bluuebunny/crossref_metadata_2025 huggingface dataset:
WHO OWNS PRAGMATISM?
Authors: KUKLICK BRUCE
Published: February 2017

In the opening years of the twentieth century a furious contest broke out over the meaning of pragmatism in professional philosophical circles in the United States. When William James introduced his idea to the learned public at the University of California in 1898, he credited Charles Peirce as its prime mover. After James's lecture became known, Peirce, an impossible man who did not know on which side his bread was buttered, re-christened his brainchild pragmaticism to make sure no one confused it with the foolishness of James. When John Dewey made his mark and critiques of pragmatism emerged, Dewey said that we should not argue about a brand name. Nonetheless, he still gave his own philosophy a new designation, dubbing it instrumentalism to avoid the charges unleashed against James. Were there, then, three styles of this speculative tendency? Arthur O. Lovejoy was an unrelenting opponent of the tendency. In 1908 he mocked these thinkers, and wrote in the Journal of Philosophy, Psychology, and Scientific Methods a captivating and long-cited essay, “The Thirteen Pragmatisms.”
Labour-Market Outsiders, Italian Justices and the Right to Social Assistance
Authors: Levi Luca Martino
Published: February 2017

Constitutional right to social assistance in Italy – Lack of a universally-accessible, albeit conditional and means-tested, scheme against absolute poverty – Separation of powers – Textualism – Framers’ original understanding – Living constitutionalism and courts’ relationship with public opinion – Italian, EU and international constraints on citizenship and duration-of-residence requirements – Fiscal sustainability
Freedom to negotiate: a proposal extricating ‘capacity’ from ‘consent’
Authors: Brosnan Liz , Flynn Eilionóir
Published: February 2017

In this paper, we seek to radically reframe the legal construct of consent from a disability perspective. Drawing on feminist scholarship and human rights standards around ‘free and informed consent’, we apply a concept of freedom to negotiate to laws regulating both consent to sex and medical treatment – key areas in which the legal agency of people with disabilities (especially people with cognitive disabilities) is routinely denied, restricted or ignored. We set out the essential ingredients for reframing consent: namely, legal personhood, freedom to negotiate and understanding. We also outline conditions (i.e. coercion, undue influence and power imbalances) that impede valid consent. This represents a first attempt to move beyond labelling adults with certain disabilities as lacking the ‘mental capacity’ necessary to give valid consent – in order to explore in more depth particular expressions of consent or refusal and seek new validity criteria, beyond the label of ‘mental incapacity’.
Conversations between the proponents of the new paradigm of legal capacity
Authors: Dhanda Amita
Published: February 2017

In a bid to promote consensus, this response article parses the subtle difference of meaning and emphasis that subsists between the various proponents of the new paradigm of legal capacity by closely reading four articles included in this issue of the Journal.
Organizational Psychology and the Tipping Point of Professional Identity
Authors: Ryan Ann Marie , Ford J. Kevin
Published: February 2017

Using concepts from the literature on individual and collective identity, we argue that organizational psychologists are at a tipping point with regard to identity. Assertions regarding a lack of distinctiveness from other fields, ambiguity in individual identification with the field among new entrants, hyperadaptation to external forces, and a failure to manage within-identity dynamics associated with science and practice are presented. These assertions are supported with descriptions of the nature of growth in the field, challenges in academic psychology departments, and calls for changing research agendas. With the aim of engaging others in collective sensemaking, alternative future scenarios for organizational psychology are presented.
Corrections for Criterion Reliability in Validity Generalization: A False Prophet in a Land of Suspended Judgment
Authors: LeBreton James M. , Scherer Kelly T. , James Lawrence R.
Published: February 2017

The results of meta-analytic (MA) and validity generalization (VG) studies continue to be impressive. In contrast to earlier findings that capped the variance accounted for in job performance at roughly 16%, many recent studies suggest that a single predictor variable can account for between 16 and 36% of the variance in some aspect of job performance. This article argues that this “enhancement” in variance accounted for is often attributable not to improvements in science but to a dumbing down of the standards for the values of statistics used in correction equations. With rare exceptions, applied researchers have suspended judgment about what is and is not an acceptable threshold for criterion reliability in their quest for higher validities. We demonstrate a statistical dysfunction that is a direct result of using low criterion reliabilities in corrections for attenuation. Corrections typically applied to a single predictor in a VG study are instead applied to multiple predictors. A multiple correlation analysis is then conducted on corrected validity coefficients. It is shown that the corrections often used in single predictor studies yield a squared multiple correlation that appears suspect. Basically, the multiple predictor study exposes the tenuous statistical foundation of using abjectly low criterion reliabilities in single predictor VG studies. Recommendations for restoring scientific integrity to the meta-analyses that permeate industrial–organizational (I–O) psychology are offered.
Symbols, Strategies, and Choices for International Relations Scholarship After September 11
Authors: Leheny David
Published: February 2017

