bluuebunny/crossref_metadata_2025 huggingface dataset:
THE WOMAN TO THE PLOW; AND THE MAN TO THE HEN-ROOST: WIVES, HUSBANDS AND BEST-SELLING BALLADS IN SEVENTEENTH-CENTURY ENGLAND
Authors: Marsh Christopher
Published: November 2018

This paper investigates the representation of marital relations in some of the most successful broadside ballads published in seventeenth-century England. It explains the manner in which these have been selected as part of a funded research project, and it proceeds to question an existing historiographical emphasis on ballads in which marriages were portrayed as under threat due to a combination of wifely failings (scolding, adultery, violence) and husbandly shortcomings (sexual inadequacy, jealousy, weakness). Best-selling ballads were much more sympathetic to married women in particular than we might have expected, and the implications of this for our understanding of the ballad market and early modern culture more generally may be significant. These ballads, it is argued, were often aimed particularly at women, and they grew out of an interesting negotiation between male didacticism and female taste. Throughout the paper, an attempt is made to understand ballads as songs and visual artefacts, rather than merely as texts.
‘WHO THE HELL ARE ORDINARY PEOPLE?’ ORDINARINESS AS A CATEGORY OF HISTORICAL ANALYSIS
Authors: Langhamer Claire
Published: November 2018

Ordinariness was a frequently deployed category in the political debates of 2016. According to one political leader, the vote for Brexit was ‘a victory for ordinary, decent people who've taken on the establishment and won’. In making this claim, Nigel Farage sought to link a dramatic political moment with a powerful, yet conveniently nebulous, construction of the ordinary person. In this paper, I want to historicise recent use of the category by returning to another moment when ordinariness held deep political significance: the years immediately following the Second World War. I will explore the range of values, styles and specific behaviours that gave meaning to the claim to be ordinary; consider the relationship between ordinariness, everyday experience and knowledge; and map the political work ordinariness was called upon to perform. I argue that the immediate post-war period was a critical moment in the formation of ordinariness as a social category, an affective category, a moral category, a consumerist category and, above all, a political category. Crucially, ordinariness itself became a form of expertise, a finding that complicates our understanding of the ‘meritocratic moment’.
ANTI-SOCIALISM, LIBERALISM AND INDIVIDUALISM: RETHINKING THE REALIGNMENT OF SCOTTISH POLITICS, 1945–1970
Authors: Petrie Malcolm
Published: November 2018

This paper presents an alternative interpretation of Scottish politics between 1945 and 1970, a period that witnessed the decline of a once-powerful Unionist tradition, the revival of Liberalism and the rise of the Scottish National party (SNP). While existing accounts have focused principally upon social and economic factors, this study foregrounds the role of ideology and rhetoric. During the 1940s and early 1950s, Scottish Unionists were, like their Conservative colleagues elsewhere in Britain, able to construct a popular, but essentially negative, anti-socialist coalition that prioritised the defence of individual liberty. This electoral alliance, defined by opposition to Labour's programme of nationalisation and expressed via an individualist idiom, was able to attract broad support; it was, however, always provisional, and proved increasingly difficult to sustain after the Conservative party returned to office in 1951. It was, this paper suggests, the fragmenting of this anti-socialist coalition in the late 1950s and early 1960s that created the opportunity for both the Liberals and the SNP to present alternative renderings of this individualist appeal, and to emerge as credible political alternatives. Crucially, by the 1960s, individual liberty was beginning to be understood in constitutional rather than economic terms.
Clapham revisited: the decline of the Norwich worsted industry (c. 1700–1820)
Authors: Sugden Keith
Published: November 2018

This study utilises several sources of male occupational data to track the decline of the Norwich worsted industry, c. 1700–1820. The data show that the industry began to fall away during the second half of the eighteenth century, if not sooner, and earlier than has been previously realised. The transfer of the industry to the north of England began before the introduction of steam-powered spinning or weaving. Market competition, notably from Lancashire printed fustians and cottons, and the loss of export trade through war, were the likely causal factors.
Kick-Starting Female Careers
Authors: Hentschel Tanja , Horvath Lisa Kristina , Peus Claudia , Sczesny Sabine
Published: November 2018

Abstract. Entrepreneurship programs often aim at increasing women’s lower entrepreneurial activities. We investigate how advertisements for entrepreneurship programs can be designed to increase women’s application intentions. Results of an experiment with 156 women showed that women indicate (1) lower self-ascribed fit to and interest in the program after viewing a male-typed image (compared to a gender-neutral or female-typed image) in the advertisement; and (2) lower self-ascribed fit to and interest in the program as well as lower application intentions if the German masculine linguistic form of the term “entrepreneur” (compared to the gender-fair word pair “female and male entrepreneur”) is used in the recruitment advertisement. Women’s reactions are most negative when both a male-typed image and the masculine linguistic form appear in the advertisement. Self-ascribed fit and program interest mediate the relationship of advertisement characteristics on application intentions.
Suppressive effect of syndecan ectodomains and N-desulfated heparins on osteoclastogenesis via direct binding to macrophage-colony stimulating factor
Authors: Kim Jin-Man , Lee Kyunghee , Kim Mi Yeong , Shin Hong-In , Jeong Daewon
Published: November 2018

