Effects of vitamin B12 on plasma melatonin rhythm in humans: increased light sensitivity phase-advances the circadian clock?

Vitamin B12 (methylcobalamin) was administered orally (3 mg/day) to 9 healthy subjects for 4 weeks. Nocturnal melatonin levels after exposure to bright light (ca. 2500 lx) were determined, as well as the levels of plasma melatonin over 24 h. The timing of sleep was also recorded. Vitamin B12 was given blind to the subjects and crossed over with placebo. We found that the 24-h melatonin rhythm was significantly phase-advanced (1.1 h) in the vitamin B12 trial as compared with that in the placebo trial. In addition, the 24-h mean of plasma melatonin level was much lower in the vitamin B12 trial than with the placebo. Furthermore, the nocturnal melatonin levels during bright light exposure were significantly lower in the vitamin B12 trial than with the placebo. On the other hand, vitamin B12 did not affect the timing of sleep. These findings raise the possibility that vitamin B12 phase-advances the human circadian rhythm by increasing the light sensitivity of the circadian clock.     

Seasonality in human sleep.

The timing of sleep and sleep EEG parameters in 10 healthy male subjects were investigated in four seasons under controlled conditions. The phase of nocturnal sleep was delayed about one and a half hours in winter as compared to that in summer. The duration of stage 4 sleep decreased and REM sleep increased significantly in winter compared with summer. The seasonality in the timing of sleep can be explained by photoperiodic time cues, but the changes in sleep EEG parameters are difficult to explain in terms of photoperiod.     

Termination of asymmetric cell division and differentiation of stomata

Stomata consist of a pair of guard cells that mediate gas and water-vapour exchange between plants and the atmosphere. Stomatal precursor cells-meristemoids-possess a transient stem-cell-like property and undergo several rounds of asymmetric divisions before further differentiation. Here we report that the Arabidopsis thaliana basic helix-loop-helix (bHLH) protein MUTE is a key switch for meristemoid fate transition. In the absence of MUTE, meristemoids abort after excessive asymmetric divisions and fail to differentiate stomata. Constitutive overexpression of MUTE directs the entire epidermis to adopt guard cell identity. MUTE has two paralogues: FAMA, a regulator of guard cell morphogenesis, and SPEECHLESS (SPCH). We show that SPCH directs the first asymmetric division that initiates stomatal lineage. Together, SPCH, MUTE and FAMA bHLH proteins control stomatal development at three consecutive steps: initiation, meristemoid differentiation and guard cell morphogenesis. Our findings highlight the roles of closely related bHLHs in cell type differentiation in plants and animals.     

A high-resolution environmental change record since 19 cal ka BP in Pumoyum Co,southern Tibet

A 380-cm-long sediment core was acquired from the deep water area of Pumoyum Co, southern Tibet. Twenty-five plant residue samples were selected, and organic carbon stable isotopes were obtained using the AMS ¹⁴C chronological method. The ¹⁴C age and carbon reservoir effect were calibrated with surface sedimentation rate measurements using ²¹⁰Pb dating. Results showed that the core sediment deposited over 19 cal ka BP. Based on a multi-proxy analysis of TOC and IC contents, grain size and pollen assemblage data, the palaeoclimatic evolution of Pumoyum Co was reconstructed since the last glacial. Pumoyum Co was a shallow lake prior to 16.2 cal ka BP; although the glacier around the lake began to melt due to increasing temperatures, climate was still cold and dry. In the interval of 16.2–11.8 cal ka BP, the sedimentary environment fluctuated drastically and frequently. Two cold-events occurred at 14.2 and 11.8 cal ka BP, and these may correspond to the Older Dryas and the Younger Dryas events, respectively. After 11.8 cal ka BP, Pumoyun Co developed into the deep lake as it is now. The lake water temperature was relatively lower at that time because of influx of cold water from glacial meltwater entering the lake. As a result, the multi-proxy indicators showed no sign of warm conditions. Comparisons between the sedimentary record of Pumoyum Co with that of other lakes of the same age in southern Tibet indicate a warmer climate following the last deglaciation influenced the southeastern Tibetan Plateau. These results imply that the southwest Asian monsoon gradually became stronger since the deglaciation during its expansion to the inner plateau. The glacial-supplied water of the lake responded sensitively to cold-events. The entire southern Tibet region was dominantly influenced climatically by the southwest Asian monsoon during the Holocene.     

ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.     

