Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes.

We describe a codon 299 mutation in the glucokinase gene in a British pedigree with maturity-onset diabetes of the young (MODY) resulting in a substitution of glycine to arginine. One out of fifty patients diagnosed with classical late-onset type 2 diabetes mellitus was also found to have this mutation. All nine relatives of this patient who have inherited the mutation have type 2 diabetes, although six others without the mutation are also present with diabetes. The discovery that glucokinase mutations can cause MODY and was also found in ten affected members of a pedigree with type 2 diabetes in which MODY had not previously been considered indicates that diagnosis based on molecular pathology will be helpful in understanding the aetiology of type 2 diabetes.     

Chitin in the epidermal cuticle of a vertebrate (Paralipophrys trigloides,Blenniidae, Teleostei)

Lectin binding, endo-chitinase binding and enzymatic degradation studies show that the epidermal cuticle of the bony fishParalipophrys trigloides (Blenniidae) is chitinous. This is the first evidence that a vertebrate species possesses a chitinous tissue. Recently aXenopus gene has been identified which has significant sequence similarity to the catalytic domain of yeast chitin synthase III, a chitin producing enzyme^1,2. Taken together these two findings imply that chitin synthesis capability may be a basic vertebrate feature.     

Strain-resolved community proteomics reveals recombining genomes of acidophilic bacteria

Microbes comprise the majority of extant organisms, yet much remains to be learned about the nature and driving forces of microbial diversification. Our understanding of how microorganisms adapt and evolve can be advanced by genome-wide documentation of the patterns of genetic exchange, particularly if analyses target coexisting members of natural communities. Here we use community genomic data sets to identify, with strain specificity, expressed proteins from the dominant member of a genomically uncharacterized, natural, acidophilic biofilm. Proteomics results reveal a genome shaped by recombination involving chromosomal regions of tens to hundreds of kilobases long that are derived from two closely related bacterial populations. Inter-population genetic exchange was confirmed by multilocus sequence typing of isolates and of uncultivated natural consortia. The findings suggest that exchange of large blocks of gene variants is crucial for the adaptation to specific ecological niches within the very acidic, metal-rich environment. Mass-spectrometry-based discrimination of expressed protein products that differ by as little as a single amino acid enables us to distinguish the behaviour of closely related coexisting organisms. This is important, given that microorganisms grouped together as a single species may have quite distinct roles in natural systems and their interactions might be key to ecosystem optimization. Because proteomic data simultaneously convey information about genome type and activity, strain-resolved community proteomics is an important complement to cultivation-independent genomic (metagenomic) analysis of microorganisms in the natural environment.     

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.     

A spectrograph for exoplanet observations calibrated at the centimetre-per-second level

The best spectrographs are limited in stability by their calibration light source. Laser frequency combs are the ideal calibrators for astronomical spectrographs. They emit a spectrum of lines that are equally spaced in frequency and that are as accurate and stable as the atomic clock relative to which the comb is stabilized. Absolute calibration provides the radial velocity of an astronomical object relative to the observer (on Earth). For the detection of Earth-mass exoplanets in Earth-like orbits around solar-type stars, or of cosmic acceleration, the observable is a tiny velocity change of less than 10 cm s(-1), where the repeatability of the calibration--the variation in stability across observations--is important. Hitherto, only laboratory systems or spectrograph calibrations of limited performance have been demonstrated. Here we report the calibration of an astronomical spectrograph with a short-term Doppler shift repeatability of 2.5 cm s(-1), and use it to monitor the star HD 75289 and recompute the orbit of its planet. This repeatability should make it possible to detect Earth-like planets in the habitable zone of star or even to measure the cosmic acceleration directly.     

Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation

Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ～7% of human malignancies and ～60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.     

PLC步进式伺服系统的研究

本文主要研究可编程序控制器(PLC)在步进式伺服系统中的应用。提出采用EX100PLC主机,辅以32点DC输出模块(DO32)或轴向定位模块(MC11)来控制步进电机,并用于精密磨床的进给控制的两种方案,分别进行了硬软件设计、完成实验室试验,并对两种控制方案的特点进行了分析研究。     

关于H性质和Schur性质的一些结果

本文在局部凸空间中定义了H性质和Schur性质,考虑了这两种性质在积空间和商空间的遗传。同时,也得到了具无条件基的Banach空间具H性质或Schur性质的充要条件。