层状多孔晶体的结构，充满活力和动态的研究

Separation of highly similar molecules and understanding the underlying mechanism are of paramount theoretical and practical importance, but visualization of the host-guest structure, energy, or dynamism is very difficult and many details have been overlooked. Here, we report a new porous coordination polymer featuring hierarchical porosity and delicate flexibility, in which the three structural isomers of xylene (also similar disubstituted benzene derivatives) can be efficiently separated with an elution sequence inversed with those for conventional mechanisms. More importantly, the separation mechanism is comprehensively and quantitatively visualized by single-crystal X-ray crystallography coupled with multiple computational simulation methods, in which the small apertures not only fit best the smallest para-isomer like molecular sieves, but also show seemingly trivial yet crucial structural alterations to distinguish the meta- and ortho-isomers via a gating mechanism, while the large channels allow fast guest diffusion and enable the structural/energetic effects to be accumulated in the macroscopic level.

• http://feeds.nature.com/~r/srep/rss/current/~3/pJwMx4sjcSg/srep11537

[详细]

音乐训练，个体差异和鸡尾酒会问题

Are musicians better able to understand speech in noise than non-musicians? Recent findings have produced contradictory results. Here we addressed this question by asking musicians and non-musicians to understand target sentences masked by other sentences presented from different spatial locations, the classical ‘cocktail party problem’ in speech science. We found that musicians obtained a substantial benefit in this situation, with thresholds ~6 dB better than non-musicians. Large individual differences in performance were noted particularly for the non-musically trained group. Furthermore, in different conditions we manipulated the spatial location and intelligibility of the masking sentences, thus changing the amount of ‘informational masking’ (IM) while keeping the amount of ‘energetic masking’ (EM) relatively constant. When the maskers were unintelligible and spatially separated from the target (low in IM), musicians and non-musicians performed comparably. These results suggest that the characteristics of speech maskers and the amount of IM can influence the magnitude of the differences found between musicians and non-musicians in multiple-talker “cocktail party” environments. Furthermore, considering the task in terms of the EM-IM distinction provides a conceptual framework for future behavioral and neuroscientific studies which explore the underlying sensory and cognitive mechanisms contributing to enhanced “speech-in-noise” perception by musicians.

• http://feeds.nature.com/~r/srep/rss/current/~3/hP0gjr8rSzo/srep11628

[详细]

使用体外生物膜模型评估细菌性阴道病或非细菌性阴道炎阴道加德纳菌分离株的毒力潜力

Gardnerella vaginalis is the most common species found in bacterial vaginosis (BV). However, it is also present in a significant proportion of healthy women and G. vaginalis vaginal colonization does not always lead to BV. In an effort to better understand the differences between G. vaginalis isolated from women with a positive (BV) versus a negative (non-BV) diagnosis of BV, we compared the virulence potential of 7 BV and 7 non-BV G. vaginalis isolates and assessed the virulence factors related to biofilm formation, namely: initial adhesion and cytotoxic effect, biofilm accumulation, susceptibility to antibiotics, and transcript levels of the known vaginolysin, and sialidase genes. Furthermore, we also determined the ability of G. vaginalis to displace lactobacilli previously adhered to HeLa cells. Our results showed that non-BV strains were less virulent than BV strains, as suggested by the lower cytotoxicity and initial adhesion to Hela cells. Significant differences in expression of known virulence genes were also detected, further suggesting a higher virulence potential of the BV associated G. vaginalis. Importantly, we demonstrated that BV associated G. vaginalis were able to displace pre-coated vaginal protective lactobacilli and we hypothesize this to be a trigger for BV development.

