Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic ...contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom‐designed gene panel. We selected 55 leukoencephalopathy‐related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.
About 13.3% of adult patients with leukoencephalopathy were definitively disgnosed with known, apparently pathological or novel mutations.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The effects of recombinant preparations of human interferon-gamma (rIFN-gamma) and tumor necrosis factor (rTNF), alone or in combination, on class I or class II major histocompatibility complex (MHC) ...antigen induction were studied using K562, a multipotent hematopoietic precursor cell line. Class I antigens were weakly induced by rIFN-gamma; however, rTNF at any concentration examined (1-1000 U/ml) showed no effect on the induction of class I or class II antigens in the cells. rIFN-gamma (600 U/ml) induced approximately 20% of the cells to express class I antigens after 72-h exposure, whereas 81% of the cells demonstrated class I antigens on their cell surfaces when the cells were simultaneously exposed to 600 U/ml of rIFN-gamma and 1000 U/ml of rTNF. The class II MHC antigens were not induced by the treatments with rIFN-gamma or rTNF, alone or in combination. A synergistic increase of mRNA for class I MHC molecules was demonstrated by treatments of the cells with rIFN-gamma and rTNF in combination. rTNF, but not rIFN-gamma, weakly induced granulocyte-monocyte antigens on the cell surface; however, no synergism was observed on the induction of these antigens by the combined treatments with rIFN-gamma and rTNF. These results indicate that class I MHC antigen expression on K562 cells can be induced by IFN-gamma in cooperation with TNF in a manner different from myeloid antigen expression.
The effect of nisoldipine, a dihydropyridine Ca2+ antagonist, on the platelet cytosolic Ca2+ concentration (Ca2+i), platelet aggregation, and various coagulation and fibrinolysis parameters was ...assessed in normotensive patients with coronary artery disease (CAD). Eleven patients with angiographically confirmed CAD (4 men, 7 women aged 67.3 +/- 5.4 years) were administered nisoldipine at 10 mg/day for two weeks. The Ca2+i was determined by use of fura2-loaded platelets, platelet aggregation was measured with an aggregometer, and coagulation/fibrinolysis parameters were measured by standard methods. Nisoldipine did not significantly affect blood pressure or heart rate. However, the Ca2+i decreased significantly (P<0.05) and platelet aggregation was also significantly inhibited. Plasma D-dimer levels decreased significantly (P<0.01). Thus, nisoldipine not only suppressed platelet activation but also affected the coagulation system, suggesting that it is not only a vasodilator and platelet inhibitor but also an antithrombotic agent.
Optogenetic approaches for studying neuronal functions have proven their utility in the neurosciences. However, optogenetic tools capable of inducing synaptic plasticity at the level of single ...synapses have been lacking. Here, we engineered a photoactivatable (pa)CaMKII by fusing a light-sensitive domain, LOV2, to CaMKIIα. Blue light or two-photon excitation reversibly activated paCaMKII. Activation in single spines was sufficient to induce structural long-term potentiation (sLTP) in vitro and in vivo. paCaMKII activation was also sufficient for the recruitment of AMPA receptors and functional LTP in single spines. By combining paCaMKII with protein activity imaging by 2-photon FLIM-FRET, we demonstrate that paCaMKII activation in clustered spines induces robust sLTP via a mechanism that involves the actin-regulatory small GTPase, Cdc42. This optogenetic tool for dissecting the function of CaMKII activation (i.e., the sufficiency of CaMKII rather than necessity) and for manipulating synaptic plasticity will find many applications in neuroscience and other fields.
A new approach to β-Ga2O3 single crystal growth was studied, using the vertical Bridgman (VB) method in ambient air, while measuring the β-Ga2O3 melting temperature and investigating the effects of ...crucible composition and shape. β-Ga2O3 single crystals 25mm in diameter were grown in platinum–rhodium alloy crucibles in ambient air, with no adhesion of the crystals to the crucible wall. Single crystal growth without a crystal seed was realized by (100) faceted growth with a growth direction perpendicular to the (100) faceted plane.
