bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of iodine in excess on seminiferous tubular structure and epididymal sperm character in male rats
Authors: Chandra Amar K , Chakraborty Arijit
Published: February 2017

Excess iodine induced public health problems are now emerging in many iodine sufficient regions for indiscriminate intake of iodine through various iodized products. It has been reported that excess iodine can disrupt overall male reproductive physiology by generating oxidative stress in the testis. However, information on the possible effect of iodine in excess on spermatozoa found less. In the present investigation flow cytometric techniques and scanning electron microscopy (SEM) have been used to study the spermatozoal functional as well as structural status under the influence of excess iodine; generation of ROS in the spermatozoa as evident by DCFDA, altered acrosomal integrity as observed by fluorescence lectin staining method and depolarized mitochondrial membrane potential (ΔΨm) noticed by JC‐1 staining. Ultrastructure of seminiferous tubule after excess iodine exposure indicated severe deterioration of seminiferous tubular surface architecture. Significant increase in spermatozoal DNA fragmentation and apoptotic sperms were found by acridine orange and Annexin V, respectively, however the plasma membrane integrity/viability was decreased as evident by propidium iodide staining in various incremental doses and durations under iodine excess. The study reveals that excess iodine could cause apoptosis of spermatozoal cells by inducing ROS that ultimately affects male fertility potential.
Inborn errors of metabolism associated with psychosis: literature review and case–control study using exome data from 5090 adult individuals
Authors: Trakadis Yannis J. , Fulginiti Vanessa , Walterfang Mark
Published: February 2017

A literature review was conducted, using the computerized “Online Mendelian Inheritance in Man” (OMIM) and PubMed, to identify inborn errors of metabolism (IEM) in which psychosis may be a predominant feature or the initial presenting symptom. Different combinations of the following keywords were searched using OMIM: “psychosis”, “schizophrenia”, or “hallucinations” and “metabolic”, “inborn error of metabolism”, “inborn errors of metabolism”, “biochemical genetics”, or “metabolic genetics”. The OMIM search generated 126 OMIM entries, 40 of which were well known IEM. After removing IEM lacking evidence in PubMed for an association with psychosis, 29 OMIM entries were identified. Several of these IEM are treatable. They involve different small organelles (lysosomes, peroxisomes, mitochondria), iron or copper accumulation, as well as defects in other met‐abolic pathways (e.g., defects leading to hyperammonemia or homocystinemia). A clinical checklist summarizing the key features of these conditions and a guide to clinical approach are provided. The genes corresponding to each of these con‐ditions were identified. Whole exome data from 2545 adult cases with schizophrenia and 2545 unrelated controls, accessed via the Database of Genotypes and Phenotypes (dbGaP), were analyzed for rare functional variants in these genes. The odds ratio of having a rare functional variant in cases versus controls was calculated for each gene. Eight genes are significantly associated with schizophrenia (p < 0.05, OR >1) using an unselected group of adult patients with schizophrenia. Increased awareness of clinical clues for these IEM will optimize referrals and timely metabolic interventions.
New and Uncommon Fatty Acids in Lipids of Deep‐Sea Foraminifera
Authors: Kharlamenko Vladimir I. , Svetashev Vasily I. , Tarasova Tatyana S.
Published: February 2017

Fatty acids (FA) of agglutinating foraminifera of two genera, Bathysiphon and Rhabdammina, collected from a depth of 3307–3377 m in the Kuril Basin, Sea of Okhotsk, and adjacent deep‐sea waters of the Pacific Ocean, were analyzed. In lipids of two Bathysiphon species, in addition to common FA typical for marine organisms, the uncommon ∆4 and ∆7 monoenoic acids and ∆4,7‐dienoic acid were found in noticeable amounts. FA of two Rhabdammina species included also such uncommon acids as ∆5,8,11,14–21:4, ∆5,8,11,14–22:4, and ∆5,8,11,14–23:4, which are homologues to arachidonic acid. High levels of cis‐vaccenic and arachidonic acids were typical for lipids of all the studied species. At the same time, we observed a substantial difference in FA composition between members of these two genera. Using GC and GC–MS of FAME, pyrrolidide and DMOX derivatives, the structures of 10 new FA were confirmed: ∆4‐i‐16:1 (1.1–0.6%), ∆7‐i‐21:1 (0.4%), ∆7‐ai‐21:1 (0.3–0.8%), ∆4,11–18:2 (0.3–0.9%), ∆4,7–20:2 (8.8%), ∆7,12–20:2 (0.4–0.6%), ∆4,7–21:2 (0.6%), ∆7,12–22:2 (6.4–2.1%); ∆5,8,11,14–22:4 (1.2–2.0%), and ∆5,8,11,14–23:4 (1.7–2.3%). The origin of the new FA and the role of foraminifera FA in deep‐sea communities are discussed.
Margaret cavendish contre robert hooke: le duel impossible
Authors: Aït-Touati Frédérique
Published: February 2017

