Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv(+)) fast-spiking interneurons, have been proposed as underlying causes of ...several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv(+) GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv(+) interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv(+) interneurons resulted in reduced numbers of Pv(+) neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv(+) neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.
The specification of neuronal cell types in the developing neural tube is orchestrated by signaling centers. However, how patterned territories of the central nervous system (CNS) are organized into ...structures with appropriate size and shape is still unclear. We report that in the absence of the mouse transcription factor mBtd/Sp8, a posterior shift of the isthmic organizer (IsO) occurs, suggesting a crucial role for Sp8 in this process. In addition, large patches of cells ectopically expressing Fgf8, Otx2 and/or Wnt1 in the rostral hindbrain are detected in Sp8 mutant embryos. In this context, midbrain dopaminergic neurons are found posterior to the IsO. Furthermore, we provide evidence that cell proliferation in the mid- and hindbrain is tightly controlled by Sp8 activity. Our observations are consistent with a role for Sp8 in restricting Fgf8 expression at the IsO.
Chapter 4 - Area Patterning of the Mammalian Cortex O'Leary, D.D.M.; Stocker, A.M.; Zembrzycki, A.
Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification in the Developing CNS and PNS,
2013
Book Chapter
The peptide hormone urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co-released with insulin and ...potentiates glucose-stimulated somatostatin secretion via cognate receptors on delta cells. Further, we found that islets lacking endogenous Ucn3 have fewer delta cells, reduced somatostatin content, impaired somatostatin secretion, and exaggerated insulin release, and that these defects are rectified by treatment with synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque models of diabetes and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control, whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease.
This article offers a survey of the past fifty years' literature on oral history and ethics, arguing that oral historians' approaches to ethics have emerged from two major fears: the fear of failing ...as researchers and the fear of failing our narrators and doing harm. These professional and personal fears have evolved through three distinct but overlapping phases: postwar positivism, the subjective turn, and contemporary interdisciplinarity. Confronting them makes it possible to understand the complex questions behind oral historians' preoccupations. This sheds light on how oral history has evolved and expanded as a field, and what we hope it can and will achieve.
The four most popular water models in molecular dynamics were studied in large-scale simulations of Brownian motion of colloidal particles in optical tweezers and then compared with experimental ...measurements in the same time scale. We present the most direct comparison of colloidal polystyrene particle diffusion in molecular dynamics simulations and experimental data on the same time scales in the ballistic regime. The four most popular water models, all of which take into account electrostatic interactions, are tested and compared based on yielded results and resources required. Three different conditions were simulated: a freely moving particle and one in a potential force field with two different strengths based on 1 pN/nm and 10 pN/nm. In all cases, the diameter of the colloidal particle was 50 nm. The acquired data were compared with experimental measurements performed using optical tweezers with position capture rates as high as 125 MHz. The experiments were performed in pure water on polystyrene particles with a 1 μm diameter in special microchannel cells.
The digital turn has had a profound impact on the practice of oral history. This article calls for a robust and critical reflection on how this turn has impacted both the process of conducting ...interviews and our efforts to analyze and disseminate them. Using a feminist and humanistic approach to oral history, we examine the ethical and methodological implications of databasing and indexing software, of putting our interviews on the Web, and of engaging with tech capitalism. We argue that oral history interviewing and interpretation are, ideally, intentionally slow processes, while digital technology prides itself on its speed, leading us to ask: how do we reconcile the two?
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•Graphene oxide-supported survivin molecular beacons (GONS@SurMB) were designed .•The LOD=24nM for complementyary DNA at 37°C have been achieved.•U-87 MG cells were successfully ...transfected with GONS@SurMB probes.•GONS@SurMB exhibit single-nucleotide polymorphism for Sur mRNA in astrocytes.•GONS nanocarriers do not decrease astrocytes viability up to 33μg/mL (MTT test).
While a significant progress has recently been made in therapy of many cancers, the cure for some high grade cancers, such as the astrocytic cancers, remains elusive. In the latter case, specificity and functionality of the brain tissue limit the options available to surgical and chemotherapeutic treatments. In view of the prospects of reversible blood-brain barrier opening, we have investigated the possibility of a transfection of malignant astrocyte cells with novel graphene oxide nanosheet (GONS) nanocarrier-supported molecular beacons (MB) encoded for the detection of a biomarker survivin (Sur). The behavior of GONS-supported SurMBs (GONS@SurMB) has been characterized using fluorescence spectroscopy, SEM, TEM, Raman spectroscopy, melting transients, resonance elastic light scattering, and cell viability testing. With the GONS@SurMB, we have achieved the limit of detection for tDNA at 37°C: LOD=24nM (S/N=3). In tests with complementary targets and mismatched strands, the proposed fluorescent turn-on GONS@SurMB probes have shown a single-nucleotide polymorphism sensitivity. We have demonstrated the transfection of U-87 MG astrocyte cells with GONS@SurMB nanocarriers which release SurMB upon mRNA detection. The MTT tests indicate that the GONS carrier concentrations up to 133μg/mL are not cytotoxic to astrocyte cells, although a cell assembly has been encountered at higher carrier concentrations. The GONS alone does not assemble appreciably up to 80μg/mL. The proposed method can be used for the detection of Sur mRNA in malignant cells and the GONS@SurMB nanocarriers can also be considered as viable candidates for future gene therapy of brain cancers.
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