Precipitous weakening of quartz at the α–β phase inversion

Crystalline quartz has long been identified as among the weakest of abundant crustal minerals. This weakness is particularly evident around the α–β phase inversion at 573°C, in which Si–O bonds undergo a displacive structural transformation from trigonal to hexagonal symmetry. Here we present data using indentation testing methodologies that highlight the precipitous extent of the transformational weakening. Although the indentations are localized over relatively small specimen contact areas, the data quantify the essential deformation and fracture properties of quartz in a predominantly (but not exclusively) compressive stress field, at temperatures and pressures pertinent to conditions in the earth's crust.     

Methyltransferase Contingencies in the Pathway of Everninomicin D Antibiotics and Analogues

Everninomicins are orthoester oligosaccharide antibiotics with potent activity against multidrug-resistant bacterial pathogens. Everninomicins act by disrupting ribosomal assembly in a distinct region in comparison to clinically prescribed drugs. We employed microporous intergeneric conjugation with Escherichia coli to manipulate Micromonospora for targeted gene-replacement studies of multiple putative methyltransferases across the octasaccharide scaffold of everninomicin effecting the A₁, C, F, and H rings. Analyses of gene-replacement and genetic complementation mutants established the mutability of the everninomicin scaffold through the generation of 12 previously unreported analogues and, together with previous results, permitted assignment of the ten methyltransferases required for everninomicin biosynthesis. The in vitro activity of A₁- and H-ring-modifying methyltransferases demonstrated the ability to catalyze late-stage modification of the scaffold on an A₁-ring phenol and H-ring C-4’ hydroxy moiety. Together these results establish the potential of the everninomicin scaffold for modification through mutagenesis and in vitro modification of advanced biosynthetic intermediates.     

Evaluation of standard and real fire exposures on thermal response of rail car floor assembly

This work developed a computational methodology to evaluate and compare standard fire exposures such as those outlined in ASTM E119 with real fire exposures and determine the difference in the temperature rise of a rail car floor assembly. The real fire exposures simulated in this work were identified in a review of incidents and consisted of a constantly-fed diesel fuel spill, a localized trash fire, and a gasoline spill simulated from a collision of the railcar with an automobile. These realistic fire exposures were applied to a variety of exemplar rail cars representative of single-level and bi-level passenger cars. These floor assembly models exposed to realistic fires were simulated in Fire Dynamics Simulator (FDS). The thermal exposure at the underside of railcar provided by FDS was coupled with a thermal model in ABAQUS, which provided the evolution of temperature in different components of the floor assembly. The standard scenarios were simulated for 2 hours instead of the typical 30 minutes to identify the appropriate exposure duration in ASTM E119, which can better represent a real fire scenario. The average and maximum temperatures predicted at the unexposed surface for both scenarios were compared with the threshold values given in NFPA 130.     

The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

嵌入式设备网络安全的实际解决方案

嵌入式设备在很多应用场合正在和因特网相连接，比如蜂窝电话、机顶盒、无线接入点、医疗设备和公共信息电话亭。当这些能够上网的设备与因特网连接，但是没有足够的安全考虑时，他们将很容易受到攻击，这些攻击包括无意的访问和恶意攻击。如果没有一些相应安全措施，这些攻击可能会使设备的功能、操作以及包含的信息遭受破坏。     

Thermomechanical finite-element model of shell behavior in continuous casting of steel

A coupled finite-element model, CON2D, has been developed to simulate temperature, stress, and shape development during the continuous casting of steel, both in and below the mold. The model simulates a transverse section of the strand in generalized plane strain as it moves down at the casting speed. It includes the effects of heat conduction, solidification, nonuniform superheat dissipation due to turbulent fluid flow, mutual dependence of the heat transfer and shrinkage on the size of the interfacial gap, the taper of the mold wall, and the thermal distortion of the mold. The stress model features an elastic-viscoplastic creep constitutive equation that accounts for the different responses of the liquid, semisolid, delta-ferrite, and austenite phases. Functions depending on temperature and composition are employed for properties such as thermal linear expansion. A contact algorithm is used to prevent penetration of the shell into the mold wall due to the internal liquid pressure. An efficient two-step algorithm is used to integrate these highly nonlinear equations. The model is validated with an analytical solution for both temperature and stress in a solidifying slab. It is applied to simulate continuous casting of a 120 mm billet and compares favorably with plant measurements of mold wall temperature, total heat removal, and shell thickness, including thinning of the corner. The model is ready to investigate issues in continuous casting such as mold taper optimization, minimum shell thickness to avoid breakouts, and maximum casting speed to avoid hot-tear crack formation due to submold bulging.