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Background: Obesity is among the most serious public health problems worldwide, with few safe pharmaceutical interventions. Natural products have become an important source of potential anti-obesity therapeutics. Dihydromyricetin (DHM) exerts antidiabetic effects. The biochemical target of DHM, however, has been unknown. It is crucial to identify the biochemical target of DHM for elucidating its physiological function and therapeutic value.Objectives: The objective of this study was to identify the biochemical target of DHM.Methods: An abundant antiadipogenic flavanonol was extracted from the herbal plant Ampelopsis grossedentata through bioassay-guided fractionation and characterized with high-resolution LC-MS and 1H and 13C nuclear magnetic resonance. Antiadipogenic experiments were done with mouse 3T3-L1 preadipocytes. A biochemical target of the chemical of interest was identified with drug affinity responsive target stability assay. Direct interactions between the chemical of interest and the protein target in vitro were predicted with molecular docking and subsequently confirmed with surface plasmon resonance. Expression levels of peroxisome proliferator-activated receptor γ (PPARγ), which is associated with 78-kDa glucose-regulated protein (GRP78), were measured with real-time qPCR.Results: DHM was isolated, purified, and structurally characterized. Cellular studies showed that DHM notably reduced intracellular oil droplet formation in 3T3-L1 cells with a median effective concentration of 294 μM (i.e., 94 μg/mL). DHM targeted the ATP binding site of GRP78, which is associated with adipogenesis. An equilibrium dissociation constant between DHM and GRP78 was 21.8 μM. In 3T3-L1 cells upon treatment with DHM at 50 μM (i.e., 16 μg/mL), the expression level of PPARγ was downregulated to 53.9% of the solvent vehicle control's level.Conclusions: DHM targets GRP78 in vitro. DHM is able to reduce lipid droplet formation in 3T3-L1 cells through a mode of action that is plausibly associated with direct interactions between GRP78 and DHM, which is a step forward in determining potential applications of DHM as an anti-obesity agent. [ABSTRACT FROM AUTHOR]

Organophosphorus (OP) compounds can bind covalently to many types of proteins and form protein adducts. These protein adducts can indicate the exposure to and neurotoxicity of OPs. In the present work, we studied adduction of tubulin with the OP insecticide profenofos in vitro and optimized the method for detection of adducted peptides. Porcine tubulin was incubated with profenofos and was then digested with trypsin, followed by mass spectrometric identification of the profenofos-modified tubulin and binding sites. With solvent-assisted digestion (80% acetonitrile in digestion solution), the protein was digested for peptide identification, especially for some peptides with low mass. The MALDI-TOF-MS and LC-ESI-TOF-MS analysis results showed that profenofos bound covalently to Tyr83 in porcine α-tubulin (TGTY* 83 R) and to Tyr281 in porcine β-tubulin (GSQQY* 281 R) with a mass increase of 166.02 Da from the original peptide fragments of porcine tubulin proteins. Tyrosine adduct sites were also confirmed by MALDI-TOF/TOF-MS analysis. This result may partially explain the neurotoxicity of profenofos at low doses and prolonged periods of exposure. [ABSTRACT FROM AUTHOR]

Organophosphate (OP) and organophosphate ester (OPE) adducts of albumin are valuable biomarkers for retrospective verification of exposure. In the present study, our goal was to determine whether OPE flame retardants (OPE FRs) and OPE plasticizers can covalently bind to human serum albumin (HSA), which would allow the resulting adducts to be used to evaluate exposure. Eleven OPE FRs and plasticizers were examined in a HSA-adduct in vitro assay. Pure HSA was incubated with the target OPEs, as well as with an OP insecticide (profenofos) positive control. After enzymatic cleavage with pepsin or Glu-C, the digested albumin was analyzed by matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) and liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-ToF-MS). Under optimized HSA assay conditions, tyrosine adducts were formed at Y 411 and Y 148 /Y 150 with a characteristic mass shift for phosphorylation (Δ m / z 166) for the profenofos positive control. However, no such phosphorylated peptides were detected for the 11 target OPEs. This negative result suggests that these OPEs have very different affinities from the OP insecticide. They are less reactive or they may specifically interact with other proteins. [ABSTRACT FROM AUTHOR]

