In Vivo Albumin-Binding of a C-Functionalized Cyclam Platform for 64Cu-PET/CT Imaging in Breast Cancer Model

An improved glucose-chelator-albumin bioconjugate (GluCAB) derivative, GluCAB-2^Mal, has been synthesized and studied for in vivo ⁶⁴Cu-PET/CT imaging in breast cancer mice models together with its first-generation analogue GluCAB-1^Mal. The radioligand works on the principle of tumor targeting through the enhanced permeability and retention (EPR) effect with a supportive role played by glucose metabolism. [⁶⁴Cu]Cu-GluCAB-2^Mal (99 % RCP) exhibited high serum stability with immediate binding to serum proteins. In vivo experiments for comparison between tumor targeting of [⁶⁴Cu]Cu-GluCAB-2^Mal and previous-generation [⁶⁴Cu]Cu-GluCAB-1^Mal encompassed microPET/CT imaging and biodistribution analysis in an allograft E0771 breast cancer mouse model. Tumor uptake of [⁶⁴Cu]Cu-GluCAB-2^Mal was clearly evident with twice as much accumulation as compared to its predecessor and a tumor/muscle ratio of up to 5 after 24 h. Further comparison indicated a decrease in liver accumulation for [⁶⁴Cu]Cu-Glu-CAB-2^Mal.     

Application of Mono‐ and Disaccharides in Drug Targeting and Efficacy

Carbohydrates and their conjugates play important roles in many biological processes including fertilization, differentiation, development, immune response, and infection. Their activities are largely dependent on the properties of terminal mono‐ or disaccharides. Galactose, mannose, fucose, glucose, sialic acid, etc., are commonly used as powerful scaffolds installed on drug molecules for targeting specific tissues including brain, liver, and cancers, and as epitopes for enhancing the targeting of various vaccines. This review focuses on the influence of their structural variations, including changes in sugar type, substituent groups and their positions, as well as length of linker portion, on the targeting of drugs or their efficacy. Particular attention is paid to the targeting properties of mono‐ and disaccharides applied in drug design and discovery.     

Human catalase is imported and assembled in peroxisomes of Saccharomyces cerevisiae

To study the conservation of peroxisomal targeting signals, we have determined the intracellular localization of human peroxisomal catalase when expressed in yeast. Using immunofluorescence, differential centrifugation and immunoelectron microscopy, we show that the protein is targeted to the peroxisomes of the heterologous cell and assembled in its active tetrameric form. These data show the conservation of the catalase targeting signal and import specificity between human and yeast peroxisomes.     

Multiple Na,K-ATPase Subunits Colocalize in the Brush Border of Mouse Choroid Plexus Epithelial Cells

(1) Background: The unusual accumulation of Na,K-ATPase complexes in the brush border membrane of choroid plexus epithelial cells have intrigued researchers for decades. However, the full range of the expressed Na,K-ATPase subunits and their relation to the microvillus cytoskeleton remains unknown. (2) Methods: RT-PCR analysis, co-immunoprecipitation, native PAGE, mass spectrometry, and differential centrifugation were combined with high-resolution immunofluorescence histochemistry, proximity ligase assays, and stimulated emission depletion (STED) microscopy on mouse choroid plexus cells or tissues in order to resolve these issues. (3) Results: The choroid plexus epithelium expresses Na,K-ATPase subunits α1, α2, β1, β2, β3, and phospholemman. The α1, α2, β1, and β2, subunits are all localized to the brush border membrane, where they appear to form a complex. The ATPase complexes may stabilize in the brush border membrane via anchoring to microvillar actin indirectly through ankyrin-3 or directly via other co-precipitated proteins. Aquaporin 1 (AQP1) may form part of the proposed multi-protein complexes in contrast to another membrane protein, the Na-K-2Cl cotransporter 1 (NKCC1). NKCC1 expression seems necessary for full brush border membrane accumulation of the Na,K-ATPase in the choroid plexus. (4) Conclusion: A multitude of Na,K-ATPase subunits form molecular complexes in the choroid plexus brush border, which may bind to the cytoskeleton by various alternative actin binding proteins.     

Stimuli-Responsive Nanomaterials for Smart Tumor-Specific Phototherapeutics

Phototherapy, a type of photoresponsive regulation of biological activities, together with additional stimuli-responsive features, offers significant potential for enhancing the precision and efficacy of cancer treatments. To achieve tumor-specific therapeutics, numerous studies have focused on the development of smart phototherapeutic nanomaterials (PNMs) that can respond to endogenous pathological characteristics (e. g., mild acidity, the overproduction of glutathione, the overproduction of hydrogen peroxide, the overexpression of specific surface receptors, etc.) present in the tumor and/or exogenous stimuli. Such responsiveness can effectively improve the physicochemical properties, cellular uptake, tumor-targeting performance, and pharmacokinetic profile of PNMs. Herein, we will systematically discuss recent advances in this field. Moreover, potential challenges and future directions in the development of stimuli-responsive PNMs are also presented to support the development of this emerging cutting-edge research area.     

Economic selection of process mean and lot‐sizing decisions for multi‐newsvendor supply chain

Two related problems are integrated in this paper, the first is the targeting problem and another is production/inventory decisions in a supply chain. The supply chain under consideration consists of a supplier of raw material, a single producer, and multiple newsvendors. The producer can adjust the process mean before starting the production run. Once set to a certain target value, the process mean is not changed until the production lot is completed. At the end of a production run, the producer screens the lot and uses specification limits to evaluate the quality of the item. Nonconforming items are scrapped with no salvage value; however, conforming items are delivered to newsvendors who are subjected to random demand. If demand on a newsvendor in a season is lower than anticipated, surplus items will be returned to the producer at a certain transportation cost. We first develop a mathematical model that maximizes the expected total profit of the supply chain. Then, a table for two special functions is devised to simplify the solution method and is used to find the optimal solution of the proposed model. We also study the significance of this integration by comparing the performance of the proposed model with an independent model where the process mean selection and lot‐sizing decisions are found separately.     

轰炸光电瞄准主控计算机系统软件设计

我军现役主战轰炸机均未配备光电瞄准系统,其轰瞄设备为纯光学目视老设备,夜间及复杂气象条件下无法观测目标,不能完成精确轰炸,需要配备光电瞄准系统;主控计算机系统设计为目前轰炸光电瞄准系统实现过程中待研究的关键技术;为解决轰炸光电瞄准主控计算机系统的软件设计问题,采用分层设计思想,设计了应用程序层、操作系统层和板级支持包(BSP)组成的主控计算机软件结构;采用自顶向下的设计思想,设计了基于ARM-VxWorks实现方案的性能稳定、较为成熟的主控计算机系统软件;结果表明用这种方案实现轰炸光电瞄准系统主控计算机,缩短了开发时间、减小了风险,可以提高开发效率,能够满足军用计算机实现方案的要求.     

Territorial targeting in EU private law

In a series of rulings given in the last few years, the Court of Justice of the European Union (EU) has made use of the concept of targeting by a trader of a particular territorial market as a device for determining the scope of European legislation on private law. The concept is of particular importance in the context of trading activities conducted by means of the Internet, though its significance is not confined to such activities. In particular, the European Court has used the concept of targeting for the purpose of restricting the substantive ambit of intellectual property rights created or harmonised by EU legislation. On the other hand, it has avoided use of the concept of targeting in the context of EU legislation allocating jurisdiction between the courts of the Member States, even in respect of disputes involving intellectual property, except where a legislative text specifically invokes such a concept. The instant paper endeavours to review the position as currently established by the European case-law, and to predict the likely further developments.