Frantzenfraser1739

Translation factor 5A (eIF5A) is one of the most conserved proteins involved in protein synthesis. It plays a key role during the elongation of polypeptide chains, and its activity is critically dependent on hypusination, a post-translational modification of a specific lysine residue through two consecutive enzymatic steps carried out by deoxyhypusine synthase (DHS), with spermidine as substrate, and deoxyhypusine hydroxylase (DOHH). It is well-established that eIF5A is overexpressed in several cancer types, and it is involved in various diseases such as HIV-1 infection, malaria, and diabetes; therefore, the development of inhibitors targeting both steps of the hypusination process is considered a promising and challenging therapeutic strategy. One of the most efficient inhibitors of the hypusination process is the spermidine analog N1-guanyl-1,7-diaminoheptane (GC7). GC7 interacts in a specific binding pocket of the DHS completely blocking its activity; however, its therapeutic use is limited by poor selectivity and restricted bioavailability. Here we have performed a comparative study between human DHS (hDHS) and archaeal DHS from crenarchaeon Sulfolobus solfataricus (aDHS) to understand the structural and dynamical features of the GC7 inhibition. The advanced metadynamics (MetaD) classical molecular dynamics simulations show that the GC7 interaction is less stable in the thermophilic enzyme compared to hDHS that could underlie a lower inhibitory capacity of the hypusination process in Sulfolobus solfataricus. To confirm this hypothesis, we have tested GC7 activity on S. solfataricus by measuring cellular growth, and results have shown the lack of inhibition of aIF5A hypusination in contrast to the established effect on eukaryotic cellular growth. These results provide, for the first time, detailed molecular insights into the binding mechanism of GC7 to aDHS generating the basis for the design of new and more specific DHS inhibitors.During their infective stages, hookworms release excretory-secretory (E-S) products, small molecules, and proteins to help evade and suppress the host's immune system. Small molecules found in E-S products of mammalian hookworms include nematode derived metabolites like ascarosides, which are composed of the sugar ascarylose linked to a fatty acid side chain. The most abundant proteins found in hookworm E-S products are members of the protein family known as Ancylostoma secreted protein (ASP). In this study, two ascarosides and their fatty acid moieties were synthesized and tested for in vitro binding to Na-ASP-2 using both a ligand competition assay and microscale thermophoresis. The fatty acid moieties of both ascarosides tested and ascr#3, an ascaroside found in rat hookworm E-S products, bind to Na-ASP-2's palmitate binding cavity. These molecules were confirmed to bind to the palmitate but not the sterol binding sites. An ascaroside, oscr#10, which is not found in hookworm E-S products, does not bind to Na-ASP-2. More studies are required to determine the structural basis of ascarosides binding by Na-ASP-2 and to understand the physiological significance of these observations.Lithium-ion batteries (LIBs), used for energy supply and storage equipment, have been widely applied in consumer electronics, electric vehicles, and energy storage systems. However, the urgent demand for high energy density batteries and the shortage of lithium resources is driving scientists to develop high-performance materials and find alternatives. Low-volume expansion carbon material is the ideal choice of anode material. However, the low specific capacity has gradually become the shortcoming for the development of LIBs and thus developing new carbon material with high specific capacity is urgently needed. In addition, developing alternatives of LIBs, such as sodium ion batteries and potassium-ion batteries, also puts forward demands for new types of carbon materials. As is well-known, the design of high-performance electrodes requires a deep understanding on the working mechanism and the structural evolution of active materials. On this issue, ex-situ techniques have been widely applied to investigate the electrode materials under special working conditions, and provide a lot of information. Unfortunately, these observed phenomena are difficult to reflect the reaction under real working conditions and some important short-lived intermediate products cannot be captured, leading to an incomplete understanding of the working mechanism. In-situ techniques can observe the changes of active materials in operando during the charge/discharge processes, providing the concrete process of solid electrolyte formation, ions intercalation mechanism, structural evolutions, etc. Herein, this review aims to provide an overview on the characters of carbon materials in alkali ion batteries and the role of in-situ techniques in developing carbon materials.Oxidative nucleic acid modifications have attracted increasing attention in recent years since they have been found to be related to a number of diseases including cancer. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG) are the typical markers of oxidative modification of DNA and RNA, respectively, and they are emerging biomarkers for the early detection of diseases. Urine is a favored biofluid for biomarker discovery due to its noninvasiveness to patients. Fenebrutinib price Accurate quantification of these oxidative nucleic acid modifications still has challenges because their amounts in urine are very low and the interferences in urine samples are complicated. Herein, we developed and validated an accurate and robust solid-phase extraction (SPE) coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous quantification of these oxidative nucleic acid modifications in human urine. Stable isotope dilution strategy was utilized and the method shows good precision on intraday and interday measurements. Meanwhile, recovery was satisfactory by utilizing the Oasis hydrophilic-lipophilic balance (HLB) cartridge for sample pretreatment at three spiked levels. We successfully quantified urinary 8-OHdG and 8-OHG from 60 gastric cancer patients and 70 healthy controls by using this method. The measured contents of 8-OHdG and 8-OHG in urine from gastric cancer patients are both increased, compared with those in urine from healthy controls, indicating these oxidative nucleic acid modifications could act as potential non-invasive markers for early diagnosis of gastric cancer. Moreover, the present study will stimulate investigations of the effects of oxidative stress and nucleic acid modifications on the initiation and progression of gastric cancer.