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nterventions on health outcomes in humanitarian crises is extremely limited, and numerous methodological limitations limit the ability to determine associative, let alone causal, relationships.Lateral WS2-MoS2 heterostructures are synthesized by a shortcut one-step growth recipe with low-cost and soluble salts. The 2D spatial distributions of the built-in potential and the related electric field of the lateral WS2-MoS2 heterostructure are quantitatively analyzed by scanning Kelvin probe force microscopy revealing the fundamental attributes of the lateral heterostructure devices.In the more than 1 billion primary-care visits each year in the United States, the majority of patients bring more than one distinct concern, yet many leave with "unmet" concerns (i.e., ones not addressed during visits). Unmet concerns have potentially negative consequences for patients' health, and may pose utilization-based financial burdens to health care systems if patients return to deal with such concerns. One solution to the problem of unmet concerns is the communication skill known as up-front agenda setting, where physicians (after soliciting patients' chief concerns) continue to solicit patients' concerns to "exhaustion" with questions such as "Are there some other issues you'd like to address?" Although this skill is trainable and efficacious, it is not yet a panacea. This article uses conversation analysis to demonstrate that patients understand up-front agenda-setting questions in ways that hamper their effectiveness. Specifically, we demonstrate that up-front agenda-setting questions are understood as making relevant "new problems" (i.e., concerns that are either totally new or "new since last visit," and in need of diagnosis), and consequently bias answers away from "non-new problems" (i.e., issues related to previously diagnosed concerns, including much of chronic care). Suggestions are made for why this might be so, and for improving up-front agenda setting. Data are 144 videotapes of community-based, acute, primary-care, outpatient visits collected in the United States between adult patients and 20 family-practice physicians.The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 1) is a potent lung carcinogen in laboratory animals and is believed to play a key role in the development of lung cancer in smokers. Metabolic activation of NNK leads to the formation of pyridyloxobutyl DNA adducts, a critical step in its mechanism of carcinogenesis. In addition to DNA nucleobase adducts, DNA phosphate adducts can be formed by pyridyloxobutylation of the oxygen atoms of the internucleotidic phosphodiester linkages. We report the use of a liquid chromatography-nanoelectrospray ionization-high-resolution tandem mass spectrometry technique to characterize 30 novel pyridyloxobutyl DNA phosphate adducts in calf thymus DNA (CT-DNA) treated with 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc, 2), a regiochemically activated form of NNK. A (15)N3-labeled internal standard was synthesized for one of the most abundant phosphate adducts, dCp[4-oxo-4-(3-pyridyl)butyl]dC (CpopC), and this standard was used to quantify CpopC and to estimate the levels of other adducts in the NNKOAc-treated CT-DNA. Formation of DNA phosphate adducts by NNK in vivo was further investigated in rats treated with NNK acutely (0.1 mmol/kg once daily for 4 days by subcutaneous injection) and chronically (5 ppm in drinking water for 10, 30, 50, and 70 weeks). This study provides the first comprehensive structural identification and quantitation of a panel of DNA phosphate adducts of a structurally complex carcinogen and chemical support for future mechanistic studies of tobacco carcinogenesis in humans.Proliferation, integration, and neurite extension of PC12 cells, a widely used culture model for cholinergic neurons, were studied in nanocellulose scaffolds biosynthesized by Gluconacetobacter xylinus to allow a three-dimensional (3D) extension of neurites better mimicking neuronal networks in tissue. The interaction with control scaffolds was compared with cationized nanocellulose (trimethyl ammonium betahydroxy propyl [TMAHP] cellulose) to investigate the impact of surface charges on the cell interaction mechanisms. Furthermore, coatings with extracellular matrix proteins (collagen, fibronectin, and laminin) were investigated to determine the importance of integrin-mediated cell attachment. Cell proliferation was evaluated by a cellular proliferation assay, while cell integration and neurite propagation were studied by simultaneous label-free Coherent anti-Stokes Raman Scattering and second harmonic generation microscopy, providing 3D images of PC12 cells and arrangement of nanocellulose fibrils, respectively. Cell attachment and proliferation were enhanced by TMAHP modification, but not by protein coating. Protein coating instead promoted active interaction between the cells and the scaffold, hence lateral cell migration and integration. Irrespective of surface modification, deepest cell integration measured was one to two cell layers, whereas neurites have a capacity to integrate deeper than the cell bodies in the scaffold due to their fine dimensions and amoeba-like migration pattern. Neurites with lengths of >50 μm were observed, successfully connecting individual cells and cell clusters. In conclusion, TMAHP-modified nanocellulose scaffolds promote initial cellular scaffold adhesion, which combined with additional cell-scaffold treatments enables further formation of 3D neuronal networks.Evolution typically arrives at convergent phenotypic solutions to common challenges of natural selection. However, diverse molecular and physiological mechanisms may generate phenotypes