Enhancing Pharmacy Faculty Well-Being and Productivity While Reducing Burnout.

Objective To explore methods that pharmacy programs can use to redefine their work environment to reduce stress, improve well-being, and increase faculty productivity.Findings To demonstrate a culture of support, organizations should consider a five-fold approach to enhancing and maintaining faculty well-being, including optimizing faculty and staff support, establishing a faculty development and mentoring program, permitting flexibility in work schedules, improving productivity of meetings, and managing communication tools. Individuals can also take measures to improve their well-being, including controlling email, giving attention to faculty citizenship, implementing stress reduction and coping techniques, and maintaining boundaries between work and home.Summary This article discusses approaches that have been shown to reduce burnout and provides strategies organizations and individuals can implement to improve productivity and faculty well-being. While certain areas, such as faculty wellness and productivity, have been well-studied in the pharmacy and health professions literature, significant gaps were identified in other areas, including alternate work arrangements. In some cases, data from the business sector can be extrapolated to pharmacy education; however, inferences from effective corporate strategies may not be transferable to the culture and expectations of academia. While there is significant overlap between institutional and individual strategies, a culture of communication, collaboration, support, and citizenship is foundational. There is no single strategy that will work for everyone, and flexibility is important to develop an individualized approach.

Perceptions of programs that orient non-practice faculty to the pharmacy profession: A pilot study.

INTRODUCTION: Faculty collaboration across disciplines plays an important role in pharmacy education, and in particular, the American Association of Colleges of Pharmacy (AACP) faculty survey asks whether colleges/schools of pharmacy (C/SOPs) have programs available to orient non-practice faculty to the profession of pharmacy. The purpose of this pilot study was to characterize perceptions of the importance and effectiveness of such programs, and to examine barriers to their successful implementation. METHODS: An online survey was developed to collect demographic information and perceived importance, effectiveness, and barriers of programs designed to orient non-practice faculty to the pharmacy profession. The survey was posted to the AACP Connect Council of Deans and Council of Faculties listservs and responses were gathered and analyzed using descriptive statistics. RESULTS: Responses from 157 individuals representing 90C/SOPs were collected. While the majority (82%) of respondents rated programs that orient non-practice faculty to the pharmacy profession as extremely or very important, only 17% rated such programs as extremely or very effective. Lack of time was identified as the primary barrier. Differences were identified between various interest groups, including practice vs. non-practice disciplines and administrators vs. non-administrators. CONCLUSIONS: Programs to orient non-practice faculty to the pharmacy profession were perceived to be important; however, such programs were found to lack efficacy.

Purine molecules in Parkinson's disease: Analytical techniques and clinical implications.

Parkinson's disease (PD) is a neurodegenerative disorder that primarily affects patients over the age of 65. PD is characterized by loss of neurons in the substantia nigra and dopamine deficiency in the striatum. Once PD is clinically diagnosed by the observation of motor dysfunction, the disease is already in its advance stages. Consequently, there is a major push to identify clinical biomarkers that are useful for the earlier detection of PD. Using untargeted metabolomics, several research groups have identified purine molecules, and specifically urate, as important biomarkers related to PD. This review will summarize recent findings in the field of purine metabolomics and biomarker identification for PD, including in the areas of PD pathophysiology, diagnosis, prognosis and treatment. In addition, this article will summarize and examine the primary research techniques that are employed to quantify purine molecules in both experimental systems and human subjects.

Integrated use of LC/MS/MS and LC/Q-TOF/MS targeted metabolomics with automated label-free microscopy for quantification of purine metabolites in cultured mammalian cells.

Purine metabolites have been implicated as clinically relevant biomarkers of worsening or improving Parkinson's disease (PD) progression. However, the identification of purine molecules as biomarkers in PD has largely been determined using non-targeted metabolomics analysis. The primary goal of this study was to develop an economical targeted metabolomics approach for the routine detection of purine molecules in biological samples. Specifically, this project utilized LC/MS/MS and LC/QTOF/MS to accurately quantify levels of six purine molecules in samples from cultured N2a murine neuroblastoma cells. The targeted metabolomics workflow was integrated with automated label-free digital microscopy, which enabled normalization of purine concentration per unit cell in the absence of fluorescent dyes. The established method offered significantly enhanced selectivity compared to previously published procedures. In addition, this study demonstrates that a simple, quantitative targeted metabolomics approach can be developed to identify and quantify purine metabolites in biological samples. We envision that this method could be broadly applicable to quantification of purine metabolites from other complex biological samples, such as cerebrospinal fluid or blood.

