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Background: Accurate classification of sites of interest on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) images is an important diagnostic requirement for the differentiation of prostate cancer (PCa) from foci of physiologic uptake. We developed a deep learning and radiomics framework to perform lesion-level and patient-level classification on PSMA PET images of patients with PCa., Methods: This was an IRB-approved, HIPAA-compliant, retrospective study. Lesions on [ 18 F]DCFPyL PET/CT scans were assigned to PSMA reporting and data system (PSMA-RADS) categories and randomly partitioned into training, validation, and test sets. The framework extracted image features, radiomic features, and tissue type information from a cropped PET image slice containing a lesion and performed PSMA-RADS and PCa classification. Performance was evaluated by assessing the area under the receiver operating characteristic curve (AUROC). A t-distributed stochastic neighbor embedding (t-SNE) analysis was performed. Confidence and probability scores were measured. Statistical significance was determined using a two-tailed t test., Results: PSMA PET scans from 267 men with PCa had 3794 lesions assigned to PSMA-RADS categories. The framework yielded AUROC values of 0.87 and 0.90 for lesion-level and patient-level PSMA-RADS classification, respectively, on the test set. The framework yielded AUROC values of 0.92 and 0.85 for lesion-level and patient-level PCa classification, respectively, on the test set. A t-SNE analysis revealed learned relationships between the PSMA-RADS categories and disease findings. Mean confidence scores reflected the expected accuracy and were significantly higher for correct predictions than for incorrect predictions (P < 0.05). Measured probability scores reflected the likelihood of PCa consistent with the PSMA-RADS framework., Conclusion: The framework provided lesion-level and patient-level PSMA-RADS and PCa classification on PSMA PET images. The framework was interpretable and provided confidence and probability scores that may assist physicians in making more informed clinical decisions., (© 2022. The Author(s).)

Disease management is gaining importance in workplace health promotion given the aging workforce and rising chronic disease prevalence. The Chronic Disease Self-Management Program (CDSMP) is an effective intervention widely offered in diverse community settings; however, adoption remains low in workplace settings. As part of a larger NIH-funded randomized controlled trial, this study examines the effectiveness of a worksite-tailored version of CDSMP (wCDSMP [ n = 72]) relative to CDSMP (&lsquo;Usual Care&rsquo; [ n = 109]) to improve health and work performance among employees with one or more chronic conditions. Multiple-group latent-difference score models with sandwich estimators were fitted to identify changes from baseline to 6-month follow-up. Overall, participants were primarily female (87%), non-Hispanic white (62%), and obese (73%). On average, participants were age 48 (range: 23⁻72) and self-reported 3.25 chronic conditions (range: 1⁻16). The most commonly reported conditions were high cholesterol (45%), high blood pressure (45%), anxiety/emotional/mental health condition (26%), and diabetes (25%). Among wCDSMP participants, significant improvements were observed for physically unhealthy days (u&Delta; = &minus;2.07, p = 0.018), fatigue (u&Delta; = &minus;2.88, p = 0.002), sedentary behavior (u&Delta; = &minus;4.49, p = 0.018), soda/sugar beverage consumption (u&Delta; = &minus;0.78, p = 0.028), and fast food intake (u&Delta; = &minus;0.76, p = 0.009) from baseline to follow-up. Significant improvements in patient⁻provider communication (u&Delta; = 0.46, p = 0.031) and mental work limitations (u&Delta; = &minus;8.89, p = 0.010) were also observed from baseline to follow-up. Relative to Usual Care, wCDSMP participants reported significantly larger improvements in fatigue, physical activity, soda/sugar beverage consumption, and mental work limitations ( p < 0.05). The translation of Usual Care (content and format) has potential to improve health among employees with chronic conditions and increase uptake in workplace settings.

