scholarly journals Design and Development of Autotaxin Inhibitors

2021 ◽  
Vol 14 (11) ◽  
pp. 1203
Author(s):  
Yi Jia ◽  
Yan Li ◽  
Xu-Dong Xu ◽  
Yu Tian ◽  
Hai Shang
Keyword(s):  
Rational Design ◽  
Structural Diversity ◽  
Inflammatory Disorder ◽  
Advantages And Disadvantages ◽  
Nucleotide Pyrophosphatase ◽  
Inhibitor Type ◽  
Design Ideas ◽  
G Protein Coupled ◽  
Hydrolysis Of ◽  
Positive Effect

Autotaxin (ATX) is the only enzyme of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP2) family with lysophospholipase D (lysoPLD) activity, which is mainly responsible for the hydrolysis of extracellular lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA can induce various responses, such as cell proliferation, migration, and cytokine production, through six G protein-coupled receptors (LPA1-6). This signaling pathway is associated with metabolic and inflammatory disorder, and inhibiting this pathway has a positive effect on the treatment of related diseases, while ATX, as an important role in the production of LPA, has been shown to be associated with the occurrence and metastasis of tumors, fibrosis and cardiovascular diseases. From mimics of ATX natural lipid substrates to the rational design of small molecule inhibitors, ATX inhibitors have made rapid progress in structural diversity and design over the past 20 years, and three drugs, GLPG1690, BBT-877, and BLD-0409, have entered clinical trials. In this paper, we will review the structure of ATX inhibitors from the perspective of the transformation of design ideas, discuss the advantages and disadvantages of each inhibitor type, and put forward prospects for the development of ATX inhibitors in the future.

scholarly journals PEER DESIGNERS AS STRONG INFLUENCERS ON THE DESIGN PROCESS OF FOOD STARTUPS

2021 ◽  
Vol 1 ◽  
pp. 2409-2418
Author(s):  
Summer D. Jung ◽  
Erika Perttunen ◽  
Senni Kirjavainen ◽  
Tua Björklund ◽  
Sohyeong Kim
Keyword(s):  
Design Process ◽  
Qualitative Data ◽  
Design Research ◽  
Positive Impact ◽  
Peer Influences ◽  
Design Team ◽  
Food And Beverage ◽  
Design Ideas ◽  
Different Sources ◽  
Positive Effect

AbstractAs design research expands its horizon, there has been a recent rise in studies on nontraditional designers. Previous studies have noted the positive effect of diversity in generating ideas. Among different sources of influence, peers outside the design team have been noted for their positive impact on the design process, yet the research on this topic is still in its early stages. Using qualitative data from 40 small and medium-sized enterprises (SMEs) in the American and Finnish food and beverage industries, the current study examines their interactions with other SMEs, shedding light on the influence of peers on creating new design solutions. The findings suggest that peer companies can act as a frequent and impactful source of inspiration for product design ideas. The most prevalent forms of interaction were co-creating products, sharing information, and sharing ingredients. Furthermore, the interactions were voluntary, organic, and improvisational in nature, and physical proximity or previous connections often initiated the interactions. Taken together, a great number of peer influences contributed towards creative new solutions.

Enzymatic Hydrolysis of PET: Structural Diversity and Kinetic Properties of Cutinases from Thermobifida

2014 ◽  
Vol 31 ◽  
pp. S88
Author(s):  
Altijana Hromic ◽  
Doris Ribitsch ◽  
Andrzej Lyskowski ◽  
Georg Steinkellner ◽  
Helmut Schwab ◽  
...  
Keyword(s):  
Enzymatic Hydrolysis ◽  
Structural Diversity ◽  
Kinetic Properties ◽  
Hydrolysis Of

Improved Enzymatic Depolymerization of Chitosan by Ionic Liquid Pretreatment and the Effect of Oligo-Chitosan on Intestinal Flora In Vitro