Syndecans, a family of cell surface heparan sulfate proteoglycans, regulate cell differentiation via binding of their heparan sulfate chains to growth factors and cytokines and play a role in tumor growth and progression, wound repair, and intestinal mucosal damage. However, the functional and mechanistic roles of syndecans in osteoclast differentiation and bone metabolism are yet unclear. Here, we demonstrated that post-translationally glycosylated ectodomains of syndecan-1 to 4 obtained from mammalian cells efficiently suppressed osteoclast differentiation compared to those obtained from Escherichia coli with no systems for glycosylation. A concomitant decrease in the expression of osteoclast markers such as nuclear factor of activated T cells 1 (NFATc1), c-Fos, and ATP6V0D2 was observed. In addition, heparan sulfate and selectively N-desulfated heparin derivatives with 2-O- and 6-O-sulfate groups and no anticoagulant activity in blood inhibited osteoclast differentiation. The inhibitory effects of syndecan ectodomains, heparan sulfate, and N-desulfated heparin derivatives on osteoclast differentiation were attributed to their direct binding to the macrophage-colony stimulating factor (M-CSF), resulting in the blocking of M-CSF-mediated downstream signals such as extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), p38, and Akt. Furthermore, mice injected with syndecan ectodomains, heparan sulfate, and N-desulfated heparin derivatives into periosteal regions of calvaria showed reduction in the formation of tartrate-resistant acid phosphatase (TRAP)-positive mature osteoclasts on the calvarial bone surface, thereby exhibiting decreased bone resorption. Together, these results revealed a novel role of heparan sulfate chains of syndecan ectodomains in the regulation of osteoclast differentiation.
Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis
Authors: Moon Seungtae , Im Sun-Kyoung , Kim Nackhyoung , Youn Hyesook , Park Ui-Hyun , Kim Joo-Yeon , Kim A.-Reum , An So-Jung , Kim Ji-Hoon , Sun Woong , Hwang Jin-Taek , Kim Eun-Joo , Um Soo-Jong
Published: November 2018

Although additional sex combs-like 1 (ASXL1) has been extensively described in hematologic malignancies, little is known about the molecular role of ASXL1 in organ development. Here, we show that Asxl1 ablation in mice results in postnatal lethality due to cyanosis, a respiratory failure. This lung defect is likely caused by higher proliferative potential and reduced expression of surfactant proteins, leading to reduced air space and defective lung maturation. By microarray analysis, we identified E2F1-responsive genes, including Nmyc, as targets repressed by Asxl1. Nmyc and Asxl1 are reciprocally expressed during the fetal development of normal mouse lungs, whereas Nmyc downregulation is impaired in Asxl1-deficient lungs. Together with E2F1 and ASXL1, host cell factor 1 (HCF-1), purified as an Asxl1-bound protein, is recruited to the E2F1-binding site of the Nmyc promoter. The interaction occurs between the C-terminal region of Asxl1 and the N-terminal Kelch domain of HCF-1. Trimethylation (me3) of histone H3 lysine 27 (H3K27) is enriched in the Nmyc promoter upon Asxl1 overexpression, whereas it is downregulated in Asxl1-deleted lung and -depleted A549 cells, similar to H3K9me3, another repressive histone marker. Overall, these findings suggest that Asxl1 modulates proliferation of lung epithelial cells via the epigenetic repression of Nmyc expression, deficiency of which may cause hyperplasia, leading to dyspnea.
Extracellular and ER-stored Ca2+ contribute to BIRD-2-induced cell death in diffuse large B-cell lymphoma cells
Authors: Bittremieux Mart , La Rovere Rita M. , Schuermans Marleen , Luyten Tomas , Mikoshiba Katsuhiko , Vangheluwe Peter , Parys Jan B. , Bultynck Geert
Published: November 2018

The anti-apoptotic protein Bcl-2 is upregulated in several cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). In a subset of these cancer cells, Bcl-2 blocks Ca2+-mediated apoptosis by suppressing the function of inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) located at the endoplasmic reticulum (ER). A peptide tool, called Bcl-2/IP3 receptor disruptor-2 (BIRD-2), was developed to disrupt Bcl-2/IP3R complexes, triggering pro-apoptotic Ca2+ signals and killing Bcl-2-dependent cancer cells. In DLBCL cells, BIRD-2 sensitivity depended on the expression level of IP3R2 channels and constitutive IP3 signaling downstream of the B-cell receptor. However, other cellular pathways probably also contribute to BIRD-2-provoked cell death. Here, we examined whether BIRD-2-induced apoptosis depended on extracellular Ca2+ and more particularly on store-operated Ca2+ entry (SOCE), a Ca2+-influx pathway activated upon ER-store depletion. Excitingly, DPB162-AE, a SOCE inhibitor, suppressed BIRD-2-induced cell death in DLBCL cells. However, DPB162-AE not only inhibits SOCE but also depletes the ER Ca2+ store. Treatment of the cells with YM-58483 and GSK-7975A, two selective SOCE inhibitors, did not protect against BIRD-2-induced apoptosis. Similar data were obtained by knocking down STIM1 using small interfering RNA. Yet, extracellular Ca2+ contributed to BIRD-2 sensitivity in DLBCL, since the extracellular Ca2+ buffer ethylene glycol tetraacetic acid (EGTA) blunted BIRD-2-triggered apoptosis. The protective effects observed with DPB162-AE are likely due to ER Ca2+-store depletion, since a similar protective effect could be obtained using the sarco/endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin. Thus, both the ER Ca2+-store content and extracellular Ca2+, but not SOCE, are critical factors underlying BIRD-2-provoked cell death.
Structural basis for the second step of group II intron splicing
Authors: Chan Russell T. , Peters Jessica K. , Robart Aaron R. , Wiryaman Timothy , Rajashankar Kanagalaghatta R. , Toor Navtej
Published: November 2018