Disease management is becoming increasingly important in workplace health promotion given the aging workforce, rising chronic disease prevalence, and needs to maintain a productive and competitive American workforce. Despite the widespread availability of the Chronic Disease Self-Management Program (CDSMP), and its known health-related benefits, program adoption remains low in workplace settings. The primary purpose of this study is to compare personal and delivery characteristics of adults who attended CDSMP in the workplace relative to other settings (e.g., senior centers, healthcare organizations, residential facilities). This study also contrasts characteristics of CDSMP workplace participants to those of the greater United States workforce and provides recommendations for translating CDSMP for use in workplace settings. Data were analyzed from 25,664 adults collected during a national dissemination of CDSMP. Only states and territories that conducted workshops in workplace settings were included in analyses (n = 13 states and Puerto Rico). Chi-squared tests and t-tests were used to compare CDSMP participant characteristics by delivery site type. CDSMP workplace participant characteristics were then compared to reports from the United States Bureau of Labor Statistics. Of the 25,664 CDSMP participants in this study, 1.7% (n = 435) participated in workshops hosted in worksite settings. Compared to CDSMP participants in non-workplace settings, workplace setting participants were significantly younger and had fewer chronic conditions. Differences were also observed based on chronic disease types. On average, CDSMP workshops in workplace settings had smaller class sizes and workplace setting participants attended more workshop sessions. CDSMP participants in workplace settings were substantially older and a larger proportion were female than the general United States workforce. Findings indicate opportunities to translate CDSMP for use in the workplace to reach new target audiences.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates., (Copyright © 2013 The British Pharmacological Society.)

1. The regulation of glycine concentrations within excitatory synapses is poorly understood and it has been proposed that the GLYT1 subtypes of glycine transporters play a critical role in determining resting concentrations of glycine. Selective GLYT1 inhibitors may provide pharmacological tools to probe the dynamics of synaptic glycine concentrations, which may influence the activation properties of NMDA receptor activity. 2. We have characterized the selectivity and mechanism of action of the glycine transport inhibitor N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS). The glycine transporters, GLYT1a, b and c and GLYT2a were expressed in Xenopus laevis oocytes and two electrode voltage clamp techniques and radiolabelled (3)H-glycine flux measurements were used to characterize the effects of NFPS on glycine transport. 3. NFPS inhibits glycine transport by the GLYT1a, b and c subtypes of glycine transporters, but has no effect on the GLYT2a subtype of transporter. We show that NFPS does not attain its specificity via an interaction with the Na(+), Cl(-) or glycine site, nor does it act at an intracellular site. NFPS inhibition of glycine transport is time and concentration dependent and inhibition of transport by NFPS persists after washout of NFPS from the bath solution, which suggests that inhibition by NFPS is long lasting.

Glutamate transport by the excitatory amino acid transporters (EAATs) is coupled to the co-transport of 3 Na(+) ions and 1 H(+) and the counter-transport of 1 K(+) ion, which ensures that extracellular glutamate concentrations are maintained in the submicromolar range. In addition to the coupled ion fluxes, glutamate transport activates an uncoupled anion conductance that does not influence the rate or direction of transport but may have the capacity to influence the excitability of the cell. Free Zn(2+) ions are often co-localized with glutamate in the central nervous system and have the capacity to modulate the dynamics of excitatory neurotransmission. In this study we demonstrate that Zn(2+) ions inhibit the uncoupled anion conductance and also reduce the affinity of L-aspartate for EAAT4. The molecular basis for this effect was investigated using site-directed mutagenesis. Two histidine residues in the extracellular loop between transmembrane domains three and four of EAAT4 appear to confer Zn(2+) inhibition of the anion conductance.

