A Plea for Ecological Argument Technologies

Abstract

In spite of significant research efforts, argument technologies do not seem poised to scale up as much as most commentators would hope or even predict. In this paper, I discuss what obstacles bar the way to more widespread success of argument technologies and venture some suggestions on how to circumvent such difficulties: doing so will require a significant shift in how this research area is typically understood and practiced. I begin by exploring a much broader yet closely related question: To what extent are people natively good at arguing? This issue has always been central to philosophical reflection and it has become even more urgent nowadays, with the explosion of persuasive technologies and unprecedented opportunities for large-scale social influence. The answer hinges on what aspect of argumentation is taken under consideration: evidence suggests that people are relatively bad at analyzing the structure of arguments, especially when these are presented out of context and in abstract terms; in contrast, data show that even laymen tend to excel in the interactive practice of argumentation, in particular when motivation is high and something significant is at stake. Unfortunately, current argument technologies are more closely tailored to the former type of activity than to the latter, which is the main reason behind their relative lack of success with the general public. Changing this state of affair will require a commitment to ecological argument technologies: that is, technologies designed to support real-time, engaging and meaningful argumentative interactions performed by laypeople in their ordinary life, instead of catering to the highly specific needs of a minority of niche users (typically, argumentation scholars).

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Errors as a Means of Reducing Impulsive Food Choice

Giving in to temptation of tasty food may result in long-term overweight problems. This protocol describes how to reduce imprudent preference for edible commodities during hypothetical intertemporal choices in women by associating them with errors.

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Danshen (Salvia miltiorrhiza) Compounds Improve the Biochemical Indices of the Patients with Coronary Heart Disease

Danshen was able to reduce the risk of the patients with coronary heart disease (CHD), but the mechanism is still widely unknown. Biochemical indices (lipid profile, markers of renal and liver function, and homocysteine (Hcy)) are closely associated with CHD risk. We aimed to investigate whether the medicine reduces CHD risk by improving these biochemical indices. The patients received 10 Danshen pills (27 mg/pill) in Dashen group, while the control patients received placebo pills, three times daily. The duration of follow-up was three months. The serum biochemical indices were measured, including lipid profiles (LDL cholesterol (LDL-C), HDL-C, total cholesterol (TC), triglycerides (TG), apolipoprotein (Apo) A, ApoB, ApoE, and lipoprotein (a) (Lp(a))); markers of liver function (gamma-glutamyl transpeptidase (GGT), total bilirubin (TBil), indirect bilirubin (IBil), and direct bilirubin (DBil)); marker of renal function (uric acid (UA)) and Hcy. After three-month follow-up, Danshen treatment reduced the levels of TG, TC, LDL-C, Lp(a), GGT, DBil, UA, and Hcy (). In contrast, the treatment increased the levels of HDL-C, ApoA, ApoB, ApoE, TBil, and IBil (). Conclusion. Danshen can reduce the CHD risk by improving the biochemical indices of CHD patients.

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Vascular Protective Role of Samul-Tang in HUVECs: Involvement of Nrf2/HO-1 and NO

Samul-Tang (Si-Wu-Tang, SMT), composed of four medicinal herbs, is a well-known herbal formula treating hematological disorder or gynecologic disease. However, vascular protective effects of SMT and its molecular mechanisms on the vascular endothelium, known as the central spot of vascular inflammatory process, are not reported. The aim of this study was to investigate vascular protective effects of SMT water extract in human umbilical vein endothelial cells (HUVECs). Water extract of SMT was prepared and identified by HPLC-PDA analysis. Expression of cell adhesion molecules (CAMs) and heme oxygenase-1 (HO-1) and translocation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were determined by western blot. Nuclear localization of NF-κB and Nrf2 was visualized by immunofluorescence and DNA binding activity of NF-κB was measured. ROS production, HL-60 monocyte adhesion, and intracellular nitric oxide (NO) were also measured using a fluorescent indicator. SMT suppressed NF-κB translocation and activation as well as expression of CAMs, monocyte adhesion, and ROS production induced by TNF-α in HUVECs. SMT treated HUVECs showed upregulation of HO-1 and NO which are responsible for vascular protective action. Our study suggests that SMT, a traditionally used herbal formula, protects the vascular endothelium from inflammation and might be used as a promising vascular protective drug.

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Effect of TRPV4-p38 MAPK Pathway on Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion

The aim of this study was to investigate the relationships among TRPV4, p38, and neuropathic pain in a rat model of chronic compression of the dorsal root ganglion. Mechanical allodynia appeared after CCD surgery, enhanced via the intrathecal injection of 4α-phorbol 12,13-didecanoate (4α-PDD, an agonist of TRPV4) and anisomycin (an agonist of p38), but was suppressed by Ruthenium Red (RR, an inhibitor of TRPV4) and SB203580 (an inhibitor of p38). The protein expressions of p38 and P-p38 were upregulated by 4α-PDD and anisomycin injection but reduced by RR and SB203580. Moreover, TRPV4 was upregulated by 4α-PDD and SB203580 and downregulated by RR and anisomycin. In DRG tissues, the numbers of TRPV4- or p38-positive small neurons were significantly changed in CCD rats, increased by the agonists, and decreased by the inhibitors. The amplitudes of ectopic discharges were increased by 4α-PDD and anisomycin but decreased by RR and SB203580. Collectively, these results support the link between TRPV4 and p38 and their intermediary role for neuropathic pain in rats with chronic compression of the dorsal root ganglion.

