Use of amphetamine and methamphetamine is widespread in the general population and common among patients with psychiatric disorders. Amphetamines may induce symptoms of psychosis very similar to ...those of acute schizophrenia spectrum psychosis. This has been an argument for using amphetamine-induced psychosis as a model for primary psychotic disorders. To distinguish the two types of psychosis on the basis of acute symptoms is difficult. However, acute psychosis induced by amphetamines seems to have a faster recovery and appears to resolve more completely compared to schizophrenic psychosis. The increased vulnerability for acute amphetamine induced psychosis seen among those with schizophrenia, schizotypal personality and, to a certain degree other psychiatric disorders, is also shared by non-psychiatric individuals who previously have experienced amphetamine-induced psychosis. Schizophrenia spectrum disorder and amphetamine-induced psychosis are further linked together by the finding of several susceptibility genes common to both conditions. These genes probably lower the threshold for becoming psychotic and increase the risk for a poorer clinical course of the disease.The complex relationship between amphetamine use and psychosis has received much attention but is still not adequately explored. Our paper reviews the literature in this field and proposes a stress-vulnerability model for understanding the relationship between amphetamine use and psychosis.
Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, ...but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
Nuclear Positioning Gundersen, Gregg G.; Worman, Howard J.
Cell,
03/2013, Volume:
152, Issue:
6
Journal Article
Peer reviewed
Open access
The nucleus is the largest organelle and is commonly depicted in the center of the cell. Yet during cell division, migration, and differentiation, it frequently moves to an asymmetric position ...aligned with cell function. We consider the toolbox of proteins that move and anchor the nucleus within the cell and how forces generated by the cytoskeleton are coupled to the nucleus to move it. The significance of proper nuclear positioning is underscored by numerous diseases resulting from genetic alterations in the toolbox proteins. Finally, we discuss how nuclear position may influence cellular organization and signaling pathways.
The mean linear intercept (chord) length (L(m)) is a useful parameter of peripheral lung structure as it describes the mean free distance in the air spaces. It is often misinterpreted as a measure of ..."alveolar size," and its estimation is fraught with a number of pitfalls. We present two methods for the accurate estimation of L(m): 1) the indirect method, which derives L(m) from the volume-to-surface ratio of air spaces estimated by point counting methods, and 2) the direct method, which uses a set of random intercepts and calculates L(m) from their frequency distribution, for which we introduce a new and accurate method. Both methods are efficient and, with proper precautions, unbiased. The meaning of L(m) is assessed in two different examples. In a physiological study, the effect of different inflation levels is studied, showing that L(m) critically depends on lung inflation. In an experimental study on emphysema-like changes in a genetic mouse model, the effect of heterogeneity of air space size is assessed; these results are obtained partly because of differences in lung volume due to altered recoil in the emphysematous lungs. In conclusion, although L(m) is not a robust parameter of internal lung structure because it crucially depends on lung volume, it is still a valid measure for which accurate and efficient methods are available that yield additional parameters such as size distribution or alveolar surface area.
The linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of outer and inner nuclear membrane Klarsicht, ANC-1, and Syne homology (KASH) and Sad1 and UNC-84 (SUN) proteins, respectively, ...connects the nucleus to cytoskeletal filaments and performs diverse functions including nuclear positioning, mechanotransduction, and meiotic chromosome movements. Recent studies have shed light on the source of this diversity by identifying factors associated with the complex that endow specific functions as well as those that differentially anchor the complex within the nucleus. Additional diversity may be provided by accessory factors that reorganize the complex into higher-ordered arrays. As core components of the LINC complex are associated with several diseases, understanding the role of accessory and anchoring proteins could provide insights into pathogenic mechanisms.
Proteins of the nuclear envelope (NE) are associated with a range of inherited disorders, most commonly involving muscular dystrophy and cardiomyopathy, as exemplified by Emery-Dreifuss muscular ...dystrophy (EDMD). EDMD is both genetically and phenotypically variable, and some evidence of modifier genes has been reported. Six genes have so far been linked to EDMD, four encoding proteins associated with the LINC complex that connects the nucleus to the cytoskeleton. However, 50% of patients have no identifiable mutations in these genes. Using a candidate approach, we have identified putative disease-causing variants in the SUN1 and SUN2 genes, also encoding LINC complex components, in patients with EDMD and related myopathies. Our data also suggest that SUN1 and SUN2 can act as disease modifier genes in individuals with co-segregating mutations in other EDMD genes. Five SUN1/SUN2 variants examined impaired rearward nuclear repositioning in fibroblasts, confirming defective LINC complex function in nuclear-cytoskeletal coupling. Furthermore, myotubes from a patient carrying compound heterozygous SUN1 mutations displayed gross defects in myonuclear organization. This was accompanied by loss of recruitment of centrosomal marker, pericentrin, to the NE and impaired microtubule nucleation at the NE, events that are required for correct myonuclear arrangement. These defects were recapitulated in C2C12 myotubes expressing exogenous SUN1 variants, demonstrating a direct link between SUN1 mutation and impairment of nuclear-microtubule coupling and myonuclear positioning. Our findings strongly support an important role for SUN1 and SUN2 in muscle disease pathogenesis and support the hypothesis that defects in the LINC complex contribute to disease pathology through disruption of nuclear-microtubule association, resulting in defective myonuclear positioning.