1. The effects of niflumic acid on the substrate-gated currents mediated by the glutamate transporter EAAT4 expressed in Xenopus laevis oocytes were examined using radiolabelled substrate flux measurements and two-electrode voltage clamp techniques. 2. Niflumic acid significantly enhanced the substrate-gated currents in EAAT4, without affecting the affinity of the substrates towards EAAT4. At a concentration of 300 microM, niflumic acid caused a 19 +/- 5 % reduction in L-[(3)H]glutamate uptake and no significant effect on the uptake of DL-[(3)H]aspartate. Thus, enhancement of the substrate-gated currents in EAAT4 does not correlate with the rate of substrate transport and suggests that the niflumic acid-induced currents are not thermodynamically coupled to the transport of substrate. 3. Niflumic acid and arachidonic acid co-applied with substrate to EAAT4-expressing oocytes had similar functional consequences. However, niflumic acid still enhanced the L-glutamate-gated current to the same extent in the presence and absence of a saturating dose of arachidonic acid, which suggests that the sites of action of the two compounds are distinct. 4. The EAAT4-mediated currents for the two substrates, L-glutamate and L-aspartate, were not enhanced equally by addition of the same dose of niflumic acid and the ionic composition of the niflumic acid-induced currents was not the same for the two substrates. Protons carry the L-glutamate-gated niflumic acid-induced current and both protons and chloride ions carry the L-aspartate-gated niflumic acid-induced current. 5. These results show that niflumic acid can be used to probe the functional aspects of EAAT4 and that niflumic acid and other non-steroid anti-inflammatory drugs could be used as the basis for the development of novel modulators of glutamate transporters.

1. Expression of the recombinant human excitatory amino aid transporters, EAAT1 and EAAT2, in Xenopus laevis oocytes allows electrogenic transport to be studied under voltage clamp conditions. 2. We have investigated the transport of the pharmacological substrate, L-serine-O-sulphate transport by EAAT1 and EAAT2. The EC50 values for L-serine-O-sulphate transport by EAAT2 showed a steep voltage-dependence, increasing from 152+/-11 microM at - 100 mV to 1930+/-160 microM at 0 mV. In contrast to EAAT2, EC50 values for L-serine-O-sulphate transport by EAAT1 were relatively constant over the membrane potential range of - 100 mV to 0 mV. The EC50 values for L-glutamate and D-aspartate transport, by EAAT2, were also relatively constant over this membrane potential range. 3. Chloride ions modulated the voltage-dependent changes in EC50 values for transport by EAAT2. This effect was most apparent for L-serine-O-sulphate transport, and to a lesser extent for L-glutamate and not at all for D-aspartate transport by EAAT2. 4. Extracellular sodium and proton concentrations also modulated the voltage-dependence of L-serine-O-sulphate EC50 values for EAAT2. 5. We speculate that these different properties of L-serine-O-sulphate transport by EAAT2 compared to other substrates may be due to the much stronger acidity of the sulphate group of L-serine-O-sulphate compared to carboxyl groups of L-glutamate or D-aspartate. 6. These results highlight some of the differences in the way different glutamate transporter subtypes transport substrates. This may be used to understand further the transport process and develop subtype selective inhibitors of glutamate transport.

The major cultivated potato, Solanum tuberosum, and six other related cultivated species, are hypothesized to have arisen from a group of weedy relatives indigenous to the central Andes of central Peru, Bolivia, and northern Argentina. A major problem hindering investigations of the origins of the cultivated species has been a continuing debate over the species boundaries of their putative progenitors. This study investigated the morphological phenetic species boundaries of these putative progenitors and five cultivated taxa, here collectively referred to as the Solanum brevicaule complex. Two hundred fifteen accessions of 30 taxa in the S. brevicaule complex and 42 accessions of six taxa outside of the complex were assessed for 53 morphological traits in replicate plots in a common garden, resulting in a total of over 81;t3000 data points. Phenetic analyses of these data are unable to support 30 taxa, suggesting instead a single variable complex at best only weakly divided into three widely intergrading sets of populations: (1) Peruvian and geographically adjacent Bolivian accessions (including wild species and all the cultigens), (2) Bolivian and Argentinian accessions and S. verrucosum from Mexico (including only wild species), and (3) the Bolivian and Argentinian wild species S. oplocense. These and other data suggest that Hawkes's 1990 treatment (The Potato: Evolution, Biodiversity, and Genetic Resources, Smithsonian Institute Press, Washington, DC.) of 232 morphological species is an overestimate for sect. Petota.