The group II intron and the spliceosome share a common active site architecture and are thought to be evolutionarily related. Here we report the 3.7 Å crystal structure of a eukaryotic group II intron in the lariat-3′ exon form, immediately preceding the second step of splicing, analogous to the spliceosomal P complex. This structure reveals the location of the intact 3′ splice site within the catalytic core of the group II intron. The 3′-OH of the 5′ exon is positioned in close proximity to the 3′ splice site for nucleophilic attack and exon ligation. The active site undergoes conformational rearrangements with the catalytic triplex having different configurations before and after the second step of splicing. We describe a complete model for the second step of group II intron splicing that incorporates a dynamic catalytic triplex being responsible for creating the binding pocket for 3′ splice site capture.
Modifying the cancer-immune set point using vaccinia virus expressing re-designed interleukin-2
Authors: Liu Zuqiang , Ge Yan , Wang Haiyan , Ma Congrong , Feist Mathilde , Ju Songguang , Guo Z. Sheng , Bartlett David L.
Published: November 2018

The complex immune tumour microenvironment requires an equally complex immunotherapy approach, especially when the cancer-immune set point is non-inflamed. Oncolytic viruses expressing immune activating cytokines might optimally modify the immune microenvironment and improve the antitumour effects. In this study, we have explored a variety of IL-2 constructs expressed by a tumour-selective oncolytic vaccinia virus, designed to maintain IL-2 in the tumour microenvironment to reduce systemic toxicity. An IL-2 construct combining a glycosylphosphatidylinositol (GPI) anchor with a rigid peptide linker leads to functional IL-2 expression on the tumour cell surface and in the tumour microenvironment. This virus construct effectively modifies the cancer-immune set point and treats a variety of murine tumour models with no toxic side effects. In combination with PD-1/PD-L1 blockade this virus cures most of the mice with a high tumour burden. This combination represents a treatment for cancers which are to date unresponsive to immunotherapy.
Bi-directional signaling by membrane-bound KitL induces proliferation and coordinates thymic endothelial cell and thymocyte expansion
Authors: Buono Mario , Thézénas Marie-Laëtitia , Ceroni Alessandro , Fischer Roman , Nerlov Claus
Published: November 2018

The ligand for the c-Kit receptor, KitL, exists as a membrane-associated (mKitL) and a soluble form (sKitL). KitL functions outside c-Kit activation have not been identified. We show that co-culture of c-Kit– and mKitL–expressing NIH3T3 cells results in signaling through mKitL: c-Kit–bound mKitL recruits calcium-modulating cyclophilin ligand (CAML) to selectively activate Akt, leading to CREB phosphorylation, mTOR pathway activation, and increased cell proliferation. Activation of mKitL in thymic vascular endothelial cells (VECs) induces mKitL- and Akt-dependent proliferation, and genetic ablation of mKitL in thymic VECs blocks their c-Kit responsiveness and proliferation during neonatal thymic expansion. Therefore, mKitL–c-Kit form a bi-directional signaling complex that acts in the developing thymus to coordinate thymic VEC and early thymic progenitor (ETP) expansion by simultaneously promoting ETP survival and VEC proliferation. This mechanism may be relevant to both normal tissues and malignant tumors that depend on KitL–c-Kit signaling for their proliferation.
Membrane association and remodeling by intraflagellar transport protein IFT172
Authors: Wang Qianmin , Taschner Michael , Ganzinger Kristina A. , Kelley Charlotte , Villasenor Alethia , Heymann Michael , Schwille Petra , Lorentzen Esben , Mizuno Naoko
Published: November 2018

The cilium is an organelle used for motility and cellular signaling. Intraflagellar transport (IFT) is a process to move ciliary building blocks and signaling components into the cilium. How IFT controls the movement of ciliary components is currently poorly understood. IFT172 is the largest IFT subunit essential for ciliogenesis. Due to its large size, the characterization of IFT172 has been challenging. Using giant unilamellar vesicles (GUVs), we show that IFT172 is a membrane-interacting protein with the ability to remodel large membranes into small vesicles. Purified IFT172 has an architecture of two globular domains with a long rod-like protrusion, resembling the domain organization of coatomer proteins such as COPI-II or clathrin. IFT172 adopts two different conformations that can be manipulated by lipids or detergents: 1) an extended elongated conformation and 2) a globular closed architecture. Interestingly, the association of IFT172 with membranes is mutually exclusive with IFT57, implicating multiple functions for IFT172 within IFT.
Southern Hemisphere forcing of South Asian monsoon precipitation over the past ~1 million years
Authors: Gebregiorgis D. , Hathorne E. C. , Giosan L. , Clemens S. , Nürnberg D. , Frank M.
Published: November 2018

