bluuebunny/crossref_metadata_2025 huggingface dataset:
Probing the Intramolecular Metal‐Selenoether Interaction in a Bis(iminosemiquinone)copper(II) Compound
Authors: Bubrin Martina , Paretzki Alexa , Hübner Ralph , Beyer Katharina , Schwederski Brigitte , Neugebauer Petr , Záliš Stanislav , Kaim Wolfgang
Published: October 2017

The selenoether compound [Cu(QSeMe)2] [H2QSeMe = 4,6‐di‐tert‐butyl‐2‐(2‐methylselenophenyl)aminophenol] exhibits solvate‐dependent NCuO/OCuN twisting (24° and 33°) and very weak copper–chalcogen interactions (3.30–3.55 Å) in the crystal. Structural studies as well as EPR and magnetic measurements confirm a bis(iminosemiquinone)copper(II) configuration with one ligand‐based spin in the S = ½ ground state. A spin up‐down‐up sequence is thus inferred for the (Q•–)–CuII–(Q•–) three‐spin system. UV/Vis/NIR spectroelectrochemistry in CH2Cl2/0.1 M Bu4NPF6 reveals a broad ligand‐to‐ligand intervalence charge transfer (Q2– → Q•–) band at 1910 nm for the monoanion whereas the stepwise two‐electron oxidation leads to loss of intensity in the near infrared region. DFT calculations of structure, spin density, and electronic transitions were performed to confirm the assignments of oxidation states and absorption features.
Russian soft power in Ukraine: A structural perspective
Authors: Cheskin Ammon
Published: October 2017

In this article, I adopt a structural approach to Russian soft power, switching focus from the supposed agent of power (Russia), towards the subjects of power (Ukrainians). I outline the applicability of this approach to empirical studies into soft power, demonstrating how soft power can be examined from bottom-up, discursively-focused perspectives.

The empirical analysis then traces how Ukrainians (do not) link their self-identities to discursive understanding of “Russia”. Reviewing recent insights into the relationship between soft power and affect, I argue that Ukrainians’ cultural, historical and linguistic ties with Russia often lack necessary emotional force to generate meaningful soft power.
Is acetaminophen safe in pregnancy?
Authors: Toda Katsuhiro
Published: October 2017

Graphical Abstract
Making and Breaking Microliths: A Middle Mesolithic Site at Asfordby, Leicestershire
Authors: Cooper Lynden P. , Jarvis Wayne , Bayliss Alex , Beamish Matthew G. , Bronk Ramsey Christopher , Browning Jennifer , Brettell Rhea , Cook Gordon , Evans Adrian , Heron Carl , Macphail Richard
Published: October 2017

Archaeological fieldwork preceding housing development revealed a Mesolithic site in a primary context. A central hearth was evident from a cluster of calcined flint and bone, the latter producing a modelled date for the start of occupation at 8220–7840 calbcand ending at 7960–7530 calbc(95% probability). The principal activity was the knapping of bladelets, the blanks for microlith production. Impact-damaged microliths indicated the re-tooling of hunting weaponry, while microwear analysis of other tools demonstrated hide working and butchery activity at the site. The lithics can be classified as a Honey Hill assemblage type on the basis of distinctive leaf-shaped microlithic points with inverse basal retouch.

Such assemblages have a known concentration in central England and are thought to be temporally intermediate between the conventional British Early and Late Mesolithic periods. The lithic assemblage is compared to other Honey Hill type and related Horsham type assemblages from south-eastern England. Both assemblage types are termed Middle Mesolithic and may be seen as part of wider developments in the late Preboreal and Boreal periods of north-west Europe. Rapid climatic warming at this time saw the northward expansion of deciduous woodland into north-west Europe. Emerging new ecosystems presented changes in resource patterns and the Middle Mesolithic lithic typo-technological developments reflect novel foraging strategies as adaptations to the new opportunities of Boreal forest conditions. While Honey Hill-type assemblages are seen as part of such wider processes their distinctive typological signature attests to autochthonous, regional developments of human groups infilling the landscape. Such cultural insularity may reflect changing social boundaries with reduction in mobility range and physical isolation caused by rising sea level and the creation of the British archipelago.
Taking Newton on tour: the scientific travels of Martin Folkes, 1733–1735
Authors: ROOS ANNA MARIE
Published: October 2017

Martin Folkes (1690–1754) was Newton's protégé, an English antiquary, mathematician, numismatist and astronomer who would in the latter part of his career become simultaneously president of the Royal Society and of the Society of Antiquaries. Folkes took a Grand Tour from March 1733 to September 1735, recording the Italian leg of his journey from Padua to Rome in his journal. This paper examines Folkes's travel diary to analyse his Freemasonry, his intellectual development as a Newtonian and his scientific peregrination. It shows how, in this latter area, how he used metrology to understand not only the aesthetics but also the engineering principles of antique buildings and artefacts, as well as their context and place in the Italian landscape. Using Folkes's diary, his account book of his journey in the Norwich archives, and his correspondence with other natural philosophers such as Francesco Algarotti (1712–1764), Anders Celsius (1701–1744) and Abbé Antonio Schinella Conti (1667–1749), this paper will also demonstrate to what extent Folkes's journey established his reputation as an international broker of Newtonianism, as well as the overall primacy of English scientific instrumentation to Italian virtuosi.
Comparative analysis of effects of dietary arachidonic acid and EPA on growth, tissue fatty acid composition, antioxidant response and lipid metabolism in juvenile grass carp,Ctenopharyngodon idellus
Authors: Tian Jing-jing , Lei Cai-xia , Ji Hong , Kaneko Gen , Zhou Ji-shu , Yu Hai-bo , Li Yang , Yu Er-meng , Xie Jun
Published: October 2017