that appear similar at the organismal level. How predictable are the molecular mechanisms of adaptation that underlie adaptive convergence? Interactions between toxic prey and their predators provide an excellent avenue to investigate the question of predictability because both taxa must adapt to the presence of defensive poisons. The evolution of resistance to tetrodotoxin (TTX), which binds to and blocks voltage-gated sodium channels (NaV1) in nerves and muscle, has been remarkably parallel across deep phylogenetic divides. In both predators and prey, representing three major vertebrate groups, TTX resistance has arisen through structural changes in NaV1 proteins. Fish, amphibians and reptiles, though they differ in the total number of NaV1 paralogs in their genomes, have each evolved common amino acid substitutions in the orthologous skeletal muscle NaV1.4. Many of these substitutions involve not only the same positions in the protein, but also the identical amino acid residues. Similarly, predictable convergence is observed across the family of sodium channel genes expressed in different tissues in puffer fish and in garter snakes. Trade-offs between the fundamental role of NaV1 proteins in selective permeability of Na+ and their ability to resist binding by TTX generate a highly constrained adaptive landscape at the level of the protein.Over 200 types of human papillomaviruses (HPV) have been identified that infect epithelial cells at different anatomic locations. HPVs are grouped into five genera with the alpha and beta viruses being the most commonly studied. Members of the alpha HPV genus infect genital epithelia and are the causative agents of many anogenital cancers. Beta HPVs infect cutaneous epithelia and have been suggested as co-factors in the development of non-melanoma skin cancers. Recent studies have shown that activation of DNA damage pathways is important for the productive life cycle of the alpha HPVs while the beta viruses suppress their activation. These differences likely contribute to the varying types of lesions and malignancies that are associated with these viruses.Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC). Treatment with the anti-diabetic drug metformin has been associated with reduced cancer incidence in patients with type 2 diabetes. Thus, the present study evaluated the effects of metformin on human CCA cell proliferation in vitro and in vivo and identified the microRNAs associated with its antitumor effects. Metformin inhibited the proliferation of the CCA cell lines HuCCT-1 and TFK-1 and blocked the G0 to G1 cell cycle transition, accompanied by AMP kinase pathway activation. Metformin treatment also led to marked decreases in cyclin D1 and cyclin-dependent kinase (Cdk) 4 protein levels and retinoblastoma protein phosphorylation. However, this drug did not affect p27kip protein expression. In addition, it reduced the phosphorylation of Axl, EphA10, ALK and PYK, as well as tumor proliferation in athymic nude mice with xenograft tumors. Furthermore, it markedly altered microRNA expression. These findings suggest that metformin may have clinical use in the treatment of CCA.The synthesis of a β-thiol asparagine derivative bearing a novel (2,4,6-trimethoxyphenyl)thiazolidine protecting group is described. The efficient incorporation of the amino acid into the N-termini of peptides is demonstrated as well as the utility of the β-thiol asparagine moiety for rapid ligation reactions with peptide thioesters. The streamlined synthesis of native peptide products could be accomplished using a one-pot radical desulfurization of the β-thiol auxiliary following the ligation event. The utility of the amino acid is highlighted in the efficient one-pot assembly of the HIV entry inhibitor enfuvirtide.Past research has assessed the association of single community characteristics with obesity, ignoring the spatial co-occurrence of multiple community-level risk factors. We used conditional random forests (CRF), a non-parametric machine learning approach to identify the combination of community features that are most important for the prediction of obesogenic and obesoprotective environments for children. After examining 44 community characteristics, we identified 13 features of the social, food, and physical activity environment that in combination correctly classified 67% of communities as obesoprotective or obesogenic using mean BMI-z as a surrogate. Social environment characteristics emerged as most important classifiers and might provide leverage for intervention. CRF allows consideration of the neighborhood as a system of risk factors.Various racemic and enantioenriched (trans)-X,Y-dihydroxy-X,Y-dihydronaphthoyl analogues as well as X-hydroxy-naphthoyl analogues of CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1, Setipiprant/ACT-129968) were synthesized in order to gain insight into regio- and enantioselectivity of the metabolic oxidation of 1 and to verify the structures of four metabolites that were proposed earlier in a clinical ADME study. Analytical data of the synthetic standards were compared with data from samples of biological origin. The two major metabolites M7 and M9 were unambiguously verified as 2-(2-((trans)-3,4-dihydroxy-3,4-dihydronaphthalene-1-carbonyl)- and 2-(2-((trans)-5,6-dihydroxy-5,6-dihydronaphthalene-1-carbonyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid, respectively, each composed of two enantiomers with 68% and 44% ee in favor of (+)-(3S,4S)-M7 and (+)-(5S,6S)-M9, respectively. selleck chemicals Likewise, minor metabolites M3 and M13 were identified as 2-(8-fluoro-2-(5-hydroxy-1-naphthoyl)- and 2-(8-fluoro-2-(4-hydroxy-1-naphthoyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)acetic acid, respectively.