bluuebunny/crossref_metadata_2025 huggingface dataset:
Global public goods for health: weaknesses and opportunities in the global health system
Authors: Moon Suerie , Røttingen John-Arne , Frenk Julio
Published: March 2017

Since at least the 1990s, there has been growing recognition that societies need global public goods (GPGs) in order to protect and promote public health. While the term GPG is sometimes used loosely to denote that which is ‘good’ for the global public, we restrict our use of the term to its technical definition (goods that are non-excludable and non-rival in consumption) for its useful analytical clarity. Examples of important GPGs for health include standards and guidelines, research on the causes and treatment of disease, and comparative evidence and analysis. While institutions for providing public goods are relatively well developed at the national level – being clearly recognized as a responsibility of sovereign states – institutional arrangements to do so remain fragmented and thin at the global level. For example, the World Health Organization, mandated to provide many GPGs, is not appropriately financed to do so. Three steps are needed to better govern the financing and provision of GPGs for health: first, improved data to develop a clearer picture of how much money is currently going to providing which types of GPGs; second, a legitimate global political process to decide upon priority missing GPGs, followed by estimates of total amounts needed; and third, financing streams for GPGs from governments and private sources, to be channeled through new or existing institutions. Financing should go toward fully financing some GPGs, complementing or supplementing existing national or international financing for others, or deploying funds to makepotentialGPGs less ‘excludable’ by putting them into the public domain. As globalization deepens the degree of interdependence between countries and as formerly low-income economies advance, there may be less relative need for development assistance to meet basic health care needs, and greater relative need to finance GPGs. Strengthening global arrangements for GPGs today is a worthy investment for improved global health in the years to come.
The challenge of middle-income countries to development assistance for health: recipients, funders, both or neither?
Authors: Ottersen Trygve , Moon Suerie , Røttingen John-Arne
Published: March 2017

Recent developments have transformed the role and characteristics of middle-income countries (MICs). Many stakeholders now question the appropriate role of MICs in the system of development assistance for health (DAH), and key funders have already recast their approach to these countries. The pressing question is whether MICs should be recipients, funders, both or neither. The answer has deep implications for individual countries and their citizens, and for the DAH system as a whole. We clarify the fundamental issues involved and emphasise a special feature of many MICs: mid-level gross national income per capita (GNIpc) combined with substantial health needs and large inequalities. We discuss the trade-off between concerns for capacity and need, and illustrate a capacity-based approach to setting the level of a GNIpc eligibility threshold. We also discuss how needs-based exceptions and incentive-preserving instruments can complement such a threshold. Against this background, we outline options for the future roles of MICs in various circumstances. We conclude that major players in the DAH system have reason to reconsider the criteria for allocating DAH among countries and the norms for which countries should contribute and how much.
Somewhere between Rhetoric and Reality: Environmental Constitutionalism and the Rights of Nature in Ecuador
Authors: Kotzé Louis J. , Villavicencio Calzadilla Paola
Published: March 2017

Today, numerous constitutions provide for a rights-based approach to environmental protection. Based as they are on an instrumentalist rationality that seeks to promote human entitlements to nature, the majority of these rights remain anthropocentric. Although there are growing calls within academic and activist circles to reorient rights alongside an ecocentric ontology, only one country to date has taken the bold step to bestow rights on nature in its constitution. The Ecuadorian Constitution of 2008 announces the transition from a juridical anthropocentric orientation to an ecocentric position by recognizing enforceable rights of nature. This article critically reflects on the legal significance of granting rights to nature, with specific reference to Ecuador’s constitutional experiment. It first provides a contextual description of rights in an attempt to illustrate their anthropogenic genesis, and then explores the notion of environmental rights. The following part traces the discourse that has developed over the years in relation to the rights of nature by revealing aspects of an ecocentric counter-narrative. The final part focuses specifically on the Ecuadorian constitutional regime and provides (i) a historical-contextual discussion of the events that led to the adoption of the rights of nature; (ii) an analysis of the constitutional provisions directly and indirectly related to the rights of nature; and (iii) a critical appraisal of whether those provisions, so far, measure up to the rhetoric of constitutional ecocentric rights of nature in that country.
FTO is required for myogenesis by positively regulating mTOR-PGC-1α pathway-mediated mitochondria biogenesis
Authors: Wang Xiaobo , Huang Ning , Yang Min , Wei Dandan , Tai Haoran , Han Xiaojuan , Gong Hui , Zhou Jiao , Qin Jianqiong , Wei Xiawei , Chen Honghan , Fang Tingting , Xiao Hengyi
Published: March 2017

