In recent years, numerous delivery systems based on polymers, dendrimers, and nano-scale assemblies have been developed to improve the properties of drug molecules. In general, for the drug molecules ...to be active, they must be released from these delivery systems, ideally in a selective manner at the therapeutic target. As the changes in physiological conditions are relatively subtle from one tissue to another and the concentrations of specific enzymes are often quite low, a release strategy involving the amplification of a biological signal is particularly attractive. This article describes the development of oligomers, dendrimers, and linear polymers based on self-immolative spacers. This new class of molecules is designed to undergo a cascade of intramolecular reactions in response to the cleavage of a trigger moiety, resulting in molecular fragmentation and the release of multiple reporter or drug molecules. Progress in the development of these materials as drug delivery vehicles and sensors will be highlighted.
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Polymers that depolymerize by a cascade of intramolecular reactions in response to the removal of a stabilizing end-cap can allow for an unprecedented degree of control over the polymer degradation ...process. Described here is the development of polymers comprising N,N′-dimethylethylenediamine and 4-hydroxybenzyl alcohol linked by carbamate linkages. The polycarbamate backbone is stable in aqueous solution, but removal of a protective end-cap from the amine terminus allows the diamine to cyclize, forming N,N′-dimethylimidazolidinone and releasing the phenol, which undergoes a 1,6-elimination followed by the release of CO2 to reveal the next amine to continue the cascade. These polymers therefore degrade by alternating cyclization and elimination reactions. First, a tert-butylcarbamate (Boc) group was introduced as a cleavable end-cap, and the degradation kinetics and mechanism were studied by 1H nuclear magnetic resonance (NMR) spectroscopy and size exclusion chromatography. Next, to demonstrate the degradability of these polymers under biologically relevant conditions, poly(ethylene oxide) was introduced as an end-cap via an ester linkage, to provide an amphiphilic block copolymer. This copolymer was found to assemble into cascade degradable nanoparticles that were capable of encapsulating and subsequently releasing a fluorescent dye in aqueous solution. This new class of polymers therefore provides highly promising materials that can be used for the development of medical devices, drug delivery vehicles, and tissue engineering scaffolds with unique biodegradation properties.
Many detailed cervical spine models have been developed and primarily used to investigate kinematic response of the neck in impact scenarios. However, the goal of detailed models is to predict both ...kinematic response and provide insights into injury mechanisms and thresholds through tissue-level response. The objective of this study was to verify and validate an enhanced cervical spine segment finite element model to predict tissue-level failure under four load conditions: tension, flexion, and extension using a C4–C5 segment, and compression using a C5–C6–C7 segment. Mechanical tissue test data in relevant modes of loading was used in the model, and this data was also used to model ultimate tissue failure. The predicted failure locations were representative of reported cervical spine injuries for the different modes of loading, and the predicted peak failure forces were within the reported experimental corridors. The displacement to failure of the tension simulation was lower than expected in some cases, attributed to limitations in the constitutive model. This study provided a validated approach to predict tissue-level failure for cervical spine segments, predicting the location and sequence of tissue failure, and can be applied to future full cervical spine models for the prediction of injurious loading in automotive crash scenarios.
In our effort to create imaging probes targeting the growth hormone secretagogue receptor (GHSR), we now report on the design and synthesis of fluorine and rhenium containing ghrelin analogues ...through modification of the n-octanoyl Ser-3 side chain. Fluorine analogues were designed whereby the fluorine atom is situated at the terminus of an aliphatic chain using diaminopropionic acid (Dpr) as residue-3. Truncated ghrelin(1−5) and ghrelin(1−14) fluorine-bearing analogues were prepared, the best of which had a 28 nM IC50 for GHSR. Ghrelin(1−14) analogues were also prepared containing rhenium, as a surrogate metal for technetium-99m, with a cyclopentadienylrhenium tricarbonyl being situated at the terminus of the residue-3 side chain, yielding compounds the best of which had a 35 nM IC50. This represents a rare case of incorporating rhenium into a peptide structure where the metal complex is required for biological activity. These fluorine and rhenium derivatives demonstrate the ability to modify the Ser-3 side chain of ghrelin in order to create imaging probes for the GHSR.