Four isonitrogenous and isoenergetic purified diets containing free arachidonic acid (ARA) or EPA (control group), 0·30 % ARA, 0·30 % EPA and 0·30 % ARA+EPA (equivalent) were designed to feed juvenile grass carp (10·21 (sd0·10) g) for 10 weeks. Only the EPA group presented better growth performance compared with the control group (P<0·05). Dietary ARA and EPA were incorporated into polar lipids more than non-polar lipids in hepatopancreas but not intraperitoneal fat (IPF) tissue. Fish fed ARA and EPA showed an increase of serum superoxide dismutase and catalase activities, and decrease of glutathione peroxidase activity and malondialdehyde contents (P<0·05). The hepatopancreatic TAG levels decreased both in ARA and EPA groups (P<0·05), accompanied by the decrease of lipoprotein lipase (LPL) activity in the ARA group (P<0·05). Fatty acid synthase (FAS), diacylglycerolO-acyltransferase andapoEgene expression in the hepatopancreas decreased in fish fed ARA and EPA, but only the ARA group exhibited increased mRNA level of adipose TAG lipase (ATGL) (P<0·05). Decreased IPF index and adipocyte sizes were found in the ARA group (P<0·05). Meanwhile, the ARA group showed decreased expression levels of adipogenic genes CCAAT enhancer-binding proteinα,LPLandFAS, and increased levels of the lipid catabolic genesPPARα,ATGL, hormone-sensitive lipase and carnitine palmitoyltransferase 1 (CPT-1) in IPF, whereas the EPA group only increasedPPARαandCPT-1mRNA expression and showed less levels than the ARA group. Overall, dietary EPA is beneficial to the growth performance, whereas ARA is more potent in inducing lipolysis and inhibiting adipogenesis, especially in IPF. Meanwhile, dietary ARA and EPA showed the similar preference in esterification and the improvement in antioxidant response.
Toenail selenium levels and prevalence of dyslipidaemia among Korean adults
Authors: Jang Jiyoung , Morris J. Steven , Park Kyong
Published: October 2017

Multiple studies have elucidated the antioxidant properties of Se, which are now well known among the nutrition and biomedical science communities. Recently, considerable interest has been focused on the possible association between Se exposure and risk of metabolic disease, such as lipid dysregulation; however, there is limited epidemiological data on this topic. The present study aimed to investigate associations between toenail Se levels and dyslipidaemia or individual lipid levels, and to examine the effect of dietary supplement use on these associations. We analysed baseline data from a cohort in the Yeungnam area, including 232 men and 269 women. Information on demographic, dietary and lifestyle characteristics was obtained through a self-reported questionnaire. Se levels in toenail specimens were measured using neutron activation analysis. Fasting blood lipid levels were measured during medical examinations. After adjusting for multiple confounding variables, we observed no association between toenail Se levels and dyslipidaemia or individual lipid profiles. However, the association was modified by dietary supplement use. Among the supplement users, higher toenail Se levels were associated with a higher prevalence of lipid dysregulation, whereas non-users exhibited a lower prevalence of lipid dysregulation. Associations between toenail Se levels, lipid levels and dyslipidaemia may be influenced by taking dietary supplements. Future large-scale, prospective cohort studies should be conducted to further evaluate the association between Se levels in the body and metabolic health effects in light of increasing rates of dietary supplement use.
Linguistic and extra-linguistic predictors of mutual intelligibility between Germanic languages
Authors: Gooskens Charlotte , Swarte Femke
Published: October 2017

We report on a large-scale investigation of the mutual intelligibility between five Germanic languages: Danish, Dutch, English, German and Swedish. We tested twenty language combinations using the same uniform methodology, making the results commensurable for the first time. We first tested both written and spoken language by means of cloze tests. Next we calculated linguistic distance at the levels of lexicon, orthography, phonology, morphology and syntax. We also quantified exposure and attitudes towards the test languages. Finally, we carried out a regression analysis to determine the relative importance of these linguistic and extra-linguistic predictors for the mutual intelligibility between Germanic languages. The extra-linguistic predictor exposure was the most significant factor in predicting intelligibility in the Germanic language area. The effect of attitude was very small. Lexical distance, orthographic and phonetic distances were the most important linguistic predictors of intelligibility.
Modeling the impact of orthographic coding on Czech–Polish and Bulgarian–Russian reading intercomprehension
Authors: Stenger Irina , Jágrová Klára , Fischer Andrea , Avgustinova Tania , Klakow Dietrich , Marti Roland
Published: October 2017