Role of the guanine nucleotide binding protein, Gαo, in the development of morphine tolerance and dependence.

RATIONALE: The use of morphine and other opioids for chronic pain is limited by the development of analgesic tolerance and physical dependence. Morphine produces its effects by activating the µ opioid receptor, which couples to Gαi/o-containing heterotrimeric G proteins. Evidence suggests that the antinociceptive effects of morphine are mediated by Gαo. However, the role of Gαo in the development of morphine tolerance and dependence is unknown. OBJECTIVE: The objective of the study is to evaluate the contribution of Gαo to the development of morphine tolerance and dependence in mice. METHODS: 129S6 mice lacking one copy of the Gαo gene (Gαo +/-) were administered morphine acutely or chronically. Mice were examined for tolerance to the antinociceptive action of morphine using the 52 °C hot plate as the nociceptive stimulus and for dependence by evaluating the severity of naltrexone-precipitated withdrawal. Wild-type littermates of the Gαo +/- mice were used as controls. Changes in µ receptor number and function were determined in midbrain and hindbrain homogenates using radioligand binding and µ agonist-stimulated [35S]GTPγS binding, respectively. RESULTS: Following either acute or chronic morphine treatment, all mice developed antinociceptive tolerance and physical dependence, regardless of genotype. With chronic morphine treatment, Gαo +/- mice developed tolerance faster and displayed more severe naltrexone-precipitated withdrawal in some behaviors than did wild-type littermates. Morphine tolerance was not associated with changes in µ receptor number or function in brain homogenates from either wild-type or Gαo +/- mice. CONCLUSIONS: These data suggest that the guanine nucleotide binding protein Gαo offers some protection against the development of morphine tolerance and dependence.

Basic science breaks through: New therapeutic advances in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease and is typically associated with progressive motor dysfunction, although PD patients also exhibit a variety of non-motor symptoms. The neuropathological hallmark of PD is intraneuronal inclusions containing primarily α-Synuclein (α-Syn), and several lines of evidence point to α-Syn as a key contributor to disease progression. Thus, basic research in the field of PD is largely focused on understanding the pathogenic properties of α-Syn. Over the past 2 y, these studies helped to identify several novel therapeutic strategies that have the potential to slow PD progression; such strategies include sequestration of extracellular α-Syn through immunotherapy, reduction of α-Syn multimerization or intracellular toxicity, and attenuation of the neuroinflammatory response. This review describes these and other putative therapeutic strategies, together with the basic science research that led to their identification. The current breadth of novel targets for the treatment of PD warrants cautious optimism in the fight against this devastating disease.

A cell culture model for monitoring α-synuclein cell-to-cell transfer.

The transfer of α-synuclein (α-syn) between cells has been proposed to be the primary mechanism of disease spreading in Parkinson's disease. Several cellular models exist that monitor the uptake of recombinant α-syn from the culture medium. Here we established a more physiologically relevant model system in which α-syn is produced and transferred between mammalian neurons. We generated cell lines expressing either α-syn tagged with fluorescent proteins or fluorescent tags alone then we co-cultured these cell lines to measure protein uptake. We used live-cell imaging to demonstrate intercellular α-syn transfer and used flow cytometry and high content analysis to quantify the transfer. We then successfully inhibited intercellular protein transfer genetically by down-regulating dynamin or pharmacologically using dynasore or heparin. In addition, we differentiated human induced pluripotent stem cells carrying a triplication of the α-syn gene into dopaminergic neurons. These cells secreted high levels of α-syn, which was taken up by neighboring neurons. Collectively, our co-culture systems provide simple but physiologically relevant tools for the identification of genetic modifiers or small molecules that inhibit α-syn cell-to-cell transfer.

Spreading of α-synuclein in the face of axonal transport deficits in Parkinson's disease: a speculative synthesis.