•Single-crystal growth of β-Ga2O3 was studied by the vertical Bridgman (VB) method.•β-Ga2O3 crystals were grown in platinum–rhodium alloy crucibles in ambient air.•Single crystals with (100) faceted plane were grown without seeding.•Growth direction of the crystals grown was perpendicular to the (100) faceted plane.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Bone homeostasis is regulated by communication between bone-forming mature osteoblasts (mOBs) and bone-resorptive mature osteoclasts (mOCs). However, the spatial-temporal relationship and mode of ...interaction in vivo remain elusive. Here we show, by using an intravital imaging technique, that mOB and mOC functions are regulated via direct cell-cell contact between these cell types. The mOBs and mOCs mainly occupy discrete territories in the steady state, although direct cell-cell contact is detected in spatiotemporally limited areas. In addition, a pH-sensing fluorescence probe reveals that mOCs secrete protons for bone resorption when they are not in contact with mOBs, whereas mOCs contacting mOBs are non-resorptive, suggesting that mOBs can inhibit bone resorption by direct contact. Intermittent administration of parathyroid hormone causes bone anabolic effects, which lead to a mixed distribution of mOBs and mOCs, and increase cell-cell contact. This study reveals spatiotemporal intercellular interactions between mOBs and mOCs affecting bone homeostasis in vivo.
The risk of schizophrenia is increased in offspring whose mothers experience malnutrition during pregnancy. Polyunsaturated fatty acids (PUFAs) are dietary components that are crucial for the ...structural and functional integrity of neural cells, and PUFA deficiency has been shown to be a risk factor for schizophrenia. Here, we show that gestational and early postnatal dietary deprivation of two PUFAs-arachidonic acid (AA) and docosahexaenoic acid (DHA)-elicited schizophrenia-like phenotypes in mouse offspring at adulthood. In the PUFA-deprived mouse group, we observed lower motivation and higher sensitivity to a hallucinogenic drug resembling the prodromal symptoms in schizophrenia. Furthermore, a working-memory task-evoked hyper-neuronal activity in the medial prefrontal cortex was also observed, along with the downregulation of genes in the prefrontal cortex involved in oligodendrocyte integrity and the gamma-aminobutyric acid (GABA)-ergic system. Regulation of these genes was mediated by the nuclear receptor genes Rxr and Ppar, whose promoters were hyper-methylated by the deprivation of dietary AA and DHA. In addition, the RXR agonist bexarotene upregulated oligodendrocyte- and GABA-related gene expression and suppressed the sensitivity of mice to the hallucinogenic drug. Notably, the expression of these nuclear receptor genes were also downregulated in hair-follicle cells from schizophrenia patients. These results suggest that PUFA deficiency during the early neurodevelopmental period in mice could model the prodromal state of schizophrenia through changes in the epigenetic regulation of nuclear receptor genes.
Toll-like receptor (TLR) activation is central to immunity, wherein the activation of the TLR9 subfamily members TLR9 and TLR7 results in the robust induction of type I IFNs (IFN-α/β) by means of the ...MyD88 adaptor protein. However, it remains unknown how the TLR signal "input" can be processed through MyD88 to "output" the induction of the IFN genes. Here, we demonstrate that the transcription factor IRF-7 interacts with MyD88 to form a complex in the cytoplasm. We provide evidence that this complex also involves IRAK4 and TRAF6 and provides the foundation for the TLR9-dependent activation of the IFN genes. The complex defined in this study represents an example of how the coupling of the signaling adaptor and effector kinase molecules together with the transcription factor regulate the processing of an extracellular signal to evoke its versatile downstream transcriptional events in a cell. Thus, we propose that this molecular complex may function as a cytoplasmic transductional-transcriptional processor.
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