• http://feeds.nature.com/~r/srep/rss/current/~3/IeY2hPDov60/srep11640

[详细]

重组免疫毒素传递到实体肿瘤定量允许体内和体外实验结果的直接比较

Solid tumors present challenges for delivery of protein therapeutics; current methods cannot quantify the functional effects of these agents. RG7787 (anti-mesothelin recombinant immunotoxin) is highly cytotoxic to pancreatic cancer cell lines, but with limited activity in vivo. To investigate this discrepancy, we developed a flow cytometry method to quantify the amount of RG7787 internalized per cell in tumors and used it to analyze tumor responses by determining the number of molecules of RG7787 internalized per cell in vivo and comparing it to that needed to kill cells in vitro. At a maximum tolerated dose of 7.5 mg/kg, tumor cells in vivo internalized a wide range of RG7787 with the average amount equivalent to the amount that induced growth arrest in vitro. However, 20% of cells accumulated 20,300 ITs per cell, sufficient to kill cells in vitro. At 2.5 mg/kg the top 20% of cells internalized enough RG7787 to only induce growth arrest. These data are in agreement with tumor responses; 22% regression following a 7.5 mg/kg dose and growth stabilization following 2.5 mg/kg. Comparing amounts of RIT delivered in vivo and in vitro can explain tumor responses and should facilitate the development of more active immunotoxins and other antibody based agents.

• http://feeds.nature.com/~r/srep/rss/current/~3/vpMLa3Q3CsM/srep10832

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其模块化可溶性蛋白前体的蜘蛛丝纤维结构

Spiders store spidroins in their silk glands as high concentration aqueous solutions, spinning these dopes into fibres with outstanding mechanical properties. Aciniform (or wrapping) silk is the toughest spider silk and is devoid of the short amino acid sequence motifs characteristic of the other spidroins. Using solution-state NMR spectroscopy, we demonstrate that the 200 amino acid Argiope trifasciata AcSp1 repeat unit contrasts with previously characterized spidroins, adopting a globular 5-helix bundle flanked by intrinsically disordered N- and C-terminal tails. Split-intein-mediated segmental NMR-active isotope-enrichment allowed unambiguous demonstration of modular and malleable “beads-on-a-string” concatemeric behaviour. Concatemers form fibres upon manual drawing with silk-like morphology and mechanical properties, alongside secondary structuring and orientation consistent with native AcSp1 fibres. AcSp1 structural stability varies locally, with the fifth helix denaturing most readily. The structural transition of aciniform spidroin from a mostly α-helical dope to a mixed α-helix/β-sheet-containing fibre can be directly related to spidroin architecture and stability.

• http://feeds.nature.com/~r/srep/rss/current/~3/RGsswLQGq8E/srep11502

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一种从膜相互作用的人蛋白中发现的非阳离子的细胞穿透肽及其潜在的作为蛋白质传递载体

Cell penetrating peptides (CPPs) are peptides that can be translocated into cells and used as a carrier platform for the intracellular uptake of cargo molecules. Subject to the source of CPP sequences and their positively charged nature, the cytotoxicity and immunogenicity of conventional CPPs needs to be optimized to expand their utility for biomedical applications. In addition to these safety issues, the stability of CPPs needs to be addressed since their positively charged residues are prone to interact with the biological milieu. As an effort to overcome these limitations of the current CPP technology, we isolated CPP candidate sequences and synthesized peptides from twelve isoforms of annexin, a family of membrane-interacting human proteins. The candidate screen returned a CPP rich in hydrophobic residues that showed more efficient cellular uptake than TAT-CPP. We then investigated the uptake mechanism, subcellular localization, and biophysical properties of the newly found CPP, verifying low cytotoxicity, long-term serum stability, and non-immunogenicity. Finally, model proteins conjugated to this peptide were successfully delivered into mammalian cells both in vitro and in vivo, indicating a potential use of the peptide as a carrier for the delivery of macromolecular cargos.