En 1665, Robert Hooke fait paraître son grand ouvrage de microscopie, Micrographia, véritable défense et illustration de la philosophie expérimentale. L'année suivante, Margaret Cavendish, duchesse de Newcastle, publie à compte d'auteur un traité et un roman qui attaquent les fondements mêmes de cette science nouvelle. La dispute qui s'engage à l'initiative de la duchesse s'inscrit dans le contexte d'une plus vaste controverse sur la légitimité et l'efticacité des instruments optiques en philosophie naturelle. Toutes les figures de la controverse scientifique y sont déployées. Toutes. sauf une: la riposte. Car Margaret Cavendish est seule dans ('arène. Peut-on parler de duel lorsque seule l'une des deux parties attaque? C'est ce cas particulier de dispute qui s'achève faute de combattant que cet article propose d'étudier.
The theory contribution of case study research designs
Authors: Ridder Hans-Gerd
Published: February 2017

The objective of this paper is to highlight similarities and differences across various case study designs and to analyze their respective contributions to theory. Although different designs reveal some common underlying characteristics, a comparison of such case study research designs demonstrates that case study research incorporates different scientific goals and collection and analysis of data. This paper relates this comparison to a more general debate of how different research designs contribute to a theory continuum. The fine-grained analysis demonstrates that case study designs fit differently to the pathway of the theory continuum. The resulting contribution is a portfolio of case study research designs. This portfolio demonstrates the heterogeneous contributions of case study designs. Based on this portfolio, theoretical contributions of case study designs can be better evaluated in terms of understanding, theory-building, theory development, and theory testing.
The Impact of Social Marketing Campaigns on Reducing Mental Health Stigma: Results From the 2009–2014 Time to Change Programme
Authors: Sampogna G. , Bakolis I. , Evans-Lacko S. , Robinson E. , Thornicroft G. , Henderson C.
Published: February 2017

Background

In England, during 2009–2014 the ‘Time to Change’ anti-stigma programme has included a social marketing campaign (SMC) using mass media channels, social media and social contact events but the efficacy of such approach has not been evaluated yet.

Methods

The target population included people aged between mid-twenties/mid-forties, from middle-income groups. Participants were recruited through an online market research panel, before and after each burst of the campaign (with a mean number of unique participants per each burst: 956.9 ± 170.2). Participants completed an online questionnaire evaluating knowledge [Mental Health Knowledge Schedule (MAKS)]; attitudes [Community Attitudes toward Mental Illness (CAMI)]; and behaviours [Reported and Intended Behaviour Scale (RIBS)]. Socio-demographic data and level of awareness of the SMC were also collected.

Results

A total of 10,526 people were interviewed. An increasing usage of the SMC-media channels as well as of the level of awareness of SMC was found (P < 0.001). Being aware of the SMC was found to be associated with higher score at MAKS (OR = 0.95, CI = 0.68 to 1.21; P < 0.001), at ‘tolerance and support’ CAMI subscale (OR = 0.12, CI = 0.09 to 0.16; P < 0.001), and at RIBS (OR = 0.71, CI = 0.51 to 0.92; P < 0.001), controlling for confounders.

Conclusion

The SMC represents an important way to effectively reduce stigma. Taking into account these positive findings, further population-based campaigns using social media may represent an effective strategy to challenge stigma.
TEMPORAL FREQUENCY OF SOIL TEST INFORMATION EFFECTS ON RETURNS TO POTASSIUM FERTILIZATION IN COTTON PRODUCTION
Authors: HARMON XAVIER , BOYER CHRISTOPHER N. , LAMBERT DAYTON M. , LARSON JAMES A.
Published: February 2017

Little research exists on the optimal temporal frequency between soil tests, given empirical data on potassium (K) carryover and its interaction with cotton yield. We evaluate how decreasing the temporal frequency between obtaining K soil test information affects the net present value (NPV) of cotton production. Monte Carlo simulation was used to determine NPV for cotton production using five soil test schedules ranging from soil testing annually to every fifth year. NPV of returns to K was maximized at $7,580/ac. when producers updated soil testing information every 2 years, which was $2/ac. per year greater than annual soil testing.
Exploring the Relations Between Childhood Experiences in Nature and Young Adults’ Environmental Attitudes and Behaviours
Authors: Broom Catherine
Published: February 2017

This article presents the findings of a research study with young adults who explored the connections between their early childhood experiences in nature and their attitudes and actions towards the environment in adulthood. Drawing on E. Wilson's (1984) work, environmental or ecological consciousness is theorised to connect to ecological identity and relates to an individual's deep reflection on, connection to, and engagement with the natural environment. The study's survey tool invited young adults to select various options that described their experiences in nature as children and their views of, and actions towards, the environment in the present. The findings illustrated connections between childhood experiences in nature and later views of, and actions towards, the environment. The correlations between expressed views about caring for the environment and environmentally friendly actions were surprising, however, as actions did not necessarily align with beliefs. The article concludes with recommendations based on the findings, outlining how positive attitudes and actions towards the environment may be fostered in childhood.
Association between geographic range and initial survival of Mesozoic marine animal genera: circumventing the confounding effects of temporal and taxonomic heterogeneity
Authors: Ritterbush Kathleen A. , Foote Michael
Published: February 2017

