T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis.

Multiple sclerosis is thought to be an autoimmune disease of the central nervous system mediated by T cells specific for a myelin antigen. Myelin basic protein has been studied as a potential autoantigen in the disease because of its role as an encephalitogen in experimental autoimmune encephalomyelitis and post-viral encephalomyelitis and because of the presence in the blood of multiple sclerosis patients of in vivo-activated T cells reactive to myelin basic protein. Immune involvement in multiple sclerosis has been further suggested by the association with the major histocompatibility complex class II phenotype DR2, DQw1. To define the T-cell specificity toward myelin basic protein, 15,824 short-term T-cell lines were established from multiple sclerosis subjects, subjects with other neurological diseases, and normal controls. Here we report a higher frequency of T-cell lines reactive with a DR2-associated region of myelin basic protein between residues 84-102 in patients with multiple sclerosis compared with controls. A second region, identified between residues 143-168, was recognized equally in multiple sclerosis patients and controls and was associated with the DRw11 phenotype. These DR2 and DRw11 associations were also observed among T-cell lines generated from family members of a multiple sclerosis patient. The immunodominant 84-102 peptide from myelin basic protein was both DR2- and DQw1-restricted among different T-cell lines. These results raise the possibility that this immunodominant region may be encephalitogenic in some DR2+ individuals.     

Thyrotrophin in the pars tuberalis triggers photoperiodic response

Molecular mechanisms regulating animal seasonal breeding in response to changing photoperiod are not well understood. Rapid induction of gene expression of thyroid-hormone-activating enzyme (type 2 deiodinase, DIO2) in the mediobasal hypothalamus (MBH) of the Japanese quail (Coturnix japonica) is the earliest event yet recorded in the photoperiodic signal transduction pathway. Here we show cascades of gene expression in the quail MBH associated with the initiation of photoinduced secretion of luteinizing hormone. We identified two waves of gene expression. The first was initiated about 14 h after dawn of the first long day and included increased thyrotrophin (TSH) beta-subunit expression in the pars tuberalis; the second occurred approximately 4 h later and included increased expression of DIO2. Intracerebroventricular (ICV) administration of TSH to short-day quail stimulated gonadal growth and expression of DIO2 which was shown to be mediated through a TSH receptor-cyclic AMP (cAMP) signalling pathway. Increased TSH in the pars tuberalis therefore seems to trigger long-day photoinduced seasonal breeding.     

Chenguodaite （Ag9FeTe2S4）： a new tellurosulfide mineral from the gold district of East Shandong Peninsula,China

Chenguodaite, approved by IMA-CNMMN （2004-042a）, was discovered in the Bunan quartz vein-type gold deposit in the gold district of East Shandong Peninsula. The mineral occurs in high grade Au-Ag-Cu ores, coexisting with galena, chalcopyrite, hessite, electrum, unnamed Ag6TeS2 and AglsFeBiTe3Se, enclosed and replaced by native silver and acanthite. In the reflected light microscope, the mineral has light gray color, indistinguishable anistropism and hardness around 2-3. The color indices of chenguodaite relative to ICE C illuminator are： x=0.3027, y=0.3076, Y=25.78%,λd=474 nm, Pe=3.68%, similar to those of canfieldite. The average chemical composition from 16 microprobe analyses is Ag8.97Fe1.00Te1.99S4.04, idealized to AggFeTe2S4. The polycrystalline X-ray diffraction of chenguodaite by Gandolfi camera and synchrotron oscillation photography results in 67 reflections with the 12 strongest being （relative intensity in bracket）： 6.742（69）, 6.416（39）, 5.951（33）, 3.265（100）, 2.981（24）, 2.649（22）, 2.25（24）, 2.188（71）, 2.142（22）, 2.123（31）, 2.044（23）, 1.949（33）, which are indexed to a primitive orthorhombic cell with a=12.769 （2） A, b= 14.814（2） A, c= 16.233 （1） A, V= 3070.6 A^3, Z= 9, Dcal.=6.85 g/cm^3. The name is for the late Prof. Chen Guoda, a famous Chinese geologist and the founder of Diwa-Geodepression theory of tectonics.     

Genetic dissection of the circuit for hand dexterity in primates

It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates. However, the role of the 'phylogenetically older' indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs), which act as a relay of the indirect pathway in macaque monkeys (Macaca fuscata and Macaca mulatta). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex–PN–motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies.     

Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets

Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans, but currently do not transmit efficiently among humans. The viral haemagglutinin (HA) protein is a known host-range determinant as it mediates virus binding to host-specific cellular receptors. Here we assess the molecular changes in HA that would allow a virus possessing subtype H5 HA to be transmissible among mammals. We identified a reassortant H5 HA/H1N1 virus-comprising H5 HA (from an H5N1 virus) with four mutations and the remaining seven gene segments from a 2009 pandemic H1N1 virus-that was capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognized human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but was not highly pathogenic and did not cause mortality. These results indicate that H5 HA can convert to an HA that supports efficient viral transmission in mammals; however, we do not know whether the four mutations in the H5 HA identified here would render a wholly avian H5N1 virus transmissible. The genetic origin of the remaining seven viral gene segments may also critically contribute to transmissibility in mammals. Nevertheless, as H5N1 viruses continue to evolve and infect humans, receptor-binding variants of H5N1 viruses with pandemic potential, including avian-human reassortant viruses as tested here, may emerge. Our findings emphasize the need to prepare for potential pandemics caused by influenza viruses possessing H5 HA, and will help individuals conducting surveillance in regions with circulating H5N1 viruses to recognize key residues that predict the pandemic potential of isolates, which will inform the development, production and distribution of effective countermeasures.     

High entropy state of orientationally-disordered clusters in Zr-based bulk metallic glass

A phase transformation of a metastable Zr2Ni intermetallic crystalline phase to vitrify was studied with molecular dynamics (MD) simulations based on a plastic crystal model (PCM), which utilizes the orientational disorder of molecules of plastic crystals in a class of soft matter. The simulation results show ed that computational operations in MD-PCM for the random rotati ons of the clusters in the crystalline phase around their center of gravity and subsequent annealing lead to form a dense random pa cking structure from the metastable Zr2Ni phase. These randomly-rotated clusters provide high degrees of freedom in terms of atomic positions, which results in enhancing the glass-forming ability of the alloy. The critical fraction of the number of rotated cl usters for forming the glassy phase ( fc^R) is evaluated to be 0.75 ? 0.80. Thus, the critical fraction of the number of un-rotated clusters (fc^U=1?fc^R) is close to the critical concentration of site percolation for metallic materials. The mechanism of the metastable Zr2Ni phase to vitrify with increasing f^R was analyzed with a concept of communal entropy in the free volume theory with solid- and liquid-like cells proposed by Cohen and Grest. The MD-PCM for the metastable Zr2Ni phase suggests that Zr-based bulk metallic glass (BMG) can be regarded as an alloy in a high rotation entropy state of cl usters and that glass transition takes place by percolation of th e nuclei of a liquid-like glassy phase.     

采用死区补偿和输出电流补偿的数控UPS逆变器

为在不增加传感器的情况下,改善不间断电源(U PS)逆变器的输出动静态性能,提出了一种数字控制策略。该策略利用面积等效原理,将线性负载下的死区等效为方波扰动,利用前馈对其补偿;将输出电流视为对控制系统的扰动,并利用前馈补偿,通过对输出电压的微分运算获得输出滤波电容电流值,从而在不使用电流传感器的情况下,实现了对U PS逆变器的准双环控制。在1 kVA的样机上进行实验研究,其结果在额定阻性负载下的稳态总谐波畸变率(THD)为2.49%,空载与额定负载间阶越变化下的电压调整率为6.75%。结果表明:死区补偿和输出电流补偿有效,整个控制策略的可行。     

A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1

The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage. This stress-induced DNA damage may promote ageing, tumorigenesis, neuropsychiatric conditions and miscarriages. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates β(2)-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos. Activated β(2)-adrenoreceptors promote Gs-protein-dependent activation of protein kinase A (PKA), followed by the recruitment of β-arrestins, which desensitize G-protein signalling and function as signal transducers in their own right. Here we elucidate a molecular mechanism by which β-adrenergic catecholamines, acting through both Gs-PKA and β-arrestin-mediated signalling pathways, trigger DNA damage and suppress p53 levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, β-arrestin-1 (ARRB1), activated via β(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout (Arrb1(-/-)) mice, which show preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress, and in the testes, in which paternal stress may affect the offspring's genome. Our results highlight the emerging role of ARRB1 as an E3-ligase adaptor in the nucleus, and reveal how DNA damage may accumulate in response to chronic stress.     

Cloning of adiponectin receptors that mediate antidiabetic metabolic effects

Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.