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  • American Chemical Society  (4,968)
  • Blackwell Science Ltd  (970)
  • National Academy of Sciences  (135)
  • Blackwell Science Pty
  • 1
    Publication Date: 2018-05-16
    Description: Store-operated calcium entry (SOCE), an important mechanism of Ca2+ signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca2+ signaling raises...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
    ISSN: 1442-2042
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background: This double-blind, multicenter study compared the efficacy and tolerability of tolterodine (Pharmacia, Los Angeles, USA) with that of oxybutynin (Alza, Palo Alto, USA) in Asian patients with overactive bladder. Methods: Two-hundred-and-twenty-eight adults with overactive bladder symptoms were randomized to receive tolterodine 2 mg twice daily (bid) (n = 112) or oxybutynin 5 mg bid (n = 116). After 8 weeks’ treatment, changes in micturition diary variables, patients’ perception of treatment benefit, and tolerability endpoints were determined. Results: The mean (± SD) number of micturitions/24 h decreased by 2.6 ± 2.9 (−21%) with tolterodine and 1.8 ± 4.2 (−15%) with oxybutynin (both P = 0.0001 vs baseline). The mean number of incontinence episodes/24 h decreased by 2.2 ± 2.3 (−85%) in the tolterodine group and by 1.4 ± 1.8 (−58%) in the oxybutynin group (both P = 0.0001 vs baseline). Patient perception of treatment benefit was over 70% in each treatment group. Adverse events were significantly lower in the tolterodine group compared with oxybutynin-treated patients (55% vs 82%; P = 0.001). Dry mouth was reported by significantly fewer patients on tolterodine, compared with oxybutynin (35% vs 63%; P = 0.001) and withdrawals due to adverse events were lower in the tolterodine group than with those treated with oxybutynin (10% vs 16%). There were no safety concerns. Conclusions: Tolterodine 2 mg bid is equally or more effective than oxybutynin 5 mg bid in the treatment of Asian patients with overactive bladder, and shows significantly better tolerability. This may enhance compliance during long-term treatment.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  Ultraviolet (UV) B irradiation causes many important biological changes in skin, which lead to pathophysiological alterations of the homeostatic environment.Objectives  To gain more insight into the molecular events provoked by UVB irradiation, we performed cDNA microarray analysis.Methods  Immortalized HaCaT keratinocytes were irradiated with a high cytotoxic dose of UVB (50 mJ cm−2), and total RNA was isolated. Fluorescently labelled probes were prepared by reverse transcription and were hybridized with cDNA microarray slides made using 840 cDNA clones.Results  Time-course cDNA microarray analysis revealed the global gene expression profile after UVB exposure. Of 840 genes tested, 192 genes showed changes in their expression levels at one or more of four time points. The genes were clustered into four groups according to their expression patterns in a self-organizing maps analysis. Classification of these genes into nine functional categories revealed that UVB irradiation affected several biological processes. The genes that were first upregulated and then returned to normal levels included several genes related to the inhibition of cell growth and the proteasome pathway. Conversely, the expressions of many genes involved in the cytoskeleton, signal transduction, metabolism and transcription were first downregulated or unchanged and then upregulated later, reflecting the recovery of UVB-damaged cellular activities.Conclusions  These results demonstrate the complexity of the transcriptional profile of the UVB response, and provide a basis for the global characterization of UV-regulated gene expression.
