Self-Catalyzed Hydrolysis of Nitrile-Containing RAFT Chain-Transfer Agent and Its Impact upon Polymerization Control of Methacrylic Monomers.

Self-catalyzed hydrolysis upon storage of the common RAFT chain-transfer agent (CTA) 4-cyano-4-[(thiothiopropyl)sulfanyl] pentanoic acid (CTPPA) is confirmed, where the nitrile group is transformed into an amide by catalysis from the adjacent carboxylic acid moiety. The amide-CTA (APP) is found to poorly control molecular weight evolution during polymerization of two methacrylates, methyl methacrylate (MMA) and N,N-(dimethylamino)ethyl methacrylate (DMAEMA), likely due to poor reinitiation speed in the pre-equilibrium. However, when attached to a macromolecule, the impact of this amide moiety becomes insignificant and chain extension proceeds as expected with CTPPA. In light of CTPPA and similarly hydrolyzable CTAs being extensively employed for aqueous polymerizations of methacrylates, these findings highlight the importance of CTA purity when performing RAFT polymerizations.

Blood-tumor barrier opening by MRI-guided transcranial focused ultrasound in a preclinical breast cancer brain metastasis model improves efficacy of combinatorial chemotherapy.

Patients with metastatic breast cancer have high and continually increasing rates of brain metastases. During the course of the disease, brain metastases can occur in up to 30% of these patients. In most cases, brain metastases are diagnosed after significant disease progression. The blood-tumor barrier increases the difficulty of treating brain metastasis by preventing accumulation of chemotherapy within metastases at therapeutically effective concentrations. Traditional therapies, such as surgical resection, radiotherapy, and chemotherapy, have poor efficacy, as reflected by a low median survival rate of 5-8% after post-diagnosis. Low-intensity focused ultrasound (LiFUS) is a new treatment for enhancing drug accumulation within the brain and brain malignancies. In this study, we elucidate the effect of clinical LiFUS combined with chemotherapy on tumor survival and progression in a preclinical model of triple-negative breast cancer metastasis to the brain. LiFUS significantly increased the tumor accumulation of 14C-AIB and Texas Red compared to controls (p< 0.01). LiFUS-mediated opening of the BTB is size-dependent, which is consistent with our previous studies. Mice receiving LiFUS with combinatorial Doxil and paclitaxel showed a significant increase in median survival (60 days) compared to other groups. LiFUS plus combinatorial chemotherapy of paclitaxel and Doxil also showed the slowest progression of tumor burden compared to chemotherapy alone or individual chemotherapy and LiFUS combinations. This study shows that combining LiFUS with timed combinatorial chemotherapeutic treatment is a potential strategy for improving drug delivery to brain metastases.

Addressing Vaccine Hesitancy Among Students and Families: Interventions for School Nurses.

Vaccine hesitance is a public health issue that school nurses often address in practice. It has become even more prevalent during the coronavirus disease 2019 (COVID-19) pandemic. Vaccine compliance among schoolchildren is essential to the health of an entire community, given that many pediatric illnesses are vaccine-preventable. School nurses are involved in the promotion of vaccines in a school district, as they provide health education to students and families and are responsible for vaccine surveillance. Promoting vaccine compliance as a matter of public health can be challenging for school nurses, especially if a community holds strong beliefs regarding the necessity of pediatric vaccines. This article reviews the history of vaccine mandates, addresses challenges associated with vaccine compliance, and provides interventions school nurses can use when providing care to students and families regarding vaccine hesitancy. In following the nursing process, a school nurse is able to identify students missing vaccine(s) and evaluate for hesitancy, before implementing interventions that provide education to students and families. Several cost-efficient and accessible interventions can facilitate effective education and promote vaccine compliance. School nurses can forge trusting relationships and engage in compassionate dialogue to support vaccine compliance in the school.

Characterization of passive permeability after low intensity focused ultrasound mediated blood-brain barrier disruption in a preclinical model.