Global germ line loss of fat mass- and obesity-associated (FTO) gene results in both the reduction of fat mass and lean mass in mice. The role of FTO in adipogenesis has been proposed, however, that in myogenesis has not. Skeletal muscle is the main component of body lean mass, so its connection with FTO physiologic significance need to be clarified. Here, we assessed the impact of FTO on murine skeletal muscle differentiation by in vitro and in vivo experiments. We found that FTO expression increased during myoblasts differentiation, while the silence of FTO inhibited the differentiation; in addition, skeletal muscle development was impaired in skeletal muscle FTO-deficient mice. Significantly, FTO-promoted myogenic differentiation was dependent on its m6A demethylase activity. Mechanically, we found that FTO downregulation suppressed mitochondria biogenesis and energy production, showing as the decreased mitochondria mass and mitochondrial DNA (mtDNA) content, the downregulated expression of mtDNA-encoding genes and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) gene, together with declined ATP level. Moreover, the involvement of mTOR-PGC-1α pathway in the connection between FTO and muscle differentiation is displayed, since the expression of FTO affected the activity of mTOR and rapamycin blocked FTO-induced PGC-1α transcription, along with the parallel alteration pattern of FTO expression and mTOR phosphorylation during myoblasts differentiation. Summarily, our findings provide the first evidence for the contribution of FTO for skeletal muscle differentiation and a new insight to study the physiologic significance of RNA methylation.
The cryo-thermal therapy eradicated melanoma in mice by eliciting CD4+ T-cell-mediated antitumor memory immune response
Authors: He Kun , Liu Ping , Xu Lisa X
Published: March 2017

Tumor metastasis is a major concern in tumor therapy. In our previous studies, a novel tumor therapeutic modality of the cryo-thermal therapy has been presented, highlighting its effect on the suppression of distal metastasis and leading to long-term survival in 4T1 murine mammary carcinoma model. To demonstrate the therapeutic efficacy in other aggressive tumor models and further investigate the mechanism of long-term survival induced, in this study, spontaneous metastatic murine B16F10 melanoma model was used. The cryo-thermal therapy induced regression of implanted melanoma and prolonged long-term survival while inhibiting lung metastasis. It also promoted the activation of CD4+ CD25− conventional T cells, while reduced the percentage of CD4+ CD25+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the spleen, lung and blood. Furthermore, the cryo-thermal therapy enhanced the cytolytic function of CD8+ T cells and induced differentiation of CD8+ T cells into memory stem T cell (TSCM), and differentiation of CD4+ T cells into dominant CD4-CTL, Th1 and Tfh subsets in the spleen for 90 days after the treatment. It was found that good therapeutic effect was mainly dependent on CD4+ T cells providing a durable memory antitumor immune response. At the same time, significant increase of serum IFN-γ was also observed to provide an ideal microenvironment of antitumor immunity. Further study showed that the rejection of re-challenge of B16F10 but not GL261 tumor in the treated mice in 45 or 60 days after the treatment, implied a strong systemic and melanoma-specific memory antitumor immunity induced by the treatment. Thus the cryo-thermal therapy would be considered as a new therapeutic strategy to prevent tumor recurrence and metastasis with potential clinical applications in the near future.
The mTOR signal regulates myeloid-derived suppressor cells differentiation and immunosuppressive function in acute kidney injury
Authors: Zhang Chao , Wang Shuo , Li Jiawei , Zhang Weitao , Zheng Long , Yang Cheng , Zhu Tongyu , Rong Ruiming
Published: March 2017

