RESUMEN
BACKGROUND: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo. METHODS: The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes. RESULTS: Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes. CONCLUSIONS: Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivariable model, and the large sample size, we think this is the most definitive analysis of the predictors of preclinical stroke outcome to date. Future multicenter experimental stroke trials should standardize or at least ensure a balanced representation of the biological and procedural variables identified herein as potential confounders.
Asunto(s)
Infarto de la Arteria Cerebral Media , Animales , Masculino , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/patología , Ratones , Femenino , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Accidente Cerebrovascular/diagnóstico por imagen , Imagen por Resonancia Magnética , Estudios Prospectivos , Accidente Cerebrovascular Isquémico/diagnóstico por imagenRESUMEN
The neurovascular unit (NVU) includes multiple different cell types, including neurons, astrocytes, endothelial cells, and pericytes, which respond to insults on very different time or dose scales. We defined differential vulnerability among these cell types, using response to two different insults: oxygen-glucose deprivation (OGD) and thrombin-mediated cytotoxicity. We found that neurons are most vulnerable, followed by endothelial cells and astrocytes. After temporary focal cerebral ischemia in male rats, we found significantly more injured neurons, compared with astrocytes in the ischemic area, consistent with differential vulnerability in vivo. We sought to illustrate different and shared mechanisms across all cell types during response to insult. We found that gene expression profiles in response to OGD differed among the cell types, with a paucity of gene responses shared by all types. All cell types activated genes relating to autophagy, apoptosis, and necroptosis, but the specific genes differed. Astrocytes and endothelial cells also activated pathways connected to DNA repair and antiapoptosis. Taken together, the data support the concept of differential vulnerability in the NVU and suggest that different elements of the unit will evolve from salvageable to irretrievable on different time scales while residing in the same brain region and receiving the same (ischemic) blood flow. Future work will focus on the mechanisms of these differences. These data suggest future stroke therapy development should target different elements of the NVU differently.
Asunto(s)
Astrocitos , Células Endoteliales , Neuronas , Ratas Sprague-Dawley , Animales , Masculino , Ratas , Astrocitos/metabolismo , Astrocitos/patología , Células Endoteliales/metabolismo , Neuronas/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Glucosa/deficiencia , Glucosa/metabolismo , Isquemia Encefálica/patología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/genética , Pericitos/metabolismo , Pericitos/patología , Acoplamiento Neurovascular/fisiologíaRESUMEN
BACKGROUND: Hepatitis C virus (HCV) is a major health threat in Canada. In British Columbia (BC) province, 1.6% of the population had been exposed to HCV by 2012. Prevalence and incidence of HCV are very high in populations of people who use drugs (PWUD) and sex workers (SW), who may experience unique barriers to healthcare. Consequently, they are less likely to be treated for HCV. Overcoming these barriers is critical for HCV elimination. This research sought to explore the healthcare experiences of PWUD and SW and how these experiences impact their willingness to engage in healthcare in the future, including HCV care. METHODS: Interpretive Description guided this qualitative study of healthcare experiences in BC, underpinned by the Health Stigma and Discrimination framework. The study team included people with living/lived experience of drug use, sex work, and HCV. Twenty-five participants completed in-depth semi-structured interviews on their previous healthcare and HCV-related experiences. Thematic analysis was used to identify common themes. RESULTS: Three major themes were identified in our analysis. First, participants reported common experiences of delay and refusal of care by healthcare providers, with many negative healthcare encounters perceived as rooted in institutional culture reflecting societal stigma. Second, participants discussed their choice to engage in or avoid healthcare. Many avoided all but emergency care following negative experiences in any kind of healthcare. Third, participants described the roles of respect, stigma, dignity, fear, and trust in communication in healthcare relationships. CONCLUSIONS: Healthcare experiences shared by participants pointed to ways that better understanding and communication by healthcare providers could support positive change in healthcare encounters of PWUD and SW, who are at high risk of HCV infection. More positive healthcare encounters could lead to increased healthcare engagement which is essential for HCV elimination.