Pundits and officials have been remarkably united in their assertions that the “war on terrorism” is fundamentally a new kind of war. This is troubling, because it suggests that the world has stepped into terra incognita. No one—to draw a recent comparison—has suggested that this past winter's standoff between India and Pakistan is fundamentally new, even though both nations are now nuclear powers. Indeed, in spite of the high stakes in Kashmir, the conflict feels familiar, partly because the two countries have long been mutually suspicious and often hostile, and because they are two states; we know how to think and to talk about them. And, one hopes, policymakers know how to reduce these tensions. In contrast, the war on terrorism has an almost surreal quality because of the utter novelty of the idea of a superpower fighting against a transnational, clandestine network or against the even more nebulous phenomenon of terrorism itself. Like the U.S. government, international relations scholars were caught largely unaware and were initially unprepared to offer much guidance on how the new crisis might develop.
DJ-1 maintains energy and glucose homeostasis by regulating the function of brown adipose tissue
Authors: Wu Rong , Liu Xiao-meng , Sun Jian-guang , Chen Hong , Ma Jun , Dong Meng , Peng Shengyi , Wang Ji-qiu , Ding Jian-qing , Li Dong-hao , Speakman John R , Ning Guang , Jin Wanzhu , Yuan Zengqiang
Published: February 2017

DJ-1 protein is involved in multiple physiological processes, including Parkinson’s disease. However, the role of DJ-1 in the metabolism is largely unknown. Here we found that DJ-1 maintained energy balance and glucose homeostasis via regulating brown adipose tissue (BAT) activity. DJ-1-deficient mice reduced body mass, increased energy expenditure and improved insulin sensitivity. DJ-1 deletion also resisted high-fat-diet (HFD) induced obesity and insulin resistance. Accordingly, DJ-1 transgene triggered autonomous obesity and glucose intolerance. Further BAT transplantation experiments clarified DJ-1 regulates energy and glucose homeostasis by modulating BAT function. Mechanistically, we found that DJ-1 promoted PTEN proteasomal degradation via an E3 ligase, mind bomb-2 (Mib2), which led to Akt activation and inhibited FoxO1-dependent Ucp1 (Uncoupling protein-1) expression in BAT. Consistently, ablation of Akt1 mitigated the obesity and BAT dysfunction induced by DJ-1 transgene. These findings define a new biological role of DJ-1 protein in regulating BAT function, with an implication of the therapeutic target in the treatment of metabolic disorders.
Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity
Authors: Hernandez-Fernaud Juan R. , Ruengeler Elena , Casazza Andrea , Neilson Lisa J. , Pulleine Ellie , Santi Alice , Ismail Shehab , Lilla Sergio , Dhayade Sandeep , MacPherson Iain R. , McNeish Iain , Ennis Darren , Ali Hala , Kugeratski Fernanda G. , Al Khamici Heba , van den Biggelaar Maartje , van den Berghe Peter V.E. , Cloix Catherine , McDonald Laura , Millan David , Hoyle Aoisha , Kuchnio Anna , Carmeliet Peter , Valenzuela Stella M. , Blyth Karen , Yin Huabing , Mazzone Massimiliano , Norman Jim C. , Zanivan Sara
Published: February 2017

The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.
Covalent assembly of nanoparticles as a peptidase-degradable platform for molecular MRI
Authors: Perez-Balderas Francisco , van Kasteren Sander I. , Aljabali Alaa A. A. , Wals Kim , Serres Sébastien , Jefferson Andrew , Sarmiento Soto Manuel , Khrapitchev Alexandre A. , Larkin James R , Bristow Claire , Lee Seung Seo , Bort Guillaume , De Simone Filippo , Campbell Sandra J. , Choudhury Robin P. , Anthony Daniel C. , Sibson Nicola R. , Davis Benjamin G.
Published: February 2017

Ligand-conjugated microparticles of iron oxide (MPIO) have the potential to provide high sensitivity contrast for molecular magnetic resonance imaging (MRI). However, the accumulation and persistence of non-biodegradable micron-sized particles in liver and spleen precludes their clinical use and limits the translational potential of MPIO-based contrast agents. Here we show that ligand-targeted MPIO derived from multiple iron oxide nanoparticles may be coupled covalently through peptide linkers that are designed to be cleaved by intracellular macrophage proteases. The synthesized particles possess potential characteristics for targeted MRI contrast agents, including high relaxivity, unappreciable sedimentation, clearance from circulation and no overt toxicity. Importantly, we demonstrate that these particles are rapidly degraded both in vitro and in vivo, and that the targeted probes can be used for detection of inflammation in vivo using MRI. This approach provides a platform for molecular MRI contrast agents that is potentially more suitable for translation to humans.
Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma
Authors: Beug Shawn T. , Beauregard Caroline E. , Healy Cristin , Sanda Tarun , St-Jean Martine , Chabot Janelle , Walker Danielle E. , Mohan Aditya , Earl Nathalie , Lun Xueqing , Senger Donna L. , Robbins Stephen M. , Staeheli Peter , Forsyth Peter A. , Alain Tommy , LaCasse Eric C. , Korneluk Robert G.
Published: February 2017

Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.
Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans
Authors: Kumsta Caroline , Chang Jessica T. , Schmalz Jessica , Hansen Malene
Published: February 2017