We investigate the association between geographic range and survival in Mesozoic marine animal genera. Previous work using data from the Paleobiology Database (paleobiodb.org) demonstrated greater survivorship overall among Phanerozoic genera that were widespread during their stage of first appearance, but this relationship did not hold during the Mesozoic. To explore this unexpected result, we consider geographic range in conjunction with temporal variation in survival and variation in survival among higher taxa. Because average range and average survival are negatively correlated among stages, for reasons that are still unclear, and because the data are heavily influenced by cephalopods, which include many wide-ranging and short-lived genera, the effect of geographic range on survival is obscured in the aggregate data. Thus, range is not a significant predictor of survival when data are analyzed in aggregate, but it does have a significant effect when variation in average range and average survival among stages and classes is taken into account. The best-fitting models combine range with both temporal and taxonomic heterogeneity as predictive factors. Moreover, when we take stage-to-stage variation into account, geographic range is an important predictor of survival within most classes. Cephalopod genera must be more widespread than genera in other classes for geographic range to significantly increase odds of survival, and factoring in survival heterogeneity of superfamilies further increases model fit, demonstrating a nested nature in the sensitivity of range and taxonomic aggregation.
ON THE EVENTUAL PERIODICITY OF PIECEWISE LINEAR CHAOTIC MAPS
Authors: KHAN M. ALI , RAJAN ASHVIN V.
Published: February 2017

We present a family of continuous piecewise linear maps of the unit interval into itself that are all chaotic in the sense of Li and Yorke [‘Period three implies chaos’, Amer. Math. Monthly82 (1975), 985–992] and for which almost every point (in the sense of Lebesgue) in the unit interval is an eventually periodic point of period $p,p\geq 3$, for a member of the family.
How lives became lists and scientific papers became data: cataloguing authorship during the nineteenth century
Authors: CSISZAR ALEX
Published: February 2017

TheCatalogue of Scientific Papers, published by the Royal Society of London beginning in 1867, projected back to the beginning of the nineteenth century a novel vision of the history of science in which knowledge was built up out of discrete papers each connected to an author. Its construction was an act of canon formation that helped naturalize the idea that scientific publishing consisted of special kinds of texts and authors that were set apart from the wider landscape of publishing. By recovering the decisions and struggles through which theCataloguewas assembled, this essay aims to contribute to current efforts to denaturalize the scientific paper as the dominant genre of scientific life. By privileging a specific representation of the course of a scientific life as a list of papers, theCataloguehelped shape underlying assumptions about the most valuable fruits of a scientific career. Its enumerated lists of authors’ periodical publications were quickly put to use as a means of measuring scientific productivity and reputation, as well as by writers of biography and history. Although it was first conceived as a search technology, this essay locates theCatalogue’s most consequential legacy in its uses as a technology of valuation.
Deterrent activity of hops flavonoids and their derivatives against stored product pests
Authors: Jackowski J. , Popłoński J. , Twardowska K. , Magiera-Dulewicz J. , Hurej M. , Huszcza E.
Published: February 2017

Five flavonoids from hops, two of their derivatives, along with naringenin used as a model compound, were tested for their antifeedant activity against three coleopteran stored product pests: Sitophilus granarius L., Tribolium confusum Duv. and Trogoderma granarium Everts. The introduction, into the tested flavonoid molecules, of additional structural fragments such as prenyl or dimethylpyran moiety, is proposed to significantly alter the deterrent activity of the compounds. The prenyl moiety in flavonoids increased the deterrent activity of these compounds in all three of the grain feeding species used in the tests. It is also concluded that the introduction of dimethylpyran moiety to the flavonoid structure increases its deterrent activity in S. granarius and T. confusum, but in one of the test insects, T. granarium, an increased feeding was observed in response to the introduction of dimethylpyran moiety to the flavonoid structure.
The Minories Eagle: A New Sculpture from London's Eastern Roman Cemetery
Authors: Lerz Antonietta , Henig Martin , Hayward Kevin
Published: February 2017

The limestone sculpture of an eagle firmly clasping a serpent in its beak was recovered from within the eastern Roman cemetery of London on the last day of excavations at 24–26 Minories, EC3 in September 2013. The sculpture, which is dated stylistically to the late first or early second centurya.d., had been carefully buried within the backfill of a roadside ditch no later than the mid-second century. The Minories eagle is one of the finest and earliest examples of freestone sculpture from the London cemeteries and presumably adorned the tomb of a rich and important individual or family located nearby. Petrological analysis of the sculpture has revealed it is carved from oolitic limestone quarried from the south Cotswolds. The article presents the context of the findspot and a detailed description of the eagle sculpture with an in-depth discussion of the iconography of the image and the results of the petrological examination. The Supplementary Material available online (http://journals.cambridge.org/bri) presents an account of the site stratigraphy, integrated with the specialist finds and the environmental reports.
Facets of Pantomime
Authors: Goldenberg Georg
Published: February 2017

Objectives: Exploring the nature of defective pantomime in apraxia. Methods: Critical review of behavioral associations and dissociations between defective pantomime, imitation of gestures, and real tool use. Analysis of congruencies between crucial lesions for pantomime, imitation, and tool use. Results: There are behavioral double dissociations between pantomime and imitation, and their cerebral substrates show very little overlap. Whereas defective pantomime is bound to temporal and inferior frontal lesions, imitation is mainly affected by parietal lesions. Pantomime usually replicates the motor actions of real use but on scrutiny there are important differences between the movements of real use and of pantomime that cast doubt on the assumption that pantomime is produced by the same motor programs as actual use. A more plausible proposal posits that pantomime is a communicative gesture that uses manual actions for conveying information about objects and their use. The manual actions are constructed by selection and combination of distinctive features of tools and actions. They frequently include replications of characteristic motor actions of real use, but the main criterion for selection and modification of features is the comprehensibility of the gestures rather than the accurate replication of the motor actions of real use. Conclusions: Pantomime of tool use is a communicative gesture rather than a replication of the motor actions of real use. (JINS, 2017, 23, 121–127)
Troubled Relationships under the GATS: Tensions between Market Access (Article XVI), National Treatment (Article XVII), and Domestic Regulation (Article VI)
Authors: MULLER GILLES
Published: February 2017