Asunto(s)
Hepatitis C , Trabajadores Sexuales , Humanos , Hepacivirus , Colombia Británica/epidemiología , Hepatitis C/terapia , Atención a la SaludRESUMEN
The Stroke Preclinical Assessment Network (SPAN) is a multicenter preclinical trial platform using rodent models of transient focal cerebral ischemia to address translational failure in experimental stroke. In addition to centralized randomization and blinding and large samples, SPAN aimed to introduce heterogeneity to simulate the heterogeneity embodied in clinical trials for robust conclusions. Here, we report the heterogeneity introduced by allowing the 6 SPAN laboratories to vary most of the biological and experimental model variables and the impact of this heterogeneity on middle cerebral artery occlusion (MCAo) performance. We included the modified intention-to-treat population of the control mouse cohort of the first SPAN trial (n=421) and examined the biological and procedural independent variables and their covariance. We then determined their impact on the dependent variables cerebral blood flow drop during MCAo, time to achieve MCAo, and total anesthesia duration using multivariable analyses. We found heterogeneity in biological and procedural independent variables introduced mainly by the site. Consequently, all dependent variables also showed heterogeneity among the sites. Multivariable analyses with the site as a random effect variable revealed filament choice as an independent predictor of cerebral blood flow drop after MCAo. Comorbidity, sex, use of laser Doppler flow to monitor cerebral blood flow, days after trial onset, and maintaining anesthesia throughout the MCAo emerged as independent predictors of time to MCAo. Total anesthesia duration was predicted by most independent variables. We present with high granularity the heterogeneity introduced by the biological and model selections by the testing sites in the first trial of cerebroprotection in rodent transient filament MCAo by SPAN. Rather than trying to homogenize all variables across all sites, we embraced the heterogeneity to better approximate clinical trials. Awareness of the heterogeneity, its sources, and how it impacts the study performance may further improve the study design and statistical modeling for future multicenter preclinical trials.
Asunto(s)
Ataque Isquémico Transitorio , Accidente Cerebrovascular , Ratones , Animales , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media , Proyectos de Investigación , Circulación Cerebrovascular/fisiología , Estudios Multicéntricos como AsuntoRESUMEN
Catalytic hydrogenolysis of polyolefins into valuable liquid, oil, or wax-like hydrocarbon chains for second-life applications is typically accompanied by the hydrogen-wasting co-formation of low value volatiles, notably methane, that increase greenhouse gas emissions. Catalytic sites confined at the bottom of mesoporous wells, under conditions in which the pore exerts the greatest influence over the mechanism, are capable of producing less gases than unconfined sites. A new architecture was designed to emphasize this pore effect, with the active platinum nanoparticles embedded between linear, hexagonal mesoporous silica and gyroidal cubic MCM-48 silica (mSiO2/Pt/MCM-48). This catalyst deconstructs polyolefins selectively into â¼C20-C40 paraffins and cleaves C-C bonds at a rate (TOF = 4.2 ± 0.3 s-1) exceeding that of materials lacking these combined features while generating negligible volatile side products including methane. The time-independent product distribution is consistent with a processive mechanism for polymer deconstruction. In contrast to time- and polymer length-dependent products obtained from non-porous catalysts, mSiO2/Pt/MCM-48 yields a C28-centered Gaussian distribution of waxy hydrocarbons from polyolefins of varying molecular weight, composition, and physical properties, including low-density polyethylene, isotactic polypropylene, ultrahigh-molecular-weight polyethylene, and mixtures of multiple, post-industrial polyolefins. Coarse-grained simulation reveals that the porous-core architecture enables the paraffins to diffuse away from the active platinum site, preventing secondary reactions that produce gases.
RESUMEN
BACKGROUND: The increasing prevalence of plastic waste combined with the inefficiencies of mechanical recycling has inspired interest in processes that can convert these waste streams into value-added biomaterials. To date, the microbial conversion of plastic substrates into biomaterials has been predominantly limited to polyhydroxyalkanoates production. Expanding the capabilities of these microbial conversion platforms to include a greater diversity of products generated from plastic waste streams can serve to promote the adoption of these technologies at a larger scale and encourage a more sustainable materials economy. RESULTS: Herein, we report the development of a new strain of Pseudomonas bacteria capable of converting depolymerized polyethylene into high value bespoke recombinant protein products. Using hexadecane, a proxy for depolymerized polyethylene, as a sole carbon nutrient source, we optimized media compositions that facilitate robust biomass growth above 1 × 109 cfu/ml, with results suggesting the benefits of lower hydrocarbon concentrations and the use of NH4Cl as a nitrogen source. We genomically integrated recombinant genes for green fluorescent protein and spider dragline-inspired silk protein, and we showed their expression in Pseudomonas aeruginosa, reaching titers of approximately 10 mg/L when hexadecane was used as the sole carbon source. Lastly, we demonstrated that chemically depolymerized polyethylene, comprised of a mixture of branched and unbranched alkanes, could be converted into silk protein by Pseudomonas aeruginosa at titers of 11.3 ± 1.1 mg/L. CONCLUSION: This work demonstrates a microbial platform for the conversion of a both alkanes and plastic-derived substrates to recombinant, protein-based materials. The findings in this work can serve as a basis for future endeavors seeking to upcycle recalcitrant plastic wastes into value-added recombinant proteins.
