3,802 research outputs found
Design and Implementation of Multi-Responsive Azobenzene Triggers in Self-Immolative and Degradable Polymers
Self-immolative polymers are a recently developed class of degradable polymers capable of undergoing end-to-end depolymerization following the reaction of their endcaps with appropriate stimuli. Self-immolative materials originated in the field of prodrug chemistry, and evolved into self-immolative oligomers, dendrimers, and most recently, linear polymers. Many stimuli-responsive endcaps have been developed, but typically can only respond to one stimulus. Azobenzenes are a well-known class of stimuli-responsive molecules most commonly used as photoswitches, due to their facile trans-cis isomerization. In addition to their photochemistry, azobenzenes have recently been found to be selectively reduction-sensitive, and are therefore of interest as endcaps in self-immolative polymers. The two fields of azobenzenes and self-immolative polymers have not previously been combined, and it is the work described herein that is the first to do so. This thesis demonstrates that azobenzenes can be useful as multistimuli-responsive units in self-immolative polymers.
First, the reduction-sensitivity of azobenzene was demonstrated in the context of two self-immolative polymer backbones. The synthesis and depolymerization of these materials showed that azobenzene endcaps could be successfully incorporated into – and used to trigger – self-immolative polymers. In the next study, a library of reduction-sensitive azobenzenes was prepared to determine which azobenzene compounds were most suited for use as reduction-sensitive endcaps. A 2-Cl azobenzene derivative was reduced most quickly, and this compound was incorporated as pendant units in an amphiphilic chain-shattering graft copolymer based on a poly(ester amide) backbone. It was found that these azobenzenes imparted both photo- and reduction-sensitivity to aqueous polymer assemblies, and could respond synergistically to both stimuli. In the final study, two distinct linear self-immolative polymer backbones, a polycarbamate and a polyglyoxylate, were synthesized with an azobenzene linker, and conjugated to poly(ethylene oxide) using click chemistry. The synthesized amphiphilic block copolymers were reduction-sensitive, and their aqueous assemblies were shown to encapsulate and release a hydrophobic cargo under reducing conditions. The multifaceted applicability of azobenzene was highlighted in these studies, first as a reduction-sensitive endcap, then as a dual-responsive trigger for chain-shattering poly(ester amide)s, and finally as a reduction-sensitive linker in diblock copolymers
Poly(ester amide)s with pendant azobenzenes: Multi-responsive self-immolative moieties for modulating polymer assemblies
Azobenzenes are well-known for their trans–cis photoisomerization, but it was recently demonstrated that azobenzene derivatives could also undergo reduction to trigger a 1,6-elimination and initiate de- polymerization of a self-immolative polymer. Herein we explore the optimization of azobenzenes as reduction-sensitive moieties, and their incorporation into functional materials. A library of azobenzenes with electron-withdrawing groups was synthesized, and their rates of reduction by hydrazine were deter- mined. Unexpectedly, a 2-Cl substituent increased the rate of reduction more than other electronegative or sterically-demanding substituents. Next, a new diester monomer containing the 2-Cl-azobenzene was synthesized and incorporated into a poly(ester amide) (PEA) backbone, which was then functionalized with PEO to afford an amphiphilic multi-responsive material. The photo- and reduction-sensitivity of the azobenzenes was then exploited to produce reversible and irreversible changes to the polymer nano- assemblies in water. Their responsiveness to light and/or hydrazine was studied by ultraviolet-visible (UV-Vis) spectroscopy, dynamic light scattering (DLS), and fluorescence spectroscopy of encapsulated nile red. Alternating irradiation with UV and visible light resulted in reversible trans–cis isomerization, which changed the polarity of the micelle core without disrupting the assemblies. Reduction by hydrazine resulted in the release of nile red from the micelle core, while residual assemblies were still detected by DLS, likely due to the presence of remaining hydrophobes. A combination of UV light and hydrazine resulted in the release of nile red and breakdown of the assemblies. These results suggest that the intrinsic responsiveness of azobenzene to both light and reductive stimuli can provide polymer assemblies that respond to one or more stimuli in unique and synergistic ways through a single multi-responsive unit
Non-invasive molecular imaging of inflammatory macrophages in allograft rejection.
