scholarly journals Synthetic Zippers as an Enabling Tool for Engineering of Non-Ribosomal Peptide Synthetases

2020 ◽  
Author(s):  
Kenan A. J. Bozhueyuek ◽  
Jonas Watzel ◽  
Nadya Abbood ◽  
Helge B. Bode
Keyword(s):  
High Titre ◽  
Peptide Libraries ◽  
Divide And Conquer ◽  
Gram Negative ◽  
Peptide Synthetases ◽  
Wide Range ◽  
Single Protein ◽  
Definition Of ◽  
Polypeptide Chains ◽  
Non Ribosomal Peptides

AbstractNon-ribosomal peptide synthetases (NRPSs) are the origin of a wide range of natural products, including many clinically used drugs. Engineering of these often giant biosynthetic machineries to produce novel non-ribosomal peptides (NRPs) at high titre is an ongoing challenge. Here we describe a strategy to functionally combine NRPS fragments of Gram-negative and -positive origin, synthesising novel peptides at titres up to 290 mg l-1. Extending from the recently introduced definition of eXchange Units (XUs), we inserted synthetic zippers (SZs) to split single protein NRPSs into up to three independently expressed and translated polypeptide chains. These synthetic type of NRPS (type S) enables easier access to engineering, overcomes cloning limitations, and provides a simple and rapid approach to building peptide libraries via the combination of different NRPS subunits.One Sentence SummaryDivide and Conquer: A molecular tool kit to reprogram the biosynthesis of non-ribosomal peptides.

Typologization of security regulation

2020 ◽  
pp. 20-27
Author(s):  
Denis Tikhomirov
Keyword(s):  
Social Relations ◽  
Scientific Literature ◽  
Legal Regulation ◽  
Procedural Understanding ◽  
Limited Ability ◽  
Methodological Basis ◽  
Wide Range ◽  
The Subject ◽  
Definition Of ◽  
Legal Understanding

The purpose of the article is to typologize terminological definitions of security, to find out the general, to identify the originality of their interpretations depending on the subject of legal regulation. The methodological basis of the study is the methods that made it possible to obtain valid conclusions, in particular, the method of comparison, through which it became possible to correlate different interpretations of the term "security"; method of hermeneutics, which allowed to elaborate texts of normative legal acts of Ukraine, method of typologization, which made it possible to create typologization groups of variants of understanding of the term "security". Scientific novelty. The article analyzes the understanding of the term "security" in various regulatory acts in force in Ukraine. Typological groups were understood to understand the term "security". Conclusions. The analysis of the legal material makes it possible to confirm that the issues of security are within the scope of both legislative regulation and various specialized by-laws. However, today there is no single conception on how to interpret security terminology. This is due both to the wide range of social relations that are the subject of legal regulation and to the relativity of the notion of security itself and the lack of coherence of views on its definition in legal acts and in the scientific literature. The multiplicity of definitions is explained by combinations of material and procedural understanding, static - dynamic, and conditioned by the peculiarities of a particular branch of legal regulation, limited ability to use methods of one or another branch, the inter-branch nature of some variations of security, etc. Separation, common and different in the definition of "security" can be used to further standardize, in fact, the regulatory legal understanding of security to more effectively implement the legal regulation of the security direction.

Music after the Fall

2017 ◽  
Author(s):  
Tim Rutherford-Johnson
Keyword(s):  
New Media ◽  
Contemporary Music ◽  
The United States ◽  
Art Music ◽  
Sound Art ◽  
Musical Composition ◽  
Western Art ◽  
Wide Range ◽  
Definition Of ◽  
The Cold War

By the start of the 21st century many of the foundations of postwar culture had disappeared: Europe had been rebuilt and, as the EU, had become one of the world’s largest economies; the United States’ claim to global dominance was threatened; and the postwar social democratic consensus was being replaced by market-led neoliberalism. Most importantly of all, the Cold War was over, and the World Wide Web had been born. Music After The Fall considers contemporary musical composition against this changed backdrop, placing it in the context of globalization, digitization, and new media. Drawing on theories from the other arts, in particular art and architecture, it expands the definition of Western art music to include forms of composition, experimental music, sound art, and crossover work from across the spectrum, inside and beyond the concert hall. Each chapter considers a wide range of composers, performers, works, and institutions are considered critically to build up a broad and rich picture of the new music ecosystem, from North American string quartets to Lebanese improvisers, from South American electroacoustic studios to pianos in the Australian outback. A new approach to the study of contemporary music is developed that relies less on taxonomies of style and technique, and more on the comparison of different responses to common themes, among them permission, fluidity, excess, and loss.