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Prevalence of Extended Spectrum β-Lactamase and Antimicrobial Susceptibility Pattern of Clinical Isolates of Pseudomonas from Patients of Khyber Pakhtunkhwa, Pakistan

Majority of gram negative pathogenic bacteria are responsible for extended spectrum β-lactamases (ESBLs) production, which show resistance to some newer generation of antibiotics. The study was aimed at evaluating the prevalence of ESBL and antibiotic susceptibility pattern of Pseudomonas isolates collected during 2010 to 2014 from tertiary care hospitals of Peshawar, Pakistan. Out of 3450 samples, 334 Pseudomonas spp. isolates comprised of 232 indoor and 102 outdoor patients were obtained from different specimens and their susceptibility pattern was determined against 20 antibiotics. Antimicrobial susceptibility testing was carried out using the Kirby-Bauer agar diffusion method and ESBL production was detected by Synergy Disc Diffusion technique. The mean age group of the patients was 29.9 + 9.15 years. Meronem showed best activity (91.02%) from class carbapenem, β-lactam and β-lactamase inhibitors exhibited 69.16% activity, and doxycycline had a diminished activity (10.18%) to Pseudomonas spp. Outdoor isolates were more resistant than the indoor and during the course of the study the sensitivity rate of antibiotics was gradually reducing. ESBL production was observed in 44.32% while the remaining was non-ESBL. The moderate active antibiotics were amikacin (50.7%), SCF (51.4%), TZP (52.7%), and MXF (54.1%) among ESBL producing isolates. Lack of antibiotic policy, irrational uses (3GCs particularly), and the emergence of antibiotic resistant organisms in hospitals may be causes of high antibiotic resistance.

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Editorial Board

Publication date: 16 June 2016
Source:Journal of Proteomics, Volume 142





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Proteomics offers insight to the mechanism behind Pisum sativum L. response to Pea seed-borne mosaic virus (PSbMV)

Publication date: Available online 25 May 2016
Source:Journal of Proteomics
Author(s): Hana Cerna, Martin Černý, Hana Habánová, Dana Šafářová, Kifah Abushamsiya, Milan Navrátil, Břetislav Brzobohatý
Pea seed-borne mosaic virus (PSbMV) significantly reduces yields in a broad spectra of legumes. The eukaryotic translation initiation factor has been shown to confer resistance to this pathogen, thus implying that translation and proteome dynamics play a role in resistance. This study presents the results of a proteome-wide analysis of Pisum sativum L. response to PSbMV infection. LC–MS profiling of two contrasting pea cultivars, resistant (B99) and susceptible (Raman) to PSbMV infection, detected >2300 proteins, 116 of which responded to PSbMV ten and/or twenty days post-inoculation. These differentially abundant proteins are involved in number of processes that have previously been reported in the plant-pathogen response, including protein and amino acid metabolism, stress signaling, redox homeostasis, carbohydrate metabolism, and lipid metabolism. We complemented our proteome-wide analysis work with targeted analyses of free amino acids and selected small molecules, fatty acid profiling, and enzyme activity assays. Data from these additional experiments support our findings and validate the biological relevance of the observed proteome changes. We found surprising similarities in the resistant and susceptible cultivars, which implies that a seemingly unaffected plant, with no detectable levels of PSbMV, actively suppresses viral replication.Biological significancePlant resistance to PSbMV is connected to translation initiation factors, yet the processes involved are still poorly understood at the proteome level. To the best of our knowledge, this is the first survey of the global proteomic response to PSbMV in plants. The combination of label-free LC–MS profiling and two contrasting cultivars (resistant and susceptible) provided highly sensitive snapshots of protein abundance in response to PSbMV infection. PSbMV is a member of the largest family of plant viruses and our results are in accordance with previously characterized potyvirus-responsive proteomes. Hence, the results of this study can further extend our knowledge about these pathogens. We also show that even though no viral replication is detected in the PSbMV-resistant cultivar B99, it is still significantly affected by PSbMV inoculation.

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A multi-model statistical approach for proteomic spectral count quantitation

Publication date: Available online 31 May 2016
Source:Journal of Proteomics
Author(s): Owen E. Branson, Michael A. Freitas
The rapid development of mass spectrometry (MS) technologies has solidified shotgun proteomics as the most powerful analytical platform for large-scale proteome interrogation. The ability to map and determine differential expression profiles of the entire proteome is the ultimate goal of shotgun proteomics. Label-free quantitation has proven to be a valid approach for discovery shotgun proteomics, especially when sample is limited. Label-free spectral count quantitation is an approach analogous to RNA sequencing whereby count data is used to determine differential expression. Here we show that statistical approaches developed to evaluate differential expression in RNA sequencing experiments can be applied to detect differential protein expression in label-free discovery proteomics. This approach, termed MultiSpec, utilizes open-source statistical platforms; namely edgeR, DESeq and baySeq, to statistically select protein candidates for further investigation. Furthermore, to remove bias associated with a single statistical approach a single ranked list of differentially expressed proteins is assembled by comparing edgeR and DESeq q-values directly with the false discovery rate (FDR) calculated by baySeq. This statistical approach is then extended when applied to spectral count data derived from multiple proteomic pipelines. The individual statistical results from multiple proteomic pipelines are integrated and cross-validated by means of collapsing protein groups.Biological significanceSpectral count data from shotgun proteomics experiments is semi-quantitative and semi-random, yet a robust way to estimate protein concentration. Tag-count approaches are routinely used to analyze RNA sequencing data sets. This approach, termed MultiSpec, utilizes multiple tag-count based statistical tests to determine differential protein expression from spectral counts. The statistical results from these tag-count approaches are combined in order to reach a final MultiSpec q-value to re-rank protein candidates. This re-ranking procedure is completed to remove bias associated with a single approach in order to better understand the true proteomic differences driving the biology in question. The MultiSpec approach can be extended to multiple proteomic pipelines. In such an instance, MultiSpec statistical results are integrated by collapsing protein groups across proteomic pipelines to provide a single ranked list of differentially expressed proteins. This integration mechanism is seamlessly integrated with the statistical analysis and provides the means to cross-validate protein inferences from multiple proteomic pipelines.

