Isolation and Biological Activity of a Peptidal Antibiotic P168

The structure of the xyloglucan synthesised in vitro by the particulate fraction of suspension-cultured soybean (Glycine max) cells from UDP-glucose and UDP-xylose is mainly composed of two kinds of oligosaccharide-building blocks, a heptasaccharide unit and a pentassaccharide unit [T. Hayashi and K. Matsuda, J. Biol Chem., 256, 11117 (1981)]. The synthesis of the pentasaccharide unit is probably the first step in the construction of oligosaccharide building blocks to elongate the ²-1,4-glucan backbone. This enzymatically synthesized xyloglucan was shown to have the same molecular size (M_w, 180,000) as the xyloglucan prepared from soybean cell walls by gel filtration on a Sepharose CL-6B column, and the same building blocks distributed among each fraction. A pulse-chase experiment indicated that the pentasaccharide unit was converted into the heptasaccharide unit. The conversion was regulated by the concentration of UDP-xylose.     

The ontogeny and population variability of human hepatic dihydronicotinamide riboside:quinone oxidoreductase (NQO2)

Dihydronicotinamide riboside:quinone oxidoreductase (NQO2) is an enzyme that performs reduction reactions involved in antioxidant defense. We hypothesized that NQO2 hepatic drug clearance would develop in children over time, similar to NQO1. Using human liver cytosol (n = 117), the effects of age, sex, ethnicity, and weight on NQO2 expression and activity were probed. No significant correlations were observed. Biochemical activity of NQO2 was as high at birth as in adults (0.23 ± 0.04 nmol/min/mg protein, mean ± SEM, range 0–1.83). In contrast, modeled hepatic clearance through the NQO2 pathway was up to 10% of adult levels at birth, reaching predicted adult levels (0.3 ± 0.03 L/h) at 14 years of age. Comparisons between NQO1 and NQO2 in the same livers showed that neither protein (P = 0.32) nor activity (P = 0.23) correlated, confirming both orthologs are independently regulated. Because hepatic clearance through NQO2 does not mature until teenage years, compounds detoxified by this enzyme may be more deleterious in children.     

Long COVID and its Management

The pandemic of COVID-19 is the biggest public health crisis in 21^st Century. Besides the acute symptoms after infection, patients and society are also being challenged by the long-term health complications associated with COVID-19, commonly known as long COVID. While health professionals work hard to find proper treatments, large amount of knowledge has been accumulated in recent years. In order to deal with long COVID efficiently, it is important for people to keep up with current progresses and take proactive actions on long COVID. For this purpose, this review will first introduce the general background of long COVID, and then discuss its risk factors, diagnostic indicators and management strategies. This review will serve as a useful resource for people to understand and prepare for long COVID that will be with us in the foreseeable future.     

PCR及其衍生技术在基因突变检测中的应用

许多人类遗传性疾病及某些抗艾滋病药物的抗性乃至细菌对某些抗生素的抗药性通常源于基因突变。本文对近年来在基因突变检测中应用日益广泛的各种PCR 衍生技术作一综述;重点介绍了错配PCR技术,以及我们实验室近期报道的一种快速检测喹诺酮类药物耐药大肠杆菌的错配PCR方案。 Abstract:Many inherited diseases and drug resistance have been attributed to mutations in corresponding genes.In this paper,several techniques based on PCR used in diagnosis were concluded.The development and research progress of Mismatch PCR were discussed in details.Some information about an assay that we developed for detection of antimicrobial resistance to quinolones was also described.     

Design of a Robotized Magnetic Platform for Targeted Drug Delivery in the Cochlea