The past decade has seen a highly polarized debate concerning the Japanese fiscal system, particularly the role of income tax. Several authors argue that Japanese income tax is grossly unfair to low- ...and middle-income taxpayers, while others depict it as the most progressive in the industrialized world. Indeed, many critics claim that it is too progressive, and some even denounce it as 'socialist'. What is sorely lacking is an account that places contemporary Japanese taxation, and the larger fiscal system, in a comparative and historical context. That is what this paper offers. We argue that Japan's tax system is neither highly redistributive from the rich to the poor nor vice versa-at least in the traditional way that redistribution is understood in most Western tax systems. Rather, Japan stands out for the scale of its inter-regional redistribution and the debilitating politico-economic incentives that stem from it.
Unsustainable wildlife trade is a major driver of biodiversity loss and an important public health threat. Yet, effective wildlife trade regulation is currently at odds with food security and ...economic incentives provided by this global, multibillion‐dollar industry. Given such limitations, public health and conservation resources can be aligned to target species for which trade both increases risk of extinction and threatens public health. Here, we developed a simple conservation and health trade risk (CHT) index (range: 2–50) using a case study of traded mammals based on species' extinction and zoonotic risks, weighed by the extent of their trade. We applied this index to 1161 International Union for the Conservation of Nature‐listed terrestrial mammals involved in the wildlife trade to identify 284 high‐priority species that scored high in the CHT index (CHT ≥ 18). Species ranking high for conservation, public health, and trade risks include those belonging to the orders Primates, Cetartiodactyla (even‐toed ungulates), Rodentia (rodents), Chiroptera (bats), and Carnivora (carnivores). Of the high‐priority species, 33% (n = 95) are country‐endemics and may be good candidates for trade regulations and enforcement at national scales. Our study provides a preliminary step in prioritizing species, taxonomic groups, and countries for focused wildlife trade regulation to meet both conservation and public health goals.
The wildlife trade drives biodiversity loss and zoonotic disease emergence, and the health and economic impacts of COVID‐19 have sparked discussions over stricter regulation of the wildlife trade. ...Yet regulation for conservation and health purposes is at odds with the economic incentives provided by this multibillion‐dollar industry. To understand why the wildlife trade persists despite associated biodiversity and global health threats, we used a benefit–cost approach using simple calculations to compare the economic benefits of the wildlife trade at the individual, national, and global scales to the costs of COVID‐19, severe acute respiratory syndrome (SARS), and Ebola disease across scenarios of epidemic frequency. For COVID‐19, benefits of the wildlife trade outweigh costs at individual scales, but costs far exceed benefits at national and global scales, particularly if epidemics were to become frequent. For SARS and Ebola, benefits outweigh costs at all scales, except if Ebola‐like epidemics were to become frequent. The wildlife trade produces net benefits for people who depend on wildlife for food and income but incurs net costs on stakeholders at larger scales from increased epidemic risk. While our analysis omits a variety of costs and benefits that are difficult to quantify and contrast, our analysis is meant to illustrate the distributional outcomes across stakeholder groups that could result from increased wildlife trade regulation. Importantly, the feasibility of trade regulatory policies will depend on how these benefits and costs compare across groups and would therefore need to involve accessible and attractive alternative sources of food and livelihoods for those who depend on the wildlife trade.
reduction sensitive cascade biodegradable linear polymer Dewit, Matthew A; Beaton, Annelise; Gillies, Elizabeth R
Journal of polymer science. Part A, Polymer chemistry,
15 September 2010, Letnik:
48, Številka:
18
Journal Article
Cascade degradable linear polymers offer the potential for a high degree of control over the degradation process. They comprise a backbone that is stable in the presence of an end cap, but upon ...removal of the end cap a cascade of intramolecular reactions is initiated that leads of depolymerization of the polymer backbone. Reported here is a new polymer backbone based on N,N′-dimethylethylenediamine and 2-mercaptoethanol linked by carbamates and thiocarbamates. A disulfide end cap was incorporated such that its cleavage under reducing conditions revealed the thiol of 2-mercaptoethanol, leading to alternating cyclizations of the 2-mercaptoethanol and N,N′-dimethylethylenediamine moieties to provide 1,3-oxathiolan-2-one and N,N′-dimethylimidazolidinone, respectively. The degradation was monitored by ¹H NMR and GPC. The expected products were observed, along with a portion of nondegradable polymer that was likely cyclic species. Overall, the results demonstrate the promise of this new class of polymers to degrade selectively in reducing environments such as hypoxic tumor tissue or the intracellular compartments of cells.
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