- CLIC4 regulates apical exocytosis and renal tube luminogenesis through retromer- and actin-mediated endocytic trafficking
- Chou, Szu-Yi, Hsu, Kuo-Shun, Otsu, Wataru, Hsu, Ya-Chu, Luo, Yun-Cin, Yeh, Celine, Shehab, Syed S., Chen, Jie, Shieh, Vincent, He, Guo-an, Marean, Michael B., Felsen, Diane, Ding, Aihao, Poppas, Dix P., Chuang, Jen-Zen, Sung, Ching-Hwa | Nature communications (v.7 / pp.10412 / 2016)
- Chloride intracellular channel 4 (CLIC4) is a mammalian homologue of EXC-4 whose mutation is associated with cystic excretory canals in nematodes. Here we show that CLIC4
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Chloride intracellular channel 4 (CLIC4) is a mammalian homologue of EXC-4 whose mutation is associated with cystic excretory canals in nematodes. Here we show that CLIC4-null mouse embryos exhibit impaired renal tubulogenesis. In both developing and developed kidneys, CLIC4 is specifically enriched in the proximal tubule epithelial cells, in which CLIC4 is important for luminal delivery, microvillus morphogenesis, and endolysosomal biogenesis. Adult CLIC4-null proximal tubules display aberrant dilation. In MDCK 3D cultures, CLIC4 is expressed on early endosome, recycling endosome and apical transport carriers before reaching its steady-state apical membrane localization in mature lumen. CLIC4 suppression causes impaired apical vesicle coalescence and central lumen formation, a phenotype that can be rescued by Rab8 and Cdc42. Furthermore, we show that retromer- and branched actin-mediated trafficking on early endosome regulates apical delivery during early luminogenesis. CLIC4 selectively modulates retromer-mediated apical transport by negatively regulating the formation of branched actin on early endosomes.
- Transcriptional Profiling of Host Gene Expression in Chicken Embryo Fibroblasts Infected with Reticuloendotheliosis Virus Strain HA1101.
- Miao, Ji, Bao, Yanqing, Ye, Jianqiang, Shao, Hongxia, Qian, Kun, Qin, Aijian | PloS one (v.10 / no.5 / pp.0126992 / 2015)
- Reticuloendotheliosis virus (REV), a member of the Gammaretrovirus genus in the Retroviridae family, causes an immunosuppressive, oncogenic and runting-stunting syndrome
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Reticuloendotheliosis virus (REV), a member of the Gammaretrovirus genus in the Retroviridae family, causes an immunosuppressive, oncogenic and runting-stunting syndrome in multiple avian hosts. To better understand the host interactions at the transcriptional level, microarray data analysis was performed in chicken embryo fibroblast cells at 1, 3, 5, and 7 days after infection with REV. This study identified 1,785 differentially expressed genes that were classified into several functional groups including signal transduction, immune response, biological adhesion and endocytosis. Significant differences were mainly observed in the expression of genes involved in the immune response, especially during the later post-infection time points. These results revealed that differentially expressed genes IL6, STAT1, MyD88, TLRs, NF-κB, IRF-7, and ISGs play important roles in the pathogenicity of REV infection. Our study is the first to use microarray analysis to investigate REV, and these findings provide insights into the underlying mechanisms of the host antiviral response and the molecular basis of viral pathogenesis.
