Vitamin B12 amplifies circadian phase shifts induced by a light pulse in rats

Vitamin B₁₂ (VB₁₂) is a putative modulator of the human circadian clock, improving entrainability to the 24 h light-dark cycle. The present study was intended to elucidate the mechanism of VB₁₂ action in an animal model. In male rats free-running under constant dim illumination, a single light pulse of 50–1000 lux for 20 min given at circadian time (CT) 20 induced a 0.28 to 1.08 h phase advance and at CT 14 induced a 0.54 to 2.10 h phase delay. A 3 h intracerebroventricular (icv) infusion of 30 nmol VB₁₂ starting 2 h prior to a 20 min 200 lux light pulse significantly amplified phase shifts in comparison with saline-treated or untreated controls. The mean phase advance (1.13 h) was 1.8-fold greater than that of saline-infused controls, whereas the mean phase delay (2.28 h) was 2.9-fold greater. These values were comparable to the maximal phase shifts caused by 1000 lux light pulses in untreated rats. Since the same VB₁₂ treatment alone had failed to induce a phase shift in a previous experiment, these results indicate that VB₁₂ strongly enhanced light pulse-induced phase shifts and thus augmented the entrainability of the circadian clock to light.     

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

The molecular mechanisms by which different mutations in the same gene can result in distinct disease phenotypes remain largely unknown. Truncating mutations of SOX10 cause either a complex neurocristopathy designated PCWH or a more restricted phenotype known as Waardenburg-Shah syndrome (WS4; OMIM 277580). Here we report that although all nonsense and frameshift mutations that cause premature termination of translation generate truncated SOX10 proteins with potent dominant-negative activity, the more severe disease phenotype, PCWH, is realized only when the mutant mRNAs escape the nonsense-mediated decay (NMD) pathway. We observe similar results for truncating mutations of MPZ that convey distinct myelinopathies. Our experiments show that triggering NMD and escaping NMD may cause distinct neurological phenotypes.     

Remote triggering of deep earthquakes in the 2002 Tonga sequences

It is well established that an earthquake in the Earth's crust can trigger subsequent earthquakes, but such triggering has not been documented for deeper earthquakes. Models for shallow fault interactions suggest that static (permanent) stress changes can trigger nearby earthquakes, within a few fault lengths from the causative earthquake, whereas dynamic (transient) stresses carried by seismic waves may trigger earthquakes both nearby and at remote distances. Here we present a detailed analysis of the 19 August 2002 Tonga deep earthquake sequences and show evidence for both static and dynamic triggering. Seven minutes after a magnitude 7.6 earthquake occurred at a depth of 598 km, a magnitude 7.7 earthquake (664 km depth) occurred 300 km away, in a previously aseismic region. We found that nearby aftershocks of the first mainshock are preferentially located in regions where static stresses are predicted to have been enhanced by the mainshock. But the second mainshock and other triggered events are located at larger distances where static stress increases should be negligible, thus suggesting dynamic triggering. The origin times of the triggered events do not correspond to arrival times of the main seismic waves from the mainshocks and the dynamically triggered earthquakes frequently occur in aseismic regions below or adjacent to the seismic zone. We propose that these events are triggered by transient effects in regions near criticality, but where earthquakes have difficulty nucleating without external influences.     

Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese

We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10(-4)) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10(-10); FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10(-8)) and 3p11.2 (rs2055109; P = 3.94 × 10(-8)). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10(-7)). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations.     

Pummerer-type Functionalization of Aryl and Alkenyl Selenoxides

Heteroatom-stabilized carbenium ions have been widely recognized as potential electrophilic reagents. However, in contrast with the extensive works on thionium ion series, the highly labile character of selenoxide functionalities has caused serious limitation in the synthetic use in spite of their wide potentiality as synthetic equivalents of electrophilic selonium ions. In this paper, novel generation of selonium ions and the synthetic uses of the species for Pummerer-type α-functionalization and for cycloaddition by using the novel dienophilic behavior of π-conjugated selonium cations.     

BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.     

Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes

Mice carrying mitochondrial DNA (mtDNA) with pathogenic mutations would provide a system in which to study how mutant mtDNAs are transmitted and distributed in tissues, resulting in expression of mitochondrial diseases. However, no effective procedures are available for the generation of these mice. Isolation of mouse cells without mtDNA (rho0) enabled us to trap mutant mtDNA that had accumulated in somatic tissues into rho0 cells repopulated with mtDNA (cybrids). We isolated respiration-deficient cybrids with mtDNA carrying a deletion and introduced this mtDNA into fertilized eggs. The mutant mtDNA was transmitted maternally, and its accumulation induced mitochondrial dysfunction in various tissues. Moreover, most of these mice died because of renal failure, suggesting the involvement of mtDNA mutations in the pathogeneses of new diseases.