The General Agreement on Trade in Services (GATS) was adopted in order to establish meaningful liberalization rules, while preserving the right of Members to regulate. To that end, three provisions form the centerpiece of liberalization: market access (Article XVI GATS), national treatment (Article XVII GATS), and domestic regulation (Article VI GATS). Although these provisions contain different obligations, in certain conditions they can overlap. How this issue is resolved could undermine the delicate balance between liberalization and the right to regulate. As the GATS provides no guidance, the task of determining the applicable rules has been delegated to the World Trade Organization (WTO) adjudicating bodies. This paper examines how the three provisions have been interpreted, and analyzes the most applicable way to address the diversity of barriers to trade in services.
IPHIGÉNIE EN HAÏTI: PERFORMING GLUCK'S PARIS OPERAS IN THE FRENCH COLONIAL CARIBBEAN
Authors: PREST JULIA
Published: February 2017

Gluck has been hailed as the ‘first truly international opera composer’, but his internationalism is always understood in strictly European terms. This article seeks to expand our understanding of Gluck's international scope beyond Europe and specifically into the French colonial Caribbean. Saint-Domingue (now Haiti) enjoyed the most vibrant theatrical tradition of the entire Caribbean in the eighteenth century, and three of Gluck's Paris operas that had premiered in the 1770s were given there in the 1780s. Performances of these works are examined in turn, with an emphasis on performance practices in the context of local conditions, both social and practical. Gluck's operas are seen to have reached a mixed, though segregated, audience that incorporated some free people of colour, including a small number of black people, and the first documented performance of a singer of colour in a Gluck opera is uncovered. Our understanding of Gluck's reach, reception and status is thus broadened and deepened in some significant ways, and some new areas of research are opened up.
THE IMPERIAL CORONATION OF LEOPOLD II AND MOZART, FRANKFURT AM MAIN, 1790
Authors: GLATTHORN AUSTIN
Published: February 2017

In the autumn of 1790 Mozart undertook the penultimate journey of his life to participate in the coronation of Leopold II as Holy Roman Emperor in Frankfurt am Main. His attendance and performance at this significant imperial gathering were an investment designed to improve his fortunes. But Mozart's gamble failed. Though it was a key political event, and despite its significance as one of Mozart's final sojourns, not much more is known about the music of the Frankfurt coronation. This article offers a new understanding of Leopold II's imperial accession, positing the coronation as a vibrant context for music culture. Contrary to narratives that position Mozart's concert above all others, I argue that this was far from the case according to his contemporaries. During the coronation festivities the city hosted three theatre companies and many celebrated musicians, including Ludwig Fischer, Johann Hässler, Vincenzo Righini, Antonio Salieri and Georg Vogler, among others. Frankfurt was indeed filled with musicians who cooperated with and competed against one another in the hope of attracting substantial audiences comprised of the Empire's elite. Yet for Mozart, whose concert was poorly advertised and unfortunately timed, this competition proved too intense. By investigating the musical and political events of Leopold II's imperial coronation, I assert that Mozart's investment, which had the potential to alter his life forever, was unsuccessful in part because of a rumour that caused his desired audience to leave Frankfurt temporarily the very morning his performance took place.
microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism
Authors: Hajarnis Sachin , Lakhia Ronak , Yheskel Matanel , Williams Darren , Sorourian Mehran , Liu Xueqing , Aboudehen Karam , Zhang Shanrong , Kersjes Kara , Galasso Ryan , Li Jian , Kaimal Vivek , Lockton Steven , Davis Scott , Flaten Andrea , Johnson Joshua A. , Holland William L. , Kusminski Christine M. , Scherer Philipp E. , Harris Peter C. , Trudel Marie , Wallace Darren P. , Igarashi Peter , Lee Edmund C. , Androsavich John R. , Patel Vishal
Published: February 2017

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD. Genetic deletion of the miR-17∼92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. Anti-miR-17 treatment attenuates cyst growth in short-term and long-term PKD mouse models. miR-17 inhibition also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. Mechanistically, c-Myc upregulates miR-17∼92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Pparα. Thus, miR-17 family is a promising drug target for ADPKD, and miR-17-mediated inhibition of mitochondrial metabolism represents a potential new mechanism for ADPKD progression.
A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis
Authors: Feng Qiyu , Zhang Chengliang , Lum David , Druso Joseph E. , Blank Bryant , Wilson Kristin F. , Welm Alana , Antonyak Marc A. , Cerione Richard A.
Published: February 2017

Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis. Here, we describe how a specific class of EVs, called microvesicles (MVs), activates VEGF receptors and tumour angiogenesis through a unique 90 kDa form of VEGF (VEGF90K). We show that VEGF90K is generated by the crosslinking of VEGF165, catalysed by the enzyme tissue transglutaminase, and associates with MVs through its interaction with the chaperone Hsp90. We further demonstrate that MV-associated VEGF90K has a weakened affinity for Bevacizumab, causing Bevacizumab to be ineffective in blocking MV-dependent VEGF receptor activation. However, treatment with an Hsp90 inhibitor releases VEGF90K from MVs, restoring the sensitivity of VEGF90K to Bevacizumab. These findings reveal a novel mechanism by which cancer cell-derived MVs influence the tumour microenvironment and highlight the importance of recognizing their unique properties when considering drug treatment strategies.
Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2
Authors: Wang Zhiding , Sun Dejun , Chen Guojiang , Li Ge , Dou Shuaijie , Wang Renxi , Xiao He , Hou Chunmei , Li Yan , Feng Jiannan , Shen Beifen , Han Gencheng
Published: February 2017