2011 ◽  
Vol 391-392 ◽  
pp. 1319-1323
Author(s):  
Cui Zheng ◽  
Lin Li ◽  
Hao Pang ◽  
Zhao Mei Wang ◽  
Na Li
Keyword(s):  
Ionic Liquid ◽  
Hydrogen Bonds ◽  
Molecular Hydrogen ◽  
Intestinal Flora ◽  
X Ray Diffraction ◽  
X Ray ◽  
Hydrolysis Of ◽  
Positive Effect ◽  
Enzymatic Depolymerization

It still remains challenging for effective hydrolysis of chitosan into chitosan oligomers. In this work, a pretreatment was conducted on chitosan by an ionic liquid 1-butyl-3-methylimidazolium chloride ([C4mim]Cl), aiming at improving enzymatic depolymerization of chitosan. X-ray diffraction analysis indicated that the inter- and intra-molecular hydrogen bonds within chitosan molecules were broken by [C4mim]Cl and the crystalline was destroyed. The oligo-chitosan hydrolyzed from IL-pretreated chitosan, coded as COS-IL, showed a DP of 3~5, in contrast to DP 5~8 with oligo-chitosan obtained from untreated chitosan(coded as COS-UN). COS-IL was more effective than COS-UN in inhibiting intestinal spoilage bacterials growth and it has positive effect on the growth of intestinal probiotic bacterials.

scholarly journals Business Analytics and Its Role in Managing the Competitiveness of an Enterprise

2020 ◽  
pp. 214-220
Author(s):  
Bohdan Dmitrishin ◽  
◽  
Maksym Boroviy ◽  
Keyword(s):  
Adaptive Systems ◽  
Full Potential ◽  
Business Analytics ◽  
Business Decision ◽  
Advantages And Disadvantages ◽  
Stage Of Development ◽  
Factors Influencing ◽  
Business Analysis ◽  
Enterprise Competitiveness ◽  
Positive Effect

The purpose of the article is to develop the methodological foundations of business analytics as a necessary component in the competitiveness management system of a modern enterprise. The article is devoted to solving the problem of relations business analytics (in particular business decision support systems) and systemic characteristics of enterprise competitiveness management. Substantiation of factors influencing the formation of the competitiveness of an enterprise becomes significant at this stage of development of the national economy. The publication summarizes the tasks, principles and goals of business analytics. The relations between business analytics and enterprise competitiveness is defined and structured. Business analytics aims to simplify the work of the company as much as possible, increasing the profitability of sales and minimizing losses, which will certainly have a positive effect on the competitiveness of an enterprise. It is noted that the qualitative improvement of the range and intellectual potential of an enterprise has a positive effect on the competitiveness of manufactured goods (services), personnel of an enterprise. Factors influencing the competitiveness of an enterprise are established and substantiated. The types of relations between business strategy and business analytics are analyzed. The significance and necessity of conducting business analysis for making managerial decisions are revealed. The tools of a business analyst in a rapidly changing environment are proposed. Ukrainian enterprises are recommended to use not static, but strategically-oriented adaptive systems of competitiveness management, based on the widespread use of business process modeling and business intelligence tools. Further research should be focused on the implementation of modern methods of business analytics in enterprises, taking into account the experience of the most developed countries, conducting a comparative analysis of business analysis tools to reveal their full potential, highlighting the advantages and disadvantages.

scholarly journals Revised fractional abundances and warm-season temperatures substantially improve brGDGT calibrations in lake sediments

2021 ◽  
Author(s):  
Jonathan H. Raberg ◽  
David J. Harning ◽  
Sarah E. Crump ◽  
Greg de Wet ◽  
Aria Blumm ◽  
...  
Keyword(s):  
Lake Sediments ◽  
Lake Sediment ◽  
Membrane Lipids ◽  
Warm Season ◽  
Environmental Parameters ◽  
Structural Diversity ◽  
Temperature Conductivity ◽  
Advantages And Disadvantages ◽  
Natural Logarithm ◽  
Air Temperatures