The orbital-scale timing of South Asian monsoon (SAM) precipitation is poorly understood. Here we present new SST and seawater δ18O (δ18Osw) records from the Bay of Bengal, the core convective region of the South Asian monsoon, over the past 1 million years. Our records reveal that SAM precipitation peaked in the precession band ~9 kyrs after Northern Hemisphere summer insolation maxima, in phase with records of SAM winds in the Arabian Sea and eastern Indian Ocean. Precession-band variance, however, accounts for ~30% of the total variance of SAM precipitation while it was either absent or dominant in records of the East Asian monsoon (EAM). This and the observation that SAM precipitation was phase locked with obliquity minima and was sensitive to Southern Hemisphere warming provides clear evidence that SAM and EAM precipitation responded differently to orbital forcing and highlights the importance of internal processes forcing monsoon variability.
Electrically induced and detected Néel vector reversal in a collinear antiferromagnet
Authors: Godinho J. , Reichlová H. , Kriegner D. , Novák V. , Olejník K. , Kašpar Z. , Šobáň Z. , Wadley P. , Campion R. P. , Otxoa R. M. , Roy P. E. , Železný J. , Jungwirth T. , Wunderlich J.
Published: November 2018

Antiferromagnets are enriching spintronics research by many favorable properties that include insensitivity to magnetic fields, neuromorphic memory characteristics, and ultra-fast spin dynamics. Designing memory devices with electrical writing and reading is one of the central topics of antiferromagnetic spintronics. So far, such a combined functionality has been demonstrated via 90° reorientations of the Néel vector generated by the current-induced spin orbit torque and sensed by the linear-response anisotropic magnetoresistance. Here we show that in the same antiferromagnetic CuMnAs films as used in these earlier experiments we can also control 180° Néel vector reversals by switching the polarity of the writing current. Moreover, the two stable states with opposite Néel vector orientations in this collinear antiferromagnet can be electrically distinguished by measuring a second-order magnetoresistance effect. We discuss the general magnetic point group symmetries allowing for this electrical readout effect and its specific microscopic origin in CuMnAs.
Structural basis for the recognition of sulfur in phosphorothioated DNA
Authors: Liu Guang , Fu Wencheng , Zhang Zhenyi , He Yao , Yu Hao , Wang Yuli , Wang Xiaolei , Zhao Yi-Lei , Deng Zixin , Wu Geng , He Xinyi
Published: November 2018

There have been very few reports on protein domains that specifically recognize sulfur. Here we present the crystal structure of the sulfur-binding domain (SBD) from the DNA phosphorothioation (PT)-dependent restriction endonuclease ScoMcrA. SBD contains a hydrophobic surface cavity that is formed by the aromatic ring of Y164, the pyrolidine ring of P165, and the non-polar side chains of four other residues that serve as lid, base, and wall of the cavity. The SBD and PT-DNA undergo conformational changes upon binding. The S187RGRR191 loop inserts into the DNA major groove to make contacts with the bases of the GPSGCC core sequence. Mutating key residues of SBD impairs PT-DNA association. More than 1000 sequenced microbial species from fourteen phyla contain SBD homologs. We show that three of these homologs bind PT-DNA in vitro and restrict PT-DNA gene transfer in vivo. These results show that SBD-like PT-DNA readers exist widely in prokaryotes.
Probing molecule-like isolated octahedra via phase stabilization of zero-dimensional cesium lead halide nanocrystals
Authors: Arunkumar Paulraj , Cho Han Bin , Gil Kyeong Hun , Unithrattil Sanjith , Kim Yoon Hwa , Bin Im Won
Published: November 2018

Zero-dimensional (0D) inorganic perovskites have recently emerged as an interesting class of material owing to their intrinsic Pb2+ emission, polaron formation, and large exciton binding energy. They have a unique quantum-confined structure, originating from the complete isolation of octahedra exhibiting single-molecule behavior. Herein, we probe the optical behavior of single-molecule-like isolated octahedra in 0D Cesium lead halide (Cs4PbX6, X = Cl, Br/Cl, Br) nanocrystals through isovalent manganese doping at lead sites. The incorporation of manganese induced phase stabilization of 0D Cs4PbX6 over CsPbX3 by lowering the symmetry of PbX6 via enhanced octahedral distortion. This approach enables the synthesis of CsPbX3 free Cs4PbX6 nanocrystals. A high photoluminescence quantum yield for manganese emission was obtained in colloidal (29%) and solid (21%, powder) forms. These performances can be attributed to structure-induced confinement effects, which enhance the energy transfer from localized host exciton states to Mn2+ dopant within the isolated octahedra.
Divergent trends in functional and phylogenetic structure in reptile communities across Africa
Authors: Ramm Till , Cantalapiedra Juan L. , Wagner Philipp , Penner Johannes , Rödel Mark-Oliver , Müller Johannes
Published: November 2018