Enhancing existing curricula to meet newly published adult-gerontology advanced practice registered nurse (APRN) competencies in an efficient manner presents a challenge to nurse educators. Incorporating shared, published electronic learning resources (ELRs) in existing or new courses may be appropriate in order to assist students in achieving competencies. The purposes of this project were to (a) identify relevant available ELR for use in enhancing geriatric APRN education and (b) to evaluate the educational utility of identified ELRs based on established criteria. A multilevel search strategy was used. Two independent team members reviewed identified ELR against established criteria to ensure utility. Only resources meeting all criteria were retained. Resources were found for each of the competency areas and included formats such as podcasts, Web casts, case studies, and teaching videos. In many cases, resources were identified using supplemental strategies and not through traditional search or search of existing geriatric repositories. Resources identified have been useful to advanced practice educators in improving lecture and seminar content in a particular topic area and providing students and preceptors with additional self-learning resources. Addressing sustainability within geriatric APRN education is critical for sharing of best practices among educators and for sustainability of teaching and related resources. [ABSTRACT FROM AUTHOR]

Abstract: “Snails can kill” is a statement that receives much disbelief. Yet the venom from Conus geographus, as delivered by a disposable hypodermic-like needle, has indeed killed many unsuspecting human victims. Our understanding of their milked venom the essence of these fatalities, is in itself non-existent. Here, we present the molecular mass analysis of the milked venom of C. geographus, providing the first insight into the composition of its deadly cocktail. [Copyright &y& Elsevier]

Abstract: Milked venom from cone snails represent a novel biological resource with a proven track record for drug discovery. To strengthen this correlation, we undertook a chromatographic and mass spectrometric study of individual milked venoms from Conus purpurascens. Milked venoms demonstrate extensive peptide differentiation amongst individual specimens and during captivity. Individual snails were found to lack a consistent set of described conopeptides, but instead demonstrated the ability to change venom expression, composition and post-translational modification incorporation; all variations contribute to an increase in chemical diversity and prey targeting strategies. Quantitative amino acid analysis revealed that milked venom peptides are expressed at ranges up to 3.51–121.01 μM within single milked venom samples. This provides for a 6.37–20,965 fold-excess of toxin to induce apparent IC50 for individual conopeptides identified in this study. Comparative molecular mass analysis of duct venom, milked venom and radula tooth extracts from single C. purpurascens specimens demonstrated a level of peptide continuity. Numerous highly abundant and unique conopeptides remain to be characterized. This study strengthens the notion that approaches in conopeptide drug lead discovery programs will potentially benefit from a greater understanding of the toxinological nature of the milked venoms of Conus. [Copyright &y& Elsevier]

Mental health conditions will be the largest contributor to the global health burden by 2030. Our review suggests that neglected tropical diseases (NTDs) predispose individuals to poor mental health. Factors predisposing to poor mental health include stigma and discrimination, exclusion from participating fully in society, reduced access to health and social services, lack of educational opportunities, exclusion from income-generation and employment opportunities, and restrictions in exercising civil and political rights. These characteristics are all features of NTDs, but the mental health of these sufferers has been ignored. This review raises an issue of concern and highlights the opportunities for research by psychiatrists and psychologists on NTDs. [Copyright &y& Elsevier]

Elder mistreatment (EM) is a growing and hidden problem. Nurses have a responsibility to identify potential and actual EM victims. The purpose of this article is to describe the roles of nurses on interprofessional elder mistreatment teams. Current nursing roles in the recognition and management of EM include assessment and screening, mandatory reporting, direct care, and complaint investigation. While the efforts of individual nurses in the detection and management of cases is important, EM is a complex problem that is best approached through interprofessional collaboration. In the greater Seattle area, such collaboration is accomplished through membership on the King County Elder Abuse Project teams. Nurses give expert opinion, educate team members, and provide case consultation. University faculty experience on the teams inspired the start of a Master’s pathway in Forensic Nursing, focused nursing research, and increased public policy activity and community service. Nurses on interprofessional teams gain networking opportunities as well as experience with the system that is in place to protect and serve vulnerable adults. [Copyright &y& Elsevier]