Focusing on orthography as a primary linguistic interface in every reading activity, the central research question we address here is how orthographic intelligibility can be measured and predicted between closely related languages. This paper presents methods and findings of modeling orthographic intelligibility in a reading intercomprehension scenario from the information-theoretic perspective. The focus of the study is on two Slavic language pairs: Czech–Polish (West Slavic, using the Latin script) and Bulgarian–Russian (South Slavic and East Slavic, respectively, using the Cyrillic script). In this article, we present computational methods for measuring orthographic distance and orthographic asymmetry by means of the Levenshtein algorithm, conditional entropy and adaptation surprisal method that are expected to predict the influence of orthography on mutual intelligibility in reading.
Perceived similarity between written Estonian and Finnish: Strings of letters or morphological units?
Authors: Kaivapalu Annekatrin , Martin Maisa
Published: October 2017

The distance or similarity between two languages can be objective or actual, i.e. discoverable by the tools and methods of linguists, or perceived by users of the languages. In this article two methods, the Levenshtein Distance (LD), which purports to measure the objective distance, and the Index of Perceived Similarity (IPS), which quantifies language users’ perceptions, are compared. The data are the quantitative results of a test measuring conscious perceptions of similarity between Estonian and Finnish inflectional morphology by Finnish and Estonian native speakers (‘Finns’ and ‘Estonians’) with no knowledge of and exposure to the other (‘target’) language. The results show that Finns see more similarity between Finnish and Estonian than Estonians do. Also the correlations between LD and the perception results of the Finns are statistically significant while the correlations between the LD and the IPS scores of the Estonians are not. Comments by test participants provide insights into the nature of the perceptions of similarity.
The impact of sociodemographic and health-service factors on breast-feeding in sub-Saharan African countries with high diarrhoea mortality
Authors: Ogbo Felix A , Eastwood John , Page Andrew , Efe-Aluta Oniovo , Anago-Amanze Chukwudi , Kadiri Eshioramhe A , Ifegwu Ifegwu K , Woolfenden Sue , Agho Kingsley E
Published: October 2017

Objective

The current study aimed to examine the impact of sociodemographic and health-service factors on breast-feeding in sub-Saharan African (SSA) countries with high diarrhoea mortality.

Design

The study used the most recent and pooled Demographic and Health Survey data sets collected in nine SSA countries with high diarrhoea mortality. Multivariate logistic regression models that adjusted for cluster and sampling weights were used to investigate the association between sociodemographic and health-service factors and breast-feeding in SSA countries.

Setting

Sub-Saharan Africa with high diarrhoea mortality.

Subjects

Children (n 50 975) under 24 months old (Burkina Faso (2010, N 5710); Demographic Republic of Congo (2013, N 6797); Ethiopia (2013, N 4193); Kenya (2014, N 7024); Mali (2013, N 3802); Niger (2013, N 4930); Nigeria (2013, N 11 712); Tanzania (2015, N 3894); and Uganda (2010, N 2913)).

Results

Overall prevalence of exclusive breast-feeding (EBF) and early initiation of breast-feeding (EIBF) was 35 and 44 %, respectively. Uganda, Ethiopia and Tanzania had higher EBF prevalence compared with Nigeria and Niger. Prevalence of EIBF was highest in Mali and lowest in Kenya. Higher educational attainment and frequent health-service visits of mothers (i.e. antenatal care, postnatal care and delivery at a health facility) were associated with EBF and EIBF.

Conclusions

Breast-feeding practices in SSA countries with high diarrhoea mortality varied across geographical regions. To improve breast-feeding behaviours among mothers in SSA countries with high diarrhoea mortality, breast-feeding initiatives and policies should be context-specific, measurable and culturally appropriate, and should focus on all women, particularly mothers from low socio-economic groups with limited health-service access.
Online Publication of Court Decisions in Europe
Authors: van Opijnen Marc , Peruginelli Ginevra , Kefali Eleni , Palmirani Monica
Published: October 2017

Although nowadays most courts publish decisions on the internet, substantial differences exist between European countries regarding such publication. These differences not only pertain to the extent with which judgments are published and anonymised, but also to their metadata, searchability and reusability. This article, written by Marc van Opijnen, Ginevra Peruginelli, Eleni Kefali and Monica Palmirani, contains a synthesis of a comprehensive comparative study on the publication of court decisions within all Member States of the European Union. Specific attention is paid on the legal and policy frameworks governing case law publication, actual practices, data protection issues, Open Data policies as well as the state of play regarding the implementation of the European Case Law Identifier.
Use of Mobile Technologies by Law Students in the Law Library: an Exploratory Study
Authors: Abbas Zaki , MacFarlane Andrew , Robinson Lyn
Published: October 2017

This paper outlines the first part of a wider, two-part study on the information behaviour of law students. The authors are Zaki Abbas, Andrew MacFarlane and Lyn Robinson. The background and motivation for the study have been described in a previous publication1 which reports the results of interviews with three academic law librarians. Our initial work found that although mobile technologies offered benefits to law students seeking information for their academic studies, there was concern from law librarians that the use of electronic resources via both non-mobile and mobile interfaces resulted in a loss of skills required for information retrieval due to the increasing capabilities of electronic resources’ search interfaces. To gain more insight into how law students were using mobile information resources, and to further understand the advantages and disadvantages of such resources, we extended our study to a wider cohort. This second phase, of our first part study, was conducted over two years (2013–2015). During this time, we carried out interviews with thirteen law librarians and fielded both quantitative and qualitative questionnaires to 36 law students. We also conducted a greater review of literature and examined several existing information-seeking models. We used the results of the research from this phase of study, together with the knowledge from the literature to propose a novel information-seeking behaviour (ISB) model for law students. These findings are reported within this paper. The second part of this research will look at expanding our research cohort to cover a wider audience throughout the UK and use a focus group to validate our proposed model. This will be reported in a following paper.
Reflective Learning and After Action Reviews
Authors: Russell Hélène
Published: October 2017