T cell immunoglobulin mucin-3 (Tim-3) is an immune checkpoint inhibitor and its dysregulation has been related to T cell tolerance and many immune disorders, such as tumors and infection tolerance. However, the physiopathology roles of Tim-3 in innate immunity remain elusive. Here, we demonstrate that Tim-3 inhibits macrophage phagocytosis of L. monocytogenes by inhibiting the nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway and increases bacterial burden. Tim-3 signaling promotes Nrf2 degradation by increasing its ubiquitination and, as a result, decreasing its nuclear translocation. CD36 and heme oxygenase-1 (HO-1), two downstream molecules in the Tim-3-Nrf2 signaling axis, are involved in the Tim-3- mediated immune evasion of L. monocytogenes both in vitro and in vivo. We here identified new mechanisms by which Tim-3 induces infection tolerance. By modulating the Tim-3 pathway, we demonstrate the feasibility of manipulating macrophage function as a potent tool for treating infectious diseases, such as Listeria infection.
Imaging cardiac SCN5A using the novel F-18 radiotracer radiocaine
Authors: Hooker Jacob M. , Strebl Martin G. , Schroeder Frederick A. , Wey Hsiao-Ying , Ambardekar Amrut V. , McKinsey Timothy A. , Schoenberger Matthias
Published: February 2017

The key function of the heart, a well-orchestrated series of contractions, is controlled by cardiac action potentials. These action potentials are initiated and propagated by a single isoform of voltage gated sodium channels – SCN5A. However, linking changes in SCN5A expression levels to human disease in vivo has not yet been possible. Radiocaine, an F-18 radiotracer for positron emission tomography (PET), is the first SCN5A imaging agent in the heart. Explants from healthy and failing human hearts were compared using radiocaine autoradiography to determine that the failing heart has ~30% lower SCN5A levels - the first evidence of changes in SCN5A expression in humans as a function of disease. Paving the way for translational imaging, radiocaine proved to exhibit high in vivo specific binding to the myocardium of non-human primates. We envision that SCN5A measurements using PET imaging may serve as a novel diagnostic tool to stratify arrhythmia risk and assess for progression of heart failure in patients with a broad spectrum of cardiovascular diseases.
PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration
Authors: King Helen , Thillai Kiruthikah , Whale Andrew , Arumugam Prabhu , Eldaly Hesham , Kocher Hemant M. , Wells Claire M.
Published: February 2017

It has been reported that p21-activated kinase 4 (PAK4) is amplified in pancreatic cancer tissue. PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF-mediated c-Met activation in a PI3K dependent manner. However, the functionality of PAK4 in pancreatic cancer and the contribution made by HGF signalling to pancreatic cancer cell motility remain to be elucidated. We now find that elevated PAK4 expression is coincident with increased expression levels of c-Met and the p85α subunit of PI3K. Furthermore, we demonstrate that pancreatic cancer cells have a specific motility response to HGF both in 2D and 3D physiomimetic organotypic assays; which can be suppressed by inhibition of PI3K. Significantly, we report a specific interaction between PAK4 and p85α and find that PAK4 deficient cells exhibit a reduction in Akt phosphorylation downstream of HGF signalling. These results implicate a novel role for PAK4 within the PI3K pathway via interaction with p85α. Thus, PAK4 could be an essential player in PDAC progression representing an interesting therapeutic opportunity.
Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition
Authors: Hardeman Keisha N. , Peng Chengwei , Paudel Bishal B. , Meyer Christian T. , Luong Thong , Tyson Darren R. , Young Jamey D. , Quaranta Vito , Fessel Joshua P.
Published: February 2017

Dysregulated metabolism can broadly affect therapy resistance by influencing compensatory signaling and expanding proliferation. Given many BRAF-mutated melanoma patients experience disease progression with targeted BRAF inhibitors, we hypothesized therapeutic response is related to tumor metabolic phenotype, and that altering tumor metabolism could change therapeutic outcome. We demonstrated the proliferative kinetics of BRAF-mutated melanoma cells treated with the BRAF inhibitor PLX4720 fall along a spectrum of sensitivity, providing a model system to study the interplay of metabolism and drug sensitivity. We discovered an inverse relationship between glucose availability and sensitivity to BRAF inhibition through characterization of metabolic phenotypes using nearly a dozen metabolic parameters in Principle Component Analysis. Subsequently, we generated rho0 variants that lacked functional mitochondrial respiration and increased glycolytic metabolism. The rho0 cell lines exhibited increased sensitivity to PLX4720 compared to the respiration-competent parental lines. Finally, we utilized the FDA-approved antiretroviral drug zalcitabine to suppress mitochondrial respiration and to force glycolysis in our cell line panel, resulting in increased PLX4720 sensitivity via shifts in EC50 and Hill slope metrics. Our data suggest that forcing tumor glycolysis in melanoma using zalcitabine or other similar approaches may be an adjunct to increase the efficacy of targeted BRAF therapy.
A large-scale survey on sharp injuries among hospital-based healthcare workers in China
Authors: Gao Xiaodong , Hu Bijie , Suo Yao , Lu Qun , Chen Baiyi , Hou Tieying , Qin Jin’ai , Huang Wenzhi , Zong Zhiyong
Published: February 2017