Parkinson's disease (PD) is mainly attributed to degeneration of dopamine neurons in the substantia nigra, but its etiopathogenesis also includes impaired protein clearance and axonal transport dysfunction, among others. The spread of α-synuclein (α-syn) aggregates from one neuron to another, in a prion-like manner, is hypothesized to contribute to PD progression. Axonal transport is likely to play a crucial role in this movement of α-syn aggregates between brain regions. At the same time, deficits in axonal transport are suggested to contribute to neuronal failure in PD. In this review, we discuss the apparent contradiction that axonal transport might be essential for disease progression, while dysfunction of axonal transport could simultaneously be a cornerstone of PD pathogenesis. We speculate around models that reconcile how axonal transport can play such a paradoxical role.

Opioid receptor interacting proteins and the control of opioid signaling.

Opioid receptors are seven-transmembrane domain receptors that couple to intracellular signaling molecules by activating heterotrimeric G proteins. However, the receptor and G protein do not function in isolation but their activities are modulated by several accessory and scaffolding proteins. Examples include arrestins, kinases, and regulators of G protein signaling proteins. Accessory proteins contribute to the observed potency and efficacy of agonists, but also to the direction of signaling and the phenomenon of biased agonism. This review will present current knowledge of such proteins and how they may provide targets for future drug design.

Differential control of opioid antinociception to thermal stimuli in a knock-in mouse expressing regulator of G-protein signaling-insensitive Gαo protein.

Regulator of G-protein signaling (RGS) proteins classically function as negative modulators of G-protein-coupled receptor signaling. In vitro, RGS proteins have been shown to inhibit signaling by agonists at the µ-opioid receptor, including morphine. The goal of the present study was to evaluate the contribution of endogenous RGS proteins to the antinociceptive effects of morphine and other opioid agonists. To do this, a knock-in mouse that expresses an RGS-insensitive (RGSi) mutant Gαo protein, Gαo(G184S) (Gαo RGSi), was evaluated for morphine or methadone antinociception in response to noxious thermal stimuli. Mice expressing Gαo RGSi subunits exhibited a naltrexone-sensitive enhancement of baseline latency in both the hot-plate and warm-water tail-withdrawal tests. In the hot-plate test, a measure of supraspinal nociception, morphine antinociception was increased, and this was associated with an increased ability of opioids to inhibit presynaptic GABA neurotransmission in the periaqueductal gray. In contrast, antinociception produced by either morphine or methadone was reduced in the tail-withdrawal test, a measure of spinal nociception. In whole-brain and spinal cord homogenates from mice expressing Gαo RGSi subunits, there was a small loss of Gαo expression and an accompanying decrease in basal G-protein activity. Our results strongly support a role for RGS proteins as negative regulators of opioid supraspinal antinociception and also reveal a potential novel function of RGS proteins as positive regulators of opioid spinal antinociceptive pathways.

µ-Opioid receptor coupling to Gα(o) plays an important role in opioid antinociception.

Opioid analgesics elicit their effects via activation of the mu-opioid receptor (MOR), a G protein-coupled receptor known to interact with Gα(i/o)-type G proteins. Work in vitro has suggested that MOR couples preferentially to the abundant brain Gα(i/o) isoform, Gα(o). However, studies in vivo evaluating morphine-mediated antinociception have not supported these findings. The aim of the present work was to evaluate the contribution of Gα(o) to MOR-dependent signaling by measuring both antinociceptive and biochemical endpoints in a Gα(o) null transgenic mouse strain. Male wild-type and Gα(o) heterozygous null (Gα(o) ⁺/⁻) mice were tested for opioid antinociception in the hot plate test or the warm-water tail withdrawal test as measures of supraspinal or spinal antinociception, respectively. Reduction in Gα(o) levels attenuated the supraspinal antinociception produced by morphine, methadone, and nalbuphine, with the magnitude of suppression dependent on agonist efficacy. This was explained by a reduction in both high-affinity MOR expression and MOR agonist-stimulated G protein activation in whole brain homogenates from Gα(o) ⁺/⁻ and Gα(o) homozygous null (Gα(o)⁻/⁻) mice, compared with wild-type littermates. On the other hand, morphine spinal antinociception was not different between Gα(o) ⁺/⁻ and wild-type mice and high-affinity MOR expression was unchanged in spinal cord tissue. However, the action of the partial agonist nalbuphine was compromised, showing that reduction in Gα(o) protein does decrease spinal antinociception, but suggesting a higher Gα(o) protein reserve. These results provide the first in vivo evidence that Gα(o) contributes to maximally efficient MOR signaling and antinociception.