identifying communities within Nairobi where large proportions of migrants reside. Four communities were selected for further study. In each, interviews with government officials and service providers were conducted, and focus group discussions were held with both migrants and Kenyans. Verbatim transcripts were content-analyzed using an open coding technique. Common barriers to accessing care that were shared by migrants and Kenyans included waiting times, drug availability, transportation and cost. Barriers unique to migrants were: threat of harassment; cost discrepancies between migrant and Kenyan clients; real or perceived discrimination; documentation requirements and language barriers. Despite articles from the 2010 Constitution of Kenya that assert the right to health for every person in Kenya, migrants continue to experience unique barriers in accessing healthcare. Efforts to eliminate these barriers should address policy-level interventions, strengthened networks and partnerships, improved migrant-sensitive services and especially continued research in migrant health.

A qualitative exploration of access to urban migrant healthcare in Nairobi, Kenya.

Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases.

Christine Arnold

Department of Neurological Surgery

University of California San Francisco

Viral-mediated Labeling and Transplantation of Medial Ganglionic Eminence (MGE) Cells for In Vivo Studies

Christine Arnold

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Neurological Surgery

University of California San Francisco

Viral-mediated Labeling and Transplantation of Medial Ganglionic Eminence (MGE) Cells for In Vivo Studies

Department of Neurological Surgery