A multi-center survey on sharp injuries (SIs) among hospital-based healthcare workers (HCWs) in seven provinces of China between August and December 2011 was performed. In each province, HCWs from at least 30 hospitals were surveyed by completing a SI report form adapted from the EPINet. The HCWs who declared SIs during the period were interviewed by local infection control practitioners. The survey included 361 hospitals and 206,711 HCWs, most of whom were nurses (47.5%) or doctors (28.4%). In the previous month, 17,506 SI incidents were declared by 13,110 (6.3%) HCWs, corresponding to 1,032 incidents per 1,000 HCWs per year and 121.3 per 100 occupied beds per year. The majority of the SIs was caused by a hollow-bore needle (63.0%). The source patient was identified in 73.4% of all SIs but only 4.4% of all exposures involved a source patient who tested positive for HBV (3.3%), HCV (0.4%) or HIV (0.1%). Only 4.6% of SIs were reported to the infection control team in the hospitals. In conclusion, the rate of SI among HCWs is high in China and SI represents a severe but largely neglected problem. Awareness and safety climate should be promoted to protect the safety of HCWs in China.
Association between C4, C4A, and C4B copy number variations and susceptibility to autoimmune diseases: a meta-analysis
Authors: Li Na , Zhang Jun , Liao Dan , Yang Lu , Wang Yingxiong , Hou Shengping
Published: February 2017

Although several studies have investigated the association between C4, C4A, and C4B gene copy number variations (CNVs) and susceptibility to autoimmune diseases, the results remain inconsistency for those diseases. Thus, in this study, a comprehensive meta-analysis was conducted to assess the role of C4, C4A, and C4B CNVs in autoimmune diseases in different ethnic groups. A total of 16 case-control studies described in 12 articles (8663 cases and 11099 controls) were included in this study. The pooled analyses showed that a low C4 gene copy number (GCN) (<4) was treated as a significant risk factor (odds ratio [OR] = 1.46, 95% confidence interval [CI] = 1.19–1.78) for autoimmune diseases compared with a higher GCN (>4). The pooled statistical results revealed that low C4 (<4) and low C4A (<2) GCNs could be risk factors for systemic lupus erythematosus (SLE) in Caucasian populations. Additionally, the correlation between C4B CNVs and all type of autoimmune diseases could not be confirmed by the current meta-analysis (OR = 1.07, 95% CI = 0.93–1.24). These data suggest that deficiency or absence of C4 and C4A CNVs may cause susceptibility to SLE.
High Sensitivity Terahertz Detection through Large-Area Plasmonic Nano-Antenna Arrays
Authors: Yardimci Nezih Tolga , Jarrahi Mona
Published: February 2017

Plasmonic photoconductive antennas have great promise for increasing responsivity and detection sensitivity of conventional photoconductive detectors in time-domain terahertz imaging and spectroscopy systems. However, operation bandwidth of previously demonstrated plasmonic photoconductive antennas has been limited by bandwidth constraints of their antennas and photoconductor parasitics. Here, we present a powerful technique for realizing broadband terahertz detectors through large-area plasmonic photoconductive nano-antenna arrays. A key novelty that makes the presented terahertz detector superior to the state-of-the art is a specific large-area device geometry that offers a strong interaction between the incident terahertz beam and optical pump at the nanoscale, while maintaining a broad operation bandwidth. The large device active area allows robust operation against optical and terahertz beam misalignments. We demonstrate broadband terahertz detection with signal-to-noise ratio levels as high as 107 dB.
Leukocyte TLR5 deficiency inhibits atherosclerosis by reduced macrophage recruitment and defective T-cell responsiveness
Authors: Ellenbroek Guilielmus H.J.M. , van Puijvelde Gijs H.M. , Anas Adam A. , Bot Martine , Asbach Miriam , Schoneveld Arjan , van Santbrink Peter J. , Foks Amanda C. , Timmers Leo , Doevendans Pieter A. , Pasterkamp Gerard , Hoefer Imo E. , van der Poll Tom , Kuiper Johan , de Jager Saskia C.A.
Published: February 2017

Toll-like receptors (TLR) provide a critical link between innate and adaptive immunity, both important players in atherosclerosis. Since evidence for the role of TLR5 is lacking, we aimed to establish this in the immune axis of atherosclerosis. We assessed the effect of the TLR5-specific ligand Flagellin on macrophage maturation and T-cell polarisation. Next, we generated TLR5−/−LDLr−/− chimeras to study the effect of hematopoietic TLR5 deficiency on atherosclerosis formation. Flagellin stimulation did not influence wildtype or TLR5−/− macrophage maturation. Only in wildtype macrophages, Flagellin exposure increased MCP-1 and IL6 expression. Flagellin alone reduced T-helper 1 proliferation, which was completely overruled in the presence of T-cell receptor activation. In vivo, hematopoietic TLR5 deficiency attenuated atherosclerotic lesion formation by ≈25% (1030*103 ± 63*103 vs. 792*103 ± 61*103 μm2; p = 0.013) and decreased macrophage area (81.3 ± 12.0 vs. 44.2 ± 6.6 μm2; p = 0.011). In TLR5−/− chimeric mice, we observed lower IL6 plasma levels (36.4 ± 5.6 vs. 15.1 ± 2.2 pg/mL; p = 0.003), lower (activated) splenic CD4+ T-cell content (32.3 ± 2.1 vs. 21.0 ± 1.2%; p = 0.0018), accompanied by impaired T-cell proliferative responses. In conclusion, hematopoietic TLR5 deficiency inhibits atherosclerotic lesion formation by attenuated macrophage accumulation and defective T-cell responsiveness.
In situ observation of macroscopic phase separation in cobalt hexacyanoferrate film
Authors: Takachi Masamitsu , Moritomo Yutaka
Published: February 2017