Stress-response pathways have evolved to maintain cellular homeostasis and to ensure the survival of organisms under changing environmental conditions. Whereas severe stress is detrimental, mild stress can be beneficial for health and survival, known as hormesis. Although the universally conserved heat-shock response regulated by transcription factor HSF-1 has been implicated as an effector mechanism, the role and possible interplay with other cellular processes, such as autophagy, remains poorly understood. Here we show that autophagy is induced in multiple tissues of Caenorhabditis elegans following hormetic heat stress or HSF-1 overexpression. Autophagy-related genes are required for the thermoresistance and longevity of animals exposed to hormetic heat shock or HSF-1 overexpression. Hormetic heat shock also reduces the progressive accumulation of PolyQ aggregates in an autophagy-dependent manner. These findings demonstrate that autophagy contributes to stress resistance and hormesis, and reveal a requirement for autophagy in HSF-1-regulated functions in the heat-shock response, proteostasis and ageing.
Abrupt cooling over the North Atlantic in modern climate models
Authors: Sgubin Giovanni , Swingedouw Didier , Drijfhout Sybren , Mary Yannick , Bennabi Amine
Published: February 2017

Observations over the 20th century evidence no long-term warming in the subpolar North Atlantic (SPG). This region even experienced a rapid cooling around 1970, raising a debate over its potential reoccurrence. Here we assess the risk of future abrupt SPG cooling in 40 climate models from the fifth Coupled Model Intercomparison Project (CMIP5). Contrary to the long-term SPG warming trend evidenced by most of the models, 17.5% of the models (7/40) project a rapid SPG cooling, consistent with a collapse of the local deep-ocean convection. Uncertainty in projections is associated with the models’ varying capability in simulating the present-day SPG stratification, whose realistic reproduction appears a necessary condition for the onset of a convection collapse. This event occurs in 45.5% of the 11 models best able to simulate the observed SPG stratification. Thus, due to systematic model biases, the CMIP5 ensemble as a whole underestimates the chance of future abrupt SPG cooling, entailing crucial implications for observation and adaptation policy.
Large positive in-plane magnetoresistance induced by localized states at nanodomain boundaries in graphene
Authors: Wu Han-Chun , Chaika Alexander N. , Hsu Ming-Chien , Huang Tsung-Wei , Abid Mourad , Abid Mohamed , Aristov Victor Yu , Molodtsova Olga V. , Babenkov Sergey V. , Niu Yuran , Murphy Barry E. , Krasnikov Sergey A. , Lübben Olaf , Liu Huajun , Chun Byong Sun , Janabi Yahya T. , Molotkov Sergei N. , Shvets Igor V. , Lichtenstein Alexander I. , Katsnelson Mikhail I. , Chang Ching-Ray
Published: February 2017

Graphene supports long spin lifetimes and long diffusion lengths at room temperature, making it highly promising for spintronics. However, making graphene magnetic remains a principal challenge despite the many proposed solutions. Among these, graphene with zig-zag edges and ripples are the most promising candidates, as zig-zag edges are predicted to host spin-polarized electronic states, and spin–orbit coupling can be induced by ripples. Here we investigate the magnetoresistance of graphene grown on technologically relevant SiC/Si(001) wafers, where inherent nanodomain boundaries sandwich zig-zag structures between adjacent ripples of large curvature. Localized states at the nanodomain boundaries result in an unprecedented positive in-plane magnetoresistance with a strong temperature dependence. Our work may offer a tantalizing way to add the spin degree of freedom to graphene.
Atomic structures of twin boundaries in hexagonal close-packed metallic crystals with particular focus on Mg
Authors: Pei Zongrui , Zhang Xie , Hickel Tilmann , Friák Martin , Sandlöbes Stefanie , Dutta Biswanath , Neugebauer Jörg
Published: February 2017

We have investigated twin boundaries in double-lattice hexagonal close-packed metallic materials, focusing on their atomic geometry. Combining accurate ab-initio methods and large-scale atomistic simulations we address the following two fundamental questions: (i) What are the possible intrinsic twin boundary structures in hcp crystals? (ii) Are these structures stable against small distortions? In order to help end a decade-long controversy over the experimental observations of the atomic structures of twin boundaries, we have determined the energetics, spectra, and transition mechanisms of the twin boundaries. Our results confirm that the mechanical stability controls structures which are observed.
TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury
Authors: Ding Xibing , Jin Shuqing , Tong Yao , Jiang Xi , Chen Zhixia , Mei Shuya , Zhang Liming , Billiar Timothy R. , Li Quan
Published: February 2017

Acute lung injury is a life-threatening inflammatory response caused by severe infection. Toll-like receptors in alveolar macrophages (AMΦ) recognize the molecular constituents of pathogens and activate the host’s innate immune responses. Numerous studies have documented the importance of TLR-TLR cross talk, but few studies have specifically addressed the relationship between TLR4 and TLR3. We explored a novel mechanism of TLR3 up-regulation that is induced by LPS-TLR4 signaling in a dose- and time-dependent manner in AMΦ from C57BL/6 mice, while the LPS-induced TLR3 expression was significantly reduced in TLR4−/−and Myd88−/−mice and following pretreatment with a NF-κB inhibitor. The enhanced TLR3 up-regulation in AMΦ augmented the expression of cytokines and chemokines in response to sequential challenges with LPS and Poly I:C, a TLR3 ligand, which was physiologically associated with amplified AMΦ-induced PMN migration into lung alveoli. Our study demonstrates that the synergistic effect between TLR4 and TLR3 in macrophages is an important determinant in acute lung injury and, more importantly, that TLR3 up-regulation is dependent on TLR4-MyD88-NF-κB signaling. These results raise the possibility that bacterial infections can induce sensitivity to viral infections, which may have important implications for the therapeutic manipulation of the innate immune system.
Method for Dual Viral Vector Mediated CRISPR-Cas9 Gene Disruption in Primary Human Endothelial Cells
Authors: Gong Haixia , Liu Menglin , Klomp Jeff , Merrill Bradley J. , Rehman Jalees , Malik Asrar B.
Published: February 2017

