Synthesis of Long-Chain β-Lactones and Their Antibacterial Activities against Pathogenic Mycobacteria

In the quest for new antibacterial agents, a series of novel long- and medium-chain mono- and disubstituted β-lactones was developed. Their activity against three pathogenic mycobacteria—M. abscessus, M. marinum, and M. tuberculosis—was assessed by the resazurin microtiter assay (REMA). Among the 16 β-lactones synthesized, only 3-hexadecyloxetan-2-one (VM005) exhibited promising activity against M. abscessus, whereas most of the β-lactones showed interesting activities against M. marinum, similar to that of the classical antibiotic, isoniazid. Regarding M. tuberculosis, six compounds were found to be active against this mycobacterium, with β-lactone VM008 [trans-(Z)-3-(hexadec-7-en-1-yl)-4-propyloxetan-2-one] being the best growth inhibitor. The promising antibacterial activities of the best compounds in this series suggest that these molecules may serve as leads for the development of much more efficient antimycobacterial agents.     

Pull-Down of Metalloproteins in Their Native States by Using Desthiobiotin-Based Probes

One-third of all proteins are estimated to require metals for structural stability and/or catalytic activity. Desthiobiotin probes containing metal binding groups can be used to capture metalloproteins with exposed active-site metals under mild conditions so as to prevent changes in metallation state. The proof-of-concept was demonstrated with carbonic anhydrase (CA), an open active site, Zn²⁺-containing protein. CA was targeted by using sulfonamide derivatives. Linkers of various lengths and structures were screened to determine the optimal structure for capture of the native protein. The optimized probes could selectively pull down CA from red blood cell lysate and other protein mixtures. Pull-down of differently metallated CAs was also investigated.     

Design of Trehalose-Based Amide/Sulfonamide C-type Lectin Receptor Signaling Compounds

Mincle agonists have been shown to induce inflammatory cytokine production, such as tumor necrosis factor-alpha (TNF) and promote the development of a Th1/Th17 immune response that might be crucial to development of effective vaccination against pathogens such as Mycobacterium tuberculosis. As an expansion of our previous work, a library of 6,6′-amide and sulfonamide α,α-d -trehalose compounds with various substituents on the aromatic ring was synthesized efficiently in good to excellent yields. These compounds were evaluated for their ability to activate the human C-type lectin receptor Mincle by the induction of cytokines from human peripheral blood mononuclear cells. A preliminary structure–activity relationship (SAR) of these novel trehalose diamides and sulfonamides revealed that aryl amide-linked trehalose compounds demonstrated improved activity and relatively high potency cytokine production compared to the Mincle ligand trehalose dibehenate adjuvant (TDB) and the natural ligand trehalose dimycolate (TDM) inducing dose-dependent and human-Mincle-specific stimulation in a HEK reporter cell line.     

Omega-6支撑身体，Omega-3支撑大脑：均衡摄入对儿童大脑发育的影响（网络首发、推荐阅读）

人体大脑和身体的发育，需要从食物中摄取均衡的营养物质。人类大脑是区分人类和其他动物的特征。食物中的必需脂肪酸是机体组织结构和功能的必要组成部分。Omega-6（O6）亚油酸（LA6）是皮肤组织的组成成分，且是炎症、血栓形成、免疫和其他信号分子的前体；Omega-3（O3）α-亚麻酸（ALA3），特别是其长链代谢产物——二十二碳六烯酸（DHA3），是大脑、视网膜和部分神经组织中的关键组分。从富含LA6脂肪酸（缺乏O3脂肪酸）的植物籽中提取出的廉价而优质油脂，是20世纪的西方国家食品工业生产的主要脂肪来源。在代谢通路中，高浓度的LA6脂肪酸可拮抗O3脂肪酸代谢，造成O3脂肪酸不足，因此，在给怀孕动物的饲料中，只提供富含LA6但缺乏O3脂肪酸的油脂作为唯一的脂肪来源，会导致幼崽大脑发育不良。过去20~30年的研究表明，低含量LA6且含DHA3的油脂可改善大脑的功能。近年来的研究较多集中在营养因素对大脑发育的影响，最新研究数据表明，脂肪酸平衡对营养不良儿童的大脑发育尤为重要。世界卫生组织（WHO）越来越重视大脑的营养健康，通过其下属的食品法典委员会，建议用于治疗严重急性营养不良儿童的即食治疗食品中，使用含有均衡脂肪酸组成/构成的脂肪。同样，脂肪酸均衡对老年人可能也很重要。目前，业界已经有了调整油脂成分的方法，以确保脂肪酸均衡，从而维持人体整个生命周期的大脑健康。     