Objective: The objective of this study was to evaluate basal anti-Müllerian hormone as a marker for ovarian responsiveness to fertility treatment. Study Design: Frozen basal menstrual cycle day 3 serum samples were evaluated retrospectively for anti-Müllerian hormone, inhibin B, and follicle-stimulating hormone levels in 123 in vitro fertilization cycles (93 patients) and compared with in vitro fertilization records. Results: Anti-Müllerian hormone values correlated the best with the number of retrieved oocytes (r = 0.539; P < .001) relative to age (r = −0.323; P < .01), follicle-stimulating hormone (r = −0.317; P < .01), inhibin B (P > .05), luteinizing hormone (P > .05), and estradiol (r = −0.190; P < .05). Receiver operating characteristic curve analysis demonstrated that, for the prediction of <4 oocytes retrieved, anti-Müllerian hormone had the largest area under the curve (AUC = 0.81; P = .0001) relative to age (r = 0.74; P = .005), follicle-stimulating hormone (0.71; P = .02), inhibin B (0.66; P = .03), and estradiol (0.54; P > .05). Similarly, for the prediction of ≥15 retrieved oocytes, anti-Müllerian hormone had the largest area under the curve (0.80; P = .0001) relative to age (0.63; P = .02), follicle-stimulating hormone (0.64; P = .005), inhibin B (r = 0.57; P > .05), and estradiol (0.58; P > .05). Conclusion: Anti-Müllerian hormone correlates better than age, follicle-stimulating hormone, luteinizing hormone, inhibin B, and estradiol with the number of retrieved oocytes. Receiver operating characteristic curves estimated that anti-Müllerian hormone accurately predicts ovarian responsiveness to controlled ovarian stimulation with high sensitivity and specificity. [Copyright &y& Elsevier]

Highlights: [•] Single Cone snail analysis shows m/z continuity in duct, milk and radula extracts. [•] Geographic specimen analysis shows peptide diversity in the milked venoms. [•] α-Conotoxin TxIC represents a highly post-translationally modified conotoxin. [•] Post-translational modifications influence biological and phylogenetic selectivity. [ABSTRACT FROM AUTHOR]

Background: Increases in pharmaceutical opioid sales have paralleled the quadrupling of prescription opioid overdose deaths and spikes in emergency department visits for non-medical opioid prescription overdoses. In response, federal and state governments have advanced a myriad of policies to reduce opioid availability and increase treatment access, aimed to ultimately reduce opioid-related mortality. Despite these efforts, including ACA Medicaid expansion and more robust prescription drug monitoring programs, opioid-related mortality has continued to rise in NY and 29 other states. This study examined whether geographic access to Federally Qualified Health Centers, opioid treatment programs, and buprenorphine providers mitigated opioid-related hospital visits (emergency department, inpatient, and all visits) and mortality, by county, between 2012 and 2014.Methods: The authors examined the relationships among opioid-related health outcomes and geographic access to treatment options using spatial error regression models at the county (n = 62) level in 2012 and 2014. Z-tests further assessed significant differences in access coefficients between 2012 and 2014.Results: Of the 62 counties in New York State in 2014, 54 (87.1%) showed increased opioid overdose-related emergency department rates (t = 9.125, p < 0.001), and 37 (59.7%) showed mortality rate increases (t = 1.687, p < 0.1), compared to 2012. Regression models demonstrated significant negative relationships between county-level opioid-related mortality rates and geographic access to opioid treatment programs, Federally Qualified Health Centers in both 2012 and 2014 and buprenorphine providers concentration in 2014 while adjusting for county socio-demographics (all p values < 0.05). Access coefficients were not significantly different between 2012 and 2014 (p > 0.05).Conclusions: Greater geographic access to treatment services was protective against opioid-related mortality. Access to opioid treatment may not be sufficient to mitigate opioid-related hospital visits or mortality, but may offset climbing mortality rates in select counties. [ABSTRACT FROM AUTHOR]