The mammalian target of rapamycin (mTOR) signal controls innate and adaptive immune response in multiple immunoregulatory contexts. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells of potent immunosuppressive capacity. In this study, we aimed to investigate the role of MDSCs in the protection of acute kidney injury (AKI) and the regulation of mTOR signal on MDSC’s protective role in this context. In mice AKI model, rapamycin administration was associated with improved renal function, restored histological damage and decreased CD4+ and CD8+ T-cell infiltration in kidney tissue. MDSCs, especially CD11b+Ly6G+Ly6Clow G-MDSCs were recruited to the injured kidney following the interaction of CXCL1, CXCL2 and their receptor CXCR2 after inhibiting mTOR signal with rapamycin treatment. The adoptive transfer of rapamycin-treated MDSCs into the mice with AKI significantly improved the renal function, ameliorated histologic damages and limited the infiltration of T cells in kidney tissue. In addition, the expression of pro-inflammatory cytokines IL-1β and IFN-γ mRNA was downregulated while the expression of TGF-β1 and Foxp3 mRNA was upregulated in kidney tissue after transferring rapamycin-treated MDSCs. Adoptive transfer of rapamycin-treated MDSCs also downregulated the serum levels of IL-1β, IL-6 and IFN-γ and upregulated the serum levels of TGF-β1 compared with the IR group and PBS-treated MDSC group. In in vitro study, inhibiting mTOR signal regulated the induction of MDSC towards the CD11b+Ly6G+Ly6Clow G-MDSC subset. The ability to suppress T-cell proliferation of both bone marrow–derived CD11b+Ly6G+Ly6Clow G-MDSCs and CD11b+Ly6G-Ly6Chigh M-MDSCs was enhanced by mTOR signal inhibition via upregulating the expression of Arginase-1 and iNOS. Accordingly, both G-MDSCs and M-MDSCs presented downregulated runx1 gene expression after rapamycin treatment. Taken together, our results demonstrated that MDSCs ameliorated AKI and the protective effect was enhanced by mTOR signal inhibition via promoting MDSCs recruitment, regulating the induction of MDSCs and strengthening their immunosuppressive activity.
Aberrant iPSC-derived human astrocytes in Alzheimer's disease
Authors: Jones V C , Atkinson-Dell R , Verkhratsky A , Mohamet L
Published: March 2017

The pathological potential of human astroglia in Alzheimer's disease (AD) was analysedin vitrousing induced pluripotent stem cell (iPSC) technology. Here, we report development of a human iPSC-derived astrocyte model created from healthy individuals and patients with either early-onset familial AD (FAD) or the late-onset sporadic form of AD (SAD). Our chemically defined and highly efficient model provides >95% homogeneous populations of human astrocytes within 30 days of differentiation from cortical neural progenitor cells (NPCs). All astrocytes expressed functional markers including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-1 (EAAT1), S100B and glutamine synthetase (GS) comparable to that of adult astrocytesin vivo.However, induced astrocytes derived from both SAD and FAD patients exhibit a pronounced pathological phenotype, with a significantly less complex morphological appearance, overall atrophic profiles and abnormal localisation of key functional astroglial markers. Furthermore, NPCs derived from identical patients did not show any differences, therefore, validating that remodelled astroglia are not as a result of defective neural intermediates. This work not only presents a novel model to study the mechanisms of human astrocytesin vitro, but also provides an ideal platform for further interrogation of early astroglial cell autonomous events in AD and the possibility of identification of novel therapeutic targets for the treatment of AD.
Cell-free reconstitution reveals centriole cartwheel assembly mechanisms
Authors: Guichard P. , Hamel V. , Le Guennec M. , Banterle N. , Iacovache I. , Nemčíková V. , Flückiger I. , Goldie K. N. , Stahlberg H. , Lévy D. , Zuber B. , Gönczy P.
Published: March 2017

How cellular organelles assemble is a fundamental question in biology. The centriole organelle organizes around a nine-fold symmetrical cartwheel structure typically ∼100 nm high comprising a stack of rings that each accommodates nine homodimers of SAS-6 proteins. Whether nine-fold symmetrical ring-like assemblies of SAS-6 proteins harbour more peripheral cartwheel elements is unclear. Furthermore, the mechanisms governing ring stacking are not known. Here we develop a cell-free reconstitution system for core cartwheel assembly. Using cryo-electron tomography, we uncover that the Chlamydomonas reinhardtii proteins CrSAS-6 and Bld10p together drive assembly of the core cartwheel. Moreover, we discover that CrSAS-6 possesses autonomous properties that ensure self-organized ring stacking. Mathematical fitting of reconstituted cartwheel height distribution suggests a mechanism whereby preferential addition of pairs of SAS-6 rings governs cartwheel growth. In conclusion, we have developed a cell-free reconstitution system that reveals fundamental assembly principles at the root of centriole biogenesis.
Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines
Authors: Lin Jin-Shun , Wang Fu-Li , Dong Xiao-Yang , He Wei-Wei , Yuan Yue , Chen Su , Liu Xin-Yuan
Published: March 2017