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  • 4
    ISSN: 1365-4632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A 22-year-old South Korean woman presented with a 4-month history of several nodules on both legs. She looked healthy, but suffered from tenderness and swelling of the legs. Physical examination showed multiple, nonulcerating, erythematous nodules occurring on the calves, knee joints, and thighs (〈link href="#f1-1"〉Fig. 1). A biopsy specimen of the skin revealed necrotizing vasculitis of medium-sized arteries with fibrinoid necrosis at the border between the dermis and the subcutis. Dense cellular infiltrates, including numerous neutrophils and lymphocytes, presented within and around the vessel walls as in polyarteritis nodosa, with some eosinophils (〈link href="#f1-2"〉Fig. 2A,B). There were no other generalized symptoms. She was diagnosed with cutaneous polyarteritis nodosa and was initially treated with systemic steroids. She was given an intravenous injection of Solu-Cortef, 60 mg/6 h for 7 days. This was replaced with oral prednisolone for 2 weeks. The skin lesions and symptoms improved.〈figure xml:id="f1-1"〉1〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1138-2:IJD_1138_f1-1"/〉Small, nut-sized, erythematous, brown-colored nodules and patches on the lower extremities, even above the knee joints〈figure xml:id="f1-2"〉2〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1138-2:IJD_1138_f1-2"/〉(A) Dense infiltration within and around artery (× 40). (B) Slightly expanded lobular panniculitis with vasculitis (× 100)Six months later, she complained of general weakness and recurrent skin lesions. Purified protein derivative (PPD) test gave a moderate positive reaction and chest X-ray examination showed the features of pulmonary tuberculosis: radio-opaque infiltrations in the right lower lung field. A repeated biopsy revealed mild vasculitis with more diffuse lobular infiltrations of the subcutaneous tissue compared with the former specimen.Polymerase chain reaction (PCR) and tissue culture for Mycobacterium tuberculosis were performed from a biopsy specimen. DNA was extracted from skin tissue with an AplisystemTM DNA/RNA detection kit using the resin-mediated boiling method (Stargene, Seoul, South Korea). The primers were designed on the basis of the M. tuberculosis gene IS6110 target (sense primer, 5′-CCA GAT GCA CCG TCG AAC GGC TGA T-3′ antisense primer, 5′-CGC TCG CTG AAC CGG ATC GAT GTG T-3′). The amplification was performed with uracil-N-glycosylase (UNG), to prevent carry-over contamination, and internal control primers, to correct for false-negative reaction (Kox LF, Rhienthong D, Miranda AM et al. A more reliable PCR for detection of Mycobacterium tuberculosis in clinical samples. J Clin Microbiol 1994; 32: 672–678; Longo MC, Berninger MS, Hartley JL. Use of uracil DNA glycosylase to control carry-over contamination in polymerase chain reactions. Gene 1990; 93: 125–128). According to the manufacturer's instructions, amplification was carried out for 40 cycles with denaturation at 94 °C for 40 s, annealing at 70 °C for 1 min, and extension at 72 °C for 1 min in a thermal cycler (Perkin–Elmer Cetus, Norwalk, CT, USA). The results of PCR and tissue culture for M. tuberculosis using the biopsy specimen were all negative (〈link href="#f1-3"〉Fig. 3).〈figure xml:id="f1-3"〉3〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1138-2:IJD_1138_f1-3"/〉Negative result in PCR for M. tuberculosis (negative control is not shown; M, marker; P, positive control; I, internal control; S, specimen)The patient was finally diagnosed with erythema induratum with pulmonary tuberculosis and was started on antituberculosis medication (isoniazid 400 mg, rifampicin 600 mg, ethambutol 800 mg, and pyrazinamide 1500 mg daily). She showed prompt improvement after 2 weeks of medication. After 9 months of antituberculosis therapy, her skin lesions and chest X-ray had cleared. She was followed up for 4 months with no recurrence of skin and pulmonary lesions.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Ischemic stress in the brain induces acute and massive neuronal death in the targeted area, which is followed by a second round of detrimental processes, called delayed neuronal death, in the neighboring areas. To test the hypothesis that transcriptional control plays a role in the pathophysiology of the postischemic brain, the genomic responses that occurred in the brain at 3, 6 and, 12 h, and 1, 2 or 4 days after transient middle cerebral artery occlusion (MCAO) were examined using a microarray harboring 5000 rat cDNAs. This analysis indicated that the number of up-regulated genes was gradually increased, along with the concomitant reduction in the number of down-regulated genes, until 12 h to 1 day after MCAO. It was followed by a delayed surge of down-regulated genes at 2 days after MCAO. Northern blots and immunohistological analysis confirmed the validity of these microarray data. We present a list of 85 genes that were up-regulated more than 2.3-fold between 12 h and 4 days after MCAO, which included 56 novel genes whose expression has not previously been implicated in ischemic pathophysiology. The list included genes involved in oxidative stress, inflammation, extracellular matrix (ECM), neuronal development and differentiation processes. Together these results suggest that the pathophysiology of the postischemic brain proceeds by the transcriptional activation of genes related to the process of delayed neuronal damage and/or recovery and repair.
