Accelerating growth and global expansion of antimicrobial resistance has deepened the need for discovery of novel antimicrobial agents. Antimicrobial peptides have clear advantages over conventional ...antibiotics which include slower emergence of resistance, broad-spectrum antibiofilm activity, and the ability to favourably modulate the host immune response. Broad bacterial susceptibility to antimicrobial peptides offers an additional tool to expand knowledge about the evolution of antimicrobial resistance. Structural and functional limitations, combined with a stricter regulatory environment, have hampered the clinical translation of antimicrobial peptides as potential therapeutic agents. Existing computational and experimental tools attempt to ease the preclinical and clinical development of antimicrobial peptides as novel therapeutics. This Review identifies the benefits, challenges, and opportunities of using antimicrobial peptides against multidrug-resistant pathogens, highlights advances in the deployment of novel promising antimicrobial peptides, and underlines the needs and priorities in designing focused development strategies taking into account the most advanced tools available.
β-Arrestins are proteins that bind phosphorylated heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) and contribute to the desensitization of GPCRs by uncoupling the signal ...transduction process. Resensitization of GPCR responsiveness involves agonist-mediated receptor sequestration. Overexpression of β-arrestins in human embryonic kidney cells rescued the sequestration of $\beta_2$-adrenergic receptor ($\beta_2$AR) mutants defective in their ability to sequester, an effect enhanced by simultaneous overexpression of β-adrenergic receptor kinase 1. Wild-type $\beta_2$AR sequestration was inhibited by the overexpression of two β-arrestin mutants. These findings suggest that β-arrestins play an integral role in GPCR internalization and thus serve a dual role in the regulation of GPCR function.
•The governing equation and reflection equations for a travelling string with classical and nonclassical boundaries are given.•A novel reflective wave superposition method is proposed to obtain ...analytical solutions of vibration for travelling string.•A new calculation method for vibration energy of travelling string is put forward.•The laws of energy change in boundaries under different motion conditions and boundary conditions are revealed.
The finite length model of a traveling string can be used to study the lateral vibrations in many engineering devices. The vibrational energy exchange mechanism and its characteristics are very complex, due to the axial movement and the different boundary conditions. A finite length translating tensioned string model with mixed boundary conditions is considered here in order to study the exchange of vibrational energyduring the reflection process. The boundary conditions are respectively at one end a spring-dashpot and the other a fixed boundary, together forming one kind of mixed boundary conditions. An analytical solution and energy expressions for the propagating wave are presented using a reflected wave superposition method. Firstly, a complete cycle of boundary reflections in the string is provided. To simplify the process for obtaining the response, each cycle is divided into three time intervals. Applying D’Alembert’s principle and the reflection properties, expressions for the reflected waves under these mixed boundary conditions are derived with the vibrational response solved for three time intervals. The accuracy and efficiency of the proposed method are confirmed numerically by comparison to simulations produced using a Newmark-β method solution. The comparison shows that the reflected wave superposition method solution is achievable for higher translational speeds, even the critical speed, which is not attainable from most numerical methods. The subsequent energy analytical expressions for a traveling string with these mixed boundary conditions are obtained in terms of the superposition of the traveling waves and their reflections. The properties of vibration energy exchange as a function of the translational velocity, the type of boundary and level of damping are discussed. Numerical simulation results proved that the viscous damper results in energy dissipation at the boundary, and the choice of the magnitude and direction of the translational string velocity can affect the energy of the traveling wave.
In this paper transverse vibration of an axially moving viscoelastic string with a viscous damper at one end is investigated analytically. The string is assumed to be travelling with constant ...velocity and the length of string is constant or time varying. The linear and nonlinear mathematical models are derived using the Lagrangian function and implemented using a finite element method. The method considers a time varying state space function applied to the linear model, the Newmark-Beta method is used to solve the response for the nonlinear problem numerically. The case of energy dissipated by a viscoelastic damper at one end of the string for different axial string velocities is considered. When a disturbance arrives at the boundary an exact value for the damper which provides maximum energy dissipation is investigated. Finally, numerical simulations are presented to establish the feasibility of the method.
An analytical vibration response in the time domain for an axially translating and laterally vibrating string with mixed boundary conditions is considered in this paper. The domain of the string is a ...constant, dependent upon the general initial conditions. The translating tensioned strings possess different types of mixed boundary conditions, such as fixed_dashpot, fixed_spring-dashpot, fixed_mass-spring-dashpot. An analytical solution using a reflected wave superposition method is presented for a finite translating string. Firstly, the cycle of boundary reflection for strings is provided, which is dependent upon the string length. Each cycle is divided into three time intervals according to the travelling speed and direction of the string. Applying D’Alembert’s principle and the reflection properties, expressions for the reflected waves under three different non-classical boundary conditions are derived. Then, the vibrational response of the axially translating string is solved for three time intervals by using a reflected wave superposition method. The accuracy and efficiency of the proposed method are confirmed numerically by comparison to simulations produced using a Newmark-β method solution. The energy expressions for a travelling string with a fixed_dashpot boundary condition is obtained and the time domain curves for the total energy and the change of energy at the boundaries are given.
