Conformational Stabilization of Gp41-Mimetic Miniproteins Opens Up New Ways of Inhibiting HIV-1 Fusion

Inhibition of the HIV-1 fusion process constitutes a promising strategy to neutralize the virus at an early stage before it enters the cell. In this process, the envelope glycoprotein (Env) plays a central role by promoting membrane fusion. We previously identified a vulnerability at the flexible C-terminal end of the gp41 C-terminal heptad repeat (CHR) region to inhibition by a single-chain miniprotein (named covNHR-N) that mimics the first half of the gp41 N-terminal heptad repeat (NHR). The miniprotein exhibited low stability, moderate binding to its complementary CHR region, both as an isolated peptide and in native trimeric Envs, and low inhibitory activity against a panel of pseudoviruses. The addition of a disulfide bond stabilizing the miniprotein increased its inhibitory activity, without altering the binding affinity. Here, to further study the effect of conformational stability on binding and inhibitory potency, we additionally stabilized these miniproteins by engineering a second disulfide bond stapling their N-terminal end, The new disulfide-bond strongly stabilizes the protein, increases binding affinity for the CHR target and strongly improves inhibitory activity against several HIV-1 strains. Moreover, high inhibitory activity could be achieved without targeting the preserved hydrophobic pocket motif of gp41. These results may have implications in the discovery of new strategies to inhibit HIV targeting the gp41 CHR region.     

Synthesis, biological activity, and ADME properties of novel S-DABOs/N-DABOs as HIV reverse transcriptase inhibitors

Previous studies aimed at exploring the SAR of C2-functionalized S-DABOs demonstrated that the substituent at this position plays a key role in the inhibition of both wild-type RT and drug-resistant enzymes, particularly the K103N mutant form. The introduction of a cyclopropyl group led us to the discovery of a potent inhibitor with picomolar activity against wild-type RT and nanomolar activity against many key mutant forms such as K103N. Despite its excellent antiviral profile, this compound suffers from a suboptimal ADME profile typical of many S-DABO analogues, but it could, however, represent a promising candidate as an anti-HIV microbicide. In the present work, a new series of S-DABO/N-DABO derivatives were synthesized to obtain additional SAR information on the C2-position and in particular to improve ADME properties while maintaining a good activity profile against HIV-1 RT. In vitro ADME properties (PAMPA permeation, water solubility, and metabolic stability) were also experimentally evaluated for the most interesting compounds to obtain a reliable indication of their plasma levels after oral administration.     

技术的盛宴——香港PISSARRO餐厅

Michael Young毫无疑问是一位知名度很高的工业设计师。他最近的产品设计里面包括一些自行车、水瓶、U盘和稀奇古怪的各种“小”东西。所以，他在接手这个餐厅的时候，Michael还是有点犹豫的：这和一个独立的产品设计在规模上有很大的不同，不得不考虑很多在产品设计中不存在的因素。     

赤裸的自然

1986年,一对来自意大利南部的年轻的兄弟, Ennio与Carlo Capasa,在米兰工作很长时间之后, 创立一个新的时装店——Costume National。在短短几年之后,这个服装品牌迅速成为五光十色的意大利时尚界最为著名的品牌之一。Costume National与其他成熟品牌一样崇尚自然存在主义精神,这种精神也深深扎根在两位创立者的血液中。但又有所不同, Costume National受到了非意大利传统的影响。因此,它的形象很难与常规的民族风尚联系在一起。很多人并不知道Capasa兄弟来自Lecce(位于意大利东南沿海),这个名字很容易让人联想到这可能是起源于日本,例如由Rei Kawakubo创立的 commes des Garcons品牌就是如此。这个结论是有根据的：Ennio Capasa曾经在东京与Yohji Ya－ mamoto一起工作过很多年,在他的作品中有明显的日式风格。然而,Costume National的服装并不与日本趋同,在服装的款式上有自己的独到之处。与 Yohji Yamamoto所树立的样式不同,Capasa的设计与意大利传统的裁缝业密切联系,这样做并没有约束到品牌的发展,反而提高了自身的品质。     

Synthesis,spectral, structural,Hirshfeld surface and DFT studies on bis(N-(4-fluorobenzyl)-N-(2-phenylethyl)dithiocarbamato-S,S′)zinc(II) and its use for the preparation of ZnS and ZnO nanoparticles