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  • 6
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: α-Synuclein, a pathological component of Parkinson's disease by constituting the Lewy bodies, has been suggested to be involved in membrane biogenesis via induction of amphipathic α-helices. Since the amphipathic α-helix is also known as a recognition signal of calmodulin for its target proteins, molecular interaction between α-synuclein and calmodulin has been investigated. By employing a chemical coupling reagent of N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline, α-synuclein has been shown to yield a heterodimeric 1 : 1 complex with calmodulin on sodium dodecyl sulfate–polyacrylamide gel electrophoresis in the presence and even absence of calcium, whereas β-synuclein was more dependent upon calcium for its calmodulin interaction. The selective calmodulin interaction of α-synuclein in the absence of calcium was also demonstrated with the aggregation kinetics of the synucleins in which only the α-synuclein aggregation was affected by calmodulin. A reversible binding assay confirmed that α-synuclein interacted with the Ca2+-free as well as the Ca2+-bound calmodulins with almost identical Kds of 0.35 µm and 0.31 µm, respectively, while β-synuclein preferentially recognized the Ca2+-bound form with a Kd of 0.68 µm. By using a C-terminally truncated α-synuclein of α-syn97, the calmodulin binding site(s) on α-synuclein was(were) shown to be located on the N-terminal region where the amphipathic α-helices have been suggested to be induced upon membrane interaction. By employing liposome and calmodulin in a state of being either soluble or immobilized on agarose, actual competition of α-synuclein between membranes and calmodulin was demonstrated with the observation that α-synuclein previously bound to the liposome was released upon specific interaction with the calmodulins. Taken together, these data may suggest that α-synuclein could act not only as a negative regulator for calmodulin in the presence and even absence of calcium, but it could also exert its activity at the interface between calmodulin and membranes.
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  • 7
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Dopaminergic neurotransmission is terminated by the action of the presynaptic dopamine transporter (DAT). It mediates Na+/Cl− -dependent re-uptake of extracellular dopamine (DA) into the cell, and is regarded as a major regulatory mechanism for synaptic transmission. Previous works have documented that protein kinase C (PKC) activator or inhibitor alters DA uptake by DAT, suggesting that PKC phosphorylation plays an important regulatory mechanism in DAT function. Based on the existence of consensus amino acid sequences for PKC phosphorylation, it has been postulated that PKC regulation of DAT is mediated by the direct phosphorylation of DAT protein. In this study, we try to discover whether the functional regulation of DAT by PKC is due to direct phosphorylation of DAT. The PKC null mutant hDAT, where all putative PKC phosphorylation sites are eliminated, has been constructed by the replacement of serine/threonine residues with glycines. The mutation itself showed no effect on the functional activities of DAT. The DA uptake activity of PKC null mutant was equivalent to those of wild-type hDAT (80–110% of wild-type). Phorbol ester activation of PKC inhibited DA uptake of wild-type hDAT by 35%, and staurosphorine blocked the effect of phorbol ester on DA uptake. The same phenomena was observed in PKC null mutant DAT, although no significant phosphorylation was observed by PKC activation. Confocal microscopic analysis using EGFP-fused DAT revealed that the activation of PKC by phorbol ester elicited fluorescent DAT to be internalized into the intracellular space both in wild-type and PKC null mutant DAT in a similar way. These results suggest that PKC-mediated regulation of DAT function is achieved in an indirect manner, such as phosphorylation of a mediator protein or activation of a clathrin-mediated pathway.