Identification of a factor that links apoptotic cells to phagocytes

Apoptotic cells are rapidly engulfed by phagocytes to prevent the release of potentially noxious or immunogenic intracellular materials from the dying cells, thereby preserving the integrity and function of the surrounding tissue. Phagocytes engulf apoptotic but not healthy cells, indicating that the apoptotic cells present a signal to the phagocytes, and the phagocytes recognize the signal using a specific receptor. Here, we report a factor that links apoptotic cells to phagocytes. We found that milk fat globule-EGF-factor 8 (MFG-E8), a secreted glycoprotein, was produced by thioglycollate-elicited macrophages. MFG-E8 specifically bound to apoptotic cells by recognizing aminophospholipids such as phosphatidylserine. MFG-E8, when engaged by phospholipids, bound to cells via its RGD (arginine-glycine-aspartate) motif--it bound particularly strongly to cells expressing alpha(v)beta(3) integrin. The NIH3T3 cell transformants that expressed a high level of alpha(v)beta(3) integrin were found to engulf apoptotic cells when MFG-E8 was added. MFG-E8 carrying a point mutation in the RGD motif behaved as a dominant-negative form, and inhibited the phagocytosis of apoptotic cells by peritoneal macrophages in vitro and in vivo. These results indicate that MFG-E8 secreted from activated macrophages binds to apoptotic cells, and brings them to phagocytes for engulfment.     

Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cdelta

Protein kinase C (PKC), which comprises 11 closely related isoforms, has been implicated in a wide variety of cellular processes, such as growth, differentiation, secretion, apoptosis and tumour development. Among the PKC isotypes, PKC-delta is unique in that its overexpression results in inhibition of cell growth. Here we show that mice that lack PKC-delta exhibit expansion of the B-lymphocyte population with the formation of numerous germinal centres in the absence of stimulation. The rate of proliferation in response to stimulation was greater for B cells from PKC-delta-deficient mice than for those from wild-type mice. Adoptive transfer experiments suggested that the hyperproliferation phenotype is B-cell autonomous. Production of interleukin-6 was markedly increased in B cells of PKC-delta-null mice as a result of an increase in the DNA-binding activity of NF-IL6. Furthermore, the PKC-delta-deficient mice contain circulating autoreactive antibodies and display immune-complex-type glomerulonephritis, as well as lymphocyte infiltration in many organs. These results suggest that PKC-delta has an indispensable function in negative regulation of B-cell proliferation, and is particularly important for the establishment of B-cell tolerance.     

A high-strain-rate superplastic ceramic

High-strain-rate superplasticity describes the ability of a material to sustain large plastic deformation in tension at high strain rates of the order of 10-2 to 10-1 s-1 and is of great technological interest for the shape-forming of engineering materials. High-strain-rate superplasticity has been observed in aluminium-based and magnesium-based alloys. But for ceramic materials, superplastic deformation has been restricted to low strain rates of the order of 10-5 to 10-4 s-1 for most oxides and nitrides with the presence of intergranular cavities leading to premature failure. Here we show that a composite ceramic material consisting of tetragonal zirconium oxide, magnesium aluminate spinel and alpha-alumina phases exhibits superplasticity at strain rates up to 1 s-1. The composite also exhibits a large tensile elongation, exceeding 1,050 per cent for a strain rate of 0.4 s-1. The tensile flow behaviour and deformed microstructure of the material indicate that superplasticity is due to a combination of limited grain growth in the constitutive phases and the intervention of dislocation-induced plasticity in the zirconium oxide phase. We suggest that the present results hold promise for the application of shape-forming technologies to ceramic materials.     

Clonal selection drives genetic divergence of metastatic medulloblastoma

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.     

短双歧杆菌(Bifidobacterium breve 203)α-D-半乳糖苷酶的诱导合成及部分酶性质研究

研究发现 2 5株所试肠道细菌中只有 6株双歧杆菌可以利用棉子糖良好生长 ,并且在棉子糖的诱导下产生α D 半乳糖苷酶 .9种不同糖中 ,Bifidobacter iumbreve 2 0 3可以利用葡萄糖、半乳糖、果糖、麦芽糖、乳糖、蜜二糖、棉子糖良好生长 ,但只有蜜二糖和棉子糖诱导α D 半乳糖苷酶的产生 .1 0mmol/L的棉子糖和蜜二糖对于α D 半乳糖苷酶的诱导合成是最佳浓度的 ,且此浓度下 ,棉子糖的诱导能力 (比活 7.1 3units/mg)是蜜二糖 (比活 3 .4 0units/mg)的 2倍以上 .B .breve 2 0 3菌株α D 半乳糖苷酶专一性水解α D 半乳糖苷键 ,不水解β D 半乳糖苷键 .酶反应的最适温度是 3 7℃ ,酶在 4 0℃以下稳定 ,60℃时剩余 80 %的酶活 ,65℃时剩余 2 0 %的酶活 ,70℃时失去所有的酶活 .酶在 pH5.5～ 9.5稳定 ,酶反应的最适pH是 5.5～ 6.5.Hg 、Cu2 、Ag 和PCMB强烈抑制酶的活性 ,而Co2 、Mg2 、Ca2 、Mn2 、Zn2 、EDTA和DTT对酶活性没有抑制 .