Today's brightest coherent X-ray sources, X-ray free-electron lasers, produce ultrafast X-ray pulses for which full-width at half-maximum durations as short as 3 fs have been measured. There has been ...a marked increase in the popularity of such short pulses now that optical timing techniques have begun to report an X-ray/optical delay below ∼10 fs r.m.s. errors. As a result, sub-10 fs optical pulses have been implemented at the Linac Coherent Light Source (LCLS) X-ray beamlines, thus warranting a push to reduce the error in X-ray/optical delay measurements to the 1 fs level. Here, we report a unique two-dimensional spectrogram measurement of the relative X-ray/optical delay. This easily scalable relative delay measurement already surpasses previous techniques by an order of magnitude with its sub-1 fs temporal resolution and opens up the prospect of time-resolved X-ray measurements to the attosecond community.
This paper considers the analytical free time domain response and energy in an axially translating and laterally vibrating string. The domain of the string is either a constant or variable length, ...dependent upon the general initial conditions. The translating tensioned strings possess either fixed-fixed or fixed-free boundaries. An alternative analytical solution using a reflected wave superposition method is presented for a finite translating string. Firstly, the cycles of vibration for both constant and variable length strings are provided, which for the latter are dependent upon the variable string length. Each cycle is divided into three time intervals according to the magnitude and the direction of the translating string velocity. Applying d’Alembert's method combined with the reflection properties, expressions for the reflected waves at the two boundaries are obtained. Subsequently, superposition of all of the incident and reflected waves provides results for the free vibration of the string over the three time intervals. The variation in the total mechanical energy of the string system is also shown. The accuracy and efficiency of the proposed method are confirmed numerically by comparison to simulations produced using a Newmark-Beta method solution and an existing state space function representation of the string dynamics.
Aim
Identify hotspots and areas of high species richness for Arctic marine mammals.
Location
Circumpolar Arctic.
Methods
A total of 2115 biologging devices were deployed on marine mammals from ...13 species in the Arctic from 2005 to 2019. Getis‐Ord Gi* hotspots were calculated based on the number of individuals in grid cells for each species and for phylogenetic groups (nine pinnipeds, three cetaceans, all species) and areas with high species richness were identified for summer (Jun‐Nov), winter (Dec‐May) and the entire year. Seasonal habitat differences among species’ hotspots were investigated using Principal Component Analysis.
Results
Hotspots and areas with high species richness occurred within the Arctic continental‐shelf seas and within the marginal ice zone, particularly in the “Arctic gateways” of the north Atlantic and Pacific oceans. Summer hotspots were generally found further north than winter hotspots, but there were exceptions to this pattern, including bowhead whales in the Greenland‐Barents Seas and species with coastal distributions in Svalbard, Norway and East Greenland. Areas with high species richness generally overlapped high‐density hotspots. Large regional and seasonal differences in habitat features of hotspots were found among species but also within species from different regions. Gap analysis (discrepancy between hotspots and IUCN ranges) identified species and regions where more research is required.
Main conclusions
This study identified important areas (and habitat types) for Arctic marine mammals using available biotelemetry data. The results herein serve as a benchmark to measure future distributional shifts. Expanded monitoring and telemetry studies are needed on Arctic species to understand the impacts of climate change and concomitant ecosystem changes (synergistic effects of multiple stressors). While efforts should be made to fill knowledge gaps, including regional gaps and more complete sex and age coverage, hotspots identified herein can inform management efforts to mitigate the impacts of human activities and ecological changes, including creation of protected areas.
Epidemiologic studies suggest phthalate metabolite concentrations are associated with type 2 diabetes. GDM is a strong risk factor for type 2 diabetes. Little is known about phthalates and GDM risk ...factors (i.e. 1st trimester body mass index (BMI), gestational weight gain (GWG), and 2nd trimester glucose levels).
A total of 350 women participating in Lifecodes pregnancy cohort (Boston, MA), delivered at term and had pregnancy urinary phthalate metabolite concentrations. Nine specific gravity-adjusted urinary phthalate metabolites were evaluated. General linear regression was used to assess associations between quartiles of phthalate metabolites and continuous 1st trimester BMI and late 2nd trimester blood glucose. Linear mixed models were used for total GWG. Multivariable logistic regression was used for phthalate concentrations and categorized GWG and impaired glucose tolerance defined as glucose≥140mg/dL based on a 50-gram glucose load test. Models were adjusted for potential confounders.
There were no associations between 1st trimester urinary phthalate metabolite concentrations and 1st trimester BMI. Mono-ethyl phthalate concentrations averaged across pregnancy were associated with a 2.17 increased odds of excessive GWG (95% CI: 0.98, 4.79). Second trimester mono-ethyl phthalate was associated with increased odds of impaired glucose tolerance (adj. OR: 7.18; 95% CI: 1.97, 26.15). A summary measure of di-2-ethylhexyl phthalate metabolite concentrations were inversely associated with impaired glucose tolerance (adj. OR: 0.25; adj. 95% CI: 0.08, 0.85).
Higher exposure to mono-ethyl phthalate, a metabolite of the parent compound of di-ethyl phthalate, may be associated with excessive GWG and impaired glucose tolerance; higher di-2-ethylhexyl phthalate was associated with reduced odds of impaired glucose tolerance.
•Higher 2nd trimester MEP concentrations were associated with a higher risk of IGT and excessive GWG•Higher 2nd trimester ΣDEHP metabolite concentrations were inversely associated with continuous glucose levels in 2nd trimester•No associations were found for 1st trimester urinary phthalate metabolite concentrations and GDM risk factors
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