Formalised reflective learning systems are one of the most effective and yet underutilised methods of learning. This article, written by Hélène Russell, aims to give you the tools to use after action reviews (AAR) for your information management (IM) and knowledge management (KM) projects so you can learn from your experiences for greater success in the future and also to lead AAR meetings for other professionals within your organisation, to help increase their experiential learning.
Re-evaluating Legal Citation in a Digital Landscape
Authors: Castan Melissa , Galloway Kate
Published: October 2017

Increasing access to digital works and the proliferation of digital genres has changed the way in which we conceive of information, and particularly legal information, including how it is represented within legal citation practice. This article, written by Melissa Castan and Kate Galloway, contributes to the discourse around legal citation in two ways. It first provides a theoretical justification for citation practice as an element of legal information management crucial to effective scholarship, including knowledge creation and dissemination. Secondly, and based on this theoretical foundation, it identifies the challenges facing existing legal citation practice in the face of new media, new representations of legal scholarship, and new objectives for citation practice. Finally, in this article we distil foundation principles for citation to integrate these diverse elements. To illustrate the application of these principles, the article closes with suggested citation practices designed to enhance the existing framework in this digital landscape.
Genetic and Environmental Relationships Between Depressive and Anxiety Symptoms and Cardiovascular Risk Estimates Among Korean Twins and Families
Authors: Song Yun-Mi , Sung Joohon , Lee Kayoung
Published: October 2017

We aimed to assess shared genetic correlations of depressive and anxiety symptoms with concurrent and future estimated cardiovascular risk (CVR) score in Korean twins and family members. For the relationship with Adult Treatment Panel III CVR estimate in subjects aged 30–74 years (n = 1,059, baseline and follow-up after 3.2 ± 1.2 years), Center for Epidemiological Studies Depression Scale (CES-D) and state and trait anxiety inventory (SAI and TAI) were measured at baseline. A mixed linear model for CVR scores at baseline and follow-up was applied to include depressive and anxiety symptoms, twin and family effects, income, education, alcohol use, exercise, body mass index, and baseline CVR score for follow-up analysis. Higher CES-D scores were associated with higher CVR score at baseline in men, while higher TAI score was associated with higher CVR score at follow-up in women. Heritabilities were 0.245~0.326 for CVR score, 0.320 for CES-D score, 0.367 for TAI score, and 0.482 for SAI score. There were significant common genetic correlations in the relationships of CES-D, TAI, and SAI scores with CVR scores at baseline and follow-up (after adjusting for baseline CV risk score). Shared common environmental correlations were observed in the relationships of CES-D and SAI scores with CVR score at baseline; and SAI score with CVR score at follow-up. In the within-monozygotic twin analysis, there were no associations between CES-D, TAI, and SAI scores, and CVR score. In conclusion, shared genetic and environmental influences were observed in the relationship between depressive and anxiety symptoms with concurrent and future CVR estimates.
Carinata Tolerance to Preemergence and Postemergence Herbicides
Authors: Leon Ramon G. , Ferrell Jason A. , Mulvaney Michael J.
Published: October 2017

Carinata is a new biofuel crop that was recently introduced in the southeastern USA as a winter crop. This crop is competitive after canopy closure, but there is a need for weed control options at earlier growth stages. Field experiments were conducted from 2014 to 2016 to determine the safety of several PRE and POST herbicides in carinata. Pendimethalin at 1080 g ai ha−1 applied preplant incorporated (PPI) and PRE caused no carinata injury, or plant density and yield reductions. S-metolachlor was also safe at 694, 1070, 1390, and 2780 g ai ha−1 applied at PRE, 3 d after planting (DAP) and at the 2- to 6-leaf stage. Flumioxazin at 72 g ai ha−1 applied PRE was highly injurious on carinata preventing its establishment. Among the POST herbicides evaluated, clopyralid at 210 g ae ha1 and clethodim at 136 g ai ha−1 caused minor injury to carinata but did not reduce yield compared to the nontreated control. Acifluorfen at 420 g ai ha−1, bentazon at 840 g ai ha−1, and carfentrazone at 18 g ai ha−1 applied POST to carinata caused 75 to 100% injury. Under stressful conditions (i.e. high summer temperatures) all POST herbicides caused more injury than under more favorable conditions for growth in Florida (i.e. winter). The present study identified pendimethalin, S-metolachlor, clopyralid and clethodim as potential herbicides for weed control in carinata, and flumioxazin, acifluorfen, bentazon, and carfentrazone as herbicides that can be used to control volunteer carinata plants in rotational crops.
Solar Probe Will Approach Sun Closer Than Any Prior Spacecraft
Authors: Showstack Randy
Published: October 2017

Technological improvements, including an advanced thermal protection system and innovative solar arrays, have helped to get this mission off the drawing board.
Treatment with A2A receptor antagonist KW6002 and caffeine intake regulate microglia reactivity and protect retina against transient ischemic damage
Authors: Boia Raquel , Elvas Filipe , Madeira Maria H , Aires Inês D , Rodrigues-Neves Ana C , Tralhão Pedro , Szabó Eszter C , Baqi Younis , Müller Christa E , Tomé Ângelo R , Cunha Rodrigo A , Ambrósio António F , Santiago Ana R
Published: October 2017