Human endothelial cells (ECs) are widely used to study mechanisms of angiogenesis, inflammation, and endothelial permeability. Targeted gene disruption induced by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-Associated Protein 9 (Cas9) nuclease gene editing is potentially an important tool for definitively establishing the functional roles of individual genes in ECs. We showed that co-delivery of adenovirus encoding EGFP-tagged Cas9 and lentivirus encoding a single guide RNA (sgRNA) in primary human lung microvascular ECs (HLMVECs) disrupted the expression of the Tie2 gene and protein. Tie2 disruption increased basal endothelial permeability and prevented permeability recovery following injury induced by the inflammatory stimulus thrombin. Thus, gene deletion via viral co-delivery of CRISPR-Cas9 in primary human ECs provides a novel platform to investigate signaling mechanisms of normal and perturbed EC function without the need for clonal expansion.
NMR metabolic fingerprints of murine melanocyte and melanoma cell lines: application to biomarker discovery
Authors: Santana-Filho Arquimedes Paixão de , Jacomasso Thiago , Riter Daniel Suss , Barison Andersson , Iacomini Marcello , Winnischofer Sheila Maria Brochado , Sassaki Guilherme Lanzi
Published: February 2017

Melanoma is the most aggressive type of skin cancer and efforts to improve the diagnosis of this neoplasia are largely based on the use of cell lines. Metabolomics is currently undergoing great advancements towards its use to screening for disease biomarkers. Although NMR metabolomics includes both 1D and 2D methodologies, there is a lack of data in the literature regarding heteronuclear 2D NMR assignments of the metabolome from eukaryotic cell lines. The present study applied NMR-based metabolomics strategies to characterize aqueous and lipid extracts from murine melanocytes and melanoma cell lines with distinct tumorigenic potential, successfully obtaining fingerprints of the metabolites from the extracts of the cell lines by means of 2D NMR HSQC correlation maps. Relative amounts of the identified metabolites were compared between the 4 cell lines. Multivariate analysis of 1H NMR data was able not only to differentiate the melanocyte cell line from the tumorigenic ones but also distinguish among the 3 tumorigenic cell lines. We also investigated the effects of mitogenic agents, and found that they can markedly influence the metabolome of the melanocyte cell line, resembling the pattern of most proliferative cell lines.
MicroRNA-155 Controls Exosome Synthesis and Promotes Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma
Authors: Mikamori Manabu , Yamada Daisaku , Eguchi Hidetoshi , Hasegawa Shinichiro , Kishimoto Tomoya , Tomimaru Yoshito , Asaoka Tadafumi , Noda Takehiro , Wada Hiroshi , Kawamoto Koichi , Gotoh Kunihito , Takeda Yutaka , Tanemura Masahiro , Mori Masaki , Doki Yuichiro
Published: February 2017

The cancer drug gemcitabine (GEM) is a key drug for treating pancreatic ductal adenocarcinoma (PDAC), but PDAC cells develop chemoresistance after long-term administration. Since the tolerance was immediately spread to every PDAC tissue in a patient, it is assumed that some certain efficient mechanisms underlay in the development of chemoresistance. Changes in the levels of particular microRNAs or alterations in intercellular communication play a dominant role in chemoresistance development, and recent data also suggest that exosomes play an important role in this process. In this study, we revealed that the loop conferred chemoresistance in PDAC cells. The loop was as follows; 1, The long-term exposure of GEM increased miR-155 expression in PDAC cells. 2, The increase of miR-155 induced two different functions; exosome secretion and chemoresistance ability via facilitating the anti-apoptotic activity. 3, Exosome deliver the miR-155 into the other PDAC cells and induce the following function. The target therapy to miR-155 or the exosome secretion effectively attenuated the chemoresistance, and these results were validated with both clinical samples and in vivo experiments. This mechanism represents a novel therapeutic target in GEM treatment to PDAC.
PDI regulates seizure activity via NMDA receptor redox in rats
Authors: Kim Ji Yang , Ko Ah-Rhem , Hyun Hye-Won , Min Su-Ji , Kim Ji-Eun
Published: February 2017

