1,553 research outputs found
Causes of microcephaly in human—theoretical considerations
No full textAs is evident from the theme of the Research Topic “Small Size, Big Problem: Understanding the Molecular Orchestra of Brain Development from Microcephaly,” the pathomechanisms leading to mirocephaly in human are at best partially understood. As molecular cell biologists and developmental neurobiologists, we present here a treatise with theoretical considerations that systematically dissect possible causes of microcephaly, which we believe is timely. Our considerations address the cell types affected in microcephaly, that is, the cortical stem and progenitor cells as well as the neurons and macroglial cell generated therefrom. We discuss issues such as progenitor cell types, cell lineages, modes of cell division, cell proliferation and cell survival. We support our theoretical considerations by discussing selected examples of factual cases of microcephaly, in order to point out that there is a much larger range of possible pathomechanisms leading to microcephaly in human than currently known
The major tyrosine-sulfated protein of the bovine anterior pituitary is a secretory protein present in gonadotrophs, thyrotrophs, mammotrophs, and corticotrophs.
No full textThe anterior pituitary is a complex secretory tissue known to contain several sulfated macromolecules. In the present study, we identified the major tyrosine-sulfated protein of the bovine anterior pituitary and investigated its cellular and subcellular localization. This protein consisted of two tyrosine-sulfated polypeptides of molecular weight 86,000 and 84,000 that were highly homologous to each other. In agreement with previous biochemical studies, the tyrosine-sulfated protein of Mr 86,000/84,000 was found to be secretory, as it was observed in the matrix of secretory granules by immunoelectron microscopy. Immunofluorescence studies indicated that the tyrosine-sulfated, secretory protein of Mr 86,000/84,000, referred to as TSP 86/84, was present in all endocrine cells except for some somatotrophic cells. Higher levels of immunoreactivity for TSP 86/84 were observed in gonadotrophic and thyrotrophic than in mammotrophic and corticotrophic cells. This appeared to result from the occurrence of TSP 86/8 4 in all secretory granules of the former cells and in only some secretory granules of the latter cells. We discuss the possibility that TSP 86/84 may have a role in the packaging of several distinct peptides hormones into secretory granules. One, though not the only, possible function of tyrosine sulfation may concern the sorting of this protein in the Golgi complex
chi((3)) nonlinear susceptibility in II-VI compounds and applications for squeezed light generation in semiconductors
No full textWe have measured the nonlinear refractive index near half-bandgap (E(g)/2) in ZnS and ZnSe by self-phase modulation experiments. The ratio of the nonlinear phase shift and the total optical absorption losses is critically dependent on the detuning from E(g)/2. Efficient quadrature squeezing was obtained at a centre wavelength of 780 nm in ZnS and at 960 nm in ZnSe. The scheme we employed can generally be applied to semiconductors, and opens the way for squeezed light generation over a wide range of wavelengths
Neocortical neurogenesis in development and evolution-Human-specific features
No full textIn this review, we focus on human-specific features of neocortical neurogenesis in development and evolution. Two distinct topics will be addressed. In the first section, we discuss the expansion of the neocortex during human evolution and concentrate on the human-specific gene ARHGAP11B. We review the ability of ARHGAP11B to amplify basal progenitors and to expand a primate neocortex. We discuss the contribution of ARHGAP11B to neocortex expansion during human evolution and its potential implications for neurodevelopmental disorders and brain tumors. We then review the action of ARHGAP11B in mitochondria as a regulator of basal progenitor metabolism, and how it promotes glutaminolysis and basal progenitor proliferation. Finally, we discuss the increase in cognitive performance due to the ARHGAP11B-induced neocortical expansion. In the second section, we focus on neocortical development in modern humans versus Neanderthals. Specifically, we discuss two recent findings pointing to differences in neocortical neurogenesis between these two hominins that are due to a small number of amino acid substitutions in certain key proteins. One set of such proteins are the kinetochore-associated proteins KIF18a and KNL1, where three modern human-specific amino acid