Despite extensive research on ecological community compositions, general patterns across large-scale environmental gradients have remained unclear. A widely used explanatory model is the stress dominance hypothesis (SDH), predicting that the relative influence of environmental filtering is greater in stressful habitats while competition is more important in benign environments. Here, we test the SDH using African squamates as a model system to facilitate general predictions on community structures amidst changing global environments. For the first time we investigate changes in functional, phylogenetic and species diversity across continental, environmental gradients within a multidimensional, phylogenetically informed approach. Results suggest that phylogenetic patterns of African squamates were likely shaped by clade-specific biogeographic histories, whereas functional structure reflects SDH predictions. We further detected significant structuring at both local and regional spatial scales, emphasizing the impact of regional-historical processes on local assemblages, and the need for broad conceptual frameworks to detect general patterns of community composition.
Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab
Authors: Chin S. Michael , Kimberlin Christopher R. , Roe-Zurz Zygy , Zhang Pamela , Xu Allison , Liao-Chan Sindy , Sen Debasish , Nager Andrew R. , Oakdale Nicole Schirle , Brown Colleen , Wang Feng , Yang Yuting , Lindquist Kevin , Yeung Yik Andy , Salek-Ardakani Shahram , Chaparro-Riggers Javier
Published: November 2018

4-1BB (CD137,TNFRSF9) is an inducible costimulatory receptor expressed on activated T cells. Clinical trials of two agonist antibodies, utomilumab (PF-05082566) and urelumab (BMS-663513), are ongoing in multiple cancer indications, and both antibodies demonstrate distinct activities in the clinic. To understand these differences, we solved structures of the human 4-1BB/4-1BBL complex, the 4-1BBL trimer alone, and 4-1BB bound to utomilumab or urelumab. The 4-1BB/4-1BBL complex displays a unique interaction between receptor and ligand when compared with other TNF family members. Furthermore, our ligand-only structure differs from previously published data. Utomilumab, a ligand-blocking antibody, binds 4-1BB between CRDs 3 and 4. In contrast, urelumab binds 4-1BB CRD-1, away from the ligand binding site. Finally, cell-based assays demonstrate utomilumab is a milder agonist than urelumab. Collectively, our data provide a deeper understanding of the 4-1BB signaling complex, providing a template for future development of next generation 4-1BB targeted biologics.
Long term but not short term exposure to obesity related microbiota promotes host insulin resistance
Authors: Foley Kevin P. , Zlitni Soumaya , Denou Emmanuel , Duggan Brittany M. , Chan Rebecca W. , Stearns Jennifer C. , Schertzer Jonathan D.
Published: November 2018

The intestinal microbiota and insulin sensitivity are rapidly altered after ingestion of obesogenic diets. We find that changes in the composition of the fecal microbiota precede changes in glucose tolerance when mice are fed obesogenic, low fiber, high fat diets (HFDs). Antibiotics alter glycemia during the first week of certain HFDs, but antibiotics show a more robust improvement in glycemic control in mice with protracted obesity caused by long-term feeding of multiple HFDs. Microbiota transmissible dysglycemia and glucose intolerance only occur when germ-free mice are exposed to obesity-related microbes for more than 45 days. We find that sufficient host exposure time to microbiota derived from HFD-fed mice allows microbial factors to contribute to insulin resistance, independently from increased adiposity in mice. Our results are consistent with intestinal microbiota contributing to chronic insulin resistance and dysglycemia during prolonged obesity, despite rapid diet-induced changes in the taxonomic composition of the fecal microbiota.
Src-transformed cells hijack mitosis to extrude from the epithelium
Authors: Anton Katarzyna A. , Kajita Mihoko , Narumi Rika , Fujita Yasuyuki , Tada Masazumi
Published: November 2018

At the initial stage of carcinogenesis single mutated cells appear within an epithelium. Mammalian in vitro experiments show that potentially cancerous cells undergo live apical extrusion from normal monolayers. However, the mechanism underlying this process in vivo remains poorly understood. Mosaic expression of the oncogene vSrc in a simple epithelium of the early zebrafish embryo results in extrusion of transformed cells. Here we find that during extrusion components of the cytokinetic ring are recruited to adherens junctions of transformed cells, forming a misoriented pseudo-cytokinetic ring. As the ring constricts, it separates the basal from the apical part of the cell releasing both from the epithelium. This process requires cell cycle progression and occurs immediately after vSrc-transformed cell enters mitosis. To achieve extrusion, vSrc coordinates cell cycle progression, junctional integrity, cell survival and apicobasal polarity. Without vSrc, modulating these cellular processes reconstitutes vSrc-like extrusion, confirming their sufficiency for this process.
Adaptation to sub-optimal hosts is a driver of viral diversification in the ocean
Authors: Enav Hagay , Kirzner Shay , Lindell Debbie , Mandel-Gutfreund Yael , Béjà Oded
Published: November 2018

Cyanophages of theMyoviridaefamily include generalist viruses capable of infecting a wide range of hosts including those from different cyanobacterial genera. While the influence of phages on host evolution has been studied previously, it is not known how the infection of distinct hosts influences the evolution of cyanophage populations. Here, using an experimental evolution approach, we investigated the adaptation of multiple cyanophage populations to distinct cyanobacterial hosts. We show that when infecting an “optimal” host, whose infection is the most efficient, phage populations accumulated only a few mutations. However, when infecting “sub-optimal” hosts, different mutations spread in the phage populations, leading to rapid diversification into distinct subpopulations. Based on our results, we propose a model demonstrating how shifts in microbial abundance, which lead to infection of “sub-optimal” hosts, act as a driver for rapid diversification of viral populations.
Vibrational fingerprint of localized excitons in a two-dimensional metal-organic crystal
Authors: Corva M. , Ferrari A. , Rinaldi M. , Feng Z. , Roiaz M. , Rameshan C. , Rupprechter G. , Costantini R. , Dell’Angela M. , Pastore G. , Comelli G. , Seriani N. , Vesselli E.
Published: November 2018