An automated treatment planning strategy for highly noncoplanar radiotherapy arc trajectories

Radiation therapy is a technology-driven cancer treatment modality that has experienced significant advances over the last decades, due to multidisciplinary contributions that include engineering and computing. Recent technological developments allow the use of noncoplanar volumetric modulated arc therapy (VMAT), one of the most recent photon treatment techniques, in clinical practice. In this work, an automated noncoplanar arc trajectory optimization framework designed in two modular phases is presented. First, a noncoplanar beam angle optimization algorithm is used to obtain a set of noncoplanar irradiation directions. Then, anchored in these directions, an optimization strategy is proposed to compute an optimal arc trajectory. The computational experiments considered a pool of twelve difficult head-and-neck tumor cases. It was possible to observe that, for some of these cases, the optimized noncoplanar arc trajectories led to significant treatment planning quality improvements, when compared with coplanar VMAT treatment plans. Although these experiments were done in a research environment treatment planning software (matRad), the conclusions can be of interest for a clinical setting: automated procedures can simplify the current treatment workflow, produce high-quality treatment plans, making better use of human resources and allowing for unbiased comparisons between different treatment techniques.     

RLPAS: Reinforcement Learning-based Proactive Auto-Scaler for Resource Provisioning in Cloud Environment

Mobile Networks and Applications - Public cloud system offers Infrastructure-as-a-Service (IaaS) to deliver the computational resources on demand. Resource requirements of a cloud environment are...     

Alteration of the Route to Menaquinone towards Isochorismate-Derived Metabolites

Chorismate and isochorismate constitute branch-point intermediates in the biosynthesis of many aromatic metabolites in microorganisms and plants. To obtain unnatural compounds, we modified the route to menaquinone in Escherichia coli. We propose a model for the binding of isochorismate to the active site of MenD ((1R,2S, 5S,6S)-2-succinyl-5-enolpyruvyl-6-hydroxycyclohex-3-ene-1-carboxylate (SEPHCHC) synthase) that explains the outcome of the native reaction with α-ketoglutarate. We have rationally designed variants of MenD for the conversion of several isochorismate analogues. The double-variant Asn117Arg–Leu478Thr preferentially converts (5S,6S)-5,6-dihydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHD), the hydrolysis product of isochorismate, with a >70-fold higher ratio than that for the wild type. The single-variant Arg107Ile uses (5S,6S)-6-amino-5-hydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHA) as substrate with >6-fold conversion compared to wild-type MenD. The novel compounds have been made accessible in vivo (up to 5.3 g L⁻¹). Unexpectedly, as the identified residues such as Arg107 are highly conserved (>94 %), some of the designed variations can be found in wild-type SEPHCHC synthases from other bacteria (Arg107Lys, 0.3 %). This raises the question for the possible natural occurrence of as yet unexplored branches of the shikimate pathway.     

Effect of processing on the microbiological quality and safety of chicken carcasses at slaughterhouse

Microbiological contamination of chicken meat depends on the conditions under which the animals are reared, slaughtered and processed. The aim of this study was to determine the influence of farm origin and processing stages at slaughterhouse on the microbial safety and quality of chicken. Samples of chicken carcasses from three different farms were taken from a slaughterhouse. Mesophiles, Escherichia coli, coagulase positive Staphylococcci counts, presence of Listeria monocytogenes,Campylobacter and Salmonella were determined at five sampling points: after defeathering, after evisceration, after washing, after chilling and after cutting. Chilling reduced log numbers of mesophiles, coagulase positive Staphylococci and E. coli by 0.85, 1.52 and 2.2 log units, respectively. Salmonella was not detected after chilling. High prevalence of Campylobacter spp was observed at all the stages ranging between 84% and 100%. L. monocytogenes was not detected in chicken carcasses after defeathering. However, it was detected after evisceration and after washing and chilling. The most critical stage for L. monocytogenes contamination was the portioning operation, the prevalence in breast and legs being 88% and 84%, respectively.