1. gamma-Aminobutyric acid (GABA) and trans-4-aminocrotonic acid (TACA) have been shown to activate GABAC receptors. In this study, a range of C2, C3, C4 and N-substituted GABA and TACA analogues were examined for activity at GABAC receptors. 2. The effects of these compounds were examined by use of electrophysiological recording from Xenopus oocytes expressing the human rho 1 subunit of GABAC receptors with the two-electrode voltage-clamp method. 3. trans-4-Amino-2-fluorobut-2-enoic acid was found to be a potent agonist (KD = 2.43 microM). In contrast, trans-4-amino-2-methylbut-2-enoic acid was found to be a moderately potent antagonist (IC50 = 31.0 microM and KB = 45.5 microM). These observations highlight the possibility that subtle structural substitutions may change an agonist into an antagonist. 4. 4-Amino-2-methylbutanoic acid (KD = 189 microM), 4-amino-2-methylenebutanoic acid (KD = 182 microM) and 4-amino-2-chlorobutanoic acid (KD = 285 microM) were weak partial agonists. The intrinsic activities of these compounds were 12.1%, 4.4% and 5.2% of the maximal response of GABA, respectively. These compounds more effectively blocked the effects of the agonist, GABA, giving rise to KB values of 53 microM and 101 microM, respectively. 5. The sulphinic acid analogue of GABA, homohypotaurine, was found to be a potent partial agonist (KD = 4.59 microM, intrinsic activity 69%). 6. It was concluded that substitution of a methyl or a halo group in the C2 position of GABA or TACA is tolerated at GABAC receptors. However, there was dramatic loss of activity when these groups were substituted at the C3, C4 and nitrogen positions of GABA and TACA. 7. Molecular modelling studies on a range of active and inactive compounds indicated that the agonist/competitive antagonist binding site of the GABAC receptor may be smaller than that of the GABAA and GABAB receptors. It is suggested that only compounds that can attain relatively flat conformations may bind to the GABAC receptor agonist/competitive antagonist binding site.

A loop structure, formed by the putative disulfide bridging of Cys198 and Cys209, is a principal element of the ligand binding site in the glycine receptor (GlyR). Disruption of the loop's tertiary structure by Ser mutations of these Cys residues either prevented receptor assembly on the cell surface, or created receptors unable to be activated by agonists or to bind the competitive antagonist, strychnine. Mutation of residues Lys200, Tyr202 and Thr204 within this loop reduced agonist binding and channel activation sensitivities by up to 55-, 520- and 190-fold, respectively, without altering maximal current sizes, and mutations of Lys200 and Tyr202 abolished strychnine binding to the receptor. Removal of the hydroxyl moiety from Tyr202 by mutation to Phe profoundly reduced agonist sensitivity, whilst removal of the benzene ring abolished strychnine binding, thus demonstrating that Tyr202 is crucial for both agonist and antagonist binding to the GlyR. Tyr202 also influences receptor assembly on the cell surface, with only large chain substitutions (Phe, Leu and Arg, but not Thr, Ser and Ala) forming functional receptors. Our data demonstrate the presence of a second ligand binding site in the GlyR, consistent with the three-loop model of ligand binding to the ligand-gated ion channel superfamily.

The interaction between C1q and immune complexes is inhibited by 1-anilino-8-naphthalenesulfonate (ANS) in the concentration range of 2-4 mM. ANS binds to Clq with a 20-fold higher affinity than to IgG [(1986) Mol. Immunol. 23, 39-44] and therefore it is possible to label only C1q with ANS in the presence of IgG. Under such conditions no inhibition is observed. Addition of monomer IgG to a solution of C1q-bound ANS did not significantly alter the fluorescence of the ANS. However when oligomeric IgG was added there was a 2-fold increase in fluorescence over the same IgG concentration range. When C1q was pretreated with diethylpyrocarbonate there was little change in the fluorescence when IgG oligomers were added to C1q:ANS solutions. These results suggest that C1q undergoes conformational changes upon binding to IgG oligomers.