Long-lived excitons formed upon visible light absorption play an essential role in photovoltaics, photocatalysis, and even in high-density information storage. Here, we describe a self-assembled two-dimensional metal-organic crystal, composed of graphene-supported macrocycles, each hosting a single FeN4center, where a single carbon monoxide molecule can adsorb. In this heme-like biomimetic model system, excitons are generated by visible laser light upon a spin transition associated with the layer 2D crystallinity, and are simultaneously detected via the carbon monoxide ligand stretching mode at room temperature and near-ambient pressure. The proposed mechanism is supported by the results of infrared and time-resolved pump-probe spectroscopies, and by ab initio theoretical methods, opening a path towards the handling of exciton dynamics on 2D biomimetic crystals.
Systemic neurotransmitter responses to clinically approved and experimental neuropsychiatric drugs
Authors: Noori Hamid R. , Mervin Lewis H. , Bokharaie Vahid , Durmus Özlem , Egenrieder Lisamon , Fritze Stefan , Gruhlke Britta , Reinhardt Giulia , Schabel Hans-Hendrik , Staudenmaier Sabine , Logothetis Nikos K. , Bender Andreas , Spanagel Rainer
Published: November 2018

Neuropsychiatric disorders are the third leading cause of global disease burden. Current pharmacological treatment for these disorders is inadequate, with often insufficient efficacy and undesirable side effects. One reason for this is that the links between molecular drug action and neurobehavioral drug effects are elusive. We use a big data approach from the neurotransmitter response patterns of 258 different neuropsychiatric drugs in rats to address this question. Data from experiments comprising 110,674 rats are presented in the Syphad database [www.syphad.org]. Chemoinformatics analyses of the neurotransmitter responses suggest a mismatch between the current classification of neuropsychiatric drugs and spatiotemporal neurostransmitter response patterns at the systems level. In contrast, predicted drug–target interactions reflect more appropriately brain region related neurotransmitter response. In conclusion the neurobiological mechanism of neuropsychiatric drugs are not well reflected by their current classification or their chemical similarity, but can be better captured by molecular drug–target interactions.
Predicting accurate cathode properties of layered oxide materials using the SCAN meta-GGA density functional
Authors: Chakraborty Arup , Dixit Mudit , Aurbach Doron , Major Dan T.
Published: November 2018

Layered lithium intercalating transition metal oxides are promising cathode materials for Li-ion batteries. Here, we scrutinize the recently developed strongly constrained and appropriately normed (SCAN) density functional method to study structural, magnetic, and electrochemical properties of prototype cathode materials LiNiO2, LiCoO2, and LiMnO2 at different Li-intercalation limits. We show that SCAN outperforms earlier popular functional combinations, providing results in considerably better agreement with experiment without the use of Hubbard parameters, and dispersion corrections are found to have a small effect. In particular, SCAN fares better than Perdew–Burke–Ernzerhof (PBE) functional for the prediction of band-gaps and absolute voltages, better than PBE+U for the electronic density of states and voltage profiles, and better than both PBE and PBE+U for electron densities and in operando lattice parameters. This overall better performance of SCAN may be ascribed to improved treatment of localized states and a better description of short-range dispersion interactions.
FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis
Authors: van Golen Rowan F. , Olthof Pim B. , Lionarons Daniël A. , Reiniers Megan J. , Alles Lindy K. , Uz Zehra , de Haan Lianne , Ergin Bulent , de Waart Dirk R. , Maas Adrie , Verheij Joanne , Jansen Peter L. , Damink Steven W. Olde , Schaap Frank G. , van Gulik Thomas M. , Heger Michal
Published: November 2018

Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree.
Proportion of neuropathic pain in the back region in chronic low back pain patients -a multicenter investigation
Authors: Li Jun , He Jing , Li Hu , Fan Bi-Fa , Liu Bo-Tao , Mao Peng , Jin Yi , Cheng Zhu-Qiang , Zhang Ting-Jie , Zhong Zhi-Fang , Li Si-Ji , Zhu Sai-Nan , Feng Yi
Published: November 2018

Neuropathy can contribute to low back pain (LBP) in the region of the back. Our study investigated the proportion of neuropathic pain (NP) in low back region in chronic LBP patients from multicenter and clinics in China and identified associated factors. Assessment was made using a questionnaire and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS, only tested in low back region), as well as Quantitative Sensory Testing (QST, merely applied to the low back region), the Hospital Anxiety and Depression Scale (HADS) and the Oswestry Disability Index (ODI). Our questionnaire collected demographic information, behavioral habits and medical records. 2116 outpatients over 18 years old complaining of LBP lasting more than 3 months were enrolled in this study. The NP proportion in low back region in chronic LBP patients was 2.8%. Multivariable logistic regression analysis showed that histories of lumbar surgery, abdominal or pelvic surgery, and drinking alcohol were independent positive predictors for LBP of predominantly neuropathic origin (LBNPO), while history of low back sprain and frequently carrying weight as independent negative predictor. Using these parameters may help the identification of patients with chronic LBP likely to develop NP leading to improved treatment outcomes.
LIP formation and protracted lower mantle upwelling induced by rifting and delamination
Authors: Petersen Kenni Dinesen , Schiffer Christian , Nagel Thorsten
Published: November 2018