- Senior GRADE methodologists encounter challenges as part of WHO guideline development panels: an inductive content analysis
- Alexander, P.E., Li, S.A., Gionfriddo, M.R., Stoltzfus, R.J., Neumann, I., Brito, J.P., Djulbegovic, B., Montori, V.M., Schunemann, H.J., Guyatt, G.H. | Journal of clinical epidemiology (v.70 / pp.123-128 / 20160895-4356)
- Background: The World Health Organization (WHO) classifies a substantial proportion of their recommendations as strong despite low or very low confidence (certainty) in e
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Background: The World Health Organization (WHO) classifies a substantial proportion of their recommendations as strong despite low or very low confidence (certainty) in estimates of effect. Such discordant recommendations are often inconsistent with Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance. Objective: To gain the perspective of senior WHO methodology chairs regarding panels' use of GRADE, particularly regarding discordant recommendations. Data sources: Senior active GRADE methodologists who had served on at least two WHO panels and were an author on at least one peer-reviewed published article on GRADE methodology. Methods: Five eligible methodologists participated in detailed semistructured interviews. Respondents answered questions regarding how they were viewed by other panelists and WHO leadership, and how they handled situations when panelists made discordant recommendations they felt were inappropriate. They also provided information on how the process can be improved. Interviews were recorded and transcribed, and inductive content analysis was used to derive codes, categories, and emergent themes. Results: Three themes emerged from the interviews of five methodologists: (1) The perceived role of methodologists in the process, (2) Contributors to discordant recommendations, and (3) Strategies for improvement. Salient findings included (1) a perceived tension between methodologists and WHO panels as a result of panel members' resistance to adhering to GRADE guidance; (2) both financial and nonfinancial conflicts of interest among panel members as an explanation for discordant recommendations; and (3) the need for greater clarity of, and support for, the role of methodologists as co-chairs of panels. Conclusions: These findings suggest that the role of the GRADE methodologist as a co-chair needs to be clarified by the WHO leadership. They further suggest the need for additional training for panelists, quality monitoring, and feedback to ensure optimal use of GRADE in guideline development at WHO.
- The relationship between socio-economic status and access to eye health services in the UK: a systematic review
- Knight, A., Lindfield, R. | Public health (v.129 / no.2 / pp.94-102 / 20150033-3506)
- Abstract Objectives Lower socio-economic status has been shown to adversely affect access to general health care. This study aims to determine the existence and nature
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Abstract Objectives Lower socio-economic status has been shown to adversely affect access to general health care. This study aims to determine the existence and nature of an association between socio-economic status and access to eye health services in the UK. Study design Systematic review. Methods Search terms were run in four databases and reviewed against a pre-agreed set of inclusion and exclusion criteria by two independent reviewers. Quality of studies was assessed according to calculations of statistical significance, size of effect, primary research question and a quality score against an adapted STROBE checklist. Results Good quality studies included in the review most commonly concluded that lower socio-economic groups had less access to eye health services than higher socio-economic groups. However there were a comparable number of studies that concluded that there was no association. This discrepancy was largely attributed to different ways of measuring socio-economic status, access, and types of eye health services, and so studies did not compare the same thing. The evidence base was of low quality, limiting the ability of this review to make definitive conclusions. Conclusions The review concluded that there is equal and weak evidence of lower socio-economic groups having reduced access to eye health services in the UK, and there being no association. This subject would benefit from further research to improve the quality of the evidence base. Highlights There were few high quality studies exploring this association. There were few studies from the highstreet or tertiary services. There were issues with the heterogeneity between studies meaning that comparison was difficult. Further research on this topic would support improved service planning.
- Allergic rhinitis phenotypes based on mono-allergy or poly-allergy.
- Gelardi, Matteo, Ciprandi, Giorgio, Incorvaia, Cristoforo, Buttafava, Serena, Leo, Eleonora, Iannuzzi, Lucia, Quaranta, Nicola, Frati, Franco | Inflammation research : official journal of the European Histamine Research Society ... [et al.] (v.64 / no.6 / pp.373-375 / 20151023-3830)
- Allergic rhinitis (AR) is characterized by typical symptoms that are dependent on inflammation. Poly-allergy is a frequent phenomenon. Phenotyping AR represents an up-to-
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Allergic rhinitis (AR) is characterized by typical symptoms that are dependent on inflammation. Poly-allergy is a frequent phenomenon. Phenotyping AR represents an up-to-date issue.