Although great success has been achieved in asymmetric fluoroalkylation reactions via nucleophilic or electrophilic processes, the development of asymmetric radical versions of this type of reactions remains a formidable challenge because of the involvement of highly reactive radical species. Here we report a catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes with commercially available fluoroalkylsulfonyl chlorides as the radical sources, providing a versatile platform to access four types of enantioenriched α-tertiary pyrrolidines bearing β-perfluorobutanyl, trifluoromethyl, difluoroacetyl and even difluoromethyl groups in excellent yields and with excellent enantioselectivity. The key to success is not only the introduction of the CuBr/chiral phosphoric acid dual-catalytic system but also the use of silver carbonate to suppress strong background and side hydroamination reactions caused by a stoichiometric amount of the in situ generated HCl. Broad substrate scope, excellent functional group tolerance and versatile functionalization of the products make this approach very practical and attractive.
Iron minerals within specific microfossil morphospecies of the 1.88 Ga Gunflint Formation
Authors: Lepot Kevin , Addad Ahmed , Knoll Andrew H. , Wang Jian , Troadec David , Béché Armand , Javaux Emmanuelle J.
Published: March 2017

Problematic microfossils dominate the palaeontological record between the Great Oxidation Event 2.4 billion years ago (Ga) and the last Palaeoproterozoic iron formations, deposited 500–600 million years later. These fossils are often associated with iron-rich sedimentary rocks, but their affinities, metabolism, and, hence, their contributions to Earth surface oxidation and Fe deposition remain unknown. Here we show that specific microfossil populations of the 1.88 Ga Gunflint Iron Formation contain Fe-silicate and Fe-carbonate nanocrystal concentrations in cell interiors. Fe minerals are absent in/on all organically preserved cell walls. These features are consistent with in vivo intracellular Fe biomineralization, with subsequent in situ recrystallization, but contrast with known patterns of post-mortem Fe mineralization. The Gunflint populations that display relatively large cells (thick-walled spheres, filament-forming rods) and intra-microfossil Fe minerals are consistent with oxygenic photosynthesizers but not with other Fe-mineralizing microorganisms studied so far. Fe biomineralization may have protected oxygenic photosynthesizers against Fe2+ toxicity during the Palaeoproterozoic.
Patterns of cell cycle checkpoint deregulation associated with intrinsic molecular subtypes of human breast cancer cells
Authors: Bower Jacquelyn J. , Vance Leah D. , Psioda Matthew , Smith-Roe Stephanie L. , Simpson Dennis A. , Ibrahim Joseph G. , Hoadley Katherine A. , Perou Charles M. , Kaufmann William K.
Published: March 2017

Genomic instability is a hallmark of breast cancer, contributes to tumor heterogeneity, and influences chemotherapy resistance. Although Gap 2 and mitotic checkpoints are thought to prevent genomic instability, the role of these checkpoints in breast cancer is poorly understood. Here, we assess the Gap 2 and mitotic checkpoint functions of 24 breast cancer and immortalized mammary epithelial cell lines representing four of the six intrinsic molecular subtypes of breast cancer. We found that patterns of cell cycle checkpoint deregulation were associated with the intrinsic molecular subtype of breast cancer cell lines. Specifically, the luminal B and basal-like cell lines harbored two molecularly distinct Gap 2/mitosis checkpoint defects (impairment of the decatenation Gap 2 checkpoint and the spindle assembly checkpoint, respectively). All subtypes of breast cancer cell lines examined displayed aberrant DNA synthesis/Gap 2/mitosis progression and the basal-like and claudin-low cell lines exhibited increased percentages of chromatid cohesion defects. Furthermore, a decatenation Gap 2 checkpoint gene expression signature identified in the cell line panel correlated with clinical outcomes in breast cancer patients, suggesting that breast tumors may also harbor defects in decatenation Gap 2 checkpoint function. Taken together, these data imply that pharmacological targeting of signaling pathways driving these phenotypes may lead to the development of novel personalized treatment strategies for the latter two subtypes which currently lack targeted therapeutic options because of their triple negative breast cancer status.
Towards Personalized Medicine in Melanoma: Implementation of a Clinical Next-Generation Sequencing Panel
Authors: de Unamuno Bustos Blanca , Murria Estal Rosa , Pérez Simó Gema , de Juan Jimenez Inmaculada , Escutia Muñoz Begoña , Rodríguez Serna Mercedes , Alegre de Miquel Victor , Llavador Ros Margarita , Ballester Sánchez Rosa , Nagore Enguídanos Eduardo , Palanca Suela Sarai , Botella Estrada Rafael
Published: March 2017

