Intercellular lacunae: sequestered microenvironments in stimulated leukocyte cultures

Zusammenfassung In Zellkulturen menschlicher Leukocyten wurden nach Stimulation zur Blasten-Transformation elektronenmikroskopische Verbindungen zwischen sich berührenden Zellen nachgewiesen, die wahrscheinlich dem Übertritt spezifischer Plasmabestand dienen.     

Gap junction adhesion is necessary for radial migration in the neocortex

Radial glia, the neuronal stem cells of the embryonic cerebral cortex, reside deep within the developing brain and extend radial fibres to the pial surface, along which embryonic neurons migrate to reach the cortical plate. Here we show that the gap junction subunits connexin 26 (Cx26) and connexin 43 (Cx43) are expressed at the contact points between radial fibres and migrating neurons, and acute downregulation of Cx26 or Cx43 impairs the migration of neurons to the cortical plate. Unexpectedly, gap junctions do not mediate neuronal migration by acting in the classical manner to provide an aqueous channel for cell-cell communication. Instead, gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton to enable leading process stabilization along radial fibres as well as the subsequent translocation of the nucleus. These results indicate that gap junction adhesions are necessary for glial-guided neuronal migration, raising the possibility that the adhesive properties of gap junctions may have an important role in other physiological processes and diseases associated with gap junction function.     

A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size

Autosomal recessive primary microcephaly is a potential model in which to research genes involved in human brain growth. We show that two forms of the disorder result from homozygous mutations in the genes CDK5RAP2 and CENPJ. We found neuroepithelial expression of the genes during prenatal neurogenesis and protein localization to the spindle poles of mitotic cells, suggesting that a centrosomal mechanism controls neuron number in the developing mammalian brain.     

Effect of TiO_2 nanoparticles on hydrogen evolution reaction activity of Ni coatings

The electrocatalytic activity of electrodeposited Ni and Ni–TiO_2 coatings with regard to the alkaline hydrogen evolution reaction(HER) was investigated. The Ni coatings were electrodeposited from an acid chloride bath at different current densities, and their HER activities were examined in a 1.0-mol·L~(-1) KOH medium. The variations in the HER activity of the Ni coatings with changes in surface morphology and composition were examined via the electrochemical dissolution and incorporation of nanoparticles. Electrochemical analysis methods were used to monitor the HER activity of the test electrodes; this activity was confirmed via the quantification of gases that evolved during the analysis. The obtained results demonstrated that the Ni–TiO_2 nanocomposite test electrode exhibited maximum activity toward the alkaline HER. The surface appearance, composition, and the phase structure of all developed coatings were analyzed using scanning electron microscopy(SEM), energy dispersive spectroscopy(EDS), and X-ray diffraction(XRD), respectively. The improvement in the electrocatalytic activity of Ni–TiO_2 nanocomposite coating toward HER was attributed to the variation in surface morphology and increased number of active sites.     

Governing a Collective Bad: Social Learning in the Management of Crop Diseases

Systemic Practice and Action Research - There has been strong research interest in designing and testing learning approaches for enhancing and sustaining the capacity of communities to manage...     

A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers

Cyclin D1 is a component of the core cell cycle machinery. Abnormally high levels of cyclin D1 are detected in many human cancer types. To elucidate the molecular functions of cyclin D1 in human cancers, we performed a proteomic screen for cyclin D1 protein partners in several types of human tumours. Analyses of cyclin D1 interactors revealed a network of DNA repair proteins, including RAD51, a recombinase that drives the homologous recombination process. We found that cyclin D1 directly binds RAD51, and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein, which do not require D-cyclins for proliferation. These findings reveal an unexpected function of a core cell cycle protein in DNA repair and suggest that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers which are currently thought to be unaffected by cyclin D1 inhibition.     

Oncogenically active MYD88 mutations in human lymphoma

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt's lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.     

Leptin signaling and circuits in puberty and fertility

Leptin is an adipocyte-derived hormone involved in a myriad of physiological process, including the control of energy balance and several neuroendocrine axes. Leptin-deficient mice and humans are obese, diabetic, and display a series of neuroendocrine and autonomic abnormalities. These individuals are infertile due to a lack of appropriate pubertal development and inadequate synthesis and secretion of gonadotropins and gonadal steroids. Leptin receptors are expressed in many organs and tissues, including those related to the control of reproductive physiology (e.g., the hypothalamus, pituitary gland, and gonads). In the last decade, it has become clear that leptin receptors located in the brain are major players in most leptin actions, including reproduction. Moreover, the recent development of molecular techniques for brain mapping and the use of genetically modified mouse models have generated crucial new findings for understanding leptin physiology and the metabolic influences on reproductive health. In the present review, we will highlight the new advances in the field, discuss the apparent contradictions, and underline the relevance of this complex physiological system to human health. We will focus our review on the hypothalamic circuitry and potential signaling pathways relevant to leptin’s effects in reproductive control, which have been identified with the use of cutting-edge technologies of molecular mapping and conditional knockouts.     

Autoantibodies to the insulin receptor in juvenile onset insulin-dependent diabetes

Insulin-dependent diabetes mellitus (IDDM) usually begins in childhood or early adulthood, and its aetiology is thought to involve autoimmune damage to the islet cells that secrete insulin. To investigate an additional target of autoimmunity in IDDM we examined sera for antibodies to insulin receptors. Such antibodies were defined by their ability to compete with insulin for binding to insulin receptors and by their capacity to behave like insulin in activating lipogenesis in adipocytes. We now report the occurrence of anti-insulin receptor antibodies of the IgM class in the sera of 10 of 22 IDDM patients obtained before their treatment with exogenous insulin. Furthermore, two of five IDDM patients who were initially negative developed anti-insulin receptor antibodies during treatment with human or pork insulin. These findings suggest that autoimmunity to the insulin receptor may contribute to the pathophysiology of IDDM.