• http://feeds.nature.com/~r/srep/rss/current/~3/MVPn7XO9QXU/srep11719

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通过氟化调谐锐钛矿的电子结构

A highly fluorinated anatase lattice has been recently reported, providing a new class of materials whose general chemical formula is Ti1−x□xX4xO2−4x (X− = F− or OH−). To characterise the complex structural features of the material and the different F environments, we here apply a computational screening procedure. After deriving a polarisable force—field from DFT simulations, we screen in a step-wise fashion a large number of possible configurations differing in the positioning of the titanium vacancies (□) and of the fluorine atoms. At each step only 10% of the configurations are retained. At the end of the screening procedure, a configuration is selected and simulated using DFT-based molecular dynamics. This allows us to analyse the atomic structure of the material, which is strongly disordered, leading to a strong decrease (by 0.8 eV) of the band gap compared to conventional anatase.

• http://feeds.nature.com/~r/srep/rss/current/~3/37trnlC3TaU/srep11553

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莫霍面地形，利用地球重力场模型和GOCE数据分析范围和褶皱西藏

The determination of the crustal structure is essential in geophysics, as it gives insight into the geohistory, tectonic environment, geohazard mitigation, etc. Here we present the latest advance on three-dimensional modeling representing the Tibetan Mohorovičić discontinuity (topography and ranges) and its deformation (fold), revealed by analyzing gravity data from GOCE mission. Our study shows noticeable advances in estimated Tibetan Moho model which is superior to the results using the earlier gravity models prior to GOCE. The higher quality gravity field of GOCE is reflected in the Moho solution: we find that the Moho is deeper than 65 km, which is twice the normal continental crust beneath most of the Qinghai-Tibetan plateau, while the deepest Moho, up to 82 km, is located in western Tibet. The amplitude of the Moho fold is estimated to be ranging from −9 km to 9 km with a standard deviation of ~2 km. The improved GOCE gravity derived Moho signals reveal a clear directionality of the Moho ranges and Moho fold structure, orthogonal to deformation rates observed by GPS. This geophysical feature, clearly more evident than the ones estimated using earlier gravity models, reveals that it is the result of the large compressional tectonic process.

• http://feeds.nature.com/~r/srep/rss/current/~3/zYktT7NyMWM/srep11681

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空间结构植物群落中的气候事件的间隙形成

Gaps play a crucial role in maintaining species diversity, yet how community structure and composition influence gap formation is still poorly understood. We apply a spatially structured community model to predict how species diversity and intraspecific aggregation shape gap patterns emerging after climatic events, based on species-specific mortality responses. In multispecies communities, average gap size and gap-size diversity increased rapidly with increasing mean mortality once a mortality threshold was exceeded, greatly promoting gap recolonization opportunity. This result was observed at all levels of species richness. Increasing interspecific difference likewise enhanced these metrics, which may promote not only diversity maintenance but also community invasibility, since more diverse niches for both local and exotic species are provided. The richness effects on gap size and gap-size diversity were positive, but only expressed when species were sufficiently different. Surprisingly, while intraspecific clumping strongly promoted gap-size diversity, it hardly influenced average gap size. Species evenness generally reduced gap metrics induced by climatic events, so the typical assumption of maximum evenness in many experiments and models may underestimate community diversity and invasibility. Overall, understanding the factors driving gap formation in spatially structured assemblages can help predict community secondary succession after climatic events.

• http://feeds.nature.com/~r/srep/rss/current/~3/7mYVh5wqrs8/srep11721

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[深入]加强基因控制的观点

Although researchers have scrutinized genes as if they were Hollywood celebrities, the stretches of regulatory DNA called enhancers have largely stayed in the background, their workings a mystery. A recent genetics meeting signaled a change: In talk after talk, researchers described where and how these quiet fixers exert their influence. One group showed how enhancers maintain the right level of sensitivity to other signals, so that they switch on genes only at the right times and places. Others explored how cells package genes and their enhancers so that they can work together properly, and how DNA forms loops that bring enhancers right to the target gene. The advances even point to strategies for exploiting these regulatory elements to treat disease, by switching off disease genes and turning up the activity of healthy ones.