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In vitro evidence of the promoting effect of testosterone in kidney stone disease: A proteomics approach and functional validation

Publication date: Available online 31 May 2016
Source:Journal of Proteomics
Author(s): Channarong Changtong, Paleerath Peerapen, Supaporn Khamchun, Kedsarin Fong-ngern, Somchai Chutipongtanate, Visith Thongboonkerd
Incidence of kidney stone disease in males is 2–4 fold greater than in females. This study aimed to determine effects of testosterone on kidney stone disease using a proteomics approach. MDCK renal tubular cells were treated with or without 20nM testosterone for seven days. Cellular proteins were extracted, resolved by 2-DE, and stained with Deep Purple fluorescence dye (n=5 gels derived from 5 independent samples/group). Spot matching, quantitative intensity analysis, and statistics revealed significant changes in levels of nine protein spots after testosterone treatment. These proteins were then identified by nanoLC-ESI-Qq-TOF MS/MS. Global protein network analysis using STRING software revealed α-enolase as the central node of protein-protein interactions. The increased level of α-enolase was then confirmed by Western blotting analysis, whereas immunofluorescence study revealed the increased α-enolase on cell surface and intracellularly. Functional analysis confirmed potential role of the increased α-enolase in enhanced calcium oxalate monohydrate (COM) crystal-cell adhesion induced by testosterone. Finally, neutralization of surface α-enolase using anti-α-enolase antibody successfully reduced the enhanced COM crystal-cell adhesion to the basal level. Our data provided in vitro evidence of promoting effect of testosterone on kidney stone disease via enhanced COM crystal-cell adhesion by the increased surface α-enolase.Biological SignificanceThe incidence of kidney stone disease in male is 2–4 folds greater than in female. One of the possible factors of the male preference is the higher testosterone hormone level. However, precise molecular mechanisms that testosterone plays in kidney stone disease remained unclear. Our present study is the first exploratory investigation on such aspect using a proteomics approach. Our data also provide a novel mechanistic aspect of how testosterone can impact the risk of kidney stone formation (i.e. the discovery that testosterone increases alpha-enolase expression on the surface of renal tubular cells that is responsible, at least in part, for crystal-cell adhesion).

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Proteomic comparisons of venoms of long-term captive and recently wild-caught Eastern brown snakes (Pseudonaja textilis) indicate venom does not change due to captivity

Publication date: Available online 27 May 2016
Source:Journal of Proteomics
Author(s): Ryan J.R. McCleary, Sindhuja Sridharan, Nathan L. Dunstan, Peter J. Mirtschin, R. Manjunatha Kini
Snake venom is a highly variable phenotypic character, and its variation and rapid evolution are important because of human health implications. Because much snake antivenom is produced from captive animals, understanding the effects of captivity on venom composition is important. Here, we have evaluated toxin profiles from six long-term (LT) captive and six recently wild-caught (RC) eastern brown snakes, Pseudonaja textilis, utilizing gel electrophoresis, HPLC-MS, and shotgun proteomics. We identified proteins belonging to the three-finger toxins, group C prothrombin activators, Kunitz-type serine protease inhibitors, and phospholipases A2, among others. Although crude venom HPLC analysis showed LT snakes to be higher in some small molecular weight toxins, presence/absence patterns showed no correlation with time in captivity. Shotgun proteomics indicated the presence of similar toxin families among individuals but with variation in protein species. Although no venom sample contained all the phospholipase A2 subunits that form the textilotoxin, all did contain both prothrombin activator subunits. This study indicates that captivity has limited effects on venom composition, that venom variation is high, and that venom composition may be correlated to geographic distribution.Biological significanceThrough proteomic comparisons, we show that protein variation within LT and RC groups of snakes (Pseudonaja textilis) is high, thereby resulting in no discernible differences in venom composition between groups. We utilize complementary techniques to characterize the venom proteomes of 12 individual snakes from our study area, and indicate that individuals captured close to one another have more similar venom gel electrophoresis patterns than those captured at more distant locations. These data are important for understanding natural variation in and potential effects of captivity on venom composition.