Lithium-ion secondary batteries (LIBs) store electric energy via Li+ deintercalation from cathode materials. The Li+ deintercalation frequently drives a first-order phase transition of the cathode material as a result of the Li-ordering or Li-concentration effect and causes a phase separation (PS) into the Li-rich and Li-poor phases. Here, we performed an in situ microscopic investigation of the PS dynamics in thin films of cobalt hexacyanoferrate, LixCo[Fe(CN)6]0.9, against Li+ deintercalation. The thick film (d = 1.5 μm) shows a characteristic macroscopic PS of several tens of μm into the green (Li1.6Co[Fe(CN)6]0.9) and black (Li.6Co[Fe(CN)6]0.9) phases in the x range of 1.0 < x < 1.6. Reflecting the substrate strain, the thin film (d = 0.5 μm) shows no trace of the PS in the entire x region. Our observation suggests that the macroscopic PS plays a significant role in the charge/discharge dynamics of the cathode.
Octreotide Attenuates Acute Kidney Injury after Hepatic Ischemia and Reperfusion by Enhancing Autophagy
Authors: Sun Huiping , Zou Shuangfa , Candiotti Keith A. , Peng Yanhua , Zhang Qinya , Xiao Weiqiang , Wen Yiyun , wu Jiao , Yang Jinfeng
Published: February 2017

Octreotide exerts a protective effect in hepatic ischemia-reperfusion (HIR) injury. However, whether octreotide preconditioning could also reduce acute kidney injury (AKI) after HIR is unknown. This study was designed to investigate the role of octreotide in AKI after HIR. Male Sprague-Dawley rats were pretreated with octreotide or octreotide combined with 3-methyladenine (autophagy inhibitor, 3MA). Plasma creatinine, inflammation markers (e.g., TNF-α and IL-6 etc.), apoptosis, autophagy and phosphorylation of protein kinase B/mammalian target of rapamycin/p70 ribosomal S6 kinase (Akt/mTOR/p70S6K) in the kidney were measured after 60 minutes of liver ischemia and 24 hours of reperfusion for each rat. Octreotide pretreatment significantly preserved renal function and reduced the severity of renal injury. Moreover, octreotide alleviated inflammation and apoptosis in the kidney after HIR. Additionally, octreotide induced autophagy and autophagy inhibition with 3MA markedly reversed the renoprotective, anti-inflammatory and anti-apoptotic effects of octreotide after HIR. Finally, octreotide abrogated the activation of phosphorylation of Akt, mTOR and p70S6K in the kidney after HIR. Our results indicate that octreotide reduced renal injury after HIR due to its induction of autophagy. The enhancement of autophagy may be potentially linked to the octreotide mediated Akt/mTOR/p70S6K pathway deactivation and reduction of kidney inflammation and apoptosis after HIR.
Ontogenetic loops in habitat use highlight the importance of littoral habitats for early life-stages of oceanic fishes in temperate waters
Authors: Polte Patrick , Kotterba Paul , Moll Dorothee , von Nordheim Lena
Published: February 2017

General concepts of larval fish ecology in temperate oceans predominantly associate dispersal and survival to exogenous mechanisms such as passive drift along ocean currents. However, for tropical reef fish larvae and species in inland freshwater systems behavioural aspects of habitat selection are evidently important components of dispersal. This study is focused on larval Atlantic herring (Clupea harengus) distribution in a Baltic Sea retention area, free of lunar tides and directed current regimes, considered as a natural mesocosm. A Lorenz curve originally applied in socio-economics to describe demographic income distribution was adapted to a 20 year time-series of weekly larval herring distribution, revealing size-dependent spatial homogeneity. Additional quantitative sampling of distinct larval development stages across pelagic and littoral areas uncovered a loop in habitat use during larval ontogeny, revealing a key role of shallow littoral waters. With increasing rates of coastal change, our findings emphasize the importance of the littoral zone when considering reproduction of pelagic, ocean-going fish species; highlighting a need for more sensitive management of regional coastal zones.
Structural environment built by AKAP12+ colon mesenchymal cells drives M2 macrophages during inflammation recovery
Authors: Yang Jun-Mo , Lee Hye Shin , Seo Ji Hae , Park Ji-Hyeon , Gelman Irwin H. , Lo Eng H. , Kim Kyu-Won
Published: February 2017