Asunto(s)
Alcanos , Polietileno , Proteínas Recombinantes/genética , Carbono , Materiales BiocompatiblesRESUMEN
BACKGROUND: Despite the implementation and expansion of public health and harm reduction strategies aimed at preventing and reversing overdoses, rates of overdose-related events and fatalities continue to rise in British Columbia. The COVID-19 pandemic created a second, concurrent public health emergency that further exacerbated the illicit drug toxicity crisis, reinforced existing social inequities and vulnerabilities, and highlighted the precariousness of systems in place that are meant to protect the health of communities. By exploring the perspectives of people with recent experience of illicit substance use, this study sought to characterize how the COVID-19 pandemic and associated public health measures influenced risk and protective factors related to unintentional overdose by altering the environment in which people live and use substances, influencing the ability of people who use substances to be safe and well. METHODS: One-on-one semi-structured interviews were conducted by phone or in-person with people who use illicit substances (n = 62) across the province. Thematic analysis was performed to identify factors shaping the overdose risk environment. RESULTS: Participants pointed to factors that increased risk of overdose, including: [1] physical distancing measures that created social and physical isolation and led to more substance use alone without bystanders nearby able to respond in the event of an emergency; [2] early drug price spikes and supply chain issues that created inconsistencies in drug availability; [3] increasing toxicity and impurities in unregulated substances; [4] restriction of harm reduction services and supply distribution sites; and [5] additional burden placed on peer workers on the frontlines of the illicit drug toxicity crisis. Despite these challenges, participants highlighted factors that protected against overdose and substance-related harm, including the emergence of new programs, the resiliency of communities of people who use substances who expanded their outreach efforts, the existence of established social relationships, and the ways that individuals consistently prioritized overdose response over concerns about COVID-19 transmission to care for one another. CONCLUSIONS: The findings from this study illustrate the complex contextual factors that shape overdose risk and highlight the importance of ensuring that the needs of people who use substances are addressed in future public health emergency responses.
Asunto(s)
COVID-19 , Sobredosis de Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Drogas Ilícitas , Trastornos Relacionados con Sustancias , Humanos , Colombia Británica/epidemiología , Pandemias , COVID-19/epidemiología , Sobredosis de Droga/epidemiología , Sobredosis de Droga/prevención & control , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
INTRODUCTION: Lives lost in North America due to the unregulated drug poisoning emergency are preventable and those who survive an opioid overdose may suffer long-term disability. Rates of opioid overdose more than doubled following the onset of the COVID-19 pandemic in British Columbia, Canada. MATERIALS AND METHODS: Our analytical sample was comprised of 1447 participants from the 2018, 2019, and 2021 Harm Reduction Client Survey who responded yes or no to having experienced an opioid overdose in the past 6 months. Participants were recruited from harm reduction sites from across British Columbia. We used logistic regression to explore associations of experiencing an opioid overdose. RESULTS: Overall, 21.8% of participants reported experiencing an opioid overdose in the last six months (18.2% in 2019 and 26.6% in 2021). The following factors were positively associated with increased adjusted odds of experiencing a non-fatal opioid overdose: cis men relative to cis women (AOR 1.49, 95% CI 1.10-2.02), unstably housed compared to people with stable housing (AOR 1.87, 95% CI 1.40-2.50), and participants from 2021 compared to those from 2019 (AOR 3.06, 95% CI 1.57-5.97). The effects of both previous experience of a stimulant overdose and having witnessed an opioid overdose depended on the year of study, with both effects decreasing over subsequent years. CONCLUSIONS: Overdoses have increased over time; in 2021 more than one in four participants experienced an overdose. There is an urgent need for policy and program development to meaningfully address the unregulated drug poisoning emergency through acceptable life-saving interventions and services to prevent overdoses and support overdose survivors.