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Quantitative proteomics and phosphoproteomics of sugar beet monosomic addition line M14 in response to salt stress

Publication date: Available online 24 May 2016
Source:Journal of Proteomics
Author(s): Bing Yu, Jinna Li, Jin Koh, Craig Dufresne, Na Yang, Shishi Qi, Yongxue Zhang, Chunquan Ma, Benjamin V. Duong, Sixue Chen, Haiying Li
Salinity is a major abiotic stress affecting plant growth, development and agriculture productivity. Understanding the molecular mechanisms of salt stress tolerance will provide valuable information for effective crop engineering and breeding. Sugar beet monosomic addition line M14 obtained from the intercross between Beta vulgaris L. and Beta corolliflora Zoss exhibits tolerance to salt stress. In this study, the changes in the M14 proteome and phosphoproteome induced by salt stress were analyzed. We report the characteristics of the M14 plants under 0, 200, and 400mM NaCl using label-free quantitative proteomics approaches. Protein samples were subjected to total proteome profiling using LC-MS/MS and phosphopeptide enrichment to identify phosphopeptides and phosphoproteins. A total of 2182 proteins were identified and 114 proteins showed differential levels under salt stress. Interestingly, 189 phosphoproteins exhibited significant changes at the phosphorylation level under salt stress. Several signaling components associated with salt stress were found, e.g. 14-3-3 and mitogen-activated protein kinases (MAPK). Fifteen differential phosphoproteins and proteins involved in signal transduction were tested at the transcriptional level. The results revealed the short-term salt responsive mechanisms of the special sugar beet M14 line using label-free quantitative phosphoproteomics.Biological significanceSugar beet monosomic addition line M14 is a special germplasm with salt stress tolerance. Analysis of the M14 proteome and phosphoproteome under salt stress has provided insight into specific response mechanisms underlying salt stress tolerance. Reversible protein phosphorylation regulates a wide range of cellular processes such as transmembrane signaling, intracellular amplification of signals, and cell-cycle control. This study has identified significantly changed proteins and phosphoproteins, and determined their potential relevance to salt stress response. The knowledge gained can be potentially applied to improving crop salt tolerance.

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A Proteomic Road To Acquire An Accurate Serological Diagnosis For Human Tegumentary Leishmaniasis

Publication date: Available online 1 June 2016
Source:Journal of Proteomics
Author(s): B.S.S. Lima, S.F. Pires, L.C. Fialho, E.J. Oliveira, R.A. Machado-de-Avila, C. Chávez-Olórtegui, A.D. Chapeaurouge, J. Perales, H.M. Andrade
Diagnostic tools are important for clinical management and epidemiological evaluation of Tegumentary (TL) and Visceral (VL) Leishmaniasis. Serology is not frequently used for the diagnosis of the TL form because low antibody titers and cross-reaction with VL. Therefore, it is crucial to identify specific and immunogenic antigens from species associated with the TL form. Here we employed a proteomic approach coupled to an in silico analysis and identified the most abundant and immunogenic proteins from Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum. Of 16 species specific proteins, nine were from the species causative of the TL form (L. amazonensis and L. braziliensis). In silico analysis revealed 18 B-cell epitopes with 0% similarity to Trypanosoma cruzi orthologs and, therefore, less likely to crossreact with sera of patients with Chagas disease. Two proteins reacted exclusively with serum from TL patients and presented several B-cell epitopes without similarity to T. cruzi orthologs: the hypothetical protein GI 134063939 and the metallo-peptidase Clan MA(E)-Family M3. The immunoassay revealed nine peptides with strong reactivity to sera from TL patients. These proteins and peptides may be good candidates to improve the specificity and sensibility of serological tests aiming to diagnose the TL of this neglected human disease.Biological significanceAs no gold-standard test for tegumentary leishmaniasis (TL) exists, a combination of different diagnostic techniques is often necessary to obtain precise results.Thus, the identification of species-specific, highly immunogenic and abundant proteins that stimulate the humoral immune response in the host should help in the development of serological tests for human TL. Herein we searched for these potential antigens in Leishmania species related to American Leishmaniasis (L. amazonensis, L. braziliensis and L. infantum). To this end, we employed an immunoproteomic approach using proteins from these Leishmania species and sera from TL and Visceral Leishmaniasis (VL) patients. Our study unveils specific proteins and peptides that may represent antigens that will help the efforts to improve the accuracy of serological tests to diagnose the TL form.

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Profiling the proteomics in honeybee worker brains submitted to the proboscis extension reflex

Publication date: Available online 31 May 2016
Source:Journal of Proteomics
Author(s): Anally Ribeiro da Silva Menegasso, Marcel Pratavieira, Juliana de Saldanha da Gama Fischer, Paulo Costa Carvalho, Thaisa Cristina Roat, Osmar Malaspina, Mario Sergio Palma
The proboscis extension reflex (PER) is an unconditioned stimulus (US) widely used to access the ability of honeybees to correlate it with a conditioned stimulus (CS) during learning and memory acquisition. However, little is known about the biochemical/genetic changes in worker honeybee brains induced by the PER alone. The present investigation profiled the proteomic complement associated with the PER to further the understanding of the major molecular transformations in the honeybee brain during the execution of an US. In the present study, a quantitative shotgun proteomic approach was employed to assign the proteomic complement of the honeybee brain. The results were analyzed under the view of protein networking for different processes involved in PER behavior. In the brains of PER -stimulated individuals, the metabolism of cyclic/heterocyclic/aromatic compounds was activated in parallel with the metabolism of nitrogenated compounds, followed by the up-regulation of carbohydrate metabolism, the proteins involved with the anatomic and cytoskeleton; the down-regulation of the anatomic development and cell differentiation in other neurons also occurred.SignificanceThe assay of proboscis extension reflex is frequently used to access honeybees' ability to correlate an unconditioned stimulus with a conditioned stimulus (such as an odor) to establish learning and memory acquisition. The reflex behavior of proboscis extension was associated with various conditioned stimuli, and the biochemical/genetic evaluation of the changes occurring in honeybee brains under these conditions reflect the synergistic effects of both insect manipulations (training to answer to an unconditioned stimulus and training to respond to a conditioned stimulus). Little or no information is available regarding the biochemical changes stimulated by an unconditioned stimulus alone, such as the proboscis extension reflex. The present investigation characterizes the proteomic changes occurring in the brains of honeybee workers submitted to proboscis extension reflex. A series of metabolic and cellular processes were identified to be related to the reflex of an unconditioned stimulus. This strategy may be reproduced to further understand the processes of learning and memory acquisition in honeybees.