- Lipid Requirements for the Enzymatic Activity of MraY Translocases and in Vitro Reconstitution of the Lipid II Synthesis Pathway
- Henrich, Erik, Ma, Yi, Engels, Ina, Munch, Daniela, Otten, Christian, Schneider, Tanja, Henrichfreise, Beate, Sahl, Hans-Georg, Dotsch, Volker, Bernhard, Frank | The Journal of biological chemistry (v.291 / no.5 / pp.2535-2546 / 20160021-9258)
- Screening of new compounds directed against key protein targets must continually keep pace with emerging antibiotic resistances. Although periplasmic enzymes of bacterial
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Screening of new compounds directed against key protein targets must continually keep pace with emerging antibiotic resistances. Although periplasmic enzymes of bacterial cell wall biosynthesis have been among the first drug targets, compounds directed against the membrane-integrated catalysts are hardly available. A promising future target is the integral membrane protein MraY catalyzing the first membrane associated step within the cytoplasmic pathway of bacterial peptidoglycan biosynthesis. However, the expression of most MraY homologues in cellular expression systems is challenging and limits biochemical analysis. We report the efficient production of MraY homologues from various human pathogens by synthetic cell-free expression approaches and their subsequent characterization. MraY homologues originating from Bordetella pertussis , Helicobacter pylori , Chlamydia pneumoniae , Borrelia burgdorferi , and Escherichia coli as well as Bacillus subtilis were co-translationally solubilized using either detergent micelles or preformed nanodiscs assembled with defined membranes. All MraY enzymes originating from Gram-negative bacteria were sensitive to detergents and required nanodiscs containing negatively charged lipids for obtaining a stable and functionally folded conformation. In contrast, the Gram-positive B. subtilis MraY not only tolerates detergent but is also less specific for its lipid environment. The MraY #x00B7;nanodisc complexes were able to reconstitute a complete in vitro lipid I and lipid II forming pipeline in combination with the cell-free expressed soluble enzymes MurA-F and with the membrane-associated protein MurG. As a proof of principle for future screening platforms, we demonstrate the inhibition of the in vitro lipid II biosynthesis with the specific inhibitors fosfomycin, feglymycin, and tunicamycin.
- New trends in guided nanotherapies for digestive cancers: A systematic review
- Fernandes, E., Ferreira, J.A., Andreia, P., Luis, L., Barroso, S., Sarmento, B., Santos, L.L. | Journal of controlled release : official journal of the Controlled Release Society (v.209 / pp.288-307 / 20150168-3659)
- Digestive tract tumors are among the most common and deadliest malignancies worldwide, mainly due to late diagnosis and lack of efficient therapeutics. Current treatments
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Digestive tract tumors are among the most common and deadliest malignancies worldwide, mainly due to late diagnosis and lack of efficient therapeutics. Current treatments essentially rely on surgery associated with (neo)adjuvant chemotherapy agents. Despite an upfront response, conventional drugs often fail to eliminate highly aggressive clones endowed with chemoresistant properties, which are responsible for tumor recurrence and disease dissemination. Synthetic drugs also present severe adverse systemic effects, hampering the administration of biologically effective dosages. Nanoencapsulation of chemotherapeutic agents within biocompatible polymeric or lipid matrices holds great potential to improve the pharmacokinetics and efficacy of conventional chemotherapy while reducing systemic toxicity. Tagging nanoparticle surfaces with specific ligands for cancer cells, namely monoclonal antibodies or antibody fragments, has provided means to target more aggressive clones, further improving the selectivity and efficacy of nanodelivery vehicles. In fact, over the past twenty years, significant research has translated into a wide array of guided nanoparticles, providing the molecular background for a new generation of intelligent and more effective anti-cancer agents. Attempting to bring awareness among the medical community to emerging targeted nanopharmaceuticals and foster advances in the field, we have conducted a systematic review about this matter. Emphasis was set on ongoing preclinical and clinical trials for liver, colorectal, gastric and pancreatic cancers. To the best of our knowledge this is the first systematic and integrated overview on this field. Using a specific query, 433 abstracts were gathered and narrowed to 47 manuscripts when matched against inclusion/exclusion criteria. All studies showed that active targeting improves the effectiveness of the nanodrugs alone, while lowering its side effects. The main focus has been on hepatocarcinomas, mainly by exploring glycans as homing molecules. Other ligands such as peptides/small proteins and antibodies/antibody fragments, with affinity to either tumor vasculature or tumor cells, have also been widely and successfully applied to guide nanodrugs to gastrointestinal carcinomas. Conversely, few solutions have been presented for pancreatic tumors. To this date only three nanocomplexes have progressed beyond pre-clinical stages: i) PK2, a galactosamine-functionalized polymeric-DOX formulation for hepatocarcinomas; ii) MCC-465, an anti-(myosin heavy chain a) immunoliposome for advanced stage metastatic solid tumors; and iii) MBP-426, a transferrin-liposome-oxaliplatin conjugate, also for advanced stage tumors. Still, none has been approved for clinical use. However, based on the high amount of pre-clinical studies showing enthusiastic results, the number of clinical trials is expected to increase in the near future. A more profound understanding about the molecular nature of chemoresistant clones and cancer stem cell biology will also contribute to boost the field of guided nanopharmacology towards more effective solutions.