Molecular diagnostics are increasingly performed routinely in the diagnosis and management of patients with melanoma due to the development of novel therapies that target specific genetic mutations. The development of next-generation sequencing (NGS) technologies has enabled to sequence multiple cancer-driving genes in a single assay, with improved sensitivity in mutation detection. The main objective of this study was the design and implementation of a melanoma-specific sequencing panel, and the identification of the spectrum of somatic mutations in a series of primary melanoma samples. A custom panel was designed to cover the coding regions of 35 melanoma-related genes. Panel average coverage was 2,575.5 reads per amplicon, with 92,8% of targeted bases covered ≥500×. Deep coverage enabled sensitive discovery of mutations in as low as 0.5% mutant allele frequency. Eighty-five percent (85/100) of the melanomas had at least one somatic mutation. The most prevalent mutated genes were BRAF (50%;50/199), NRAS (15%;15/100), PREX2 (14%;14/100), GRIN2A (13%;13/100), and ERBB4 (12%;12/100). Turn-around-time and costs for NGS-based analysis was reduced in comparison to conventional molecular approaches. The results of this study demonstrate the cost-effectiveness and feasibility of a custom-designed targeted NGS panel, and suggest the implementation of targeted NGS into daily routine practice.
Correction: Corrigendum: Surface mediated cooperative interactions of drugs enhance mechanical forces for antibiotic action
Authors: Ndieyira Joseph W. , Bailey Joe , Patil Samadhan B. , Vögtli Manuel , Cooper Matthew A. , Abell Chris , McKendry Rachel A. , Aeppli Gabriel
Published: March 2017

Scientific Reports 7:Article number: 41206; published online: 03 February 2017; updated: 23 March 2017 This Article contains errors. An additional affiliation for Samadhan B. Patil was omitted. The correct affiliations for this Author are listed below: Departments of Medicine, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London NW3 2QG, UK.
Correction: Corrigendum: Word pair classification during imagined speech using direct brain recordings
Authors: Martin Stephanie , Brunner Peter , Iturrate Iñaki , Millán José del R. , Schalk Gerwin , Knight Robert T. , Pasley Brian N.
Published: March 2017

Scientific Reports 6: Article number: 25803; published online: 11 May 2016; updated: 23 March 2017 This Article contains errors in the order of Figures 1, 2 and 3. Figure 1 was published as Figure 2, Figure 2 was published as Figure 3 and Figure 3 was published as Figure 1. The correct Figures appear below.
The theory of parallel climate realizations as a new framework for teleconnection analysis
Authors: Herein Mátyás , Drótos Gábor , Haszpra Tímea , Márfy János , Tél Tamás
Published: March 2017

Teleconnections are striking features of the Earth climate system which appear as statistically correlated climate-related patterns between remote geographical regions of the globe. In a changing climate, however, the strength of teleconnections might change, and an appropriate characterization of these correlations and their change (more appropriate than detrending the time series) is lacking in the literature. Here we present a novel approach, based on the theory of snapshot attractors, corresponding in our context to studying parallel climate realizations. Imagining an ensemble of parallel Earth systems, instead of the single one observed (i.e., the real Earth), the ensemble, after some time, characterizes the appropriate probabilities of all options permitted by the climate dynamics, reflecting the internal variability of the climate. We claim that the relevant quantities for characterizing teleconnections in a changing climate are correlation coefficients taken over the temporally evolving ensemble in any time instant. As a particular example, we consider the teleconnections of the North Atlantic Oscillation (NAO). In a numerical climate model, we demonstrate that this approach provides the only statistically correct characterization, in contrast to commonly used temporal correlations evaluated along single detrended time series. The teleconnections of the NAO are found to survive the climate change, but their strength might be time-dependent.
Erratum: Finding Stable Graphene Conformations from Pull and Release Experiments with Molecular Dynamics
Authors: Yamaletdinov Ruslan D. , Pershin Yuriy V.
Published: March 2017