• http://www.sciencemag.org/content/348/6242/1407.summary?rss=1

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转录因子结合基序中的不同程度的复杂度

Binding of transcription factors to DNA is one of the keystones of gene regulation. The existence of statistical dependencies between binding site positions is widely accepted, while their relevance for computational predictions has been debated. Building probabilistic models of binding sites that may capture dependencies is still challenging, since the most successful motif discovery approaches require numerical optimization techniques, which are not suited for selecting dependency structures. To overcome this issue, we propose sparse local inhomogeneous mixture (Slim) models that combine putative dependency structures in a weighted manner allowing for numerical optimization of dependency structure and model parameters simultaneously. We find that Slim models yield a substantially better prediction performance than previous models on genomic context protein binding microarray data sets and on ChIP-seq data sets. To elucidate the reasons for the improved performance, we develop dependency logos, which allow for visual inspection of dependency structures within binding sites. We find that the dependency structures discovered by Slim models are highly diverse and highly transcription factor-specific, which emphasizes the need for flexible dependency models. The observed dependency structures range from broad heterogeneities to sparse dependencies between neighboring and non-neighboring binding site positions.

• http://nar.oxfordjournals.org/cgi/content/short/gkv577v1?rss=1

[详细]

脂肪酸酰胺水解酶催化脂选择键：结构灵活，门控残基和多个结合口袋

by Giulia Palermo, Inga Bauer, Pablo Campomanes, Andrea Cavalli, Andrea Armirotti, Stefania Girotto, Ursula Rothlisberger, Marco De Vivo

The fatty acid amide hydrolase (FAAH) regulates the endocannabinoid system cleaving primarily the lipid messenger anandamide. FAAH has been well characterized over the years and, importantly, it represents a promising drug target to treat several diseases, including inflammatory-related diseases and cancer. But its enzymatic mechanism for lipid selection to specifically hydrolyze anandamide, rather than similar bioactive lipids, remains elusive. Here, we clarify this mechanism in FAAH, examining the role of the dynamic paddle, which is formed by the gating residues Phe432 and Trp531 at the boundary between two cavities that form the FAAH catalytic site (the “membrane-access” and the “acyl chain-binding” pockets). We integrate microsecond-long MD simulations of wild type and double mutant model systems (Phe432Ala and Trp531Ala) of FAAH, embedded in a realistic membrane/water environment, with mutagenesis and kinetic experiments. We comparatively analyze three fatty acid substrates with different hydrolysis rates (anandamide > oleamide > palmitoylethanolamide). Our findings identify FAAH’s mechanism to selectively accommodate anandamide into a multi-pocket binding site, and to properly orient the substrate in pre-reactive conformations for efficient hydrolysis that is interceded by the dynamic paddle. Our findings therefore endorse a structural framework for a lipid selection mechanism mediated by structural flexibility and gating residues between multiple binding cavities, as found in FAAH. Based on the available structural data, this exquisite catalytic strategy for substrate specificity seems to be shared by other lipid-degrading enzymes with similar enzymatic architecture. The mechanistic insights for lipid selection might assist de-novo enzyme design or drug discovery efforts.

• http://feeds.plos.org/~r/ploscompbiol/NewArticles/~3/ZcUBeWXwsAY/info%3Adoi%2F10.1371%2Fjournal.pcbi.1004231

[详细]