- Marine natural products as inhibitors of cystathionine beta-synthase activity
- Thorson, M.K., Van Wagoner, R.M., Harper, M.K., Ireland, C.M., Majtan, T., Kraus, J.P., Barrios, A.M. | Bioorganic medicinal chemistry letters (v.25 / no.5 / pp.1064-1066 / 20150960-894x)
- A library consisting of characterized marine natural products as well as synthetic derivatives was screened for compounds capable of inhibiting the production of hydrogen
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A library consisting of characterized marine natural products as well as synthetic derivatives was screened for compounds capable of inhibiting the production of hydrogen sulfide (H 2 S) by cystathionine beta-synthase (CBS). Eight hits were validated and shown to inhibit CBS activity with IC 50 values ranging from 83 to 187 mu;M. The majority of hits came from a series of synthetic polyandrocarpamine derivatives. In addition, a modified fluorogenic probe for H 2 S detection with improved solubility in aqueous solutions is reported.
- Material need insecurities, control of diabetes mellitus, and use of health care resources: results of the Measuring Economic Insecurity in Diabetes study.
- Berkowitz, Seth A, Meigs, James B, DeWalt, Darren, Seligman, Hilary K, Barnard, Lily S, Bright, Oliver-John M, Schow, Marie, Atlas, Steven J, Wexler, Deborah J | JAMA internal medicine (v.175 / no.2 / pp.257-265 / 20152168-6106)
- Increasing access to care may be insufficient to improve the health of patients with diabetes mellitus and unmet basic needs (hereinafter referred to as material need ins
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Increasing access to care may be insufficient to improve the health of patients with diabetes mellitus and unmet basic needs (hereinafter referred to as material need insecurities). How specific material need insecurities relate to clinical outcomes and the use of health care resources in a setting of near-universal access to health care is unclear.
- Community, virtue and the White British poor
- Merry, Michael S, Manley, David, Harris, Richard | Dialogues in human geography (v.6 / no.1 / pp.50-68 / 20162043-8206)
- Whilst media and political rhetoric in Britain is sceptical and often outright damning of the (presumed) morals and behaviours of the White marginalized poor, our aim is
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Whilst media and political rhetoric in Britain is sceptical and often outright damning of the (presumed) morals and behaviours of the White marginalized poor, our aim is to explore the conditions under which successful communities are nevertheless built. Specifically, we examine the features of community and stress its importance both for belonging and bonding around shared norms and practices and for fostering the necessary bridging essential for interacting and cooperating with others. In considering what it means to foster a community that acts as a breakwater against the tides of stigma or disadvantage, we pay special attention to what we will call enabling conditions #x2013; essential features that communities either can or should be able to provide or that exist independent of communities and are indispensable for accessing opportunities in the wider society. We detail the dynamics of White poverty and exclusion before turning our attention to possible responses to these challenges. In searching for viable responses to stigma and disadvantage, we compare some different typologies of community presently available to the White poor in Britain and examine whether these are sufficient to satisfy the enabling conditions associated with more robust forms of group membership.
- Phenotype-Guided Natural Products Discovery Using Cytological Profiling
- Ochoa, Jessica L., Bray, Walter M., Lokey, R. Scott, Linington, Roger G. | Journal of natural products (v.78 / no.9 / pp.2242-2248 / 20150163-3864)
- Phenotype-guided natural products discovery is emerging as a useful new discovery tool that addresses challenges in early, unbiased natural product biological annotation.
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Phenotype-guided natural products discovery is emerging as a useful new discovery tool that addresses challenges in early, unbiased natural product biological annotation. These high-content approaches yield screening results that report directly on the impact of test compounds on cellular processes in target organisms and can be used to predict the modes of action of bioactive constituents from primary screening data. In this study we explored the use of our recently implemented cytological profiling platform for the isolation of compounds with a specific, predefined mode of action, namely, induction of mitotic arrest. Screening of a microbially derived extract library revealed six extracts whose cytological profiles clustered closely with those of known antimitotic agents from the pure compound training set. Subsequent examination of one of these extracts revealed the presence of two separate bioactive constituents, each of which possessed a unique cytological profile. The first, diketopiperazine XR334 ( 3 ), recapitulated the observed antimitotic phenotype of the original extract, demonstrating that cytological profiling can be used for the targeted isolation of compounds with specific modes of action. The second, nocapyrone L ( 6 ), possessed a cytological profile that clustered with known calcium channel modulators, in line with previous published activities for this compound class, indicating that cytological profiling is a flexible and powerful platform for the de novo characterization of compound modes of action. Graphic Abstract ACS Electronic Supporting Info
- Imagination inflation in the mirror: Can imagining others' actions induce false memories of self-performance?
- | Acta psychologica (v.158 / pp.51-60 / 20150001-6918)
- Imagining oneself performing a simple action can trigger false memories of self-performance, a phenomenon called imagination inflation. However, people can, and often do,
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Imagining oneself performing a simple action can trigger false memories of self-performance, a phenomenon called imagination inflation. However, people can, and often do, imagine others' behavior and actions. According to a visual-similarity account, imagining another person's actions should induce the same kind of memory error, a false memory of self-performance. We tested this account in three experiments, in which performance was followed by imagination. In the imagination phase, participants were asked to either imagine themselves or to imagine another person performing actions, some of which were not previously performed. Two weeks later, a surprise source-memory test was administered in which participants had to decide whether a depicted action had been performed or not performed. Results revealed that imagining another person can trigger false memories of self-performance. However, visual similarity between performance and imagination predicted the amount of false memories only for other-imagination but not for self-imagination. These findings are consistent with research suggesting that other- and self-imagination rely on different mechanisms: While other-imagination primarily involves visual imagery, self-imagination primarily involves motor imagery. Accordingly, false action memories from other-imagination may result from visual similarity, whereas false action memories from self-imagination may result from motor simulation.
- The postapocalyptic imagination
- Doyle, Briohny | Thesis eleven (v.131 / no.1 / pp.99-113 / 20150725-5136)
- Apocalypse as a literary genre, as well as a political and religious agenda, has been criticized by writers such as Lee Quinby and Katherine Keller for its formula, which
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Apocalypse as a literary genre, as well as a political and religious agenda, has been criticized by writers such as Lee Quinby and Katherine Keller for its formula, which tends toward punishment for transgression and salvation of an elect. These same writers critique postapocalypse for its propensity for nihilism and portrayal of a human species #x2018;beyond redemption #x2019;. But perhaps it is precisely this refusal to redeem that endows postapocalypse with dangerous possibilities. The postapocalypse does not have to be considered (and subsequently neutralized) via the same moral underpinnings that structure apocalypse. This paper frames postapocalypse not as a literature of pessimism or warning but as a radical context to explore dangerous possibilities without rehearsing apocalypse #x2019;s characteristic damnation, salvation and enforcement of a horizon of revelation that simultaneously works to obliterate aberrant possibilities. In order to explore these claims, the process of thinking beyond revelation in apocalypse is defined here as #x2018;the postapocalyptic imagination #x2019;. Its expressions are found in postapocalyptic texts, but also in other kinds of texts that respond to, and in some cases resist, the teleological drive of late capitalist narratives of endless progress. The postapocalyptic world is host to mutations, amalgamations and strange appropriations of forms and ideas left in the wreckage beyond the end. It is the task of the postapocalyptic imagination to explore what possibilities these #x2018;abominations #x2019; might offer. This paper considers the motifs, characters and settings of postapocalyptic texts, alongside some of the anxieties and critiques they express.
- Chloride-induced corrosion of steel in cracked concrete-Part II: Corrosion rate prediction models
- Otieno, M., Beushausen, H., Alexander, M. | Cement and concrete research (v.79 / pp.386-394 / 20160008-8846)
- Chloride-induced corrosion rate (i corr ) prediction models for RC structures in the marine tidal zone that incorporate the influence of crack width (w cr ), cover (c
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Chloride-induced corrosion rate (i corr ) prediction models for RC structures in the marine tidal zone that incorporate the influence of crack width (w cr ), cover (c) and concrete quality are proposed. Parallel corrosion experiments were carried out for 2¼years by exposing one half of 210 beam specimens (120x130x375mm long) to accelerated laboratory corrosion (cyclic wetting and drying) while the other half underwent natural corrosion in the tidal zone. Experimental variables were w cr (0, incipient crack, 0.4, 0.7mm), c (20, 40mm), binder type (PC, PC/GGBS, PC/FA) and w/b ratio (0.40, 0.55). The two proposed models (one each for accelerated and natural i corr ) can aid not only in quantifying the propagation phase, but also provide a novel way to select c, w cr and concrete quality.
- Bioactive natural products with anti-herpes simplex virus properties.
- Hassan, Sherif T S, Masar??kov?, Radka, Berchov?, Kate?ina | Journal of pharmacy and pharmacology (v.67 / no.10 / pp.1325-1336 / 20150022-3573)
- In this review, we highlight and summarise the most promising extracts, fractions and pure compounds as potential anti-herpes simplex virus (HSV) agents derived from micr
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In this review, we highlight and summarise the most promising extracts, fractions and pure compounds as potential anti-herpes simplex virus (HSV) agents derived from microorganisms, marine organisms, fungi, animals and plants. The role of natural products in the development of anti-HSV drugs will be discussed.
- Components of Springer fibers associated to closed orbits for the symmetric pairs (Sp(2n),Sp(2p)xSp(2q)) and (SO(2n),GL(n)), II
- Barchini, L., Zierau, R. | Journal of pure and applied algebra (v.219 / no.4 / pp.1103-1121 / 20150022-4049)
- This is the second of two articles that consider the pairs of complex reductive groups (G,K)=(Sp(2n),Sp(2p)xSp(2q)) and (SO(2n),GL(n)) and components of Springer fibers a
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This is the second of two articles that consider the pairs of complex reductive groups (G,K)=(Sp(2n),Sp(2p)xSp(2q)) and (SO(2n),GL(n)) and components of Springer fibers associated to closed K-orbits in the flag variety of G. In the first an algorithm is given to compute the associated variety of any discrete series representation of G R = Sp(p,q) and SO @? (2n) and to concretely describe the corresponding component of a Springer fiber. These results are used here to compute associated cycles of discrete series representations. For each Harish-Chandra cell containing a discrete series representation, a particular discrete series representation is identified for which the structure of the component is sufficiently simple that the multiplicity in the associated cycle can be calculated. Coherent continuation is then applied to compute associated cycles of all representations in such a cell.
- Dutch senior medical students and disaster medicine: a national survey.
- Mortelmans, Luc J M, Bouman, Stef J M, Gaakeer, Menno I, Dieltiens, Greet, Anseeuw, Kurt, Sabbe, Marc B | International journal of emergency medicine (v.8 / no.1 / pp.77 / 20151865-1372)
- Medical students have been deployed in victim care of several disasters throughout history. They are corner stones in first-line care in recent pandemic planning. Further
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Medical students have been deployed in victim care of several disasters throughout history. They are corner stones in first-line care in recent pandemic planning. Furthermore, every physician and senior medical student is expected to assist in case of disaster situations, but are they educated to do so? Being one of Europe #039;s densest populated countries with multiple nuclear installations, a large petrochemical industry and also at risk for terrorist attacks, The Netherlands bear some risks for incidents. We evaluated the knowledge on Disaster Medicine in the Dutch medical curriculum. Our hypothesis is that Dutch senior medical students are not prepared at all.
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