Transition from one- to two-dimensional island growth on metal (110) surfaces induced by anisotropic corner rounding

We propose a kinetic model to describe the temperature dependence of the shape of islands formed during submonolayer epitaxy on anisotropic metal surfaces. Our model reveals that anisotropic corner rounding is the key atomic process responsible for a transition in island shape, from chain structures at lower temperatures, to compact islands at higher temperatures. Exploiting data for the temperature and flux scaling of the island density, we analyze such behavior observed experimentally in Cu/Pd(110) epitaxy, estimating activation barriers of 0.45 and 0.3 eV for anisotropic terrace diffusion, and 0.65 eV for the slow corner-rounding process

Asteroids' physical models from combined dense and sparse photometry and scaling of the YORP effect by the observed obliquity distribution

The larger number of models of asteroid shapes and their rotational states derived by the lightcurve inversion give us better insight into both the nature of individual objects and the whole asteroid population. With a larger statistical sample we can study the physical properties of asteroid populations, such as main-belt asteroids or individual asteroid families, in more detail. Shape models can also be used in combination with other types of observational data (IR, adaptive optics images, stellar occultations), e.g., to determine sizes and thermal properties. We use all available photometric data of asteroids to derive their physical models by the lightcurve inversion method and compare the observed pole latitude distributions of all asteroids with known convex shape models with the simulated pole latitude distributions. We used classical dense photometric lightcurves from several sources and sparse-in-time photometry from the U.S. Naval Observatory in Flagstaff, Catalina Sky Survey, and La Palma surveys (IAU codes 689, 703, 950) in the lightcurve inversion method to determine asteroid convex models and their rotational states. We also extended a simple dynamical model for the spin evolution of asteroids used in our previous paper. We present 119 new asteroid models derived from combined dense and sparse-in-time photometry. We discuss the reliability of asteroid shape models derived only from Catalina Sky Survey data (IAU code 703) and present 20 such models. By using different values for a scaling parameter cYORP (corresponds to the magnitude of the YORP momentum) in the dynamical model for the spin evolution and by comparing synthetics and observed pole-latitude distributions, we were able to constrain the typical values of the cYORP parameter as between 0.05 and 0.6.Comment: Accepted for publication in A&A, January 15, 201

First events from the CNGS neutrino beam detected in the OPERA experiment

The OPERA neutrino detector at the underground Gran Sasso Laboratory (LNGS) was designed to perform the first detection of neutrino oscillations in appearance mode, through the study of nu_mu to nu_tau oscillations. The apparatus consists of a lead/emulsion-film target complemented by electronic detectors. It is placed in the high-energy, long-baseline CERN to LNGS beam (CNGS) 730 km away from the neutrino source. In August 2006 a first run with CNGS neutrinos was successfully conducted. A first sample of neutrino events was collected, statistically consistent with the integrated beam intensity. After a brief description of the beam and of the various sub-detectors, we report on the achievement of this milestone, presenting the first data and some analysis results.Comment: Submitted to the New Journal of Physic

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US)

Kinase inhibitors for the treatment of inflammatory and autoimmune disorders

Drugs targeting inhibition of kinases for the treatment of inflammation and autoimmune disorders have become a major focus in the pharmaceutical and biotech industry. Multiple kinases from different pathways have been the targets of interest in this endeavor. This review describes some of the recent developments in the search for inhibitors of IKK2, Syk, Lck, and JAK3 kinases. It is anticipated that some of these compounds or newer inhibitors of these kinases will be approved for the treatment of rheumatoid arthritis, psoriasis, organ transplantation, and other autoimmune diseases

Identification of Human IKK-2 Inhibitors of Natural Origin (Part I): Modeling of the IKK-2 Kinase Domain, Virtual Screening and Activity Assays

BACKGROUND: Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits. METHODOLOGY/PRINCIPAL FINDINGS: We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2. CONCLUSIONS/SIGNIFICANCE: We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request

Preparation of CS-MWNT and its biocompatibility

本研究利用壳聚糖和碳纳米管具有生物活性及对骨细胞的高亲和性，从组成和结构仿生的思路出发，把无机碳纳米管与有机壳聚糖两种材料复合，制备出界面结合好、溶解性好、稳定性好和分散性高的壳聚糖共价接枝碳纳米管复合膜，得到具有生物活性和生物相容性，能够促进骨细胞增殖、分化和引导骨组织器官再生的骨修复材料。 以壳聚糖和多壁碳纳米管为材料，用混酸对多壁碳纳米管表面进行羧基化修饰，使其与含有氨基的壳聚糖发生酰化反应，制备出一种新型的壳聚糖共价接枝碳纳米管复合膜，并探讨温度、pH值、乙酸浓度和材料配比等条件对制备复合膜的影响；采用透射电镜（TEM）、扫描电镜（SEM）、红外光谱（FTIR）、X射线光电子能谱（X...The thought and main points of the design for Carbon nanotubes/chitosan composite were put forward according to structural feature of nature bone which is made of inorganic and organic, since both carbon nanotubes and chitosan are attractive biocompatibility and biological activity to osteoblast. A novel Chitosan grafted multiwalled carbon nanotubes film (CS-MWNT) was prepared through covalently ...学位：理学硕士院系专业：材料学院生物材料系_☆生物医学工程学号：2452007115251

Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype

Purpose Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach. Methods Whole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays. Results We identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70. Conclusion This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching