Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT Receptor and Dual 5-HT/5-HT Receptor Modulators.

The serotonin 5-HT receptor (5-HTR) and 5-HTR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HTR or dual 5-HTR/5-HTR positive allosteric modulators (PAMs).

Nurse Faculty Provide Essential Support to Graduate Nursing Students During COVID-19 Pandemic.

Nurses in formal and informal leadership roles have been stretched to fulfill duties in their own role and be pulled into staffing. These emerging leaders have little energy to pursue an advanced academic degree when they are already considering leaving the profession. In a health care industry filled with ambiguity and volatility, continued efforts to support, retain, and recruit nurses in graduate leadership programs are essential.

Initial Outcomes of a Novel Irrigating Wound Protector for Reducing the Risk of Surgical Site Infection in Elective Colectomies.

Background: Surgical site infection (SSI) rates in elective colorectal surgery remain high due to intraoperative exposure of colonic bacteria at the surgical site. We aimed to evaluate 30-day SSI outcomes of a novel wound retractor that combines barrier protection with continuous wound irrigation in elective colorectal resection.

Materials And Methods: A retrospective single-center cohort-matched analysis included all patients undergoing elective colorectal resection utilizing the novel irrigating wound protector (IWP) from April 2015 to July 2019.

Profile of cortical N-methyl-D-aspartate receptor subunit expression associates with inherent motor impulsivity in rats.

Impulsivity is a multifaceted behavioral manifestation with implications in several neuropsychiatric disorders. Glutamate neurotransmission through the N-methyl-D-aspartate receptors (NMDARs) in the medial prefrontal cortex (mPFC), an important brain region in decision-making and goal-directed behaviors, plays a key role in motor impulsivity. We discovered that inherent motor impulsivity predicted responsiveness to D-cycloserine (DCS), a partial NMDAR agonist, which prompted the hypothesis that inherent motor impulsivity is associated with the pattern of expression of cortical NMDAR subunits (GluN1, GluN2A, GluN2B), specifically the protein levels and synaptosomal trafficking of the NMDAR subunits.

Integrated Functional Analysis of the Nuclear Proteome of Classically and Alternatively Activated Macrophages.

Macrophages (M) play a central role in coordinating host response to pathogens, cellular injury, and environmental stimuli. Herein, we report multidimensional, nuclear proteomic analyses of protein expression and posttranslational modifications (PTMs) that control biological processes during M activation. For this, M were incubated with IFN-/LPS and IL-4, and their differentiation to proinflammatory (M1) and anti-inflammatory (M2a, referred as M2 for simplicity throughtout the manuscript) phenotypes was confirmed by detection of CD64 and CD206 surface markers and TNF-, arginase I, and iNOS-dependent nitrite levels.

Proinflammatory Effects of Respiratory Syncytial Virus-Induced Epithelial HMGB1 on Human Innate Immune Cell Activation.

High mobility group box 1 (HMGB1) is a multifunctional nuclear protein that translocates to the cytoplasm and is subsequently released to the extracellular space during infection and injury. Once released, it acts as a damage-associated molecular pattern and regulates immune and inflammatory responses. Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants and elderly, for which no effective treatment or vaccine is currently available.

Same day discharge after thyroidectomy is safe and effective.

Unlabelled: Historically, thyroidectomies have been performed as inpatient operations due to concerns of postoperative bleeding and symptomatic hypocalcemia. We aim to demonstrate that outpatient thyroidectomy can be performed safely.

Methods: This report outlines a 7-year retrospective analysis (2009-2016) of outpatient vs inpatient thyroidectomies, with outcomes including hematoma, blood loss, recurrent laryngeal nerve injury, symptomatic hypocalcemia, and postoperative emergency room (ER) visits.

Clinical Research Nursing: Development of a Residency Program .

Clinical research nurses are essential in the coordination of clinical trials and the management of research participants. Without a stable, knowledgeable research nurse workforce, the conduct of research is affected. A research nurse residency is a novel approach to preparing new graduate nurses for the oncology research nurse role.

Activation of Human Peripheral Blood Eosinophils by Cytokines in a Comparative Time-Course Proteomic/Phosphoproteomic Study.

Activated eosinophils contribute to airway dysfunction and tissue remodeling in asthma and thus are considered to be important factors in asthma pathology. We report here comparative proteomic and phosphoproteomic changes upon activation of eosinophils using eight cytokines individually and in selected cytokine combinations in time-course reactions. Differential protein and phosphoprotein expressions were determined by mass spectrometry after 2-dimensional gel electrophoresis (2DGE) and by LC-MS/MS.

Cytokine-Induced Glucocorticoid Resistance from Eosinophil Activation: Protein Phosphatase 5 Modulation of Glucocorticoid Receptor Phosphorylation and Signaling.

The mechanisms contributing to persistent eosinophil activation and poor eosinopenic response to glucocorticoids in severe asthma are poorly defined. We examined the effect of cytokines typically overexpressed in the asthmatic airways on glucocorticoid signaling in in vitro activated eosinophils. An annexin V assay used to measure eosinophil apoptosis showed that cytokine combinations of IL-2 plus IL-4 as well as TNF-α plus IFN-γ, or IL-3, GM-CSF, and IL-5 alone significantly diminished the proapoptotic response to dexamethasone.

S-Nitrosylation Proteome Profile of Peripheral Blood Mononuclear Cells in Human Heart Failure.

Nitric oxide (NO) protects the heart against ischemic injury; however, NO- and superoxide-dependent S-nitrosylation (S-NO) of cysteines can affect function of target proteins and play a role in disease outcome. We employed 2D-GE with thiol-labeling FL-maleimide dye and MALDI-TOF MS/MS to capture the quantitative changes in abundance and S-NO proteome of HF patients (versus healthy controls, n = 30/group). We identified 93 differentially abundant (59-increased/34-decreased) and 111 S-NO-modified (63-increased/48-decreased) protein spots, respectively, in HF subjects (versus controls, fold-change | ≥1.

Changes in Proteome Profile of Peripheral Blood Mononuclear Cells in Chronic Chagas Disease.

Trypanosoma cruzi (Tc) infection causes chagasic cardiomyopathy; however, why 30-40% of the patients develop clinical disease is not known. To discover the pathomechanisms in disease progression, we obtained the proteome signature of peripheral blood mononuclear cells (PBMCs) of normal healthy controls (N/H, n = 30) and subjects that were seropositive for Tc-specific antibodies, but were clinically asymptomatic (C/A, n = 25) or clinically symptomatic (C/S, n = 28) with cardiac involvement and left ventricular dysfunction. Protein samples were labeled with BODIPY FL-maleimide (dynamic range: > 4 orders of magnitude, detection limit: 5 f-mol) and resolved by two-dimensional gel electrophoresis (2D-GE).

Eosinophil resistance to glucocorticoid-induced apoptosis is mediated by the transcription factor NFIL3.

The mainstay of asthma therapy, glucocorticoids (GCs) exert their therapeutic effects through the inhibition of inflammatory signaling and induction of eosinophil apoptosis. However, laboratory and clinical observations of GC-resistant asthma suggest that GCs' effects on eosinophil viability may depend on the state of eosinophil activation. In the present study we demonstrate that eosinophils stimulated with IL-5 show impaired pro-apoptotic response to GCs.

Restrictive Transfusion in Geriatric Trauma Patients.

To determine whether a restrictive strategy of red cell transfusion was safe in elderly trauma patients, we compared those treated with a restrictive transfusion strategy versus those who were liberally transfused. We performed a retrospective study of elderly (age ≥ 70 years) trauma patients admitted to our Level I trauma center from 2005 to 2013. Patients with a hemoglobin (Hg) < 10 g/dL after 48 hours were included.

Improved Detection of Invasive Pulmonary Aspergillosis Arising during Leukemia Treatment Using a Panel of Host Response Proteins and Fungal Antigens.

Invasive pulmonary aspergillosis (IPA) is an opportunistic fungal infection in patients undergoing chemotherapy for hematological malignancy, hematopoietic stem cell transplant, or other forms of immunosuppression. In this group, Aspergillus infections account for the majority of deaths due to mold pathogens. Although early detection is associated with improved outcomes, current diagnostic regimens lack sensitivity and specificity.

Molecular classification of outcomes from dengue virus -3 infections.

Objectives: Dengue virus (DENV) infection is a significant risk to over a third of the human population that causes a wide spectrum of illness, ranging from sub-clinical disease to intermediate syndrome of vascular complications called dengue fever complicated (DFC) and severe, dengue hemorrhagic fever (DHF). Methods for discriminating outcomes will impact clinical trials and understanding disease pathophysiology.

Study Design: We integrated a proteomics discovery pipeline with a heuristics approach to develop a molecular classifier to identify an intermediate phenotype of DENV-3 infectious outcome.

Discovery proteomics and nonparametric modeling pipeline in the development of a candidate biomarker panel for dengue hemorrhagic fever.

Secondary dengue viral infection can produce capillary leakage associated with increased mortality known as dengue hemorrhagic fever (DHF). Because the mortality of DHF can be reduced by early detection and intensive support, improved methods for its detection are needed. We applied multidimensional protein profiling to predict outcomes in a prospective dengue surveillance study in South America.

Student nurses and the electronic medical record: a partnership of academia and healthcare.

The advent of the electronic medical record has brought a new challenge to nursing education. Although most nursing students are proficient in data entry and computer skills, they often do not comprehend how the information they enter becomes a vital component of interdisciplinary team communication. Furthermore, the electronic medical record becomes a repository for information that can be retrieved for the purpose of decision support.

Quantification of cysteinyl S-nitrosylation by fluorescence in unbiased proteomic studies.

Cysteinyl S-nitrosylation has emerged as an important post-translational modification affecting protein function in health and disease. Great emphasis has been placed on global, unbiased quantification of S-nitrosylated proteins because of physiologic and oxidative stimuli. However, current strategies have been hampered by sample loss and altered protein electrophoretic mobility.

Priming of eosinophils by GM-CSF is mediated by protein kinase CbetaII-phosphorylated L-plastin.

The priming of eosinophils by cytokines leading to augmented response to chemoattractants and degranulating stimuli is a characteristic feature of eosinophils in the course of allergic inflammation and asthma. Actin reorganization and integrin activation are implicated in eosinophil priming by GM-CSF, but their molecular mechanism of action is unknown. In this regard, we investigated the role of L-plastin, an eosinophil phosphoprotein that we identified from eosinophil proteome analysis.

Proteomic analysis of serum opsonins impacting biodistribution and cellular association of porous silicon microparticles.

Mass transport of drug delivery vehicles is guided by particle properties, such as size, shape, composition, and surface chemistry, as well as biomolecules and serum proteins that adsorb to the particle surface. In an attempt to identify serum proteins influencing cellular associations and biodistribution of intravascularly injected particles, we used two-dimensional gel electrophoresis and mass spectrometry to identify proteins eluted from the surface of cationic and anionic silicon microparticles. Cationic microparticles displayed a 25-fold greater abundance of Ig light variable chain, fibrinogen, and complement component 1 compared to their anionic counterparts.

Toward the Proteome of the Human Peripheral Blood Eosinophil.

Eosinophils are granular leukocytes that have significant roles in many inflammatory and immunoregulatory responses, especially asthma and allergic diseases. We have undertaken a fairly comprehensive proteomic analysis of purified peripheral blood eosinophils from normal human donors primarily employing 2-dimensional gel electrophoresis with protein spot identification by matrix-assisted laser desorption/ionization mass spectrometry. Protein subfractionation methods employed included isoelectric focusing (Zoom(®) Fractionator) and subcellular fractionation using differential protein solubilization.

A phosphosite screen identifies autocrine TGF-beta-driven activation of protein kinase R as a survival-limiting factor for eosinophils.

The differential usage of signaling pathways by chemokines and cytokines in eosinophils is largely unresolved. In this study, we investigate signaling similarities and differences between CCL11 (eotaxin) and IL-5 in a phosphosite screen of human eosinophils. We confirm many previously known pathways of cytokine and chemokine signaling and elucidate novel phosphoregulation in eosinophils.

Cross-talk between ICAM-1 and granulocyte-macrophage colony-stimulating factor receptor signaling modulates eosinophil survival and activation.

Reversal of eosinophilic inflammation has been an elusive therapeutic goal in the management of asthma pathogenesis. In this regard, GM-CSF is a primary candidate cytokine regulating eosinophil activation and survival in the lung; however, its molecular mechanism of propagation and maintenance of stimulated eosinophil activation is not well understood. In this study, we elucidate those late interactions occurring between the GM-CSF receptor and activated eosinophil signaling molecules.