Large Igneous Provinces (LIPs) are commonly attributed to mantle plumes, hot upwellings from the deep lower mantle, apparently unrelated to plate motions. However, LIPs often form in association with rifting and breakup. Using numerical modelling, we introduce a novel idea that explains plume-like mantle upwelling by plate tectonic processes. Our model indicates that rifting-induced delamination of orogenic lithosphere can perturb the thermochemical mantle stratification and induce lower mantle upwelling which causes syn-rift LIP formation followed by protracted and enhanced mid ocean ridge basalt (MORB) generation. Our model provides an explanation for the geographical correlation between the Caledonian suture, the North Atlantic Igneous Province (NAIP) and present-day Icelandic magmatism.
The Antiarrhythmic Drug, Dronedarone, Demonstrates Cytotoxic Effects in Breast Cancer Independent of Thyroid Hormone Receptor Alpha 1 (THRα1) Antagonism
Authors: Elliott Mitchell J. , Jerzak Katarzyna J. , Cockburn Jessica G. , Safikhani Zhaleh , Gwynne William D. , Hassell John A. , Bane Anita , Silvester Jennifer , Thu Kelsie L. , Haibe-Kains Benjamin , Mak Tak W. , Cescon David W.
Published: November 2018

Previous research has suggested that thyroid hormone receptor alpha 1 (THRα1), a hormone responsive splice variant, may play a role in breast cancer progression. Whether THRα1 can be exploited for anti-cancer therapy is unknown. The antiproliferative and antitumor effects of dronedarone, an FDA-approved anti-arrhythmic drug which has been shown to antagonize THRα1, was evaluated in breast cancer cell lines in vitro and in vivo. The THRα1 splice variant and the entire receptor, THRα, were also independently targeted using siRNA to determine the effect of target knockdown in vitro. In our study, dronedarone demonstrates cytotoxic effects in vitro and in vivo in breast cancer cell lines at doses and concentrations that may be clinically relevant. However, knockdown of either THRα1 or THRα did not cause substantial anti-proliferative or cytotoxic effects in vitro, nor did it alter the sensitivity to dronedarone. Thus, we conclude that dronedarone’s cytotoxic effect in breast cancer cell lines are independent of THRα or THRα1 antagonism. Further, the depletion of THRα or THRα1 does not affect cell viability or proliferation. Characterizing the mechanism of dronedarone’s anti-tumor action may facilitate drug repurposing or the development of new anti-cancer agents.
Gradient Relationship between Increased Mean Corpuscular Volume and Mortality Associated with Cerebral Ischemic Stroke and Ischemic Heart Disease: A Longitudinal Study on 66,294 Taiwanese
Authors: Wu Tzy-Haw , Fann Jean Ching-Yuan , Chen Sam Li-Sheng , Yen Amy Ming-Fang , Wen Chiung-Jung , Lu Yun-Ru , Chen Hsiu-Hsi , Chiu Sherry Yueh-Hsia , Liou Horng-Huei
Published: November 2018

The gradient relationship between mean corpuscular volume (MCV) and mortality due to ischemic vascular disease has not been researched using a large-scale population-based study. This study evaluated the association between MCV and death attributable to cerebrovascular disease (CVD) and cardiovascular disease (CAD) in a large population- and community-based Taiwanese cohort. A longitudinal study with a 9-year follow-up was conducted to evaluate individuals aged 20 years or older who had participated in the Keelung (the northernmost city in Taiwan) community-based integrated screening (abbreviated as KCIS) program since September 1999. The mortality rates associated with CVD and CAD were classified across a range of different MCV levels. Increased MCV levels were associated with an increased risk of CVD/CAD-related death (adjusted hazard ratio [aHR] = 1.42, trend test P = 0.0119). Marginally statistically significant associations were noted for specific deaths from ischemic heart disease (aHR = 1.44, trend test P = 0.0992) and cerebral ischemic stroke (aHR = 1.66, trend test P = 0.0667), respectively, but no significant gradient relationship was noted for death from cerebral hemorrhage stroke (aHR = 1.23, trend test, P = 0.6278). A gradient relationship between baseline MCV level and CVD/CAD-related death was noted, but whether such gradient relationships existed for two specific deaths and how these relationships may be confounded by extraneous factors that were not considered here should be investigated in the future.
Embryonic origin and genetic basis of cave associated phenotypes in the isopod crustacean Asellus aquaticus
Authors: Mojaddidi Hafasa , Fernandez Franco E. , Erickson Priscilla A. , Protas Meredith E.
Published: November 2018