Macrophages exhibit phenotypic plasticity, as they have the ability to switch their functional phenotypes during inflammation and recovery. Simultaneously, the mechanical environment actively changes. However, how these dynamic alterations affect the macrophage phenotype is unknown. Here, we observed that the extracellular matrix (ECM) constructed by AKAP12+ colon mesenchymal cells (CMCs) generated M2 macrophages by regulating their shape during recovery. Notably, rounded macrophages were present in the linear and loose ECM of inflamed colons and polarized to the M1 phenotype. In contrast, ramified macrophages emerged in the contracted ECM of recovering colons and mainly expressed M2 macrophage markers. These contracted structures were not observed in the inflamed colons of AKAP12 knockout (KO) mice. Consequently, the proportion of M2 macrophages in inflamed colons was lower in AKAP12 KO mice than in WT mice. In addition, clinical symptoms and histological damage were more severe in AKAP12 KO mice than in WT mice. In experimentally remodeled collagen gels, WT CMCs drove the formation of a more compacted structure than AKAP12 KO CMCs, which promoted the polarization of macrophages toward an M2 phenotype. These results demonstrated that tissue contraction during recovery provides macrophages with the physical cues that drive M2 polarization.
In Vitro Characterization and Concerted Function of Three Core Enzymes of a Glycyl Radical Enzyme - Associated Bacterial Microcompartment
Authors: Zarzycki Jan , Sutter Markus , Cortina Niña Socorro , Erb Tobias J. , Kerfeld Cheryl A.
Published: February 2017

Many bacteria encode proteinaceous bacterial microcompartments (BMCs) that encapsulate sequential enzymatic reactions of diverse metabolic pathways. Well-characterized BMCs include carboxysomes for CO2-fixation, and propanediol- and ethanolamine-utilizing microcompartments that contain B12-dependent enzymes. Genes required to form BMCs are typically organized in gene clusters, which promoted their distribution across phyla by horizontal gene transfer. Recently, BMCs associated with glycyl radical enzymes (GREs) were discovered; these are widespread and comprise at least three functionally distinct types. Previously, we predicted one type of these GRE-associated microcompartments (GRMs) represents a B12-independent propanediol-utilizing BMC. Here we functionally and structurally characterize enzymes of the GRM of Rhodopseudomonas palustris BisB18 and demonstrate their concerted function in vitro. The GRM signature enzyme, the GRE, is a dedicated 1,2-propanediol dehydratase with a new type of intramolecular encapsulation peptide. It forms a complex with its activating enzyme and, in conjunction with an aldehyde dehydrogenase, converts 1,2-propanediol to propionyl-CoA. Notably, homologous GRMs are also encoded in pathogenic Escherichia coli strains. Our high-resolution crystal structures of the aldehyde dehydrogenase lead to a revised reaction mechanism. The successful in vitro reconstitution of a part of the GRM metabolism provides insights into the metabolic function and steps in the assembly of this BMC.
New evidence from China for the nature of the pterosaur evolutionary transition
Authors: Wang Xiaoli , Jiang Shunxing , Zhang Junqiang , Cheng Xin , Yu Xuefeng , Li Yameng , Wei Guangjin , Wang Xiaolin
Published: February 2017

Pterosaurs are extinct flying reptiles, the first vertebrates to achieve powered flight. Our understanding of the evolutionary transition between basal, predominantly long-tailed forms to derived short-tailed pterodactyloids remained poor until the discovery ofWukongopterusandDarwinopterusin western Liaoning, China. In this paper we report on a new genus and species,Douzhanopterus zhengi, that has a reduced tail, 173% the length of the humerus, and a reduced fifth pedal digit, whose first phalange is ca. 20% the length of metatarsal III, both unique characters to Monofenestra. The morphological comparisons and phylogenetic analysis presented in this paper demonstrate thatDouzhanopterusis the sister group to the ‘Painten pro-pterodactyloid’ and the Pterodactyloidea, reducing the evolutionary gap between long- and short-tailed pterosaurs.
Polymorphisms of toll-like receptors 2 and 9 and severity and prognosis of bacterial meningitis in Chinese children
Authors: Zhang Pingping , Zhang Nan , Liu Linlin , Zheng Kai , Zhu Liang , Zhu Junping , Cao Lina , Jiang Yiyuan , Liu Gang , He Qiushui
Published: February 2017

Toll-like receptors (TLRs) play a crucial role in innate immunity, protecting the host from bacterial pathogens. We investigated whether bacterial meningitis (BM) in children was associated with gene polymorphisms in TLR2 (rs3804099), TLR3 (rs3775291 and rs3775290) and TLR9 (rs352139 and rs352140). Blood samples were taken from 218 child patients with confirmed BM and 330 healthy adult controls (HC) and polymorphisms of these genes were analyzed by PCR-based sequencing. For TLR2 rs3804099, frequencies of the minor allele C were markedly higher in patients with severe BM (defined as CSF glucose concentration ≤ 1.5 mmol/L and seizures) than those without (43.5% and 40.1% vs. 30.1% and 29.1%, p = 0.008 and p = 0.016, respectively). For TLR9 rs352139, patients who carried genotype AA and minor allele A developed seizures less often than those without (OR = 0.289, p = 0.003 and OR = 0.568, p = 0.004, respectively). However, for TLR9 rs352140, patients who carried genotype TT and minor allele T developed seizures more often than those without (OR = 3.385, p = 0.004 and OR = 1.767, p = 0.004, respectively). Our finding suggested that genetic variations in TLR2 and TLR9 are associated with severity and prognosis of bacterial meningitis in Chinese children. However, the results should be interpreted with caution since the number of subjects included was limited.