substitutions underlie the prolongation of metaphase during apical progenitor mitosis. This prolongation in turn is associated with an increased fidelity of chromosome segregation to the apical progenitor progeny during modern human neocortical development, with implications for the proper formation of radial units. Another such key protein is transketolase-like 1 (TKTL1), where a single modern human-specific amino acid substitution endows TKTL1 with the ability to amplify basal radial glia, resulting in an increase in upper-layer neuron generation. TKTL1's ability is based on its action in the pentose phosphate pathway, resulting in increased fatty acid synthesis. The data imply greater neurogenesis during neocortical development in modern humans than Neanderthals due to TKTL1, in particular in the developing frontal lobe.ARHGAP11B is present in the genomes of Neanderthals and modern humans but not chimpanzee and increases the size of the neocortex during development. (The Neanderthal brain is a virtual reconstruction [Kochiyama et al., 2018, Sci. Rep. 8, 6296].) Amino acid substitutions in key proteins, such as KIF18a, KNL1, SPAG5, and TKTL1, are found in modern humans but not in chimpanzee and Neanderthals and underlie increased metaphase length and reduced lagging chromosomes during apical progenitor mitosis (KIF18a, KNL1, SPAG5) or increased basal radial glia abundance and upper-layer neuron number (TKTL1). imagePeer reviewe
Targeted Microinjection and Electroporation of Primate Cerebral Organoids for Genetic Modification
No full textThe cerebral cortex is the outermost brain structure and is responsible for the processing of sensory input and motor output; it is seen as the seat of higher-order cognitive abilities in mammals, in particular, primates. Studying gene functions in primate brains is challenging due to technical and ethical reasons, but the establishment of the brain organoid technology has enabled the study of brain development in traditional primate models (e.g., rhesus macaque and common marmoset), as well as in previously experimentally inaccessible primate species (e.g., great apes), in an ethically justifiable and less technically demanding system. Moreover, human brain organoids allow the advanced investigation of neurodevelopmental and neurological disorders. As brain organoids recapitulate many processes of brain development, they also represent a powerful tool to identify differences in, and to functionally compare, the genetic determinants underlying the brain development of various species in an evolutionary context. A great advantage of using organoids is the possibility to introduce genetic modifications, which permits the testing of gene functions. However, the introduction of such modifications is laborious and expensive. This paper describes a fast and cost-efficient approach to genetically modify cell populations within the ventricle-like structures of primate cerebral organoids, a subtype of brain organoids. This method combines a modified protocol for the reliable generation of cerebral organoids from human-, chimpanzee-, rhesus macaque-, and common marmoset-derived induced pluripotent stem cells (iPSCs) with a microinjection and electroporation approach. This provides an effective tool for the study of neurodevelopmental and evolutionary processes that can also be applied for disease modeling
Investigating cell turnover in the healthy and diseased adult human brain
No full textFor decades it was thought that cells that lost in the human central nervous system because of ageing or disease – different from other cell tissues – cannot be replaced and that in humans all neurons are generated during prenatal development. However, over the last 20 years, it became obvious that there is a certain level of adult neurogenesis in most mammals that mainly occurs in the dentate gyrus and the subventricular zone. Whether or not findings from animal studies also hold true in humans was difficult to study as direct evidence – as obtained in animals from genomic labeling using for instance nucleosides like BrdU – was not feasible in humans because of ethical considerations.The establishment of the so-called radiocarbon technique, a method taking advantage of the above-ground nuclear bomb tests during the Cold War to retrospectively birth date cells by determination of the 12C/14C ratio in genomic DNA – allowed to investigate the age and the turnover dynamics of cells in various human tissues. Applying this technique we here (i) studied whether there is adult neurogenesis in the healthy human brain, specifically within the hippocampus, (ii) studied whether there is adult