Transient retinal ischemia is a major complication of retinal degenerative diseases and contributes to visual impairment and blindness. Evidences indicate that microglia-mediated neuroinflammation has a key role in the neurodegenerative process, prompting the hypothesis that the control of microglia reactivity may afford neuroprotection to the retina against the damage induced by ischemia–reperfusion (I–R). The available therapeutic strategies for retinal degenerative diseases have limited potential, but the blockade of adenosine A2A receptor (A2AR) emerges as candidate strategy. Therefore, we evaluated the therapeutic potential of a selective A2AR antagonist (KW6002) against the damage elicited by I–R. The administration of KW6002 after I–R injury reduced microglia reactivity and inflammatory response and afforded protection to the retina. Moreover, we tested the ability of caffeine, an adenosine receptor antagonist, in mediating protection to the retina in the I–R injury model. We demonstrated that caffeine administration dually regulated microglia reactivity and cell death in the transient retinal ischemic model, depending on the reperfusion time. At 24 h of reperfusion, caffeine increased microglial reactivity, inflammatory response and cell death elicited by I–R. However, at 7 days of reperfusion, caffeine administration decreased microglia reactivity and reduced the levels of proinflammatory cytokines and cell death. Together, these results provide a novel evidence for the use of adenosine A2AR antagonists as potential therapy for retinal ischemic diseases and demonstrate the effect of caffeine on the regulation of microglia-mediated neuroinflammation in the transient ischemic model.
Hispolon suppresses metastasis via autophagic degradation of cathepsin S in cervical cancer cells
Authors: Hsin Min-Chieh , Hsieh Yi-Hsien , Wang Po-Hui , Ko Jiunn-Liang , Hsin I-Lun , Yang Shun-Fa
Published: October 2017

Hispolon, a phenolic compound isolated from Phellinus igniarius, induces apoptosis and anti-tumor effects in cancers. However, the molecular mechanism involved in hispolon-mediated tumor-suppressing activities observed in cervical cancer is poorly characterized. Here, we demonstrated that treatment with hispolon inhibited cell metastasis in two cervical cancer cell lines. In addition, the downregulation of the lysosomal protease Cathepsin S (CTSS) was critical for hispolon-mediated suppression of tumor cell metastasis in both in vitro and in vivo models. Moreover, hispolon induced autophagy, which increased LC3 conversion and acidic vesicular organelle formation. Mechanistically, hispolon inhibited the cell motility of cervical cells through the extracellular signal-regulated kinase (ERK) pathway, and blocking of the ERK pathway reversed autophagy-mediated cell motility and CTSS inhibition. Our results indicate that autophagy is essential for decreasing CTSS activity to inhibit tumor metastasis by hispolon treatment in cervical cancer; this finding provides a new perspective on molecular regulation.
Involvement of miR-451 in resistance to paclitaxel by regulating YWHAZ in breast cancer
Authors: Wang Wenrui , Zhang Lingyu , Wang Yangyang , Ding Yongxing , Chen Tiantian , Wang Yueyue , Wang Haifeng , Li Yu , Duan Kecai , Chen Sulian , Yang Qingling , Chen Changjie
Published: October 2017

MicroRNAs (miRNAs) have been identified as major post-transcriptional regulators of the initiation and progression of human cancers, including breast cancer. However, the detail role of miR-451 has not been fully elucidated in breast cancer. In this study, we aimed to investigate the biological role and molecular mechanisms of miR-451 in drug resistance in breast cancer cell lines and in xenograft model. We show that miR-451 is decreased in human breast cancer specimens and in paclitaxel-resistant (PR) cells. Ectopic expression of miR-451 could inhibit the cell migration and invasion, promoted apoptosis, induced cell-cycle arrest Furthermore, tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ) was identified as a direct target of miR-451. Remarkably, the expression of YWHAZ is inversely correlated with the level of miR-451 in human breast cancer samples. Co-treatment with miR-451 mimics and YWHAZ-siRNA significantly enhanced YWHAZ knockdown in both SKBR3/PR and MCF-7/PR cells Moreover, miR-451 markedly inhibited expression of β-catenin via YWHAZ and subsequently inhibited downstream gene cyclin D1, c-Myc expression. The results of xenograft model in vivo showed that intratumor injection of miR-451 agomir induced a tumor-suppressive effect in SKBR3/PR drug-resistant xenograft model. Taken together, our findings suggested that miR-451 might be considered as important and potential target in paclitaxel-resistant breast cancer treatment.
Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways
Authors: Kumari Puja , Saha Irene , Narayanan Athira , Narayanan Sathish , Takaoka Akinori , Kumar Nachimuthu Senthil , Tailor Prafullakumar , Kumar Himanshu
Published: October 2017