纵向基因表达数据的时间序列基因集分析

by Boris P. Hejblum, Jason Skinner, Rodolphe Thiébaut

Gene set analysis methods, which consider predefined groups of genes in the analysis of genomic data, have been successfully applied for analyzing gene expression data in cross-sectional studies. The time-course gene set analysis (TcGSA) introduced here is an extension of gene set analysis to longitudinal data. The proposed method relies on random effects modeling with maximum likelihood estimates. It allows to use all available repeated measurements while dealing with unbalanced data due to missing at random (MAR) measurements. TcGSA is a hypothesis driven method that identifies a priori defined gene sets with significant expression variations over time, taking into account the potential heterogeneity of expression within gene sets. When biological conditions are compared, the method indicates if the time patterns of gene sets significantly differ according to these conditions. The interest of the method is illustrated by its application to two real life datasets: an HIV therapeutic vaccine trial (DALIA-1 trial), and data from a recent study on influenza and pneumococcal vaccines. In the DALIA-1 trial TcGSA revealed a significant change in gene expression over time within 69 gene sets during vaccination, while a standard univariate individual gene analysis corrected for multiple testing as well as a standard a Gene Set Enrichment Analysis (GSEA) for time series both failed to detect any significant pattern change over time. When applied to the second illustrative data set, TcGSA allowed the identification of 4 gene sets finally found to be linked with the influenza vaccine too although they were found to be associated to the pneumococcal vaccine only in previous analyses. In our simulation study TcGSA exhibits good statistical properties, and an increased power compared to other approaches for analyzing time-course expression patterns of gene sets. The method is made available for the community through an R package.

• http://feeds.plos.org/~r/ploscompbiol/NewArticles/~3/n_SCI0UfvoQ/info%3Adoi%2F10.1371%2Fjournal.pcbi.1004310

[详细]

抗生素的限制可能有助于多药耐药的出现

by Uri Obolski, Gideon Y. Stein, Lilach Hadany

High antibiotic resistance frequencies have become a major public health issue. The decrease in new antibiotics' production, combined with increasing frequencies of multi-drug resistant (MDR) bacteria, cause substantial limitations in treatment options for some bacterial infections. To diminish overall resistance, and especially the occurrence of bacteria that are resistant to all antibiotics, certain drugs are deliberately scarcely used—mainly when other options are exhausted. We use a mathematical model to explore the efficiency of such antibiotic restrictions. We assume two commonly used drugs and one restricted drug. The model is examined for the mixing strategy of antibiotic prescription, in which one of the drugs is randomly assigned to each incoming patient. Data obtained from Rabin medical center, Israel, is used to estimate realistic single and double antibiotic resistance frequencies in incoming patients. We find that broad usage of the hitherto restricted drug can reduce the number of incorrectly treated patients, and reduce the spread of bacteria resistant to both common antibiotics. Such double resistant infections are often eventually treated with the restricted drug, and therefore are prone to become resistant to all three antibiotics. Thus, counterintuitively, a broader usage of a formerly restricted drug can sometimes lead to a decrease in the emergence of bacteria resistant to all drugs. We recommend re-examining restriction of specific drugs, when multiple resistance to the relevant alternative drugs already exists.

• http://feeds.plos.org/~r/ploscompbiol/NewArticles/~3/ny7l0xK19hE/info%3Adoi%2F10.1371%2Fjournal.pcbi.1004340

[详细]

运动记忆的衰减是独立的上下文变化检测

by Andrew E. Brennan, Maurice A. Smith

When the error signals that guide human motor learning are withheld following training, recently-learned motor memories systematically regress toward untrained performance. It has previously been hypothesized that this regression results from an intrinsic volatility in these memories, resulting in an inevitable decay in the absence of ongoing error signals. However, a recently-proposed alternative posits that even recently-acquired motor memories are intrinsically stable, decaying only if a change in context is detected. This new theory, the context-dependent decay hypothesis, makes two key predictions: (1) after error signals are withheld, decay onset should be systematically delayed until the context change is detected; and (2) manipulations that impair detection by masking context changes should result in prolonged delays in decay onset and reduced decay amplitude at any given time. Here we examine the decay of motor adaptation following the learning of novel environmental dynamics in order to carefully evaluate this hypothesis. To account for potential issues in previous work that supported the context-dependent decay hypothesis, we measured decay using a balanced and baseline-referenced experimental design that allowed for direct comparisons between analogous masked and unmasked context changes. Using both an unbiased variant of the previous decay onset analysis and a novel highly-powered group-level version of this analysis, we found no evidence for systematically delayed decay onset nor for the masked context change affecting decay amplitude or its onset time. We further show how previous estimates of decay onset latency can be substantially biased in the presence of noise, and even more so with correlated noise, explaining the discrepancy between the previous results and our findings. Our results suggest that the decay of motor memories is an intrinsic feature of error-based learning that does not depend on context change detection.