Abstract. Distributions of branched glycerol dialkyl glycerol tetraethers (brGDGTs) are frequently employed for reconstructing terrestrial paleotemperatures from lake sediment archives. Although brGDGTs are globally ubiquitous, the microbial producers of these membrane lipids remain unknown, precluding a full understanding of the ways in which environmental parameters control their production and distribution. Here, we advance this understanding in three ways. First, we present 43 new high-latitude lake sites characterized by low mean annual air temperatures (MATs) and high seasonality, filling an important gap in the global dataset. Second, we introduce a new approach for analyzing brGDGT data in which compound fractional abundances (FAs) are calculated within structural groups based on methylation number, methylation position, and cyclization number. Finally, we perform linear and nonlinear regressions of the resulting FAs against a suite of environmental parameters in a compiled global lake sediment dataset (n = 182). We find that our approach deconvolves temperature, conductivity, and pH trends in brGDGTs without increasing calibration errors from the standard approach. We also find that it reveals novel patterns in brGDGT distributions and provides a methodology for investigating the biological underpinnings of their structural diversity. Warm-season temperature indices outperformed MAT in our regressions, with Months Above Freezing yielding the highest-performing model (adjusted R2 = 0.91, RMSE = 1.97 °C, n = 182). The natural logarithm of conductivity had the second-strongest relationship to brGDGT distributions (adjusted R2 = 0.83, RMSE = 0.66, n = 143), notably outperforming pH in our dataset (adjusted R2 = 0.73, RMSE = 0.57, n = 154) and providing a potential new proxy for paleohydrology applications. We recommend these calibrations for use in lake sediments globally, including at high latitudes, and detail the advantages and disadvantages of each.

Nucleoapzymes: catalyst-aptamer conjugates as enzyme-mimicking structures

2019 ◽  
Vol 3 (5) ◽  
pp. 493-499 ◽  
Author(s):  
Verena Wulf ◽  
Itamar Willner
Keyword(s):  
Nucleic Acid ◽  
Variable Structure ◽  
Structural Diversity ◽  
Research Field ◽  
Dynamic Simulations ◽  
Catalytic Function ◽  
Enzyme Mimicking ◽  
G Quadruplex ◽  
Catalytic Sites ◽  
Hydrolysis Of

The conjugation of catalytic sites to sequence-specific, ligand-binding nucleic acid aptamers yields functional catalytic ensembles mimicking the catalytic/binding properties of native enzymes. These catalyst-aptamer conjugates termed ‘nucleoapzymes’ reveal structural diversity, and thus, vary in their catalytic activity, due to the different modes of conjugation of the catalytic units to the nucleic acid aptamer scaffold. The concept of nucleoapzymes is introduced with the assembly of a set of catalysts consisting of the hemin/G-quadruplex DNAzyme (hGQ) conjugated to the dopamine aptamer. The nucleoapzymes catalyze the oxidation of dopamine by H2O2 to yield aminochrome. The catalytic processes are controlled by the structures of the nucleoapzymes, and chiroselective oxidation of l-DOPA and d-DOPA by the nucleoapzymes is demonstrated. In addition, the conjugation of a Fe(III)-terpyridine complex to the dopamine aptamer and of a bis-Zn(II)-pyridyl-salen-type complex to the ATP-aptamer yields hybrid nucleoapzymes (conjugates where the catalytic site is not a biomolecule) that catalyze the oxidation of dopamine to aminochrome by H2O2 and the hydrolysis of ATP to ADP, respectively. Variable, structure-controlled catalytic activities of the different nucleoapzymes are demonstrated. Molecular dynamic simulations are applied to rationalize the structure-catalytic function relationships of the different nucleoapzymes. The challenges and perspectives of the research field are discussed.

scholarly journals Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase

2020 ◽  
Vol 295 (13) ◽  
pp. 4079-4092 ◽  
Author(s):  
Lukas Gorecki ◽  
Oksana Gerlits ◽  
Xiaotian Kong ◽  
Xiaolin Cheng ◽  
Donald K. Blumenthal ◽  
...  
Keyword(s):  
Active Center ◽  
Rational Design ◽  
Structural Diversity ◽  
Success Rates ◽  
Design Synthesis ◽  
X Ray ◽  
Pyridinium Cation ◽  
Pesticide Exposures ◽  
The Central Nervous System

Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime–based therapies whose success rates are currently limited. The pyridinium cation hampers uptake of OPs into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are nonproductive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)–inhibited human AChE, here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved in vitro reactivation of diverse OP-human AChE conjugates. Oxime group reorientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, “smart” accelerated antidotes against OP toxicity.