Cancer is a multifactorial disease and virus-mediated carcinogenesis is one of the crucial factors, which is poorly understood. Human cytomegalovirus (HCMV) is a herpesvirus and its components have been evidenced to be associated with cancer of different tissue origin. However, its role in cancer remains unknown. Here, we identified a conserved herpesviral tegument protein known as pUL48 of HCMV, encoding deubiquitinase enzyme, as having a key role in carcinogenesis. We show using deubiquitinase sufficient- and deficient-HCMV that HCMV deubiquitinase is a key in inducing enhanced cellular metabolic activity through upregulation of several anti-apoptotic genes and downregulation of several pro-apoptotic genes expression. Furthermore, HCMV deubiquitinase acquires pro-tumor functions by inhibiting PRR-mediated type I interferon via deubiquitination of TRAF6, TRAF3, IRAK1, IRF7 and STING. Taken together, our results suggest that HCMV infection may promote oncogenesis by inhibiting innate immunity of the host.
Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration
Authors: Racioppi Luigi , Lento William , Huang Wei , Arvai Stephanie , Doan Phuong L , Harris Jeffrey R , Marcon Fernando , Nakaya Helder I , Liu Yaping , Chao Nelson
Published: October 2017

Hematopoietic stem and progenitor cells (HSPCs) are predominantly quiescent in adults, but proliferate in response to bone marrow (BM) injury. Here, we show that deletion of Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) promotes HSPC regeneration and hematopoietic recovery following radiation injury. Using Camkk2-enhanced green fluorescent protein (EGFP) reporter mice, we found that Camkk2 expression is developmentally regulated in HSPC. Deletion of Camkk2 in HSPC results in a significant downregulation of genes affiliated with the quiescent signature. Accordingly, HSPC from Camkk2 null mice have a high proliferative capability when stimulated in vitro in the presence of BM-derived endothelial cells. In addition, Camkk2 null mice are more resistant to radiation injury and show accelerated hematopoietic recovery, enhanced HSPC regeneration and ultimately a prolonged survival following sublethal or lethal total body irradiation. Mechanistically, we propose that CaMKK2 regulates the HSPC response to hematopoietic damage by coupling radiation signaling to activation of the anti-proliferative AMP-activated protein kinase. Finally, we demonstrated that systemic administration of the small molecule CaMKK2 inhibitor, STO-609, to irradiated mice enhanced HSPC recovery and improved survival. These findings identify CaMKK2 as an important regulator of HSPC regeneration and demonstrate CaMKK2 inhibition is a novel approach to promoting hematopoietic recovery after BM injury.
Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice
Authors: Alvarez-Sola Gloria , Uriarte Iker , Latasa Maria U , Jimenez Maddalen , Barcena-Varela Marina , Santamaría Eva , Urtasun Raquel , Rodriguez-Ortigosa Carlos , Prieto Jesús , Corrales Fernando J , Baulies Anna , García-Ruiz Carmen , Fernandez-Checa Jose C , Berraondo Pedro , Fernandez-Barrena Maite G , Berasain Carmen , Avila Matías A
Published: October 2017

The liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short half-life. We developed a chimaeric molecule termed Fibapo in which FGF19 is covalently coupled to apolipoprotein A-I. Fibapo retains FGF19 biological activities but has significantly increased half-life and hepatotropism. Here we evaluated the pro-regenerative activity of Fibapo in two clinically relevant models where liver regeneration may be impaired: acetaminophen (APAP) poisoning, and PH in aged mice. The only approved therapy for APAP intoxication is N-acetylcysteine (NAC) and no drugs are available to stimulate liver regeneration. We demonstrate that Fibapo reduced liver injury and boosted regeneration in APAP-intoxicated mice. Fibapo improved survival of APAP-poisoned mice when given at later time points, when NAC is ineffective. Mechanistically, Fibapo accelerated recovery of hepatic glutathione levels, potentiated cell growth-related pathways and increased functional liver mass. When Fibapo was administered to old mice prior to PH, liver regeneration was markedly increased. The exacerbated injury developing in these mice upon PH was attenuated, and the hepatic biosynthetic capacity was enhanced. Fibapo reversed metabolic and molecular alterations that impede regeneration in aged livers. It reduced liver steatosis and downregulated p21 and hepatocyte nuclear factor 4 α (Hnf4α) levels, whereas it stimulated Foxm1b gene expression. Together our findings indicate that FGF19 variants retaining the metabolic and growth-promoting effects of this enterokine may be valuable for the stimulation of liver regeneration.
Regulation of RIP3 by the transcription factor Sp1 and the epigenetic regulator UHRF1 modulates cancer cell necroptosis
Authors: Yang Chengkui , Li Jun , Yu Lu , Zhang Zili , Xu Feng , Jiang Lang , Zhou Xiuxia , He Sudan
Published: October 2017

Receptor-interacting kinase-3 (RIP3) is a key regulator of necroptosis. It has been shown that the expression of RIP3 is silenced in most cancer cells and tissues due to genomic methylation. However, the regulatory mechanisms controlling RIP3 expression in cancer cells have not been fully elucidated. Here, we report that Sp1, a well-characterized zinc-finger transcription factor, directly regulates RIP3 expression in cancer cells. Knockdown of endogenous Sp1 significantly decreases the transcription of Rip3, thereby further inhibiting necroptosis. The re-expression of Sp1 restores the necroptotic response. In addition, knockdown of epigenetic regulator UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) in RIP3-null cancer cells reduces the methylation level of the Rip3 promoter. This effect is sufficient to trigger the expression of RIP3 in RIP3-null cancer cells. The induced expression of RIP3 by UHRF1 RNAi depends on the presence of Sp1. Remarkably, the ectopic expression of RIP3 in RIP3-null cancer cells results in a decrease in tumor growth in mice. Therefore, our findings offer insights into RIP3 expression control in cancer cells and suggest an inhibitory effect of RIP3 on tumorigenesis.
Long non-coding RNA SNHG20 promotes non-small cell lung cancer cell proliferation and migration by epigenetically silencing of P21 expression
Authors: Chen Zhenyao , Chen Xin , Chen Ping , Yu Shanxun , Nie Fengqi , Lu Binbin , Zhang Te , Zhou Yue , Chen Qinnan , Wei Chenchen , Wang Wei , Wang Zhaoxia
Published: October 2017