• http://feeds.plos.org/~r/ploscompbiol/NewArticles/~3/aX1rSJrurOA/info%3Adoi%2F10.1371%2Fjournal.pcbi.1004278

[详细]

皮肤移植物和培养的角质形成细胞的基因表达分析，使用合成的核糖核酸正常化揭示了洞察分化和生长控制

Background: Keratinocytes (KCs) are the most frequent cells in the epidermis, and they are often isolated and cultured in vitro to study the molecular biology of the skin. Cultured primary cells and various immortalized cells have been frequently used as skin models but their comparability to intact skin has been questioned. Moreover, when analyzing KC transcriptomes, fluctuation of polyA+ RNA content during the KCs’ lifecycle has been omitted. Results: We performed STRT RNA sequencing on 10 ng samples of total RNA from three different sample types: i) epidermal tissue (split-thickness skin grafts), ii) cultured primary KCs, and iii) HaCaT cell line. We observed significant variation in cellular polyA+ RNA content between tissue and cell culture samples of KCs. The use of synthetic RNAs and SAMstrt in normalization enabled comparison of gene expression levels in the highly heterogenous samples and facilitated discovery of differences between the tissue samples and cultured cells. The transcriptome analysis sensitively revealed genes involved in KC differentiation in skin grafts and cell cycle regulation related genes in cultured KCs and emphasized the fluctuation of transcription factors and non-coding RNAs associated to sample types. Conclusions: The epidermal keratinocytes derived from tissue and cell culture samples showed highly different polyA+ RNA contents. The use of SAMstrt and synthetic RNA based normalization allowed the comparison between tissue and cell culture samples and thus proved to be valuable tools for RNA-seq analysis with translational approach. Transciptomics revealed clear difference both between tissue and cell culture samples and between primary KCs and immortalized HaCaT cells.

• http://www.biomedcentral.com/1471-2164/16/476

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血统：基因组结果重新燃起的法律行

'Kennewick Man' sequencing shows Native American roots.

• http://feeds.nature.com/~r/nature/rss/current/~3/R2gAf0C5PQw/522404a

[详细]

人的心脏和骨骼肌中蛋白质的转录组学、抗体定义为基础的分析

Background: To understand cardiac and skeletal muscle function, it is important to define and explore their molecular constituents and also to identify similarities and differences in the gene expression in these two different striated muscle tissues. Here, we have investigated the genes and proteins with elevated expression in cardiac and skeletal muscle in relation to all other major human tissues and organs using a global transcriptomics analysis complemented with antibody-based profiling to localize the corresponding proteins on a single cell level. Results: Our study identified a comprehensive list of genes expressed in cardiac and skeletal muscle. The genes with elevated expression were further stratified according to their global expression pattern across the human body as well as their precise localization in the muscle tissues. The functions of the proteins encoded by the elevated genes are well in line with the physiological functions of cardiac and skeletal muscle, such as contraction, ion transport, regulation of membrane potential and actomyosin structure organization. A large fraction of the transcripts in both cardiac and skeletal muscle correspond to mitochondrial proteins involved in energy metabolism, which demonstrates the extreme specialization of these muscle tissues to provide energy for contraction. Conclusions: Our results provide a comprehensive list of genes and proteins elevated in striated muscles. A number of proteins not previously characterized in cardiac and skeletal muscle were identified and localized to specific cellular subcompartments. These proteins represent an interesting starting point for further functional analysis of their role in muscle biology and disease.