BackgroundMacrophages represent a critical cell type in host defense, development and homeostasis. The ability to image non-invasively pro-inflammatory macrophage infiltrate into a transplanted organ may provide an additional tool for the monitoring of the immune response of the recipient against the donor graft. We therefore decided to image in vivo sialoadhesin (Sn, Siglec 1 or CD169) using anti-Sn mAb (SER-4) directly radiolabelled with (99m)Tc pertechnetate.MethodsWe used a heterotopic heart transplantation model where allogeneic or syngeneic heart grafts were transplanted into the abdomen of recipients. In vivo nanosingle-photon emission computed tomography (SPECT/CT) imaging was performed 7 days post transplantation followed by biodistribution and histology.ResultsIn wild-type mice, the majority of (99m)Tc-SER-4 monoclonal antibody cleared from the blood with a half-life of 167 min and was located predominantly on Sn(+) tissues in the spleen, liver and bone marrow. The biodistribution in the transplantation experiments confirmed data derived from the non-invasive SPECT/CT images, with significantly higher levels of (99m)Tc-SER-4 observed in allogeneic grafts (9.4 (±2.7) %ID/g) compared to syngeneic grafts (4.3 (±10.3) %ID/g) (p = 0.0022) or in mice which received allogeneic grafts injected with (99m)Tc-IgG isotype control (5.9 (±0.6) %ID/g) (p = 0.0185). The transplanted heart to blood ratio was also significantly higher in recipients with allogeneic grafts receiving (99m)Tc-SER-4 as compared to recipients with syngeneic grafts (p = 0.000004) or recipients with allogeneic grafts receiving (99m)Tc-IgG isotype (p = 0.000002).ConclusionsHere, we demonstrate that imaging of Sn(+) macrophages in inflammation may provide an important additional and non-invasive tool for the monitoring of the pathophysiology of cellular immunity in a transplant model
A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.
Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics
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Public Performance Metrics: Driving Physician Motivation and Performance
Introduction: As providers transition from “fee-for-service” to “pay-for-performance” models, focus has shifted to improving performance. This trend extends to the emergency department (ED) where visits continue to increase across the United States. Our objective was to determine whether displaying public performance metrics of physician triage data could drive intangible motivators and improve triage performance in the ED.Methods: This is a single institution, time-series performance study on a physician-in-triage system. Individual physician baseline metrics—number of patients triaged and dispositioned per shift—were obtained and prominently displayed with identifiable labels during each quarterly physician group meeting. Physicians were informed that metrics would be collected and displayed quarterly and that there would be no bonuses, punishments, or required training; physicians were essentially free to do as they wished. It was made explicit that the goal was to increase the number triaged, and while the number dispositioned would also be displayed, it would not be a focus, thereby acting as this study’s control. At the end of one year, we analyzed metrics.Results: The group’s average number of patients triaged per shift were as follows: Q1-29.2; Q2-31.9; Q3-34.4; Q4-36.5 (Q1 vs Q4, p < 0.00001). The average numbers of patients dispositioned per shift were Q1-16.4; Q2-17.8; Q3-16.9; Q4-15.3 (Q1 vs Q4, p = 0.14). The top 25% of Q1 performers increased their average numbers triaged from Q1-36.5 to Q4-40.3 (ie, a statistically insignificant increase of 3.8 patients per shift [p = 0.07]). The bottom 25% of Q1 performers, on the other hand, increased their averages from Q1-22.4 to Q4-34.5 (ie, a statistically significant increase of 12.2 patients per shift [p = 0.0013]).Conclusion: Public performance metrics can drive intangible motivators (eg, purpose, mastery, and peer pressure), which can be an effective, low-cost strategy to improve individual performance, achieve institutional goals, and thrive in the pay-for-performance era
Demonstrating Photon Ring Existence with Single-Baseline Polarimetry
Images of supermassive black hole accretion flows contain features of both
curved spacetime and plasma structure. Inferring properties of the spacetime
from images requires modeling the plasma properties, and vice versa. The Event
Horizon Telescope Collaboration has imaged near-horizon millimeter emission
from both Messier 87* (M87*) and Sagittarius A* (Sgr A*) with
very-long-baseline interferometry (VLBI) and has found a preference for
magnetically arrested disk (MAD) accretion in each case. MAD accretion enables
spacetime measurements through future observations of the photon ring, the