scholarly journals Size-adjusted aortic valve area: refining the definition of severe aortic stenosis

2020 ◽  
Author(s):  
Branka Vulesevic ◽  
Naozumi Kubota ◽  
Ian G Burwash ◽  
Claire Cimadevilla ◽  
Sarah Tubiana ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Predictive Accuracy ◽  
Severe Aortic Stenosis ◽  
Aortic Valve Area ◽  
Obese Patients ◽  
Derivation Cohort ◽  
Wide Range ◽  
Definition Of ◽  
Diagnostic And Prognostic Value ◽  
Valve Area

Abstract Aims Severe aortic valve stenosis (AS) is defined by an aortic valve area (AVA) <1 cm2 or an AVA indexed to body surface area (BSA) <0.6 cm/m2, despite little evidence supporting the latter approach and important intrinsic limitations of BSA indexation. We hypothesized that AVA indexed to height (H) might be more applicable to a wide range of populations and body morphologies and might provide a better predictive accuracy. Methods and results In 1298 patients with degenerative AS and preserved ejection fraction from three different countries and continents (derivation cohort), we aimed to establish an AVA/H threshold that would be equivalent to 1.0 cm2 for defining severe AS. In a distinct prospective validation cohort of 395 patients, we compared the predictive accuracy of AVA/BSA and AVA/H. Correlations between AVA and AVA/BSA or AVA/H were excellent (all R2 > 0.79) but greater with AVA/H. Regressions lines were markedly different in obese and non-obese patients with AVA/BSA (P < 0.0001) but almost identical with AVA/H (P = 0.16). AVA/BSA values that corresponded to an AVA of 1.0 cm2 were markedly different in obese and non-obese patients (0.48 and 0.59 cm2/m2) but not with AVA/H (0.61 cm2/m for both). Agreement for the diagnosis of severe AS (AVA < 1 cm2) was significantly higher with AVA/H than with AVA/BSA (P < 0.05). Similar results were observed across the three countries. An AVA/H cut-off value of 0.6 cm2/m [HR = 8.2(5.6–12.1)] provided the best predictive value for the occurrence of AS-related events [absolute AVA of 1 cm2: HR = 7.3(5.0–10.7); AVA/BSA of 0.6 cm2/m2 HR = 6.7(4.4–10.0)]. Conclusion In a large multinational/multiracial cohort, AVA/H was better correlated with AVA than AVA/BSA and a cut-off value of 0.6 cm2/m provided a better diagnostic and prognostic value than 0.6 cm2/m2. Our results suggest that severe AS should be defined as an AVA < 1 cm2 or an AVA/H < 0.6 cm2/m rather than a BSA-indexed value of 0.6 cm2/m2.

scholarly journals The tridecaptins: non-ribosomal peptides that selectively target Gram-negative bacteria

2021 ◽  
Author(s):  
Samantha J. Bann ◽  
Ross D. Ballantine ◽  
Stephen A. Cochrane
Keyword(s):  
Gram Negative Bacteria ◽  
Antibacterial Peptides ◽  
Gram Negative ◽  
Non Ribosomal Peptides

Tridecaptins are a re-emerging class of non-ribosomal antibacterial peptides (NRAPs) with potent activity against highly problematic strains of Gram-negative bacteria.

Cubical Agda: A dependently typed programming language with univalence and higher inductive types

2021 ◽  
Vol 31 ◽  
Author(s):  
ANDREA VEZZOSI ◽  
ANDERS MÖRTBERG ◽  
ANDREAS ABEL
Keyword(s):  
Programming Language ◽  
Type Theory ◽  
Type Checking ◽  
Dependent Type Theory ◽  
Wide Range ◽  
General Schema ◽  
Direct Definition ◽  
Inductive Types ◽  
Definition Of ◽  
Cubical Type Theory

Abstract Proof assistants based on dependent type theory provide expressive languages for both programming and proving within the same system. However, all of the major implementations lack powerful extensionality principles for reasoning about equality, such as function and propositional extensionality. These principles are typically added axiomatically which disrupts the constructive properties of these systems. Cubical type theory provides a solution by giving computational meaning to Homotopy Type Theory and Univalent Foundations, in particular to the univalence axiom and higher inductive types (HITs). This paper describes an extension of the dependently typed functional programming language Agda with cubical primitives, making it into a full-blown proof assistant with native support for univalence and a general schema of HITs. These new primitives allow the direct definition of function and propositional extensionality as well as quotient types, all with computational content. Additionally, thanks also to copatterns, bisimilarity is equivalent to equality for coinductive types. The adoption of cubical type theory extends Agda with support for a wide range of extensionality principles, without sacrificing type checking and constructivity.