Two new complexes, bis(N-(2-phenylethyl)-N-(4-fluorobenzyl)dithiocarbamato-S,S′)zinc(II) (1) and bis(N-(2-phenylethyl)-N-(4-chlorobenzyl)dithiocarbamato-S,S′)zinc(II) (2), have been synthesized and characterized by various physicochemical techniques. Structure of 1 has been determined by single crystal X-ray diffraction. Complex 1 is a dimer. Zinc atom is four coordinated with a distorted tetrahedral environment. Geometry optimization, geometrical parameters, molecular electrostatic potential (MEPs) and frontier molecular orbital analysis of dimeric and monomeric structures of 1 have been carried out by DFT methods and compared with the experimental X-ray diffraction data. The noncovalent interactions in the complex 1 have been analyzed using Hirshfeld surface analysis. 1 and 2 have been used as single source precursors for the preparation of zinc sulfide and zinc oxide nanoparticles. As-prepared zinc sulfides and zinc oxides have been characterized by powder X-ray diffraction (PXRD), scanning electron microscope (SEM), UV–vis absorption, photoluminence and energy dispersive X-ray spectroscopy (EDS). X-ray diffraction study reveals that zinc sulfides and zinc oxides are composed of rhombohedral and hexagonal phases, respectively. Photocatalytic activities of zinc sulfides and zinc oxides were evaluated by degradation of rhodamine B in aqueous solution under UV light irradiation. The results demonstrated the capability of zinc sulfides and zinc oxides as photocatalyst under UV irradiation to degrade the dye.     

Soft‐Lithographed Up‐Converted Distributed Feedback Visible Lasers Based on CdSe–CdZnS–ZnS Quantum Dots

The development of a solution‐deposited up‐converted distributed feedback laser prototype is presented. It employs a sol–gel silica/germania soft‐lithographed microcavity and CdSe–CdZnS–ZnS quantum dot/sol–gel zirconia composites as optical gain material. Characterization of the linear and nonlinear optical properties of quantum dots establishes their high absorption cross‐sections in the one‐ and two‐ photon absorption regimes to be 1 × 10^?14 cm² and 5 × 10⁴ GM, respectively. In addition, ultrafast transient absorption dynamics measurements of the graded seal quantum dots reveal that the Auger recombination lifetime is 220 ps, a value two times higher than that of the corresponding CdSe core. These factors enable the use of such quantum dots as optically pumped gain media, operating in the one‐ and two‐photon absorption regime. The incorporation of CdSe–CdZnS–ZnS quantum dots within a zirconia host matrix affords a quantum‐dot ink that can be directly deposited on our soft‐lithographed distributed feedback grating to form an all‐solution‐processed microcavity laser.     

Toward a better understanding of multifunctional cement-based materials: The impact of graphite nanoplatelets (GNPs)

The impact of graphite nanoplatelets (GNPs) on the physical and mechanical properties of cementitious nanocomposites was investigated. A market-available premixed mortar was modified with 0.01% by weight of cement of commercial GNPs characterized by two distinctively different aspect ratios.The rheological behavior of the GNP-modified fresh admixtures was thoroughly evaluated. Hardened cementitious nanocomposites were investigated in terms of density, microstructure (Scanning Electron Microscopy, SEM and micro–Computed Tomography, μ-CT), mechanical properties (three-point bending and compression tests), and physical properties (electrochemical impedance spectroscopy, EIS and thermal conductivity measurements). At 28 days, all GNP-modified mortars showed about 12% increased density. Mortars reinforced with high aspect ratio GNPs exhibited the highest compressive and flexural strength: about 14% and 4% improvements compared to control sample, respectively. Conversely, low aspect ratio GNPs led to cementitious nanocomposites characterized by 36% decreased electrical resistivity combined with 60% increased thermal conductivity with respect to the control sample.     

准备出发

在经过多年品牌形象的发展后，意大利国家航空公司（Alitatia）决定聘请著名的设计师马西莫伊欧萨·吉尼（Massimo losa Ghini）为该品牌设计一种新型的现代形象。马西莫伊欧萨·吉尼本人与Ferrari形象品牌的合作在近年取得了巨大的成功。