image feature composed of near-orbiting photons. The ordered fields and
relatively weak Faraday rotation of MADs yield rotationally symmetric
polarization when viewed at modest inclination. In this letter, we utilize this
symmetry along with parallel transport symmetries to construct a gain-robust
interferometric quantity that detects the transition between the weakly lensed
accretion flow image and the strongly lensed photon ring. We predict a shift in
polarimetric phases on long baselines and demonstrate that the photon rings in
M87* and Sgr A* can be unambiguously detected {with sensitive, long-baseline
measurements. For M87* we find that photon ring detection in snapshot
observations requires mJy sensitivity on G baselines at
230 GHz and above, which could be achieved with space-VLBI or higher-frequency
ground-based VLBI. For Sgr A*, we find that interstellar scattering inhibits
photon ring detectability at 230 GHz, but mJy sensitivity on
G baselines at 345 GHz is sufficient, which is accessible from the
ground. For both sources, these sensitivity requirements may be relaxed by
repeated observations and averaging.Comment: 14 pages, 7 figures, Accepted to ApJ
Concurrent extrahepatic autoimmunity in autoimmune hepatitis: implications for diagnosis, clinical course and long term outcome
Concurrent extrahepatic autoimmune disease (CEHAID) associated with autoimmune hepatitis (AIH) have been incorporated into the diagnostic criteria stipulated by the International Autoimmune Hepatitis Group (IAIHG). Large comprehensive cohort data on the extrahepatic autoimmunity in AIH remain scanty AIM: To systematically assess features and clinical impact of CEHAID on AIH METHODS: Clinical records of 562 patients with AIH from two tertiary centres in the United Kingdom were retrospectively reviewed RESULTS: Prevalence of CEHAID in patients with AIH were 42%. Autoimmune thyroid disease was the commonest CEHAID associated with AIH (101/562, 18%). Autoimmune skin diseases were more prevalent in AIH-2 than AIH-1 (21.9% vs.7%, p=0.009). Personal history of CEHAID was more commonly found in AIH patients with than without first degree family history of CEHAID [(48/86, 55.8% vs 169/446, 37.9%), p=0.002]. AIH patients with CEHAID were more often female [201/236 (85.2%), p=0.008], had higher post-treatment IAIHG score (22 vs. 20, p<0.001), less reactivity to smooth muscle antibodies (49.8% vs 65%, p<0.001), more likely to have mild fibrosis at diagnosis (20.9% vs. 6.5%, p<0.001), less often had ascites (6.3% vs. 13.6%, p=0.008) and coagulopathy (1.18 vs. 1.27, p=0.013) at presentation. Presence of CEHAID, however, did not significantly affect disease progression, prognosis and survival in AIH CONCLUSIONS: Our study confirms the strong association of CEHAID with AIH. Association between personal and familial extrahepatic autoimmunity especially among first degree relatives was evident. Presence of CEHAID may influence clinical phenotype of AIH at presentation but without notable impact on the long term clinical outcome
In Vitro Tumor Models: Advantages, Disadvantages, Variables, and Selecting the Right Platform
In vitro tumor models have provided important tools for cancer research and serve as low-cost screening platforms for drug therapies; however, cancer recurrence remains largely unchecked due to metastasis, which is the cause of the majority of cancer related deaths. The need for an improved understanding of the progression and treatment of cancer has pushed for increased accuracy and physiological relevance of in vitro tumor models. As a result, in vitro tumor models have concurrently increased in complexity and their output parameters further diversified, since these models have progressed beyond simple proliferation, invasion, and cytotoxicity screens and have begun recapitulating critical steps in the metastatic cascade, such as intravasation, extravasation, angiogenesis, matrix remodeling, and tumor cell dormancy. Advances in tumor cell biology, 3D cell culture, tissue engineering, biomaterials, microfabrication, and microfluidics have enabled rapid development of new in vitro tumor models that often incorporate multiple cell types, extracellular matrix materials, and spatial and temporal introduction of soluble factors. Other innovations include the incorporation of perfusable microvessels to simulate the tumor vasculature and model intravasation and extravasation. The drive towards precision medicine has increased interest in adapting in vitro tumor models for patient-specific therapies, clinical management, and assessment of metastatic potential. Here, we review the wide range of current in vitro tumor models and summarize their advantages, disadvantages, and suitability in modeling specific aspects of the metastatic cascade and drug treatment
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