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Species and tissues specific differentiation of processed animal proteins in aquafeeds using proteomics tools

Publication date: Available online 4 June 2016
Source:Journal of Proteomics
Author(s): J.D. Rasinger, H. Marbaix, M. Dieu, O. Fumière, S. Mauro, M. Palmblad, M. Raes, M.H.G. Berntssen
The rapidly growing aquaculture industry drives the search for sustainable protein sources in fish feed. In the European Union (EU) since 2013 non-ruminant processed animal proteins (PAP) are again permitted to be used in aquafeeds. To ensure that commercial fish feeds do not contain PAP from prohibited species, EU reference methods were established. However, due to the heterogeneous and complex nature of PAP complementary methods are required to guarantee the safe use of this fish feed ingredient. In addition, there is a need for tissue specific PAP detection to identify the sources (i.e. bovine carcass, blood, or meat) of illegal PAP use. In the present study, we investigated and compared different protein extraction, solubilisation and digestion protocols on different proteomics platforms for the detection and differentiation of prohibited PAP. In addition, we assessed if tissue specific PAP detection was feasible using proteomics tools. All work was performed independently in two different laboratories. We found that irrespective of sample preparation gel-based proteomics tools were inappropriate when working with PAP. Gel-free shotgun proteomics approaches in combination with direct spectral comparison were able to provide quality species and tissue specific data to complement and refine current methods of PAP detection and identification.SignificanceTo guarantee the safe use of processed animal protein (PAP) in aquafeeds efficient PAP detection and monitoring tools are required. The present study investigated and compared various proteomics workflows and shows that the application of shotgun proteomics in combination with direct comparison of spectral libraries provides for the desired species and tissue specific classification of this heat sterilized and pressure treated (≥133°C, at 3bar for 20min) protein feed ingredient.

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Metabolic profiling of potential lung cancer biomarkers using bronchoalveolar lavage fluid and the integrated direct infusion/ gas chromatography mass spectrometry platform

Publication date: Available online 30 May 2016
Source:Journal of Proteomics
Author(s): Belén Callejón-Leblic, Tamara García-Barrera, Jesús Grávalos-Guzmán, Antonio Pereira-Vega, José Luis Gómez-Ariza
Lung cancer is one of the ten most common causes of death worldwide, so that the search for early diagnosis biomarkers is a very challenging task. Bronchoalveolar lavage fluid (BALF) provides information on cellular and biochemical epithelial surface of the lower respiratory tract constituents and no previous metabolomic studies have been performed with BALF samples from patients with lung cancer. Therefore, this fluid has been explored looking for new contributions in lung cancer metabolism. In this way, two complementary metabolomics techniques based on direct infusion high resolution mass spectrometry (DI-ESI-QTOF-MS) and gas chromatography mass spectrometry (GC-MS) have been applied to compare statistically differences between lung cancer (LC) and control (C) BALF samples, using partial least square discriminant analysis (PLS-DA) in order to find and identify potential biomarkers of the disease. A total of 42 altered metabolites were found in BALF from LC. The metabolic pathway analysis showed that glutamate and glutamine metabolism pathway was mainly altered by this disease. In addition, we assessed the biomarker specificity and sensitivity according to the area under the receiver operator characteristic (ROC) curves, indicating that glycerol and phosphoric acid were potential sensitive and specific biomarkers for lung cancer diagnosis and prognosis.Biological SignificanceThe search for early diagnosis of lung cancer is a very challenging task because of the high mortality associated to this disease and its critical linkage to the initiation of treatment. Bronchoalveolar lavage fluid provides information on cellular and biochemical epithelial surface of the lower respiratory tract constituents and no previous metabolomic studies have been performed with BALF samples from patients with lung cancer. Since BALF is in close interaction with lung tissue it is a more representative sample of lung status than other peripheral biofluids as blood or urine studied in previous works. Therefore, this study represents an innovative contribution in this topic that complement previous investigations about lung cancer, opening up new possibilities for understanding the pathogenesis of this disease and the use of efficient biomarkers.Therefore, this fluid has been explored looking for new contributions in lung cancer metabolism. In this way, two complementary metabolomic techniques based on direct infusion high resolution mass spectrometry (DI-ESI-QTOF-MS) and gas chromatography mass spectrometry (GC-MS) have been applied to compare statistically sifnificant differences between lung cancer (LC) and control (C) BALF samples, using partial least square discriminant analysis (PLS-DA) in order to find and identify potential biomarkers of the disease. A total of 42 altered metabolites were found in BALF from LC. The metabolic pathway analysis showed that glutamate and glutamine metabolism pathway was mainly altered by this disease. In addition, we assessed the biomarker specificity and sensitivity according to the area under the receiver operator characteristic (ROC) curves, indicating that glycerol and phosphoric acid were potential sensitive and specific biomarkers for lung cancer diagnosis and prognosis.