Asunto(s)
Sobredosis de Droga , Sobredosis de Opiáceos , Masculino , Humanos , Femenino , Colombia Británica/epidemiología , Sobredosis de Opiáceos/epidemiología , Estudios Transversales , Fentanilo , Pandemias , Sobredosis de Droga/prevención & control , Analgésicos Opioides/uso terapéuticoRESUMEN
N-Heterocyclic carbenes (NHCs) are powerful organocatalysts, but practical applications often require in situ generation from stable precursors that "mask" the NHC reactivity via reversible binding. Previously established "masks" are often simple small molecules, such that the NHC structure is used to control both catalytic activity and activation temperature, leading to undesirable tradeoffs. Herein, we show that NHC-carbodiimide (CDI) adducts can be masked precursors for switchable organocatalysis and that the CDI substituents can control the reaction profile without changing the NHC structure. Large electronic variations on the CDI (e.g., alkyl versus aryl) drastically change the catalytically active temperature, whereas smaller perturbations (e.g., different para-substituted phenyls) tune the catalyst release within a narrower window. This control was demonstrated for three classic NHC-catalyzed reactions, each influencing the NHC-CDI equilibrium in different ways. Our results introduce a new paradigm for controlling NHC organocatalysis as well as present practical considerations for designing appropriate masks for various reactions.
RESUMEN
Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues-such as incomplete mechanistic knowledge and faulty clinical trial design-a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.
Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular , Anciano , Animales , Encéfalo , Isquemia Encefálica/terapia , Estudios de Factibilidad , Humanos , Infarto de la Arteria Cerebral Media/terapia , Masculino , Ratones , Accidente Cerebrovascular/terapiaRESUMEN
The immobilization of homogeneous catalysts onto supports to improve recyclability while maintaining catalytic efficiency is often a trial-and-error process limited by poor control of the local catalyst environment and few strategies to append catalysts to support materials. Here, we introduce a modular heterogenous catalysis platform that addresses these challenges. Our approach leverages the well-defined interiors of self-assembled Pd12L24 metal-organic cages/polyhedra (MOCs): simple mixing of a catalyst-ligand of choice with a polymeric ligand, spacer ligands, and a Pd salt induces self-assembly of Pd12L24-cross-linked polymer gels featuring endohedrally catalyst-functionalized junctions. Semi-empirical calculations show that catalyst incorporation into the MOC junctions of these materials has minimal affect on the MOC geometry, giving rise to well-defined nanoconfined catalyst domains as confirmed experimentally using several techniques. Given the unique network topology of these freestanding gels, they are mechanically robust regardless of their endohedral catalyst composition, allowing them to be physically manipulated and transferred from one reaction to another to achieve multiple rounds of catalysis. Moreover, by decoupling the catalyst environment (interior of MOC junctions) from the physical properties of the support (the polymer matrix), this strategy enables catalysis in environments where homogeneous catalyst analogues are not viable, as demonstrated for the Au(I)-catalyzed cyclization of 4-pentynoic acid in aqueous media.
Asunto(s)
Metales , Polímeros , Catálisis , Geles , LigandosRESUMEN
Astrocytes protect neurons during cerebral injury through several postulated mechanisms. Recent therapeutic attention has focused on enhancing or augmenting the neuroprotective actions of astrocytes but in some instances astrocytes can assume a neurotoxic phenotype. The signaling mechanisms that drive astrocytes toward a protective versus toxic phenotype are not fully known but cell-cell signaling via proteases acting on cell-specific receptors underlies critical mechanistic steps in neurodevelopment and disease. The protease activated receptor (PAR), resides in multiple brain cell types, and most PARs are found on astrocytes. We asked whether neuron-generated thrombin constituted an important astrocyte activation signal because our previous studies have shown that neurons contain prothrombin gene and transcribed protein. We used neuron and astrocyte mono-cell cultures exposed to oxygen-glucose deprivation and a model of middle cerebral artery occlusion. We found that ischemic neurons secrete thrombin into culture media, which leads to astrocyte activation; such astrocyte activation can be reproduced with low doses of thrombin. Media from prothrombin-deficient neurons failed to activate astrocytes and adding thrombin to such media restored activation. Astrocytes lacking PAR1 did not respond to neuron-generated thrombin. Induced astrocyte activation was antagonized dose-dependently with thrombin inhibitors or PAR1 antagonists. Ischemia-induced astrocyte activation in vivo was inhibited after neuronal prothrombin knockout, resulting in larger strokes. Restoring prothrombin to neurons with a lentiviral gene vector restored astrocyte activation and reduced stroke damage. We conclude that neuron-generated thrombin, released during ischemia, acts via PAR1 and may cause astrocyte activation and paracrine neuroprotection.