scholarly journals IL-33 and MRGPRX2-Triggered Activation of Human Skin Mast Cells—Elimination of Receptor Expression on Chronic Exposure, but Reinforced Degranulation on Acute Priming

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 341 ◽  
Author(s):  
Zhao Wang ◽  
Sven Guhl ◽  
Kristin Franke ◽  
Metin Artuc ◽  
Torsten Zuberbier ◽  
...  
Keyword(s):  
Mast Cells ◽  
Human Skin ◽  
Chronic Exposure ◽  
Prolonged Exposure ◽  
Receptor Expression ◽  
Dependent Manner ◽  
High Affinity ◽  
High Affinity Ige Receptor ◽  
G Protein Coupled ◽  
Positive Effect

Clinically relevant exocytosis of mast cell (MC) mediators can be triggered by high-affinity IgE receptor (FcεRI)-aggregation (allergic route) or by the so-called pseudo-allergic pathway elicited via MAS-related G protein-coupled receptor-X2 (MRGPRX2). The latter is activated by drugs and endogenous neuropeptides. We recently reported that FcεRI-triggered degranulation is attenuated when human skin mast cells are chronically exposed to IL-33. Here, we were interested in the regulation of the MRGPRX2-route. Chronic exposure of skin MCs to IL-33 basically eliminated the pseudo-allergic/neurogenic route as a result of massive MRGPRX2 reduction. This downregulation seemed to partially require c-Jun N-terminal Kinase (JNK), but not p38, the two kinases activated by IL-33 in skin MCs. Surprisingly, however, JNK had a positive effect on MRGPRX2 expression in the absence of IL-33. This was evidenced by Accell®-mediated JNK knockdown and JNK inhibition. In stark contrast to the dampening effect upon prolonged exposure, IL-33 was able to prime for increased degranulation by MRGPRX2 ligands when administered directly before stimulation. This supportive effect depended on p38, but not on JNK activity. Our data reinforce the concept that exposure length dictates whether IL-33 will enhance or attenuate secretion. IL-33 is, thus, the first factor to acutely enhance MRGPRX2-triggered degranulation. Finally, we reveal that p38, rarely associated with MC degranulation, can positively affect exocytosis in a context-dependent manner.

Recent Advances in the Fabrication of All-Solid-State Nanostructured TiO2-Based Z-scheme Heterojunctions for Environmental Remediation

2020 ◽  
Vol 20 (9) ◽  
pp. 5861-5873 ◽  
Author(s):  
Meiqi Du ◽  
Shengxin Cao ◽  
Xiaozhou Ye ◽  
Jianfeng Ye
Keyword(s):  
Solid State ◽  
Charge Carrier ◽  
Environmental Remediation ◽  
Rational Design ◽  
High Efficiency ◽  
Photogenerated Charge Carrier ◽  
Advantages And Disadvantages ◽  
Recent Advances ◽  
Photocatalytic System ◽  
Carrier Separation

Nanostructured TiO2-based Z-scheme heterojunctions have been widely accepted to be among the most effective photocatalysts for environmental remediation owing to their broadened light absorbance, high efficiency of photogenerated charge carrier separation, and well-preserved strong oxidation and reduction capability. In this review, we will first introduce the photogenerated charge carrier transportation mechanism of three different types of Z-scheme heterojunction systems, namely, liquid-phase Z-scheme photocatalytic system, all-solid-state indirect Z-scheme photocatalytic system, and all-solid-state direct Z-scheme photocatalytic system. Subsequently, we will describe the recent advances toward the rational design and fabrication of all-solid-state nanostructured TiO2-based Z-scheme heterojunctions. The applications of the thus-constructed all-solid-state nanostructured TiO2-based Z-scheme heterojunctions in the degradation of volatile organic compounds, removal of waste water organic pollutants, and upgradation of greenhouse gas CO2 will then be presented one by one. Finally, the advantages and disadvantages of all-solid-state nanostructured TiO2-based Z-scheme heterojunction for photocatalytic environmental remediation will be briefly discussed, and the direction of future development will be prospected as well.

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