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Modulating the endometrial epithelial proteome and secretome in preparation for pregnancy: The role of ovarian steroid and pregnancy hormones

Publication date: Available online 2 June 2016
Source:Journal of Proteomics
Author(s): David W. Greening, Hong P.T. Nguyen, Jemma Evans, Richard J. Simpson, Lois A. Salamonsen
Dialogue between an appropriately developed embryo and hormonally-primed endometrium is essential to achieve implantation and establish pregnancy. Importantly, the point-of-first-contact between the embryo and the maternal-endometrium occurs at the endometrial luminal epithelium (LE). Implantation events occur within the uterine cavity microenvironment regulated by local factors. Defects in embryo-endometrial communication likely underlie unexplained infertility; enhanced knowledge of this communication, specifically at initial maternal-fetal contact may reveal targets to enhance fertility. Using a human endometrial luminal-epithelial (LE) cell line (ECC1), this targeted proteomic study reveals unique protein changes in both cellular (98% unique identifications) and secreted (96% unique identifications) proteins in the transition to the progesterone-dominated secretory (receptive) phase and subsequently to pregnancy, mediated by embryo-derived human chorionic gonadotropin (hCG). This analysis identified 157 progesterone-regulated cellular proteins, with further 193 significantly altered in response to hCG. Cellular changes were associated with metabolism, basement membrane and cell connectivity, proliferation and differentiation. Secretome analysis identified 1059 proteins; 123 significantly altered by progesterone, and 43 proteins altered by hCG, including proteins associated with cellular adhesion, extracellular-matrix organization, developmental growth, growth factor regulation, and cell signaling. Collectively, our findings reveal dynamic intracellular and secreted protein changes in the endometrium that may modulate successful establishment of pregnancy.Biological significanceThis study provides unique insights into the developmental biology of embryo implantation using targeted proteomics by identifying endometrial epithelial cellular and secreted protein changes in response to ovarian steroid hormones and pregnancy hormones that are essential for receptivity and implantation.

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Chinese Herbal Medicine for Functional Abdominal Pain Syndrome: From Clinical Findings to Basic Understandings

Functional abdominal pain syndrome (FAPS) is one of the less common functional gastrointestinal disorders. Conventional therapy has unsatisfactory response to it so people turn to Chinese medicine for help. Currently, we reviewed the whole picture of Chinese herbal medicine (CHM) clinical and basic application in the treatment of FAPS, especially the traditional Chinese medicine (TCM) syndrome, the single herb, and Chinese medicine formulae, thus to provide a solid base to further develop evidence-based study for this common gastrointestinal complaint in the future. We developed the search strategy and set the inclusion and exclusion criteria for article search. From the included articles, we totally retrieved 586 records according to our searching criteria, of which 16 were duplicate records and 291 were excluded for reasons of irrelevance. The full text of 279 articles was retrieved for detailed assessment, of which 123 were excluded for various reasons. The number one used single herb is Radix Ginseng. The most common syndrome was liver qi depression. The most frequently used classic formula was Si-Mo-Tang. This reflected the true situation of clinical practice of Chinese medicine practitioners and could be further systematically synthesized as key points of the therapeutic research for FAPS.

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Efficacy of Linezolid and Fosfomycin in Catheter-Related Biofilm Infection Caused by Methicillin-Resistant Staphylococcus aureus

As long-standing clinical problems, catheter-related infections and other chronic biofilm infections are more difficult to treat due to the high antibiotic resistance of biofilm. Therefore, new treatments are needed for more effective bacteria clearance. In this study, we evaluated the antibacterial activities of several common antibiotics alone and their combinations against biofilm-embedded methicillin-resistant staphylococcus aureus (MRSA) infections, both in vitro and in vivo. In brief, fosfomycin, levofloxacin, and rifampin alone or in combination with linezolid were tested in vitro against planktonic and biofilm-embedded MRSA infection in three MRSA stains. The synergistic effects between linezolid and the other three antibiotics were assessed by fractional inhibitory concentration index (FICI) and time-kill curves, where the combination of linezolid plus fosfomycin showed the best synergistic effect in all strains. For further evaluation in vivo, we applied the combination of linezolid and fosfomycin in a catheter-related biofilm rat model and found that viable bacteria counts in biofilm were significantly reduced after treatment (). In summary, we have shown here that the combination of linezolid and fosfomycin treatment had improved therapeutic effects on biofilm-embedded MRSA infection both in vitro and in vivo, which provided important basis for new clinical therapy development.

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Formation of Aldehydic Phosphatidylcholines during the Anaerobic Decomposition of a Phosphatidylcholine Bearing the 9-Hydroperoxide of Linoleic Acid

Lipid oxidation-derived carbonyl compounds are associated with the development of various physiological disorders. Formation of most of these products has recently been suggested to require further reactions of oxygen with lipid hydroperoxides. However, in rat and human tissues, the formation of 4-hydroxy-2-nonenal is greatly elevated during hypoxic/ischemic conditions. Furthermore, a previous study found an unexpected result that the decomposition of a phosphatidylcholine (PC) bearing the 13-hydroperoxide of linoleic acid under a nitrogen atmosphere afforded 9-oxononanoyl-PC rather than 13-oxo-9,11-tridecadienoyl-PC as the main aldehydic PC. In the present study, products of the anaerobic decomposition of a PC bearing the 9-hydroperoxide of linoleic acid were analysed by electrospray ionization mass spectrometry. 9-Oxononanoyl-PC (ONA-PC) and several well-known bioactive aldehydes including 12-oxo-9-hydroperoxy-(or oxo or hydroxy)-10-dodecenoyl-PCs were detected. Hydrolysis of the oxidized PC products, methylation of the acids obtained thereby, and subsequent gas chromatography-mass spectroscopy with electron impact ionization further confirmed structures of some of the key aldehydic PCs. Novel, hydroxyl radical-dependent mechanisms of formation of ONA-PC and peroxyl-radical dependent mechanisms of formation of the rest of the aldehydes are proposed. The latter mechanisms will mainly be relevant to tissue injury under hypoxic/anoxic conditions, while the former are relevant under both normoxia and hypoxia/anoxia.