Asunto(s)
Astrocitos/metabolismo , Isquemia Encefálica/metabolismo , Neuronas/metabolismo , Accidente Cerebrovascular/etiología , Animales , Encéfalo/metabolismo , Supervivencia Celular/fisiología , Ratones , Neurogénesis/fisiología , Accidente Cerebrovascular/metabolismoRESUMEN
Reactions facilitating inversion of alkene stereochemistry are rare, sought-after transformations in the field of modern organic synthesis. Although a number of isomerization reactions exist, most methods require specific, highly activated substrates to achieve appreciable conversion without side product formation. Motivated by stereoinvertive epoxide carbonylation reactions, we developed a two-step epoxidation/deoxygenation process that results in overall inversion of alkene stereochemistry. Unlike most deoxygenation systems, carbon monoxide was used as the terminal reductant, preventing difficult postreaction separations, given the gaseous nature of the resulting carbon dioxide byproduct. Various alkyl-substituted cis- and trans-epoxides can be reduced to trans- and cis-alkenes, respectively, in >99:1 stereospecificity and up to 95% yield, providing an alternative to traditional, direct isomerization approaches.
Asunto(s)
Alquenos/química , Catálisis , Humanos , EstereoisomerismoRESUMEN
We report the regioselective carbonylation of 2,2-disubstituted epoxides to ß,ß-disubstituted ß-lactones. Mechanistic studies revealed epoxide ring-opening as the turnover limiting step, an insight that facilitated the development of improved reaction conditions using weakly donating, ethereal solvents. A wide range of epoxides can be carbonylated to ß-lactones, which are subsequently ring-opened to produce ketone-based aldol adducts, providing an alternative to the Mukaiyama aldol reaction. Enantiopure epoxides were demonstrated to undergo the carbonylation/ring-opening process with retention of stereochemistry to form enantiopure ß-hydroxy esters.
Asunto(s)
Compuestos Epoxi/química , Cetonas/química , EstereoisomerismoRESUMEN
We report an alternative pathway to the Wacker oxidation of internal olefins involving epoxidation of trans-alkenes followed by a mild and highly regioselective isomerization to give the major ketone isomers in 66-98% yield. Preliminary kinetics and isotope labeling studies suggest epoxide ring opening as the turnover limiting step in our proposed mechanism. A similar catalytic system was applied to the kinetic resolution of select trans-epoxides to give synthetically useful selectivity factors of 17-23 for benzyl-substituted substrates.
RESUMEN
BACKGROUND AND PURPOSE: We showed previously robust neuroprotection with the thrombin inhibitor argatroban and now sought additional support for its neuroprotective potential. METHODS: We used behavioral and histological end points; rigorously blinded the study groups; extended the treatment window to 3 hours after ischemia onset; and used 2 separate models. First, 2-hour filament middle cerebral artery occlusion in 64 male Sprague-Dawley rats was followed by learning and memory testing and quantitative histomorphometry. Randomly assigned treatment was 0.45 mg argatroban, saline, or 0.4 U thrombin. Second, we used the quantal bioassay (n=272) after 2-hour middle cerebral artery occlusion to detect the longest time delay after which therapy failed. RESULTS: Argatroban powerfully and significantly reversed learning and memory deficits because of focal ischemia compared with saline or thrombin (P<0.03; ANOVA). Argatroban was significantly (P<0.05; t test with Bonferroni) protective when given immediately or after 1, 2, 3, but not 4 hours delay. CONCLUSIONS: We obtained supportive evidence for argatroban protection of the neurovascular unit using behavioral and histological measurements at realistic therapeutic time windows.
Asunto(s)
Ácidos Pipecólicos/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Trombina/antagonistas & inhibidores , Animales , Arginina/análogos & derivados , Encéfalo/patología , Isquemia Encefálica/tratamiento farmacológico , Curva de Aprendizaje , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/psicología , SulfonamidasRESUMEN
An ongoing challenge in polymer chemistry is accessing diverse block copolymers from multiple polymerization mechanisms and monomer classes. One strategy to accomplish this goal without intermediate compatibilization steps is the use of universal mediators. Thiocarbonyl thio (TCT) functional groups are well-known mediators to combine radical with either cationic or anionic polymerization, but a sequential cationic-anionic universal mediator system has never been reported. Herein, we report a TCT universal mediator that can sequentially perform photocontrolled cationic polymerization and thioacyl anionic group transfer polymerization to access poly(ethyl vinyl ether)-block-poly(thiirane) polymers for the first time. Thermal analyses of these block copolymers provide evidence of microphase separation. The success of this system, along with the established compatibility of radical polymerization, enabled us to further chain extend the cationic-anionic diblock using radical polymerization of N-isopropylacrylamide. The resulting terpolymer represents the first example of a triblock made from three different monomer classes incorporated via three different mechanisms without any end-group modification steps. The development of this simple, sequential synthesis using a universal mediator approach opens up new possibilities by providing facile access to diverse block copolymers of vinyl ethers, thiiranes, and acrylamides.