BACKGROUND: Systemic drug delivery to the central nervous system is limited by presence of the blood-brain barrier (BBB). Low intensity focused ultrasound (LiFUS) is a non-invasive technique to disrupt the BBB, though there is a lack of understanding of the relationship between LiFUS parameters, such as cavitation dose, time of sonication, microbubble dose, and the time course and magnitude of BBB disruption. Discrepancies in these data arise from experimentation with modified, clinically untranslatable transducers and inconsistent parameters for sonication. In this report, we characterize microbubble and cavitation doses as LiFUS variables as they pertain to the time course and size of BBB opening with a clinical Insightec FUS system. METHODS: Female Nu/Nu athymic mice were exposed to LiFUS using the ExAblate Neuro system (v7.4, Insightec, Haifa, Israel) following target verification with magnetic resonance imaging (MRI). Microbubble and cavitation doses ranged from 4-400 µL/kg, and 0.1-1.5 cavitation dose, respectively. The time course and magnitude of BBB opening was evaluated using fluorescent tracers, ranging in size from 105-10,000 Da, administered intravenously at different times pre- or post-LiFUS. Quantitative autoradiography and fluorescence microscopy were used to quantify tracer accumulation in brain. RESULTS: We observed a microbubble and cavitation dose dependent increase in tracer uptake within brain after LiFUS. Tracer accumulation was size dependent, with 14C-AIB (100 Da) accumulating to a greater degree than larger markers (~ 625 Da-10 kDa). Our data suggest opening of the BBB via LiFUS is time dependent and biphasic. Accumulation of solutes was highest when administered prior to LiFUS mediated disruption (2-fivefold increases), but was also significantly elevated at 6 h post treatment for both 14C-AIB and Texas Red. CONCLUSION: The magnitude of LiFUS mediated BBB opening correlates with concentration of microbubbles, cavitation dose as well as time of tracer administration post-sonication. These data help define the window of maximal BBB opening and applicable sonication parameters on a clinically translatable and commercially available FUS system that can be used to improve passive permeability and accumulation of therapeutics targeting the brain.

Simple and Rapid Adhesion of Commodity Polymer Substrates under Ambient Conditions Using Complexed Alkylboranes.

Adhesives are ubiquitous in manufacturing spanning nearly all sectors from healthcare and photovoltaics to aerospace and electronics. Yet many commercial polymers remain challenging to adhere, necessitating either pretreatment, mechanical fastening, or adhesive processes that involve specialized equipment, high temperature/vacuum, and long cure times. Thus, rapid-cure adhesives for polymers that can set under ambient conditions using simple procedures are desirous because they offer cost savings, faster production, and greater design freedom to producers. Herein, we report a powerful adhesive platform that bonds a wide scope of commodity polymers via (hydrogen) atom transfer and free-radical (graft) polymerization initiated with a trialkylborane-ligand complex and isocyanate decomplexing agent. The developed adhesive formulation is air-stable, bulk, and operates in air at room temperature using a high-glass-transition temperature polyacrylate, i.e., poly(isobornyl acrylate). The alkylborane-initiated bonding process is rapid (∼30 min), requires minimal surface preparation (cleaning and mild roughening), and successfully bonds seven diverse substrates including polytetrafluoroethylene, polyethylene, polypropylene, polycarbonate, nylon, polymethylmethacrylate, and polyvinylchloride. This contribution uniquely investigates the process-property relationships for the adhesive formulation, lap-shear performance, mechanism of failure, and a reactive additive for enhancing the adhesive's glass-transition temperature to ∼120 °C (polyhedral oligomeric silsesquioxane or POSS) to widen its operation temperature. We envision that the reported alkylborane-initiated adhesion platform could hold promise in the automotive, aerospace, and marine sectors as means for rapid manufacturing and structural adhesion.

Alkylborane-Initiated Thiol-Ene Networks for the Synthesis of Thick and Highly Loaded Nanocomposites.

Thiol-ene nanocomposites were synthesized for the first time using an alkylborane-ligand initiator complex under bulk and ambient conditions without external light or thermal stimuli. Initiation was triggered by the in situ decomplexation of an air-stable trialkylborane-amine complex to liberate trialkylborane, which rapidly autoxidizes with atmospheric oxygen and generates free radicals to drive thiol-ene polymerization. This chemically activated mode of initiation uniquely affords thiol-ene nanocomposites with an unrivaled carbon nanotube (CNT) loading of 1.3 wt % and thicknesses of ∼6.7 mm by circumventing restrictions imposed by long pathlengths and light-impeding fillers during photoinitiation. Alkylborane initiation also exhibited advantageous polymerization rates, equivalent to photoinitiation, resulting in network formation and gelation within minutes. Systematic studies were conducted to evaluate comparable alkylborane- and photo-initiated nanocomposites under progressively higher loadings and larger specimen thicknesses, revealing an enhancement or better retainment of mechanical performance in alkylborane-initiated nanocomposites.

The de novo design of a biocompatible and functional integral membrane protein using minimal sequence complexity.