scholarly journals Amphipathic Peptide Antibiotics with Potent Activity against Multidrug-Resistant Pathogens

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 438
Author(s):  
Jingru Shi ◽  
Chen Chen ◽  
Dejuan Wang ◽  
Ziwen Tong ◽  
Zhiqiang Wang ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Multidrug Resistant ◽  
Peptide Antibiotics ◽  
Biofilm Inhibition ◽  
Amphipathic Peptide ◽  
Host Defense Peptides ◽  
Gram Negative ◽  
Wide Range ◽  
New Antibiotics ◽  
Low Toxicity

The emergence and prevalence of multidrug-resistant (MDR) bacteria have posed a serious threat to public health. Of particular concern are methicillin-resistant Staphylococcus aureus (MRSA) and blaNDM, mcr-1 and tet(X)-positive Gram-negative pathogens. The fact that few new antibiotics have been approved in recent years exacerbates this global crisis, thus, new alternatives are urgently needed. Antimicrobial peptides (AMPs) originated from host defense peptides with a wide range of sources and multiple functions, are less prone to achieve resistance. All these characteristics laid the foundation for AMPs to become potential antibiotic candidates. In this study, we revealed that peptide WW307 displayed potent antibacterial and bactericidal activity against MDR bacteria, including MRSA and Gram-negative bacteria carrying blaNDM-5, mcr-1 or tet(X4). In addition, WW307 exhibited great biofilm inhibition and eradication activity. Safety and stability experiments showed that WW307 had a strong resistance against various physiological conditions and displayed relatively low toxicity. Mechanistic experiments showed that WW307 resulted in membrane damage by selectively targeting bacterial membrane-specific components, including lipopolysaccharide (LPS), phosphatidylglycerol (PG), and cardiolipin (CL). Moreover, WW307 dissipated membrane potential and triggered the production of reactive oxygen species (ROS). Collectively, these results demonstrated that WW307 represents a promising candidate for combating MDR pathogens.

scholarly journals Definitions and Prevalence of Multimorbidity in Large Database Studies: A Scoping Review

2021 ◽  
Vol 18 (4) ◽  
pp. 1673
Author(s):  
Ying Pin Chua ◽  
Ying Xie ◽  
Poay Sian Sabrina Lee ◽  
Eng Sing Lee
Keyword(s):  
Scoping Review ◽  
Chronic Conditions ◽  
Meta Analysis ◽  
Epidemiological Studies ◽  
Cross Sectional ◽  
Coding Systems ◽  
Wide Range ◽  
Scoping Reviews ◽  
Retrospective Cohort Studies ◽  
Definition Of

Background: Multimorbidity presents a key challenge to healthcare systems globally. However, heterogeneity in the definition of multimorbidity and design of epidemiological studies results in difficulty in comparing multimorbidity studies. This scoping review aimed to describe multimorbidity prevalence in studies using large datasets and report the differences in multimorbidity definition and study design. Methods: We conducted a systematic search of MEDLINE, EMBASE, and CINAHL databases to identify large epidemiological studies on multimorbidity. We used the Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Reviews (PRISMA-ScR) protocol for reporting the results. Results: Twenty articles were identified. We found two key definitions of multimorbidity: at least two (MM2+) or at least three (MM3+) chronic conditions. The prevalence of multimorbidity MM2+ ranged from 15.3% to 93.1%, and 11.8% to 89.7% in MM3+. The number of chronic conditions used by the articles ranged from 15 to 147, which were organized into 21 body system categories. There were seventeen cross-sectional studies and three retrospective cohort studies, and four diagnosis coding systems were used. Conclusions: We found a wide range in reported prevalence, definition, and conduct of multimorbidity studies. Obtaining consensus in these areas will facilitate better understanding of the magnitude and epidemiology of multimorbidity.

scholarly journals A Fish Galectin-8 Possesses Direct Bactericidal Activity

2020 ◽  
Vol 22 (1) ◽  
pp. 376
Author(s):  
Tengfei Zhang ◽  
Shuai Jiang ◽  
Li Sun
Keyword(s):  
Bactericidal Activity ◽  
Bacterial Pathogens ◽  
Bactericidal Effect ◽  
Immune Defense ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Animal Cells ◽  
Gram Negative ◽  
Tongue Sole ◽  
Wide Range