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  • 8
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is activated by a variety of cellular or environmental stresses. Proper regulation of the SAPK/JNK pathway may be critical for cell survival or death under various conditions. In this study, we report the molecular cloning of novel isoforms of JIP-1, which harbor a putative phosphotyrosine interaction domain and a helix-loop-helix domain, as well as an SH3 homologous region in the C terminus. Northern analysis indicates that transcription variant jip-1 is expressed in brain and kidney and transcription variants jip-2 and jip-3 are specifically expressed in brain. In situ hybridization data showed that the hybridized jip messages were heavily concentrated in adult brain, and were particularly enriched in the cerebral cortex and hippocampus, the brain regions vulnerable to pathological states such as hypoxia-ischemia, epilepsy, and Alzheimer’s disease. All the deduced protein products of the jip transcription variants appear to have a similar property in that they inhibit the SAPK/JNK stimulation when overexpressed. Inhibition of SAPK activation by overexpression of the novel isoform JIP-2a resulted in suppression of etoposide-induced cell death in a neuroglioma cell line, N18TG. These findings suggest that JIP may play an important role in regulation of the SAPK pathway that is involved in stress-induced cellular responses.
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  • 9
    ISSN: 1442-2042
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background: We investigated changes in zinc concentrations in serum and prostatic tissue after an intraprostatic injection of zinc, and compared two forms of zinc delivery: solution and liposome.Methods: Ninety-six male Wistar rats were used in the study (24 controls, 72 test rats). The test animals were randomly divided into two groups and were injected intraprostatically with 2 mL of 0.04 mol/L zinc sulfate according to the form of zinc delivery. Nine rats in each test group were sacrificed 1 day, 7, 14 and 28 days after injection, and 24 normal rats were injected intraprostatically with 2 mL of distilled water as controls. Serum and prostatic zinc concentrations of each group were measured by inductively coupled plasma atomic emission spectrometry. Blood chemistries, routine urinalysis, urine culture and histopathologic examination were also performed.Results: Serum zinc concentrations did not change significantly after the intraprostatic injection of zinc. Prostatic zinc concentrations were found to be significantly greater (P 〈 0.05) in zinc-injected groups than in the control group. The intraprostatic injection of zinc solution and zinc liposome increased zinc levels in both ventral and dorsolateral lobes significantly. Prostatic zinc levels increased progressively following injection, reaching a peak level in 7 days and maintaining a high value throughout the experimental period. The prostatic zinc level of the 1-day zinc liposome group was higher than that of the 1-day zinc solution group, while no significant difference was observed between the solution and liposome group in 7, 14, 28 days. No abnormal findings were observed in any of the laboratory and histopathologic examinations; however, an acute inflammatory response was observed in the 1-day groups.Conclusion: These findings suggest that an intraprostatic injection of zinc in normal rats increases and maintains the prostatic zinc level for at least 4 weeks without causing any systemic or local toxicities. These findings suggest the potentially important clinical applicability of local zinc to the treatment of chronic prostatitis.
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  • 10
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Point mutations such as G93A and A4V in the human Cu/Zn-superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase-3 (GSK-3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimer's disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol-3-kinase (PI3-K)/Akt and GSK-3 pathway as well as the caspase-3 pathway, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PI3-K/Akt, GSK-3, heat shock transcription factor-1 (HSTF-1), cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK-3β-mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK-3β inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK-3β inhibitor increased their viability by activating HSTF-1 and by reducing cytochrome c release, caspase-3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3-K/Akt and GSK-3β. These results suggest that the G93A or A4V mutations inhibit PI3-K/Akt and activate GSK-3β and caspase-3, thus becoming vulnerable to oxidative stress, and that the GSK-3β-mediated cell death mechanism is important in G93A and A4V cell death.
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