Redox modulation of cysteine residues is one of the post-translational modifications of N-methyl-D-aspartate receptor (NMDAR). Protein disulfide isomerases (PDI), an endoplasmic reticulum (ER) chaperone, plays a crucial role in catalyzing disulfide bond formation, reduction, and isomerization. In the present study, we found that PDI bound to NMDAR in the normal hippocampus, and that this binding was increased in chronic epileptic rats. In vitro thiol reductase assay revealed that PDI increased the amount of thiols on full-length recombinant NR1 protein. PDI siRNA, 5–5′-dithio-bis(2-nitrobenzoic acid) (DTNB), bacitracin and PDI antibody reduced seizure susceptibility in response to pilocarpine. In addition, PDI knockdown effectively ameliorated spontaneous seizure activity in chronic epileptic rats. Anticonvulsive effects of PDI siRNA were correlated to the reduction of the amount of free- and nitrosothiols on NMDAR, accompanied by the inhibition of PDI activity. However, PDI knockdown did not lead to alteration in basal neurotransmission or ER stress under physiological condition. These findings provide mechanistic insight into sulfhydration of disulfide bonds on NMDAR by PDI, and suggest that PDI may represent a target of potential therapeutics for epilepsy, which avoids a possible side effect on physiological receptor functionality.
Quick and inexpensive paraffin-embedding method for dynamic bone formation analyses
Authors: Porter Amy , Irwin Regina , Miller Josselyn , Horan Daniel J. , Robling Alexander G. , McCabe Laura R.
Published: February 2017

We have developed a straightforward method that uses paraffin-embedded bone for undemineralized thin sectioning, which is amenable to subsequent dynamic bone formation measurements. Bone has stiffer material properties than paraffin, and therefore has hereforto usually been embedded in plastic blocks, cured and sectioned with a tungsten carbide knife to obtain mineralized bone sections for dynamic bone formation measures. This process is expensive and requires special equipment, experienced personnel, and time for the plastic to penetrate the bone and cure. Our method utilizes a novel way to prepare mineralized bone that increases its compliance so that it can be embedded and easily section in paraffin blocks. The approach is simple, quick, and costs less than 10% of the price for plastic embedded bone sections. While not effective for static bone measures, this method allows dynamic bone analyses to be readily performed in laboratories worldwide which might not otherwise have access to traditional (plastic) equipment and expertise.
A one-week 5-choice serial reaction time task to measure impulsivity and attention in adult and adolescent mice
Authors: Remmelink Esther , Chau Uyen , Smit August B. , Verhage Matthijs , Loos Maarten
Published: February 2017

Many psychiatric disorders emerge during adolescence. The study of executive functions in animal models of these disorders critically requires short-duration tasks measuring these functions before the animal ages. Here, a novel 5-choice serial reaction time task (5-CSRTT) protocol is presented, to measure attention and impulsivity within one week, without scheduled food deprivation and with little animal handling. Mice were allowed 24-h/day task access from their home-cage, during which they could self-pace task progression and earn unlimited food rewards depending on task performance. Manipulation of task parameters in this self-paced 5-CSRTT protocol (SP-5C) affected attentional performance and impulsivity to a similar extent as previously observed in the 5-CSRTT. Task activity followed intrinsic circadian rhythm, distinctive for the SP-5C protocol, with task performance stable over the day. The sensitivity of the SP-5C protocol to detect strain differences between C57BL/6J, DBA/2 J, BXD16 and BXD62 mice was demonstrated as well as its suitability for testing adolescent mice. Acute administration of the muscarinic acetylcholine receptor antagonist scopolamine impaired attentional performance, providing initial pharmacological validation of the task. The SP-5C substantially shortens the assessment of impulsivity and attention, increases test efficiency and enables the assessment of adolescent mouse models of psychiatric disorders.
Comparative proteomic analysis of horseweed (Conyza canadensis) biotypes identifies candidate proteins for glyphosate resistance
Authors: González-Torralva Fidel , Brown Adrian P. , Chivasa Stephen
Published: February 2017

Emergence of glyphosate-resistant horseweed (Conyza canadensis) biotypes is an example of how unrelenting use of a single mode of action herbicide in agricultural weed control drives genetic adaptation in targeted species. While in other weeds glyphosate resistance arose from target site mutation or target gene amplification, the resistance mechanism in horseweed uses neither of these, being instead linked to reduced herbicide uptake and/or translocation. The molecular components underpinning horseweed glyphosate-resistance remain unknown. Here, we used anin vitroleaf disc system for comparative analysis of proteins extracted from control and glyphosate-treated tissues of glyphosate-resistant and glyphosate-susceptible biotypes. Analysis of shikimic acid accumulation,ABC-transportergene expression, and cell death were used to select a suitable glyphosate concentration and sampling time for enriching proteins pivotal to glyphosate resistance. Protein gel analysis and mass spectrometry identified mainly chloroplast proteins differentially expressed between the biotypes before and after glyphosate treatment. Chloroplasts are the organelles in which the shikimate pathway, which is targeted by glyphosate, is located. Calvin cycle enzymes and proteins of unknown function were among the proteins identified. Our study provides candidate proteins that could be pivotal in engendering resistance and implicates chloroplasts as the primary sites driving glyphosate-resistance in horseweed.
Ubiquitin C-terminal hydrolase37 regulates Tcf7 DNA binding for the activation of Wnt signalling
Authors: Han Wonhee , Lee Hyeyoon , Han Jin-Kwan
Published: February 2017