RESUMEN
The development of robust methods for the synthesis of chemically recyclable polymers with tunable properties is necessary for the design of next-generation materials. Polyoxazolidinones (POxa), polymers with five-membered urethanes in their backbones, are an attractive target because they are strongly polar and have high thermal stability, but existing step-growth syntheses limit molar masses and methods to chemically recycle POxa to monomer are rare. Herein, we report the synthesis of high molar mass POxa via ring-opening metathesis polymerization of oxazolidinone-fused cyclooctenes. These novel polymers show <5% mass loss up to 382-411 °C and have tunable glass transition temperatures (14-48 °C) controlled by the side chain structure. We demonstrate facile chemical recycling to monomer and repolymerization despite moderately high monomer ring-strain energies, which we hypothesize are facilitated by the conformational restriction introduced by the fused oxazolidinone ring. This method represents the first chain growth synthesis of POxa and provides a versatile platform for the study and application of this emerging subclass of polyurethanes.
RESUMEN
BACKGROUND: North America and the province of British Columbia (BC), Canada, is experiencing an unprecedented number of overdose deaths. In BC, overdose has become the leading cause of death for people between the ages of 10-59 years old. In January 2023, BC decriminalized personal possession of a number of illegal substances with one aim being to address overdose deaths through stigma reduction and promoting access to substance use services. METHODS: We conducted a qualitative study to understand people who use drugs' (PWUD) perceptions of the new decriminalization policy, immediately prior to its' implementation (October-December 2022). To contextualize decriminalization within broader drug policy, we also asked PWUD what they perceived as the priority issues drug policy ought to address and the necessary solutions. Our final sample included 38 participants who used illegal drugs in the past month. RESULTS: We identified four themes: 1) The illicit drug supply as the main driver of drug toxicity deaths 2) Concerns about the impact of decriminalization on drug toxicity deaths 3) Views towards decriminalization as a policy response in the context of the drug toxicity crisis 4) Regulation as a symbol of hope for reducing drug toxicity deaths. CONCLUSION: From our data it became clear that many anticipated that decriminalization would have minimal or no impact on the overdose crisis. Regulation was perceived as the necessary policy approach for effectively and candidly addressing the drivers of the ongoing overdose crisis. These findings are important as jurisdictions consider different approaches to moving away from prohibition-based drug policy.
Asunto(s)
Sobredosis de Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Drogas Ilícitas , Trastornos Relacionados con Sustancias , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Colombia Británica/epidemiología , Sobredosis de Droga/epidemiología , Sobredosis de Droga/prevención & control , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
Supported platinum nanoparticle catalysts are known to convert polyolefins to high-quality liquid hydrocarbons using hydrogen under relatively mild conditions. To date, few studies using platinum grafted onto various metal oxide (MxOy) supports have been undertaken to understand the role of the acidity of the oxide support in the carbon-carbon bond cleavage of polyethylene under consistent catalytic conditions. Specifically, two Pt/MxOy catalysts (MxOy = SrTiO3 and SiO2-Al2O3; Al = 3.0 wt %, target Pt loading 2 wt % Pt â¼1.5 nm), under identical catalytic polyethylene hydrogenolysis conditions (T = 300 °C, P(H2) = 170 psi, t = 24 h; Mw = â¼3,800 g/mol, Mn = â¼1,100 g/mol, D = 3.45, Nbranch/100C = 1.0), yielded a narrow distribution of hydrocarbons with molecular weights in the range of lubricants (Mw = < 600 g/mol; Mn < 400 g/mol; D = 1.5). While Pt/SrTiO3 formed saturated hydrocarbons with negligible branching, Pt/SiO2-Al2O3 formed partially unsaturated hydrocarbons (<1 mol % alkenes and â¼4 mol % alkyl aromatics) with increased branch density (Nbranch/100C = 5.5). Further investigations suggest evidence for a competitive hydrocracking mechanism occurring alongside hydrogenolysis, stemming from the increased acidity of Pt/SiO2-Al2O3 compared to Pt/SrTiO3. Additionally, the products of these polymer deconstruction reactions were found to be independent of the polyethylene feedstock, allowing the potential to upcycle polyethylenes with various properties into a value-added product.