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Subcritical Water Technology for Enhanced Extraction of Biochemical Compounds from Chlorella vulgaris

Subcritical water extraction (SWE) technology has been used for the extraction of active compounds from different biomass materials with low process cost, mild operating conditions, short process times, and environmental sustainability. With the limited application of the technology to microalgal biomass, this work investigates parametrically the potential of subcritical water for high-yield extraction of biochemicals such as carbohydrates and proteins from microalgal biomass. The SWE process was optimized using central composite design (CCD) under varying process conditions of temperature (180–374°C), extraction time (1–20 min), biomass particulate size (38–250 μm), and microalgal biomass loading (5–40 wt.%). Chlorella vulgaris used in this study shows high volatile matter (83.5 wt.%) and carbon content (47.11 wt.%), giving advantage as a feedstock for biofuel production. The results showed maximum total carbohydrate content and protein yields of 14.2 g/100 g and 31.2 g/100 g, respectively, achieved under the process conditions of 277°C, 5% of microalgal biomass loading, and 5 min extraction time. Statistical analysis revealed that, of all the parameters investigated, temperature is the most critical during SWE of microalgal biomass for protein and carbohydrate production.

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Measuring functioning and disability after a disaster: results from the typhoon Haiyan/Yolanda-affected areas of the Philippines.

The most commonly reported data after natural disasters are the number of deceased and displaced and the structural and economic damage, whereas disability data are often lacking. Our study assessed disability among the survivors of the Haiyan/Yolanda typhoon that struck Philippines in 2013 and is aimed to identify which context-level variables are associated with higher disability. We used a cross-sectional design and administered a household questionnaire, an individual sociodemographic questionnaire, and the WHODAS 2.0 to 1982 adults. Logistic regression analysis was carried out to address the degree to which demographic variables, effects of the typhoon, individual health state, and rural or urban residence were associated with higher disability. Those aged above 65, employed individuals, students, those not living in their households, and those with one or more health condition or rating their own as health moderate or very poor had higher likelihood of having severe disability. Survivors living in rural contexts and those who received tools/materials to repair their houses were less likely to have higher disability. This study outlines that disability can and should be used as an indicator in surveys after emergencies to identify the most vulnerable groups, thus guiding policies, reconstruction strategies, and health and social interventions. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Influence of repetitive peripheral magnetic stimulation on neural plasticity in the motor cortex related to swallowing.

The aim of this study was to evaluate the effect of repetitive peripheral magnetic stimulation at two different frequencies (20 and 30 Hz) on cortical excitability in motor areas related to swallowing in healthy individuals. The study participants were 10 healthy normal volunteers (two women and eight men, age range 25-36 years). Repetitive peripheral magnetic stimulation was applied to the submandibular muscle using a parabolic coil at the site where contraction of the suprahyoid muscles was elicited. Stimulation was continued for 10 min (total 1200 pulses) at 20 Hz on 1 day and at 30 Hz on another day, with the stimulation strength set at 90% of the intensity that elicited pain. The motor-evoked potential amplitude of suprahyoid muscles was assessed before, immediately after, and 30 min after stimulation. Stimulations at both 20 and 30 Hz significantly increased motor-evoked potential amplitude (P

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Discovery of new [1,4]dioxino[2,3-f]quinazoline-based inhibitors of EGFR including the T790M/L858R mutant

Publication date: 1 July 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
Author(s): Xuemei Qin, Zhipeng Li, Leifu Yang, Peng Liu, Liming Hu, Chengchu Zeng, Zhiyong Pan
A novel series of 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives were designed, synthesized and evaluated as reversible and noncovalent epidermal growth factor receptor (EGFR) inhibitors. Most of the compounds exhibited good potency against EGFR^wt and some showed moderate to excellent potency against EGFR^T790M/L858R mutant. The half-maximal inhibitory concentration (IC50) values of twenty-one compounds against EGFR^wt were less than 50nM, and those of six compounds were less than 10nM. The IC50 values of eleven compounds against EGFR^T790M/L858R were less than 100nM. Among these, compound b1 displayed the most potent inhibitory activity against EGFR^wt (IC50=2.0nM) and EGFR^T790M/L858R (IC50=6.9nM). Compounds with excellent inhibitory activities against EGFR^wt and EGFR^T790M/L858R kinase inhibitory activities showed good antiproliferative activities against H358 and A549 cells. Docking study was performed to position compound b1 into the EGFR active pocket to determine the probable binding conformation.