The Tcf/Lef family of transcription factors mediates the Wnt/β-catenin pathway that is involved in a wide range of biological processes, including vertebrate embryogenesis and diverse pathogenesis. Post-translational modifications, including phosphorylation, sumoylation and acetylation, are known to be important for the regulation of Tcf/Lef proteins. However, the importance of ubiquitination and ubiquitin-mediated regulatory mechanisms for Tcf/Lef activity are still unclear. Here, we newly show that ubiquitin C-terminal hydrolase 37 (Uch37), a deubiquitinase, interacts with Tcf7 (formerly named Tcf1) to activate Wnt signalling. Biochemical analyses demonstrated that deubiquitinating activity of Uch37 is not involved in Tcf7 protein stability but is required for the association of Tcf7 to target gene promoter in both Xenopus embryo and human liver cancer cells. In vivo analyses further revealed that Uch37 functions as a positive regulator of the Wnt/β-catenin pathway downstream of β-catenin stabilization that is required for the expression of ventrolateral mesoderm genes during Xenopus gastrulation. Our study provides a new mechanism for chromatin occupancy of Tcf7 and uncovers the physiological significance of Uch37 during early vertebrate development by regulating the Wnt/β-catenin pathway.
Heterogeneous Nucleation of Trichloroethylene Ozonation Products in the Formation of New Fine Particles
Authors: Wang Ning , Sun Xiaomin , Chen Jianmin , Li Xiang
Published: February 2017

Free radicals in atmosphere have played an important role in the atmospheric chemistry. The chloro-Criegee free radicals are produced easily in the decomposition of primary ozonide (POZ) of the trichloroethylene, and can react with O2, NO, NO2, SO2 and H2O subsequently. Then the inorganic salts, polar organic nitrogen and organic sulfur compounds, oxygen-containing heterocyclic intermediates and polyhydroxy compounds can be obtained. The heterogeneous nucleation of oxidation intermediates in the formation of fine particles is investigated using molecular dynamics simulation. The detailed nucleation processes are reported. According to molecular dynamics simulation, the nucleation with a diameter of 2 nm is formed in the Organic Compounds-(NH4)2SO4-H2O system. The spontaneous nucleation is an important process in the formation of fine particles in atmosphere. The model study gives a good example from volatile organic compounds to new fine particles.
A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties
Authors: Zaini Mohamad A. , Müller Christine , Ackermann Tobias , Reinshagen Jeanette , Kortman Gertrud , Pless Ole , Calkhoven Cornelis F.
Published: February 2017

An important part of the beneficial effects of calorie restriction (CR) on healthspan and lifespan is mediated through regulation of protein synthesis that is under control of the mechanistic target of rapamycin complex 1 (mTORC1). As one of its activities, mTORC1 stimulates translation into the metabolic transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) isoform Liver-specific Inhibitory Protein (LIP). Regulation of LIP expression strictly depends on a translation re-initiation event that requires a conserved cis-regulatory upstream open reading frame (uORF) in the C/EBPβ-mRNA. We showed before that suppression of LIP in mice, reflecting reduced mTORC1-signaling at the C/EBPβ level, results in CR-type of metabolic improvements. Hence, we aim to find possibilities to pharmacologically down-regulate LIP in order to induce CR-mimetic effects. We engineered a luciferase-based cellular reporter system that acts as a surrogate for C/EBPβ-mRNA translation, emulating uORF-dependent C/EBPβ-LIP expression under different translational conditions. By using the reporter system in a high-throughput screening (HTS) strategy we identified drugs that reduce LIP. The drug Adefovir Dipivoxil passed all counter assays and increases fatty acid β-oxidation in a hepatoma cell line in a LIP-dependent manner. Therefore, these drugs that suppress translation into LIP potentially exhibit CR-mimetic properties.
miR-2478 inhibits TGFβ1 expression by targeting the transcriptional activation region downstream of the TGFβ1 promoter in dairy goats
Authors: Li Zhuanjian , Lan Xianyong , Han Ruili , Wang Jing , Huang Yongzhen , Sun Jiajie , Guo Wenjiao , Chen Hong
Published: February 2017

In a previous study, miR-2478 was demonstrated to be up-regulated in dairy goat mammary glands during peak lactation compared with the dry period. However, the detailed mechanisms by which miR-2478 regulates physiological lactation and mammary gland development in dairy goats remain unclear. In this study, we used bioinformatics analysis and homologous cloning to predict the target genes of miR-2478 and selected INSR, FBXO11, TGFβ1 and ING4 as candidate target genes of miR-2478. Subsequently, by targeting the 5′UTR of the TGFβ1 gene, we verified that miR-2478 significantly inhibited TGFβ1 transcription and the Pearson’s correlation coefficient between miR-2478 expression and TGFβ1 expression was −0.98. Furthermore, we identified the potential promoter and transcription factor binding regions of TGFβ1 and analyzed the potential mechanisms of interaction between miR-2478 and TGFβ1. Dual-luciferase reporter assays revealed that two regions, spanning from −904 to −690 bp and from −79 to +197 bp, were transcription factor binding regions of TGFβ1. Interesting, the miR-2478 binding sequence was determined to span from +123 to +142 bp in the TGFβ1 gene promoter. Thus, our results have demonstrated that miR-2478 binds to the core region of the TGFβ1 promoter and that it affects goat mammary gland development by inhibiting TGFβ1 transcription.
Doxorubicin-loaded platelets as a smart drug delivery system: An improved therapy for lymphoma
Authors: Xu Peipei , Zuo Huaqin , Chen Bing , Wang Ruju , Ahmed Arsalan , Hu Yong , Ouyang Jian
Published: February 2017