Inner ear disorders' treatment remains challenging due to anatomical barriers. Robotic assistance seems to be a promising approach to enhance inner ear treatments and, more particularly, lead to effective targeted drug delivery into the human cochlea. In this paper we present a combination of a micro-macro system that was designed and realized in order to efficiently control the navigation of magnetic nanoparticles in an open-loop scheme throughout the cochlea, considering that the magnetic particles cannot be located in real time.In order to respect the anatomical constraints, we established the characteristics that the new platform must present then proceeded to the design of the latter. The developed system is composed of a magnetic actuator that aims to guide nanoparticles into the cochlea. Mounted on a robotic manipulator, it ensures its positioning around the patient's head. The magnetic device integrates four parallelepiped-rectangle permanent magnets. Their arrangement in space, position and orientation, allows the creation of an area of convergence of magnetic forces where nanoparticles can be pushed/pulled to. To ensure the reachability of the desired orientations and positions, a 3 DOF robot based on a Remote Centre of Motion (RCM) mechanism was developed. It features three concurrent rotational joints that generate a spherical workspace around the head. The control of the latter is based on kinematic models.A prototype of this platform was realized to validate the actuation process. Both magnetic actuator and robotic manipulator were realized using an additive manufacturing approach. We also designed a virtual human head with a life-size cochlea inside. A laser was mounted on the end effector to track the positioning of the actuator. This permitted to experimentally prove the capacity of the robotic system to reach the desired positions and orientations in accordance with the medical needs.This promising robotic approach, makes it possible to overcome anatomical barriers and steer magnetic nanoparticles to a targeted location in the inner ear and, more precisely, inside the cochlea.     

Various proteinase inhibitors decrease prolactin and growth hormone release by anterior pituitary cells

Proteinase inhibitors were tested for their ability to inhibit prolactin (PRL) and growth hormone (GH) release by cultured anterior pituitary cells of the rat. Inhibitors of microbial origin (chymostatin, elastatinal, leupeptin) had either no or a moderate effect on hormone release while some tripeptide aldehydes, especially those with lysine at their C terminus, inhibited markedly PRL and to a lesser extent GH release. Boc-DPhe-Phe-lysinal was the most effective on lactotrophs inhibiting PRL release more than 50% at 10(-4) M. The site(s) of action of tripeptide aldehydes remain to be elucidated.     

β-Carboline alkaloids induce structural plasticity and inhibition of SARS-CoV-2 nsp3 macrodomain more potently than remdesivir metabolite GS-441524: computational approach

The nsp3 macrodomain is implicated in the viral replication, pathogenesis and host immune responses through the removal of ADP-ribosylation sites during infections of coronaviruses including the SARS-CoV-2. It has ever been modulated by macromolecules including the ADP-ribose until Ni and co-workers recently reported its inhibition and plasticity enhancement unprecedentedly by remdesivir metabolite, GS-441524, creating an opportunity for investigating other biodiverse small molecules such as β-Carboline (βC) alkaloids. In this study, 1497 βC analogues from the HiT2LEAD chemical database were screened, using computational approaches of Glide XP docking, molecular dynamics simulation and pk-CSM ADMET predictions. Selectively, βC ligands, 129, 584, 1303 and 1323 demonstrated higher binding affinities to the receptor, indicated by XP docking scores of –10.72, –10.01, –9.63 and –9.48 kcal/mol respectively than remdesivir and GS-441524 with –4.68 and –9.41 kcal/mol respectively. Consistently, their binding free energies were –36.07, –23.77, –24.07 and –17.76 kcal/mol respectively, while remdesivir and GS-441524 showed –21.22 and –24.20 kcal/mol respectively. Interestingly, the selected βC ligands displayed better stability and flexibility for enhancing the plasticity of the receptor than GS-441524, especially 129 and 1303. Their predicted ADMET parameters favour druggability and low expressions for toxicity. Thus, they are recommended as promising adjuvant/standalone anti-SARS-CoV-2 candidates for further study.Key words: SARS-CoV-2, nsp3 macrodomain, ADP-ribose, β-carboline, bioinformatics, drug design     

Active site closure facilitates juxtaposition of reactant atoms for initiation of catalysis by human dUTPase

Human dUTPase, essential for DNA integrity, is an important survival factor for cancer cells. We determined the crystal structure of the enzyme:alpha,beta-imino-dUTP:Mg complex and performed equilibrium binding experiments in solution. Ordering of the C-terminus upon the active site induces close juxtaposition of the incoming nucleophile attacker water oxygen and the alpha-phosphorus of the substrate, decreasing their distance below the van der Waals limit. Complex interactions of the C-terminus with both substrate and product were observed via a specifically designed tryptophan sensor, suitable for further detailed kinetic and ligand binding studies. Results explain the key functional role of the C-terminus.