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Dihydrochelerythrine and its derivatives: Synthesis and their application as potential G-quadruplex DNA stabilizing agents

Publication date: 1 July 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
Author(s): Rajesh Malhotra, Chhanda Rarhi, K.V. Diveshkumar, Rajib Barik, Ruhee D'cunha, Pranab Dhar, Mrinalkanti Kundu, Subrata Chattopadhyay, Subho Roy, Sourav Basu, P.I. Pradeepkumar, Saumen Hajra
A convenient route was envisaged toward the synthesis of dihydrochelerythrine (DHCHL), 4 by intramolecular Suzuki coupling of 2-bromo-N-(2-bromobenzyl)-naphthalen-1-amine derivative 5 via in situ generated arylborane. This compound was converted to (±)-6-acetonyldihydrochelerythrine (ADC), 3 which was then resolved by chiral prep-HPLC. Efficiency of DHCHL for the stabilization of promoter quadruplex DNA structures and a comparison study with the parent natural alkaloid chelerythrine (CHL), 1 was performed. A thorough investigation was carried out to assess the quadruplex binding affinity by using various biophysical and biochemical studies and the binding mode was explained by using molecular modeling and dynamics studies. Results clearly indicate that DHCHL is a strong G-quadruplex stabilizer with affinity similar to that of the parent alkaloid CHL. Compounds ADC and DHCHL were also screened against different human cancer cell lines. Among the cancer cells, (±)-ADC and its enantiomers showed varied (15–48%) inhibition against human colorectal cell line HCT116 and breast cancer cell line MDA-MB-231 albeit low enantio-specificity in the inhibitory effect; whereas DHCHL showed 30% inhibition against A431 cell line only, suggesting the compounds are indeed cancer tissue specific.

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Optimization of the phenylurea moiety in a phosphoinositide 3-kinase (PI3K) inhibitor to improve water solubility and the PK profile by introducing a solubilizing group and ortho substituents

Publication date: 1 July 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
Author(s): Hatsuo Kawada, Hirosato Ebiike, Masao Tsukazaki, Shun Yamamoto, Kohei Koyama, Mitsuaki Nakamura, Kenji Morikami, Kiyoshi Yoshinari, Miyuki Yoshida, Kotaro Ogawa, Nobuo Shimma, Takuo Tsukuda, Jun Ohwada
Phosphoinositide 3-kinase (PI3K) is a promising anti-cancer target, because various mutations and amplifications are observed in human tumors isolated from cancer patients. Our dihydropyrrolopyrimidine derivative with a phenylurea moiety showed strong PI3K enzyme inhibitory activity, but its pharmacokinetic property was poor because of lack of solubility. Herein, we report how we improved the solubility of our PI3K inhibitors by introducing a solubilizing group and ortho substituents to break molecular planarity.

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Pyrazolylbenzo[d]imidazoles as new potent and selective inhibitors of carbonic anhydrase isoforms hCA IX and XII

Publication date: 1 July 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
Author(s): Satish Kumar, Mariangela Ceruso, Tiziano Tuccinardi, Claudiu T. Supuran, Pawan K. Sharma
Novel pyrazolylbenzo[d]imidazole derivatives (2a–2f) were designed, synthesized and evaluated against four human carbonic anhydrase isoforms belonging to α family comprising of two cytosolic isoforms hCA I and II as well as two transmembrane tumor associated isoforms hCA IX and XII. Starting from these derivatives that showed high potency but low selectivity in favor of tumor associated isoforms hCA IX and XII, we investigated the impact of removing the sulfonamide group. Thus, analogs 3a–3f without sulfonamide moiety were synthesized and biological assay revealed a good activity as well as an excellent selectivity as inhibitors for tumor associated hCA IX and hCA XII and the same was analyzed by molecular docking studies.

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Editorial board

Publication date: 1 July 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13





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Design, synthesis and biological evaluation of novel tetrahydroisoquinoline quaternary derivatives as peripheral κ-opioid receptor agonists

Publication date: 1 July 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
Author(s): Ting Guo, Zongjie Gan, Jie Chen, Dechuan Wang, Ling He, Qiao Song, Yungen Xu
A novel series of tetrahydroisoquinoline quaternary derivatives 4 were synthesized as peripheral κ-opioid receptor agonists. All the target compounds were evaluated in κ-opioid receptor binding assays, and compounds 4l, 4m, and 4n exhibited high affinity for κ-opioid receptor. Furthermore, compound 4l (κKi=0.94nM) produced potent antinociceptive activity in the mouse acetic acid-induced writhing assay, with lower sedative side effects than the parent compound MB-1c.

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Antiproliferative activity and apoptosis inducing effects of nitric oxide donating derivatives of evodiamine

Publication date: 1 July 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
Author(s): Nan Zhao, Kang-tao Tian, Ke-guang Cheng, Tong Han, Xu Hu, Da-hong Li, Zhan-lin Li, Hui-ming Hua
The first series of nitric oxide donating derivatives of evodiamine were designed and prepared. NO releasing ability of all target derivatives was evaluated in BGC-823, Bel-7402 and L-02 cells. The cytotoxicity was evaluated against three human tumor cell lines (Bel-7402, A549 and BGC-823) and normal human liver cells L-02. The nitrate derivatives 11a and 11b only exhibited moderate activity and furoxan-based derivatives 13a–c, 14a and 14b showed promising activity. 13c showed good cytotoxic selectivity between tumor and normal liver cells and was further investigated for its apoptotic properties on human hepatocarcinoma Bel-7402 cells. The molecular mode of action revealed that 13c caused cell-cycle arrest at S phase and induced apoptosis in Bel-7402 cells through mitochondria-related caspase-dependent pathways.

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