RESUMEN
The predictable and controllable interaction of small organic or peptidic molecules with biological substrates is the primary reason most pharmaceuticals are narrowly decorated carbon frameworks. The inhibition or activation binding models are measurable and without side reactions that can cause pathological angst. Yet many diseases, especially those involving rapid proliferation of cells (i.e., cancer) or aggregation of peptides (e.g., heart disease, Alzheimer's disease) have not yet been cured by inhibition therapeutics. Additionally, interventional medicine is often required to alleviate such maladies by physical removal first, followed by molecular-level therapy as a second stage. Thus, there appears to be a niche for more aggressive therapeutics that may employ harsher chemical processes to realize clinical efficacy, albeit without causing catastrophic side effects. Molecules that may be considered for this challenge are not typically biomimetic, nor do they fit the traditional pharmaceutical paradigm. They may have unusual modes of action or undesired reactivity that can be lethal if not controlled. These are the outliers; potential pharmacophores that biology does not know how to manage or adapt to. This is why they may be an intriguing class of agents that needs continuous development. In this Account, we connect the under-developed enediyne family of compounds and our metalloenediyne derivatives to existing radical-based therapeutics such as bleomycin and doxorubicin to illustrate that controlled diradical reactivity, although an outlier mechanism, has a place in the therapeutic portfolio. This is self-evident in that of the 11 natural product enediynes known, 2 have clinical impact, a strong ratio. We expand on the chemical diversity of potential enediyne constructs and focus on the accessible trigger mechanisms to activate diradical formation as a method to control toxicity. Moreover, we further illustrate how electromagnetic fields can be employed to activate both molecular and larger nanomaterial constructs that carry highly concentrated payloads of reactive reagent. Finally, we describe how controlled diradical reactivity can reach beyond traditional therapeutic targets such as DNA, to peptide aggregates found in blood clots, neural fibrils, and membrane scaffolds. It is our belief that cleverly constructed frameworks with well-designed and controlled activation/reaction schemes can lead to novel therapeutics that can challenge evolving viral and bacterial invaders. From this evangelical perspective, our hope is that the conceptual framework, if not the specific designs in this Account, stimulate the readership to develop out-of-the-box therapeutic designs that may combat resistant disease targets.
Asunto(s)
Complejos de Coordinación/química , ADN/química , Enediinos/química , Radicales Libres/química , Metales Pesados/química , Complejos de Coordinación/farmacología , Daño del ADN/efectos de los fármacos , Enediinos/farmacología , Células HeLa , Humanos , Nanopartículas del Metal/químicaRESUMEN
When the COVID-19 surge hit New York City hospitals, the Division of Medical Ethics at Weill Cornell Medical College, and our affiliated ethics consultation services, faced waves of ethical issues sweeping forward with intensity and urgency. In this article, we describe our experience over an eight-week period (16 March through 10 May 2020), and describe three types of services: clinical ethics consultation (CEC); service practice communications/interventions (SPCI); and organizational ethics advisement (OEA). We tell this narrative through the prism of time, describing the evolution of ethical issues and trends as the pandemic unfolded. We delineate three phases: anticipation and preparation, crisis management, and reflection and adjustment. The first phase focused predominantly on ways to address impending resource shortages and to plan for remote ethics consultation, and CECs focused on code status discussions with surrogates. The second phase was characterized by the dramatic convergence of a rapid increase in the number of critically ill patients, a growing scarcity of resources, and the reassignment/redeployment of staff outside their specialty areas. The third phase was characterized by the recognition that while the worst of the crisis was waning, its medium- and long-term consequences continued to pose immense challenges. We note that there were times during the crisis that serving in the role of clinical ethics consultant created a sense of dis-ease as novel as the coronavirus itself. In retrospect we learned that our activities far exceeded the familiar terrain of clinical ethics consultation and extended into other spheres of organizational life in novel ways that were unanticipated before this pandemic. To that end, we defined and categorized a middle level of ethics consultation, which we have termed service practice communication intervention (SPCI). This is an underappreciated dimension of the work that ethics consult services are capable of in times of crisis. We believe that the pandemic has revealed the many enduring ways that ethics consultation services can more robustly contribute to the ethical life of their institutions moving forward.
Asunto(s)
Consultoría Ética/organización & administración , Pandemias/ética , Centros Médicos Académicos , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/epidemiología , Humanos , Ciudad de Nueva York/epidemiología , Neumonía Viral/epidemiología , SARS-CoV-2RESUMEN
Developing facile synthetic routes to multifunctional nanoparticles combining the magnetic properties of iron oxides with the optical and catalytic utility of noble metal particles remains an important goal in realizing the potential of hybrid nanomaterials. To this end, we have developed a single route to noble metal-decorated magnetic nanoparticles (Fe3O4@SiO2-M; M = Au, Pd, Ag, and PtAg) and characterized them by HRTEM and STEM/EDX imaging to reveal their nanometer size (16 nm Fe3O4 and 1-5 nm M seeds) and uniformity. This represents one of the few examples of genuine multifunctional particles on the nanoscale. We show that these hybrid structures have excellent catalytic activity for the reduction of 4-nitrophenol (knorm = 2 × 10(7) s(-1) mol(Pd)(-1); 5 × 10(6) s(-1) mol(Au)(-1); 5 × 10(5) s(-1) mol(PtAg)(-1); 7 × 10(5) s(-1) mol(Ag)(-1)). These rates are the highest reported for nano-sized comparables, and are competitive with mesoparticles of similar composition. Due to their magnetic response, the particles are also suitable for magnetic recovery and maintain >99% conversion for at least four cycles. Using this synthetic route, Fe3O4@SiO2-M particles show great promise for further development as a precursor to complicated anisotropic materials or for applications ranging from nanocatalysis to biomedical sensing.
RESUMEN
BACKGROUND AND PURPOSE: In recent years, a number of exercise programs have been developed for computer operators in order to promote movement and to reduce musculoskeletal discomfort. Tests of the effectiveness of these exercise programs, especially in field trials, are rare. The authors tested the hypothesis that doing regular, short-term (<10 days) exercises while at a workstation would decrease musculoskeletal discomfort and increase in-chair movement (ICM). SUBJECTS: Eleven directory assistance operators (8 female, 3 male) with no recent history of musculoskeletal problems volunteered. METHODS: In-chair movement was measured by tracking the center of pressure at the buttock-chair interface as subjects sat on a pressure-sensitive mat. Musculoskeletal discomfort was rated through the use of the Body Part Discomfort Scale (BPDS) and a body map. We used a revised Dataspan exercise program. Operators were tested for 2 hours, on 2 occasions: before and after doing exercises for 3- to 5-day shifts. During each test, ICM was measured during three 15-minute periods at the start of the test and at the end of hours 1 and 2. Subjects rated musculoskeletal discomfort per body part using the BPDS at 30, 60, and 120 minutes of each test. The effects of exercises on ICM and BPDS ratings were examined with a two-way repeated-measures analysis of variance with day (2) x time (3) designs. RESULTS: When subjects were doing their exercises, ICM was higher at the start and hour 1, and perceived discomfort was lower during each test period (start, hour 1, and hour 2). When not exercising, subjects' musculoskeletal discomfort increased over time and was higher during all test periods. DISCUSSION AND CONCLUSION: Exercises done by video display unit operators while at a workstation resulted in short-term decreases in both musculoskeletal discomfort and postural immobility. These results suggest that workstation exercises may be beneficial.