The Balloon-borne Large Aperture Submillimeter Telescope (BLAST) is a suborbital surveying experiment designed to study the evolutionary history and processes of star formation in local galaxies ...(including the Milky Way) and galaxies at cosmological distances. The BLAST continuum camera, which consists of 270 detectors distributed between three arrays, observes simultaneously in broadband (30%) spectral windows at 250, 350, and 500 mum. The optical design is based on a 2 m diameter telescope, providing a diffraction-limited resolution of 30 super(image ) at 250 mum. The gondola pointing system enables raster mapping of arbitrary geometry, with a repeatable positional accuracy of image30 super(image ); postflight pointing reconstruction to image5 super(image ) rms is achieved. The onboard telescope control software permits autonomous execution of a preselected set of maps, with the option of manual override. In this paper we describe the primary characteristics and measured in-flight performance of BLAST. BLAST performed a test flight in 2003 and has since made two scientifically productive long- duration balloon flights: a 100 hr flight from ESRANGE (Kiruna), Sweden to Victoria Island, northern Canada in 2005 June; and a 250 hr, circumpolar flight from McMurdo Station, Antarctica, in 2006 December.
Cell polarity relies on the asymmetric organization of cellular components and structures. Actin and microtubules are well suited to provide the structural basis for cell polarization because of ...their inherent structural polarity along the polymer lattices and intrinsic dynamics that allow them to respond rapidly to polarity cues. In general, the actin cytoskeleton drives the symmetry-breaking process that enables the establishment of a polarized distribution of regulatory molecules, whereas microtubules build on this asymmetry and maintain the stability of the polarized organization. Crosstalk coordinates the functions of the two cytoskeletal systems.
In most proliferating and migrating animal cells, the centrosome is the main site for microtubule (MT) nucleation and anchoring, leading to the formation of radial MT arrays in which MT minus ends ...are anchored at the centrosomes and plus ends extend to the cell periphery. By contrast, in most differentiated animal cell types, including muscle, epithelial and neuronal cells, as well as most fungi and vascular plant cells, MTs are arranged in noncentrosomal arrays that are non-radial. Recent studies suggest that these noncentrosomal MT arrays are generated by a three step process. The initial step involves formation of noncentrosomal MTs by distinct mechanisms depending on cell type: release from the centrosome, catalyzed nucleation at noncentrosomal sites or breakage of pre-existing MTs. The second step involves transport by MT motor proteins or treadmilling to sites of assembly. In the final step, the noncentrosomal MTs are rearranged into cell-type-specific arrays by bundling and/or capture at cortical sites, during which MTs acquire stability. Despite their relative stability, the final noncentrosomal MT arrays may still exhibit dynamic properties and in many cases can be remodeled.
Nuclear movement is critical for developmental events, cell polarity, and migration and is usually mediated by linker of nucleoskeleton and cytoskeleton (LINC) complexes connecting the nucleus to ...cytoskeletal elements. Compared to active nuclear movement, relatively little is known about homeostatic positioning of nuclei, including whether it is an active process. To explore homeostatic nuclear positioning, we developed a method to displace nuclei in adherent cells using centrifugal force. Nuclei displaced by centrifugation rapidly recentered by mechanisms that depended on cell context. In cell monolayers with wounds oriented orthogonal to the force, nuclei were displaced toward the front and back of the cells on the two sides of the wound. Nuclei recentered from both positions, but at different rates and with different cytoskeletal linkage mechanisms. Rearward recentering was actomyosin, nesprin-2G, and SUN2 dependent, whereas forward recentering was microtubule, dynein, nesprin-2G, and SUN1 dependent. Nesprin-2G engaged actin through its N terminus and microtubules through a novel dynein interacting site near its C terminus. Both activities were necessary to maintain nuclear position in uncentrifuged cells. Thus, even when not moving, nuclei are actively maintained in position by engaging the cytoskeleton through the LINC complex.
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•Homeostatic nuclear positioning in adherent cells is revealed by centrifugation•Mechanisms for homeostatic nuclear positioning are context dependent•Nesprin-2 engages both actin and microtubules for homeostatic nuclear positioning•SUN1 and SUN2 engage microtubules and actin, respectively, through nesprin-2G
It is unknown whether nuclear positioning is actively determined when the nucleus is not moving. Zhu et al. applied centrifugal force to displace the nucleus in adherent cells to reveal homeostatic nuclear positioning mechanisms involving both actin and microtubules and distinct LINC complexes in the nuclear envelope.
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