• http://www.biomedcentral.com/1471-2164/16/475

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FRAP任意漂白模式分析的通用方法

The original approach to calculating diffusion coefficients of a fluorescent probe from Fluorescence Recovery After Photobleaching (FRAP) measurements assumes bleaching with a circular laser beam of a Gaussian intensity profile. This method was used without imaging the bleached cell. An empirical equation for calculating diffusion coefficients from a rectangular bleaching geometry, created in a confocal image, was later published, however a single method allowing the calculation of diffusion coefficients for arbitrary geometry does not exist. Our simulation approach allows computation of diffusion coefficients regardless of bleaching geometry used in the FRAP experiment. It accepts a multiple-frame TIFF file, representing the experiment as input, and simulates the (pure) diffusion of the fluorescent probes (2D random walk) starting with the first post-bleach frame of the actual data. It then fits the simulated data to the real data and extracts the diffusion coefficient. We validate our approach using a well characterized diffusing molecule (DiIC18) against well-established analytical procedures. We show that the algorithm is able to calculate the absolute value of diffusion coefficients for arbitrary bleaching geometries, including exaggeratedly large ones. It is provided freely as an ImageJ plugin, and should facilitate quantitative FRAP measurements for users equipped with standard fluorescence microscopy setups.

• http://feeds.nature.com/~r/srep/rss/current/~3/J6GizwqK-IQ/srep11655

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揭示当地物种丰富度随环境梯度的新网络工具

How species richness relates to environmental gradients at large extents is commonly investigated aggregating local site data to coarser grains. However, such relationships often change with the grain of analysis, potentially hiding the local signal. Here we show that a novel network technique, the “method of reflections”, could unveil the relationships between species richness and climate without such drawbacks. We introduced a new index related to potential species richness, which revealed large scale patterns by including at the local community level information about species distribution throughout the dataset (i.e., the network). The method effectively removed noise, identifying how far site richness was from potential. When applying it to study woody species richness patterns in Spain, we observed that annual precipitation and mean annual temperature explained large parts of the variance of the newly defined species richness, highlighting that, at the local scale, communities in drier and warmer areas were potentially the species richest. Our method went far beyond what geographical upscaling of the data could unfold, and the insights obtained strongly suggested that it is a powerful instrument to detect key factors underlying species richness patterns, and that it could have numerous applications in ecology and other fields.

• http://feeds.nature.com/~r/srep/rss/current/~3/49_r50nQnxY/srep11561

[详细]

细胞因子诱导的miRNA的表达和分泌的一种新的调制识别特定的qPCR检测microRNA

microRNAs are an abundant class of small non-coding RNAs that control gene expression post-transcriptionally. Importantly, microRNA activity participates in the regulation of cellular processes and is a potentially valuable source of biomarkers in the diagnosis and prognosis of human diseases. Here we introduce miQPCR, an innovative method to quantify microRNAs expression by using Real-Time PCR. miQPCR exploits T4 RNA ligase activities to extend uniformly microRNAs’ 3′-ends by addition of a linker-adapter. The adapter is then used as ‘anchor’ to prime cDNA synthesis and throughout qPCR to amplify specifically target amplicons. miQPCR is an open, adaptable and cost-effective procedure, which offers the following advantages; i) universal elongation and reverse transcription of all microRNAs; ii) Tm-adjustment of microRNA-specific primers; iii) high sensitivity and specificity in discriminating among closely related sequences and; iv) suitable for the analysis of cellular and cell-free circulating microRNAs. Analysis of cellular and cell-free circulating microRNAs secreted by rat primary hepatocytes stimulated with cytokines and growth factors identifies for the first time a widespread modulation of both microRNAs expression and secretion. Altogether, our findings suggest that the pleiotropic activity of humoral factors on microRNAs may extensively affect liver function in response to injury and regeneration.