Chemotherapy is majorly used for the treatment of many cancers, including lymphoma. However, cytotoxic drugs, utilized in chemotherapy, can induce various side effects on normal tissues because of their non-specific distribution in the body. Natural platelets are used as drug carriers because of their biocompatibility and specific targeting to vascular disorders, such as cancer, inflammation, and thrombosis. In this work, doxorubicin (DOX) was loaded in natural platelets for treatment of lymphoma. Results showed that DOX was loaded into platelets with high drug loading and encapsulation efficiency. DOX did not significantly induce morphological and functional changes in platelets. DOX-platelet facilitated intracellular drug accumulation through “tumor cell-induced platelet aggregation” and released DOX into the medium in a pH-controlled manner. This phenomenon reduced the adverse effects and enhanced the therapeutic efficacy. The growth inhibition of lymphoma Raji cells was enhanced, and the cardiotoxicity of DOX was reduced when DOX was loaded in platelets. DOX-platelet improved the anti-tumor activity of DOX by regulating the expression of apoptosis-related genes. Thus, platelets can serve as potential drug carriers to deliver DOX for clinical treatment of lymphoma.
MIAT Is a Pro-fibrotic Long Non-coding RNA Governing Cardiac Fibrosis in Post-infarct Myocardium
Authors: Qu Xuefeng , Du Yue , Shu You , Gao Ming , Sun Fei , Luo Shenjian , Yang Ti , Zhan Linfeng , Yuan Yin , Chu Wenfeng , Pan Zhenwei , Wang Zhiguo , Yang Baofeng , Lu Yanjie
Published: February 2017

A long non-coding RNA (lncRNA), named myocardial infarction associated transcript (MIAT), has been documented to confer risk of myocardial infarction (MI). The aim of this study is to elucidate the pathophysiological role of MIAT in regulation of cardiac fibrosis. In a mouse model of MI, we found that MIAT was remarkably up-regulated, which was accompanied by cardiac interstitial fibrosis. MIAT up-regulation in MI was accompanied by deregulation of some fibrosis-related regulators: down-regulation of miR-24 and up-regulation of Furin and TGF-β1. Most notably, knockdown of endogenous MIAT by its siRNA reduced cardiac fibrosis and improved cardiac function and restored the deregulated expression of the fibrosis-related regulators. In cardiac fibroblasts treated with serum or angiotensin II, similar up-regulation of MIAT and down-regulation of miR-24 were consistently observed. These changes promoted fibroblasts proliferation and collagen accumulation, whereas knockdown of MIAT by siRNA or overexpression of miR-24 with its mimic abrogated the fibrogenesis. Our study therefore has identified MIAT as the first pro-fibrotic lncRNA in heart and unraveled the role of MIAT in the pathogenesis of MI. These findings also promise that normalization of MIAT level may prove to be a therapeutic option for the treatment of MI-induced cardiac fibrosis and the associated cardiac dysfunction.
Circulating classical monocytes are associated with CD11c+ macrophages in human visceral adipose tissue
Authors: Wouters Kristiaan , Gaens Katrien , Bijnen Mitchell , Verboven Kenneth , Jocken Johan , Wetzels Suzan , Wijnands Erwin , Hansen Dominique , van Greevenbroek Marleen , Duijvestijn Adriaan , Biessen Erik A. L. , Blaak Ellen E. , Stehouwer Coen D. A. , Schalkwijk Casper G.
Published: February 2017

Immune cell accumulation in adipose tissue (AT) is associated with the development of AT inflammation, resulting in metabolic dysfunction. Circulating immune cell patterns may reflect immune cell accumulation in expanding AT. However, data linking human leukocytes in blood and AT is lacking. We investigated whether blood immune cell populations are associated with their counterparts in subcutaneous (scAT) or visceral AT (vAT). Flow cytometry was performed on blood, scAT and vAT from 16 lean and 29 obese men. Circulating natural killer (NK)-cells, classical monocytes and nonclassical monocytes were higher in obese individuals. vAT, but not scAT, of obese individuals contained more inflammatory CD11c+ “M1” macrophages and NK cells compared to lean individuals. Blood classical monocytes were associated with CD11c+ macrophages in vAT but not scAT. This association was unrelated to expression of the adhesion molecules CD11b and CD11c or of the chemokine receptor CX3CR1 on these monocytes. Other AT immune cells were not associated with their respective counterparts in blood. Finally, CD11c+ macrophages and CD4+ T-cells in vAT were associated with their counterparts in scAT. In conclusion, blood classical monocytes reflect CD11c+ macrophages in vAT.
Machine-learned approximations to Density Functional Theory Hamiltonians
Authors: Hegde Ganesh , Bowen R. Chris
Published: February 2017