The de novo design of integral membrane proteins remains a major challenge in protein chemistry. Here, we describe the bottom-up design of a genetically-encoded synthetic membrane protein comprising only four amino acids (L, S, G and W) in the transmembrane domains. This artificial sequence, which we call REAMP for recombinantly expressed artificial membrane protein, is a single chain of 133 residues arranged into four antiparallel membrane-spanning α-helices. REAMP was overexpressed in Escherichia coli and localized to the cytoplasmic membrane with the intended transmembrane topology. Recombinant REAMP could be extracted from the cell membrane in detergent micelles and was robust and stable in vitro, containing helical secondary structure consistent with the original design. Engineered mono- and bis-histidine residues in the membrane domain of REAMP were able to coordinate heme in vitro, in a manner reminiscent of natural b-type cytochromes. This binding shifted the electrochemical potential of the cofactor, producing a synthetic hemoprotein capable of nascent redox catalysis. These results show that a highly reduced set of amino acids is sufficient to mimic some key properties of natural proteins, and that cellular biosynthesis is a viable route for the production of minimal de novo membrane sequences.

Oxygen Tolerant and Room Temperature RAFT through Alkylborane Initiation.

A reversible addition-fragmentation chain transfer (RAFT) process was developed capable of being performed at room temperature and in the presence of oxygen by initiating polymerization through an alkylborane-amine complex. This air-stable alkylborane-amine complex was chemically deblocked with carboxylic acid or isocyanate functionalities to liberate a reactive trialkylborane that consumes oxygen and generates radicals to mediate RAFT. Alkylborane-initiated RAFT (AI-RAFT) was demonstrated to allow the synthesis of a wide range of polymer molecular weights with narrow distributions. Rapid polymerization was also possible within minutes under an ambient environment without any prior deoxygenation. Optimal conditions were investigated revealing that carboxylic acids are required in larger excess to alkylborane versus isocyanates and that deblocker functionality can have an impact on polymerization kinetics, achievable molecular weight, and dispersity. Living chain-ends were confirmed by synthesizing block copolymers using AI-RAFT-derived macro-chain transfer agents. In this preliminary study, a chemically induced RAFT process is introduced without requirement of any thermal, photochemical, electrical, or mechanical stimulus capable of polymerizing acrylamide, acrylate, and methacrylate monomers in limited amounts of oxygen at room temperature.

Knowledge of palliative care and attitudes towards nursing the dying patient.

AIMS: This study examines the palliative care knowledge and attitudes towards caring for the dying patient of nurses working in care of older people settings in one rural region in Ireland. DESIGN: A cross-sectional survey design was used combining two questionnaires: the palliative care quiz for nurses (PCQN) and the thanatophobia scale (TS). RESULTS: A total of 61 nurses completed the questionnaire. There was a significant correlation found between level of knowledge and attitudes towards palliative care (p=0.007), highlighting that as participants' level of palliative care knowledge increased, attitudes become more positive. While palliative care training did not impact on the mean overall scores, there was a significant difference in the PCQN scores of those who had completed the European Certificate in Essential Palliative Care (ECEPC) compared with those who had attended information sessions within their unit. Furthermore, increasing years as a registered nurse improved palliative care knowledge and attitudes towards caring for the dying. CONCLUSION: Nurses who completed the ECEPC had better knowledge of palliative care when compared with nurses who had not undertaken the programme. This article also considers areas of focus for palliative care training.

Diagnosing and treating cannabinoid hyperemesis.

Cannabinoid hyperemesis is a newly emerging syndrome that manifests as intractable nausea and vomiting in people who regularly smoke cannabis. The signs and symptoms are relieved by bathing in hot water and by stopping smoking cannabis but are unresponsive to antiemetics. This article briefly examines the possible causes and clinical presentation of the condition and uses a case study to describe the management of patients.

The 5' untranslated region of the soybean cytosolic glutamine synthetase ß(1) gene contains prokaryotic translation initiation signals and acts as a translational enhancer in plants.

Glutamine synthetase (GS) catalyzes the synthesis of glutamine from glutamate and ammonia. In plants, it occurs as two major isoforms, a cytosolic form (GS(1)) and a nuclear encoded chloroplastic form. The focus of this paper is to determine the role of the 5'UTR of a GS(1) gene. GS(1) gene constructs with and without its 5' and 3' UTRs, driven by a constitutive promoter, were agroinfiltrated into tobacco leaves and the tissues were analyzed for both transgene transcript and protein accumulation. The constructs were also tested in an in vitro transcription/translation system and in Escherichia coli. Our results showed that while the 3'UTR functioned in the destabilization of the transcript, the 5'UTR acted as a translation enhancer in plant cells but not in the in vitro translation system. The 5'UTR of the GS(1) gene when placed in front of a reporter gene (uidA), showed a 20-fold increase in the level of GUS expression in agroinfiltrated leaves when compared to the same gene construct without the 5'UTR. The 5'UTR-mediated translational enhancement is probably another step in the regulation of GS in plants. The presence of the GS(1) 5'UTR in front of the GS(1) coding region allowed for its translation in E. coli suggesting the commonality of the translation initiation mechanism for this gene between plants and bacteria.