Mounting evidence demonstrates that long non-coding RNAs (lncRNAs) are novel transcripts governing multiple biological processes, and their dysregulation is involved in the development and progression of multiple types of cancers. Small Nucleolar RNA Host Gene 20 (SNHG20) is a 2183 bp lncRNA, and its overexpression predicts poor prognosis in colorectal cancer and hepatocellular carcinoma. However, the clinical relevance of SNHG20 and its molecular mechanisms affecting cancer cell phenotype have not been documented. Here, we found that SNHG20 was upregulated in non-small cell lung cancer (NSCLC) tissues compared with normal samples. Higher SNHG20 expression was significantly associated with advanced tumor, lymph node and metastases (TNM) stage and tumor size, as well as poorer overall survival. Moreover, knockdown of SNHG20 repressed NSCLC cell proliferation, migration and induced cell apoptosis. Mechanistic investigations revealed that SNHG20 could interact with EZH2 (enhancer of zeste homolog 2), thereby repressing P21 expression. Furthermore, rescue experiments indicated that SNHG20 functioned as an oncogene partly via repressing p21 in NSCLC cells. Taken together, our findings demonstrate that SNHG20 is a new candidate for use in NSCLC diagnosis, prognosis and therapy.
Relationships between structure, in vivo function and long-range axonal target of cortical pyramidal tract neurons
Authors: Rojas-Piloni Gerardo , Guest Jason M. , Egger Robert , Johnson Andrew S. , Sakmann Bert , Oberlaender Marcel
Published: October 2017

Pyramidal tract neurons (PTs) represent the major output cell type of the neocortex. To investigate principles of how the results of cortical processing are broadcasted to different downstream targets thus requires experimental approaches, which provide access to the in vivo electrophysiology of PTs, whose subcortical target regions are identified. On the example of rat barrel cortex (vS1), we illustrate that retrograde tracer injections into multiple subcortical structures allow identifying the long-range axonal targets of individual in vivo recorded PTs. Here we report that soma depth and dendritic path lengths within each cortical layer of vS1, as well as spiking patterns during both periods of ongoing activity and during sensory stimulation, reflect the respective subcortical target regions of PTs. We show that these cellular properties result in a structure–function parameter space that allows predicting a PT’s subcortical target region, without the need to inject multiple retrograde tracers.
MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells
Authors: Lemaçon Delphine , Jackson Jessica , Quinet Annabel , Brickner Joshua R. , Li Shan , Yazinski Stephanie , You Zhongsheng , Ira Grzegorz , Zou Lee , Mosammaparast Nima , Vindigni Alessandro
Published: October 2017

The breast cancer susceptibility proteins BRCA1 and BRCA2 have emerged as key stabilizing factors for the maintenance of replication fork integrity following replication stress. In their absence, stalled replication forks are extensively degraded by the MRE11 nuclease, leading to chemotherapeutic sensitivity. Here we report that BRCA proteins prevent nucleolytic degradation by protecting replication forks that have undergone fork reversal upon drug treatment. The unprotected regressed arms of reversed forks are the entry point for MRE11 in BRCA-deficient cells. The CtIP protein initiates MRE11-dependent degradation, which is extended by the EXO1 nuclease. Next, we show that the initial limited resection of the regressed arms establishes the substrate for MUS81 in BRCA2-deficient cells. In turn, MUS81 cleavage of regressed forks with a ssDNA tail promotes POLD3-dependent fork rescue. We propose that targeting this pathway may represent a new strategy to modulate BRCA2-deficient cancer cell response to chemotherapeutics that cause fork degradation.
Enrichment of milk with magnesium provides healthier and safer dairy products
Authors: Ben-Ishay Noa , Oknin Hilla , Steinberg Doron , Berkovich Zipi , Reifen Ram , Shemesh Moshe
Published: October 2017

Biofilms on the surfaces of milk-processing equipment are often a major source of contamination of dairy products. Members of the genus Bacillus appear to be among the most commonly found bacteria in dairy farms and processing plants. Bacillus species may thrive in dairy farm equipment and in dairy products since they can form robust biofilms during growth within milk. We found that fortification of milk with magnesium mitigated biofilm formation by Bacillus species, and thus could notably reduce dairy product spoilage. We also show that the mode of action of Mg2+ ions is specific to inhibition of transcription of genes involved in biofilm formation. Our further findings indicate that in the presence of Mg2+ bacterial cells are hypersensitive to the heat pasteurization applied during milk processing. Additionally, we demonstrated that enrichment of milk with magnesium improved technological properties of milk products such as soft cheeses. Finally, we report that there is a notable increase in the intestinal bioavailability potential of magnesium from supplemented milk compared with that from non-supplemented milk.
CETSA quantitatively verifies in vivo target engagement of novel RIPK1 inhibitors in various biospecimens
Authors: Ishii Tsuyoshi , Okai Takuro , Iwatani-Yoshihara Misa , Mochizuki Manabu , Unno Satoko , Kuno Masako , Yoshikawa Masato , Shibata Sachio , Nakakariya Masanori , Yogo Takatoshi , Kawamoto Tomohiro
Published: October 2017