Large scale Density Functional Theory (DFT) based electronic structure calculations are highly time consuming and scale poorly with system size. While semi-empirical approximations to DFT result in a reduction in computational time versus ab initio DFT, creating such approximations involves significant manual intervention and is highly inefficient for high-throughput electronic structure screening calculations. In this letter, we propose the use of machine-learning for prediction of DFT Hamiltonians. Using suitable representations of atomic neighborhoods and Kernel Ridge Regression, we show that an accurate and transferable prediction of DFT Hamiltonians for a variety of material environments can be achieved. Electronic structure properties such as ballistic transmission and band structure computed using predicted Hamiltonians compare accurately with their DFT counterparts. The method is independent of the specifics of the DFT basis or material system used and can easily be automated and scaled for predicting Hamiltonians of any material system of interest.
Mechanistic insight into the substrate specificity of 1,2-β-oligoglucan phosphorylase from Lachnoclostridium phytofermentans
Authors: Nakajima Masahiro , Tanaka Nobukiyo , Furukawa Nayuta , Nihira Takanori , Kodutsumi Yuki , Takahashi Yuta , Sugimoto Naohisa , Miyanaga Akimasa , Fushinobu Shinya , Taguchi Hayao , Nakai Hiroyuki
Published: February 2017

Glycoside phosphorylases catalyze the phosphorolysis of oligosaccharides into sugar phosphates. Recently, we found a novel phosphorylase acting on β-1,2-glucooligosaccharides with degrees of polymerization of 3 or more (1,2-β-oligoglucan phosphorylase, SOGP) in glycoside hydrolase family (GH) 94. Here, we characterized SOGP from Lachnoclostridium phytofermentans (LpSOGP) and determined its crystal structure. LpSOGP is a monomeric enzyme that contains a unique β-sandwich domain (Ndom1) at its N-terminus. Unlike the dimeric GH94 enzymes possessing catalytic pockets at their dimer interface, LpSOGP has a catalytic pocket between Ndom1 and the catalytic domain. In the complex structure of LpSOGP with sophorose, sophorose binds at subsites +1 to +2. Notably, the Glc moiety at subsite +1 is flipped compared with the corresponding ligands in other GH94 enzymes. This inversion suggests the great distortion of the glycosidic bond between subsites −1 and +1, which is likely unfavorable for substrate binding. Compensation for this disadvantage at subsite +2 can be accounted for by the small distortion of the glycosidic bond in the sophorose molecule. Therefore, the binding mode at subsites +1 and +2 defines the substrate specificity of LpSOGP, which provides mechanistic insights into the substrate specificity of a phosphorylase acting on β-1,2-glucooligosaccharides.
Preliminary evidence for a role of the adrenergic nervous system in generalized anxiety disorder
Authors: Zhang Xiaobin , Norton Joanna , Carrière Isabelle , Ritchie Karen , Chaudieu Isabelle , Ryan Joanne , Ancelin Marie-Laure
Published: February 2017

Generalized anxiety disorder (GAD) is a common chronic condition that is understudied compared to other psychiatric disorders. An altered adrenergic function has been reported in GAD, however direct evidence for genetic susceptibility is missing. This study evaluated the associations of gene variants in adrenergic receptors (ADRs) with GAD, with the involvement of stressful events. Data were obtained from 844 French community-dwelling elderly aged 65 or over. Anxiety disorders were assessed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. Eight single-nucleotide polymorphisms (SNPs) involved with adrenergic function were genotyped; adrenergic receptors alpha(1A) (ADRA1A), alpha(2A) (ADRA2A), and beta2 (ADRB2) and transcription factor TCF7L2. Questionnaires evaluated recent stressful life events as well as early environment during childhood and adolescence. Using multivariate logistic regression analyses four SNPs were significantly associated with GAD. A 4-fold modified risk was found with ADRA1A rs17426222 and rs573514, and ADRB2 rs1042713 which remained significant after Bonferroni correction. Certain variants may moderate the effect of adverse life events on the risk of GAD. Replication in larger samples is needed due to the small case number. This is the first study showing that ADR variants are susceptibility factors for GAD, further highlighting the critical role of the adrenergic nervous system in this disorder.
Automated Detection of Malarial Retinopathy in Digital Fundus Images for Improved Diagnosis in Malawian Children with Clinically Defined Cerebral Malaria
Authors: Joshi Vinayak , Agurto Carla , Barriga Simon , Nemeth Sheila , Soliz Peter , MacCormick Ian J. , Lewallen Susan , Taylor Terrie E. , Harding Simon P.
Published: February 2017

Cerebral malaria (CM), a complication of malaria infection, is the cause of the majority of malaria-associated deaths in African children. The standard clinical case definition for CM misclassifies ~25% of patients, but when malarial retinopathy (MR) is added to the clinical case definition, the specificity improves from 61% to 95%. Ocular fundoscopy requires expensive equipment and technical expertise not often available in malaria endemic settings, so we developed an automated software system to analyze retinal color images for MR lesions: retinal whitening, vessel discoloration, and white-centered hemorrhages. The individual lesion detection algorithms were combined using a partial least square classifier to determine the presence or absence of MR. We used a retrospective retinal image dataset of 86 pediatric patients with clinically defined CM (70 with MR and 16 without) to evaluate the algorithm performance. Our goal was to reduce the false positive rate of CM diagnosis, and so the algorithms were tuned at high specificity. This yielded sensitivity/specificity of 95%/100% for the detection of MR overall, and 65%/94% for retinal whitening, 62%/100% for vessel discoloration, and 73%/96% for hemorrhages. This automated system for detecting MR using retinal color images has the potential to improve the accuracy of CM diagnosis.