• http://feeds.nature.com/~r/srep/rss/current/~3/hSiUm2rKgW4/srep11590

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失踪忆阻器尚未发现

In 1971, not only the theoretical and by definition already existing ‘ideal memristor’ concept was introduced, but a real memristor device was suggested on grounds of the already known real inductors. The latter is a scientifically significant hypothesis grounded in fundamental symmetries of basic physics, here electro-magnetism. 2008 claimed the discovery of the “missing memristor.” Controversy arose: The devices were not new, and the hypothesized device needs magnetism but has no material memory, while the available devices constitute analogue memory that would work in a world without magnetism. Nevertheless, even the originator of the prediction accepted the discovery. Defenders of the 2008 claim emphasize that the devices are not merely ‘memristive systems,’ which is however a distinction defined in 1976, not 1971. We clarify widely confused concepts and maintain that the originally hypothesized real memristor device is missing and likely impossible. The argument is illustrated also by finding an ideal mechanical memristor element and purely mechanical memristive systems, and hypothesizing a real mechanical memristor device that requires inert mass just like the 1971 implied device requires magnetic induction.

• http://feeds.nature.com/~r/srep/rss/current/~3/1jtNeNiu_Ys/srep11657

[详细]

甜菜黑色焦枯病毒外壳蛋白PKA磷酸化是病毒颗粒的装配和稳定的需要

Plant virus coat proteins (CPs) play a fundamental role in protection of genomic RNAs, virion assembly, and viral movement. Although phosphorylation of several CPs during virus infection have been reported, little information is available about CP phosphorylation of the spherical RNA plant viruses. Here, we demonstrate that the CP of Beet black scorch virus (BBSV), a member of the genus Necrovirus, can be phosphorylated at threonine-41 (T41) by cAMP-dependent protein kinase (PKA)-like kinase in vivo and in vitro. Mutant viruses containing a T41A non-phosphorylatable alanine substitution, and a T41E glutamic acid substitution to mimic threonine phosphorylation were able to replicate but were unable to move systemically in Nicotiana benthamiana. Interestingly, the T41A and T41E mutants generated unstable 17 nm virus-like particles that failed to package viral genomic (g) RNA, compared with wild-type BBSV with 30 nm virions during viral infection in N. benthamiana. Further analyses showed that the T41 mutations had little effect on the gRNA-binding activity of the CP. Therefore, we propose a model whereby CP phosphorylation plays an essential role in long-distance movement of BBSV that involves formation of stable virions.

• http://feeds.nature.com/~r/srep/rss/current/~3/dlhOJeju740/srep11585

[详细]

整合素 β2替代磷酸化开关（CD18）为dok1结合尾

Integrins are involved in cell migration and adhesion. A large number of proteins interact with the cytoplasmic tails of integrins. Dok1 is a negative regulator of integrin activation and it binds to the phosphorylated membrane proximal NxxY motif in a number of integrin β tails. The β tail of the β2 integrins contains a non-phosphorylatable NxxF motif. Hence it is unclear how Dok1 associates with the β2 integrins. We showed in this study using NMR and cell based analyses that residues Ser745 and Ser756 in the integrin β2 tail, which are adjacent to the NxxF motif, are required for Dok1 interaction. NMR analyses detected significant chemical shift changes and higher affinity interactions between Dok1 phospho-tyrosine binding (PTB) domain and integrin β2 tail peptide containing pSer756 compared to pSer745. The phosphorylated β2 peptide occupies the canonical ligand binding pocket of Dok1 based on the docked structure of the β2 tail-Dok1 PTB complex. Taken together, our data suggest an alternate phosphorylation switch in β2 integrins that regulates Dok1 binding. This could be important for cells of the immune system and their functions.

• http://feeds.nature.com/~r/srep/rss/current/~3/NJM8oBz_j2w/srep11630

[详细]