We have produced a new software package for the simulation of pulsar populations, PsrPopPy, based on the Psrpop package. The codebase has been re-written in Python (save for some external libraries, ...which remain in their native Fortran), utilizing the object-oriented features of the language, and improving the modularity of the code. Pre-written scripts are provided for running the simulations in 'standard' modes of operation, but the code is flexible enough to support the writing of personalised scripts. The modular structure also makes the addition of experimental features (such as new models for period or luminosity distributions) more straightforward than with the previous code. We also discuss potential additions to the modelling capabilities of the software. Finally, we demonstrate some potential applications of the code; first, using results of surveys at different observing frequencies, we find pulsar spectral indices are best fitted by a normal distribution with mean −1.4 and standard deviation 1.0. Secondly, we model pulsar spin evolution to calculate the best fit for a relationship between a pulsar's luminosity and spin parameters. We used the code to replicate the analysis of Faucher-Giguère & Kaspi, and have subsequently optimized their power-law dependence of radio luminosity, L, with period, P, and period derivative, Ṗ. We find that the underlying population is best described by L ∝ P
−1.39±0.09
Ṗ
0.48±0.04 and is very similar to that found for γ-ray pulsars by Perera et al. Using this relationship, we generate a model population and examine the age-luminosity relation for the entire pulsar population, which may be measurable after future large-scale surveys with the Square Kilometre Array.
The first review on biomaterials for the treatment of myocardial infarction (MI) was written in 2006. In the last 5 years, the general approaches for biomaterial treatment of MI and subsequent left ...ventricular remodeling remain the same, namely, left ventricular restraints, epicardial patches, and injectable therapies. Nonetheless, there have been significant developments in this field, including advancement of biomaterial therapies to large animal pre-clinical studies and, more recently, to clinical trials. This review focuses on the progress made in the field of cardiac biomaterial treatments for MI over the last 5 years.
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•Hydrogen–deuterium exchange mass spectrometry (HDX MS) is now more routine.•Large signaling proteins can be studied with HDX MS, from kinases to GPCRs.•Membrane mimetics and HDX MS ...probe signaling complexes at the membrane.•HDX MS with membranes elucidates the role of membrane in conformation.•HDX MS can be leveraged to facilitate X-ray crystallography of large complexes.
Hydrogen–deuterium exchange (HDX) mass spectrometry (MS) can provide information about proteins that can be challenging to obtain by other means. Structure/function relationships, binding interactions, and the effects of modification have all been measured with HDX MS for a diverse and growing array of signaling proteins and multiprotein signaling complexes. As a result of hardware and software improvements, receptors and complexes involved in cellular signaling—including those associated with membranes—can now be studied. The growing body of HDX MS studies of signaling complexes at membranes is particularly exciting. Recent examples are presented to illustrate what can be learned about signaling proteins with this technique.
Discoveries of rotating radio transients and fast radio bursts (FRBs) in pulsar surveys suggest that more of such transient sources await discovery in archival data sets. Here we report on a ...single-pulse search for dispersed radio bursts over a wide range of Galactic latitudes (|b| < 60°) in data previously searched for periodic sources by Burgay et al. We re-detected 20 of the 42 pulsars reported by Burgay et al. and one rotating radio transient reported by Burke-Spolaor. No FRBs were discovered in this survey. Taking into account this result, and other recent surveys at Parkes, we corrected for detection sensitivities based on the search software used in the analyses and the different back-ends used in these surveys and find that the all-sky FRB event rate for sources with a fluence above 4.0 Jy ms at 1.4 GHz to be
${\cal R} = 4.4^{+5.2}_{-3.1} \times 10^3$
FRBs d−1 sky−1, where the uncertainties represent a 99 per cent confidence interval. While this rate is lower than inferred from previous studies, as we demonstrate, this combined event rate is consistent with the results of all systematic FRB searches at Parkes to date and does not require the need to postulate a dearth of FRBs at intermediate latitudes.
We report the synthesis of a GDP analogue, SML‐8‐73‐1, and a prodrug derivative, SML‐10‐70‐1, which are selective, direct‐acting covalent inhibitors of the K‐Ras G12C mutant relative to wild‐type ...Ras. Biochemical and biophysical measurements suggest that modification of K‐Ras with SML‐8‐73‐1 renders the protein in an inactive state. These first‐in‐class covalent K‐Ras inhibitors demonstrate that irreversible targeting of the K‐Ras guanine‐nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.
Putting a stop to Ras: Two new selective, direct‐acting covalent inhibitors of the K‐Ras G12C mutant are reported. Studies suggest that the modification of K‐Ras with SML‐8‐73‐1 renders the protein inactive. These novel covalent inhibitors demonstrate that irreversible targeting of the K‐Ras guanine‐nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.
Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or ...packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two “scaffold” proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.
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Extracellular vesicles (EVs) are natural mediators of cell-cell communication and thus potential vehicles for drug delivery. Dooley et al. describe an EV engineering platform based on two scaffold proteins, PTGFRN and BASP1, which enable high-density EV surface display and luminal loading of therapeutic cargo, leading to potent, pharmacodynamic activity in vitro and in vivo.
Isatin as an alkaloidal framework have consistently attracted attention of medicinal chemist towards development of wide range of novel therapeutic agents. This review report has discussed ...significant isatin lead molecules and their derivatives which have shown promising biological potential in recent times. The substituted isatins showing a potent pharmacological activities such as antimicrobial, antitubercular, anticancer, antioxidant, anti-histaminic, anti-HIV, antiviral, anti-inflammatory, anti-Parkinson's and antidiabetic have been described in this review. The mechanism of action leading to therapeutic activity of the respective isatin derivation has also been recorded. This review reveals that the systematic and rational modifications on isatin motif exhibited significant bio-activities which can be exploited for the development of potent novel therapeutic agents in the future studies. Hence the quest to investigate more structural alterations on isatin scaffold should be continued.
Several injectable materials have been shown to preserve or improve cardiac function as well as prevent or slow left ventricular (LV) remodeling post-myocardial infarction (MI). However, it is ...unclear as to whether it is the structural support or the bioactivity of these polymers that lead to beneficial effects. Herein, we examine how passive structural enhancement of the LV wall by an increase in wall thickness affects cardiac function post-MI using a bio-inert, non-degradable synthetic polymer in an effort to better understand the mechanisms by which injectable materials affect LV remodeling.
Poly(ethylene glycol) (PEG) gels of storage modulus G' = 0.5±0.1 kPa were injected and polymerized in situ one week after total occlusion of the left coronary artery in female Sprague Dawley rats. The animals were imaged using magnetic resonance imaging (MRI) at 7±1 day(s) post-MI as a baseline and again post-injection 49±4 days after MI. Infarct wall thickness was statistically increased in PEG gel injected vs. control animals (p<0.01). However, animals in the polymer and control groups showed decreases in cardiac function in terms of end diastolic volume, end systolic volume and ejection fraction compared to baseline (p<0.01). The cellular response to injection was also similar in both groups.
The results of this study demonstrate that passive structural reinforcement alone was insufficient to prevent post-MI remodeling, suggesting that bioactivity and/or cell infiltration due to degradation of injectable materials are likely playing a key role in the preservation of cardiac function, thus providing a deeper understanding of the influencing properties of biomaterials necessary to prevent post-MI negative remodeling.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered ...intratumorally also promote STING activation leading to direct cytotoxicity of many cell types in the tumor microenvironment (TME), systemic inflammation due to rapid tumor extravasation of the CDN, and immune ablation in the TME. These result in a failure to establish immunological memory. ExoSTING, an engineered extracellular vesicle (EV) exogenously loaded with CDN, enhances the potency of CDN and preferentially activates antigen presenting cells in the TME. Following intratumoral injection, exoSTING was retained within the tumor, enhanced local Th1 responses and recruitment of CD8
T cells, and generated systemic anti-tumor immunity to the tumor. ExoSTING at therapeutically active doses did not induce systemic inflammatory cytokines, resulting in an enhanced therapeutic window. ExoSTING is a novel, differentiated therapeutic candidate that leverages the natural biology of EVs to enhance the activity of CDNs.
We have searched three Parkes multibeam 1.4 GHz surveys for the presence of fast radio bursts (FRBs) out to a dispersion measure (DM) of 5000 pc cm−3. These surveys originally targeted the Magellanic ...Clouds (in two cases) and unidentified gamma-ray sources at mid-Galactic latitudes (in the third case) for new radio pulsars. In previous processing, none of these surveys were searched to such a high DM limit. The surveys had a combined total of 719 h of Parkes multibeam on-sky time. One known FRB, 010724, was present in our data and was detected in our analysis but no new FRBs were found. After adding in the on-sky Parkes time from these three surveys to the on-sky time (7512 h) from the five Parkes surveys analysed by Rane et al., all of which have now been searched to high DM limits, we improve the constraint on the all-sky rate of FRBs above a fluence level of 3.8 Jy ms at 1.4 GHz to
$R = 3.3^{+3.7}_{-2.2} \times 10^{3}$
events per day per sky (at the 99 per cent confidence level). Future Parkes surveys that accumulate additional multibeam on-sky time (such as the ongoing high-resolution Parkes survey of the Large Magellanic Cloud) can be combined with these results to further constrain the all-sky FRB rate.
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