The proof of target engagement (TE) is a key element for evaluating potential investment in drug development. The cellular thermal shift assay (CETSA) is expected to facilitate direct measurement of intracellular TE at all stages of drug development. However, there have been no reports of applying this technology to comprehensive animal and clinical studies. This report demonstrates that CETSA can not only quantitatively evaluate the drug-TE in mouse peripheral blood, but also confirm TE in animal tissues exemplified by using the receptor interacting protein 1 kinase (RIPK1) lead compound we have developed. Our established semi-automated system allows evaluation of the structure-activity relationship using native RIPK1 in culture cell lines, and also enables estimation of drug occupancy ratio in mouse peripheral blood mononuclear cells. Moreover, optimized tissue homogenisation enables monitoring of the in vivo drug-TE in spleen and brain. Our results indicate that CETSA methodology will provide an efficient tool for preclinical and clinical drug development.
Endogenously generated 2-aminoacrylate inhibits motility in Salmonella enterica
Authors: Borchert Andrew J. , Downs Diana M.
Published: October 2017

Members of the broadly distributed Rid/YER057c/UK114 protein family have imine/enamine deaminase activity, notably on 2-aminoacrylate (2AA). Strains of Salmonella enterica, and other organisms lacking RidA, have diverse growth phenotypes, attributed to the accumulation of 2AA. In S. enterica, 2AA inactivates a number of pyridoxal 5’-phosephate(PLP)-dependent enzymes, some of which have been linked to the growth phenotypes of a ridA mutant. This study used transcriptional differences between S. enterica wild-type and ridA strains to explore the breadth of the cellular consequences that resulted from accumulation of 2AA. Accumulation of endogenously generated 2AA in a ridA mutant resulted in lower expression of genes encoding many flagellar assembly components, which led to a motility defect. qRT-PCR results were consistent with the motility phenotype of a ridA mutant resulting from a defect in FlhD4C2 activity. In total, the results of comparative transcriptomics correctly predicted a 2AA-dependent motility defect and identified additional areas of metabolism impacted by the metabolic stress of 2AA in Salmonella enterica. Further, the data emphasized the value of integrating global approaches with biochemical genetic approaches to understand the complex system of microbial metabolism.
Cognition in the field: comparison of reversal learning performance in captive and wild passerines
Authors: Cauchoix M. , Hermer E. , Chaine A. S. , Morand-Ferron J.
Published: October 2017

Animal cognitive abilities have traditionally been studied in the lab, but studying cognition in nature could provide several benefits including reduced stress and reduced impact on life-history traits. However, it is not yet clear to what extent cognitive abilities can be properly measured in the wild. Here we present the first comparison of the cognitive performance of individuals from the same population, assessed using an identical test, but in contrasting contexts: in the wild vs. in controlled captive conditions. We show that free-ranging great tits (Parus major) perform similarly to deprived, captive birds in a successive spatial reversal-learning task using automated operant devices. In both captive and natural conditions, more than half of birds that contacted the device were able to perform at least one spatial reversal. Moreover, both captive and wild birds showed an improvement of performance over successive reversals, with very similar learning curves observed in both contexts for each reversal. Our results suggest that it is possible to study cognitive abilities of wild animals directly in their natural environment in much the same way that we study captive animals. Such methods open numerous possibilities to study and understand the evolution and ecology of cognition in natural populations.
Amyloidogenic motifs revealed by n-gram analysis
Authors: Burdukiewicz Michał , Sobczyk Piotr , Rödiger Stefan , Duda-Madej Anna , Mackiewicz Paweł , Kotulska Małgorzata
Published: October 2017

Amyloids are proteins associated with several clinical disorders, including Alzheimer’s, and Creutzfeldt-Jakob’s. Despite their diversity, all amyloid proteins can undergo aggregation initiated by short segments called hot spots. To find the patterns defining the hot spots, we trained predictors of amyloidogenicity, using n-grams and random forest classifiers. Since the amyloidogenicity may not depend on the exact sequence of amino acids but on their more general properties, we tested 524,284 reduced amino acid alphabets of different lengths (three to six letters) to find the alphabet providing the best performance in cross-validation. The predictor based on this alphabet, called AmyloGram, was benchmarked against the most popular tools for the detection of amyloid peptides using an external data set and obtained the highest values of performance measures (AUC: 0.90, MCC: 0.63). Our results showed sequential patterns in the amyloids which are strongly correlated with hydrophobicity, a tendency to form β-sheets, and lower flexibility of amino acid residues. Among the most informative n-grams of AmyloGram we identified 15 that were previously confirmed experimentally. AmyloGram is available as the web-server: http://smorfland.uni.wroc.pl/shiny/AmyloGram/ and as the R package AmyloGram. R scripts and data used to produce the results of this manuscript are available at http://github.com/michbur/AmyloGramAnalysis.