Characteristics common to animals living in subterranean environments include the reduction or absence of eyes, lessened pigmentation and enhanced sensory systems. How these characteristics have evolved is poorly understood for the majority of cave dwelling species. In order to understand the evolution of these changes, this study uses an invertebrate model system, the freshwater isopod crustacean, Asellus aquaticus, to examine whether adult differences between cave and surface dwelling individuals first appear during embryonic development. We hypothesized that antennal elaboration, as well as eye reduction and pigment loss, would be apparent during embryonic development. We found that differences in pigmentation, eye formation, and number of segments of antenna II were all present by the end of embryonic development. In addition, we found that cave and surface hatchlings do not significantly differ in the relative size of antenna II and the duration of embryonic development. To investigate whether the regions responsible for eye and pigment differences could be genetically linked to differences in article number, we genotyped F2 hybrids for the four previously mapped genomic regions associated with eye and pigment differences and phenotyped these F2 hybrids for antenna II article number. We found that the region previously known to be responsible for both presence versus absence of pigment and eye size also was significantly associated with article number. Future experiments will address whether pleiotropy and/or genetic linkage play a role in the evolution of cave characteristics in Asellus aquaticus.
Effect of Early Calf-Hood Nutrition on the Transcriptional Regulation of the Hypothalamic-Pituitary-Testicular axis in Holstein-Friesian Bull Calves
Authors: English A. M. , Byrne C. J. , Cormican P , Waters S. M. , Fair S. , Kenny D. A.
Published: November 2018

The aim of this study was to investigate the effect of early calf-hood nutrition on the transcriptomic profile of the arcuate nucleus of the hypothalamus, anterior pituitary and testes in Holstein-Friesian bulls. Holstein-Friesian bull calves with a mean (±S.D.) age and bodyweight of 19 (±8.2) days and 47.5 (±5.3) kg, respectively, were offered a high (n = 10) or low (n = 10) plane of nutrition in order to achieve an overall growth rate of 1.2 and 0.5 kg/day. At 126 (±3) days of age, calves were euthanized, hypothalamus (arcuate region), anterior pituitary and testicular parenchyma samples were harvested and RNAseq analysis was performed. There were 0, 49 and 1,346 genes differentially expressed in the arcuate nucleus, anterior pituitary and testicular tissue of bull calves on the low relative to the high plane of nutrition, respectively (P < 0.05; False Discovery Rate <0.05). Cell cycle processes in the anterior pituitary were down regulated in the low relative to the high plane of nutrition; there was no differential expression of genes related to reproductive processes. Gene expression involved in cholesterol and androgen biosynthesis in the testes were down regulated in animals on the low plane of nutrition. This study provides insight into the effect of early life plane of nutrition on the regulation of the HPT axis.
Critical Drip Size and Blue Flame Shedding of Dripping Ignition in Fire
Authors: Huang Xinyan
Published: November 2018

Dripping of molten fuels is a widely observed fire phenomenon, and, by igniting other fuels, it can promote fire spread and increase fire hazards. In this work, dripping phenomena from fires of horizontally oriented wires, coated with polyethylene (PE), are investigated in the laboratory. It is found that as long as a flame is attached to the drip, thin tissue paper can be ignited by a single drip. Below a minimum diameter (Dmin = 0.63 mm), the drip floats up. Above a critical diameter (Dcrt = 2.3 mm), a flame can remain attached to the drip and ignite tissue paper as it falls through a distance of at least 2.6 m, thereby posing a significant fire hazard. A falling burning drip appears to the eye to be a blue chain of flame as a result of persistence of vision. Photographic evidence identifies a flame-shedding process, most likely associated with continual sequential ignition of fuel vapor within a von Karman vortex street generated behind the falling burning drip. The frequency of flame shedding agrees with both the frequency of modeled vortex shedding and the frequency of the unexpected sound that is heard during the process. This is the first time that combustion characteristics of dripping fire phenomena have been studied in detail, and this helps to better evaluate the risk and hazards of wire and façade fires.
Extensions to Michaelis-Menten Kinetics for Single Parameters
Authors: Ariyawansha R. T. K. , Basnayake B. F. A. , Karunarathna A. K. , Mowjood M. I. M.
Published: November 2018

Biochemical transformation kinetics is based on the formation of enzyme-substrate complexes. We developed a robust scheme based on unit productions of enzymes and reactants in cyclic events to comply with mass action law to form enzyme-substrate complexes. The developed formalism supports a successful application of Michaelis-Menten kinetics in all biochemical transformations of single parameters. It is an essential tool to overcome some challenging healthcare and environmental issues. In developing the formalism, we defined the substrate [S]= [Product]3/4 and rate of reaction based on rate and time perspectives. It allowed us to develop two quadratic equations. The first, represents a body entity that gave a useful relationship of enzyme E = 2S0.33, and the second nutrients/feed, each giving [Enzymes] and [Enzyme-substrate complexes], simulating rate of reaction, [substrate], and their differentials. By combining [Enzymes] and [Enzyme-substrate complexes] values, this quadratic equation derives a Michaelis-Menten hyperbolic function. Interestingly, we can derive the proportionate rate of reaction and [Enzymes] values of the quadratics resulting in another Michaelis-Menten hyperbolic. What is clear from these results is that between these two hyperbolic functions, in-competitive inhibitions exist, indicating metabolic activities and growth in terms of energy levels. We validated these biochemical transformations with examples applicable to day to day life.