Galectins are a family of animal lectins with high affinity for β-galactosides. Galectins are able to bind to bacteria, and a few mammalian galectins are known to kill the bound bacteria. In fish, no galectins with direct bactericidal effect have been reported. In the present study, we identified and characterized a tandem repeat galectin-8 from tongue sole Cynoglossus semilaevis (designated CsGal-8). CsGal-8 possesses conserved carbohydrate recognition domains (CRDs), as well as the conserved HXNPR and WGXEE motifs that are critical for carbohydrate binding. CsGal-8 was constitutively expressed in nine tissues of tongue sole and up-regulated in kidney, spleen, and blood by bacterial challenge. When expressed in HeLa cells, CsGal-8 protein was detected both in the cytoplasm and in the micro-vesicles secreted from the cells. Recombinant CsGal-8 (rCsGal-8) bound to lactose and other carbohydrates in a dose dependent manner. rCsGal-8 bound to a wide range of gram-positive and gram-negative bacteria and was co-localized with the bound bacteria in animal cells. Lactose, fructose, galactose, and trehalose effectively blocked the interactions between rCsGal-8 and different bacteria. Furthermore, rCsGal-8 exerted potent bactericidal activity against some gram-negative bacterial pathogens by directly damaging the membrane and structure of the pathogens. Taken together, these results indicate that CsGal-8 likely plays an important role in the immune defense against some bacterial pathogens by direct bacterial interaction and killing.

Interaction, engagement, and perceived interactivity in single-handed interaction

2016 ◽  
Vol 26 (5) ◽  
pp. 1134-1157 ◽  
Author(s):  
Donghee Shin ◽  
Myunggoon Choi ◽  
Jang Hyun Kim ◽  
Jae-gil Lee
Keyword(s):  
Behavioral Intention ◽  
Interaction Techniques ◽  
Content Type ◽  
Thumb Movement ◽  
Wide Range ◽  
Mobile Industry ◽  
Perceived Interactivity ◽  
The Subject ◽  
Definition Of ◽  
Practical Implications

Purpose The purpose of this paper is to examine the effects of interaction techniques (e.g. swiping and tapping) and the range of thumb movement on interactivity, engagement, attitude, and behavioral intention in single-handed interaction with smartphones. Design/methodology/approach A 2×2 between-participant experiment (technological features: swiping and tapping×range of thumb movement: wide and narrow) was conducted to study the effects of interaction techniques and thumb movement ranges. Findings The results showed that the range of thumb movement had significant effects on perceived interactivity, engagement, attitude, and behavioral intention, whereas no effects were observed for interaction techniques. A narrow range of thumb movement had more influence on the interactivity outcomes in comparison to a wide range of thumb movement. Practical implications While the subject of actual and perceived interactivity has been discussed, the issue has not been applied to smartphone. Based on the research results, the mobile industry may come up with a design strategy that balances feature- and perception-based interactivity. Originality/value This study adopted the perspective of the hybrid definition of interactivity, which includes both actual and perceived interactivity. Interactivity effect outcomes mediated by perceived interactivity.

scholarly journals Combining experimental and simulation data of molecular processes via augmented Markov models

2017 ◽  
Vol 114 (31) ◽  
pp. 8265-8270 ◽  
Author(s):  
Simon Olsson ◽  
Hao Wu ◽  
Fabian Paul ◽  
Cecilia Clementi ◽  
Frank Noé
Keyword(s):  
Force Field ◽  
Structural Changes ◽  
Markov Models ◽  
Force Fields ◽  
Divide And Conquer ◽  
Simulation Data ◽  
Wide Range ◽  
Simulation And Experiment ◽  
Kinetics Of

Accurate mechanistic description of structural changes in biomolecules is an increasingly important topic in structural and chemical biology. Markov models have emerged as a powerful way to approximate the molecular kinetics of large biomolecules while keeping full structural resolution in a divide-and-conquer fashion. However, the accuracy of these models is limited by that of the force fields used to generate the underlying molecular dynamics (MD) simulation data. Whereas the quality of classical MD force fields has improved significantly in recent years, remaining errors in the Boltzmann weights are still on the order of a few kT, which may lead to significant discrepancies when comparing to experimentally measured rates or state populations. Here we take the view that simulations using a sufficiently good force-field sample conformations that are valid but have inaccurate weights, yet these weights may be made accurate by incorporating experimental data a posteriori. To do so, we propose augmented Markov models (AMMs), an approach that combines concepts from probability theory and information theory to consistently treat systematic force-field error and statistical errors in simulation and experiment. Our results demonstrate that AMMs can reconcile conflicting results for protein mechanisms obtained by different force fields and correct for a wide range of stationary and dynamical observables even when only equilibrium measurements are incorporated into the estimation process. This approach constitutes a unique avenue to combine experiment and computation into integrative models of biomolecular structure and dynamics.

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