neurogenesis in the diseased human brain, specifically in response to cortical stroke, and (iii) investigated the age and growth dynamics of brain tumors, specifically benign meningiomas.In essence we demonstrate (i) that there is a lifelong adult neurogenesis within the human hippocampus and provide an integrated model of hippocampal cell turnover dynamics, (ii) that there is no significant induction of cortical neurogenesis following ischemic cortical stroke in humans, and (iii) that the age of benign meningiomas is significantly older than that of more malignant brain tumors. The clinical implications of these findings are discussed and research projects for future studies identified.List of scientific papersI. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisén J. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013; 153:1219-27. https://doi.org/10.1016/j.cell.2013.05.002 II. Huttner HB, Bergmann O, Salehpour M, Rácz A, Tatarishvili J, Lindgren E, Csonka T, Csiba L, Hortobágyi T, Méhes G, Englund E, Solnestam BW, Zdunek S, Scharenberg C, Ström L, Ståhl P, Sigurgeirsson B, Dahl A, Schwab S, Possnert G, Bernard S, Kokaia Z, Lindvall O, Lundeberg J, Frisén J. The age and genomic integrity of neurons after cortical stroke in humans. Nat Neurosci. 2014; 17:801-3. https://doi.org/10.1038/nn.3706 III. Hagen B. Huttner , Olaf Bergmann , Mehran Salehpour, Raouf El Cheikhs, Makoto Nakamura, Angelo Tortora, Roland Coras, Elisabet Englund, Ilker Y. Eyüpoglu, Joji B. Kuramatsu, Stephan P. Kloska, Iris Kaschka, Arnd Doerfler, Stefan Schwab, Göran Possnert, Samuel Bernard and Jonas Frisén. The age and growth dynamics of meningiomas. [Submitted]</p
Preconditioning Concepts for the Therapeutic Use of Extracellular Vesicles Against Stroke
No full textVarious preclinical stroke models have demonstrated the neuroprotective effects of extracellular vesicles (EVs) obtained from several types of cells, including neurons, astrocytes, microglia, neuronal progenitor cells, bone marrow stem cells, and mesenchymal stem cells. EVs interfere with key mechanisms in stroke pathophysiology such as cell death, neuroinflammation, autophagy, and angiogenesis. The mode of action and efficacy depend on the specific EV content, including miRNAs, proteins, and lipids, which can be modified through (I) bioengineering methods, (II) choice of source cells, and (III) modification of the source cell environment. Indeed, modifying the environment by preconditioning the EV-secreting cells with oxygen-glucose deprivation or medium modification revealed superior neuroprotective effects in stroke models. Although the concept of preconditioned EVs is relatively novel, it holds promise for the future treatment of ischemic stroke. Here, we give a brief overview about the main mechanisms of EV-induced neuroprotection and discuss the current status of preconditioning concepts for EV-treatment of ischemic stroke
Argyrophilic carcinoma of the male breast. A neuroendocrine tumor containing predominantly chromogranin B (secretogranin I)
No full textArgyrophilic tumors were diagnosed in 28 of 134 (20.8%) consecutive male patients who had a carcinoma of the breast removed between 1961 and 1990. Histologically, most argyrophilic tumors showed uniform cellularity and prevalent expansive growth. Ultrastructural observation disclosed the presence of electron-dense cored granules in the cytoplasm of the tumor cells. By immunocytochemistry, 17 of 28 argyrophilic tumors (60.7%) contained chromogranin B (secretogranin I)-immunoreactive cells, whereas chromogranin A was present in four of these 17 tumors only (14.2%). Immunoblotting studies showed chromogranin B immunoreactivity similar to that found in normal neuroendocrine cells. Despite these findings, which would argue for a distinct morphologic and immunochemical entity, no statistically significant differences between argyrophilic and common male breast carcinomas were found when a number of clinicopathologic features and relapse-free survival were considered
sj-pdf-1-wso-10.1177_1747493019895662 – Supplemental material for Age-dependent clinical outcomes in primary versus oral anticoagulation-related intracerebral hemorrhage
No full textSupplemental material, sj-pdf-1-wso-10.1177_1747493019895662 for Age-dependent clinical outcomes in primary versus oral anticoagulation-related intracerebral hemorrhage by Maximilian I Sprügel, Joji B Kuramatsu, Stefan T Gerner, Jochen A Sembill, Dominik Madžar, Caroline Reindl, Tobias Bobinger, Tamara Müller, Philip Hoelter, Hannes Lücking, Tobias Engelhorn and Hagen B Huttner in International Journal of Stroke</p
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