Scientific Reports 7: Article number: 42356; published online: 14 February 2017; updated: 23 March 2017 This Article contains an error in the Acknowledgements section. “This work has been supported by the Russian Scientific Foundation grant No. 15-13-20021”. should read: “This work has been supported by the Russian Science Foundation grant No.
The Endoplasmic Reticulum Chaperone GRP78/BiP Modulates Prion Propagation in vitro and in vivo
Authors: Park Kyung-Won , Eun Kim Gyoung , Morales Rodrigo , Moda Fabio , Moreno-Gonzalez Ines , Concha-Marambio Luis , Lee Amy S. , Hetz Claudio , Soto Claudio
Published: March 2017

Prion diseases are fatal neurodegenerative disorders affecting several mammalian species, characterized by the accumulation of the misfolded form of the prion protein, which is followed by the induction of endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR). GRP78, also called BiP, is a master regulator of the UPR, reducing ER stress levels and apoptosis due to an enhancement of the cellular folding capacity. Here, we studied the role of GRP78 in prion diseases using several in vivo and in vitro approaches. Our results show that a reduction in the expression of this molecular chaperone accelerates prion pathogenesis in vivo. In addition, we observed that prion replication in cell culture was inversely related to the levels of expression of GRP78 and that both proteins interact in the cellular context. Finally, incubation of PrPSc with recombinant GRP78 led to the dose-dependent reduction of protease-resistant PrPScin vitro. Our results uncover a novel role of GRP78 in reducing prion pathogenesis, suggesting that modulating its levels/activity may offer a novel opportunity for designing therapeutic approaches for these diseases. These findings may also have implications for other diseases involving the accumulation of misfolded proteins.
Protection against oxidative stress mediated by the Nrf2/Keap1 axis is impaired in Primary Biliary Cholangitis
Authors: Wasik Urszula , Milkiewicz Małgorzata , Kempinska-Podhorodecka Agnieszka , Milkiewicz Piotr
Published: March 2017

In response to oxidative stress, nuclear factor (erythroid-derived 2)-like2 (Nrf2) induces expression of cytoprotective genes. The Nrf2 pathway is controlled by microRNAs and Kelch-like ECH-associated protein1 (Keap1).Nrf2 is stabilized when Keap1 isdegraded through the autophagy pathway in a p62-dependent manner. The inhibition of autophagy causes protein accumulation, and Keap1 is inactivated by binding to p62. We investigated the role of the Nrf2/Keap1 axis in the amelioration of oxidative stress in primary biliary cholangitis (PBC). Liver specimens from patients with PBC, with (n = 24) or without cirrhosis (n = 14), and from controls (n = 16) were used for molecular analyses. We found that Nrf2 protein levels were elevated in PBC compared to controls, but Nrf2 gene expression was significantly reduced in cirrhotic PBC. Nrf2 target gene products, HO-1 and GCLC proteins, were reduced compared to controls and reduction of Nrf2 gene expression was associated with elevated levels of microRNA-132 and microRNA-34a. Both Keap1 and p62 protein levels were substantially increased in PBC compared to controls. PBC was associated with reduced Nrf2 expression and autophagy deterioration and these impairments were more advanced in patients with cirrhosis. Aberrant Nrf2/Keap1 system integrity may affect self-defence mechanisms against oxidative stress in PBC.
BAP31 is involved in T cell activation through TCR signal pathways
Authors: Niu Kunwei , Xu Jialin , Cao Yuhua , Hou Yue , Shan Mu , Wang Yanqing , Xu Yang , Sun Mingyi , Wang Bing
Published: March 2017

BAP31 is a ubiquitously expressed endoplasmic reticulum (ER) membrane protein. The functions of BAP31 in the immune system have not been investigated due to the lack of animal models. Therefore we created a BAP31 conditional knockdown mouse by performing a knockdown of BAP31 in the thymus. In doing so, we demonstrate that the maturation of T cells is normal but the number of T cells is less in the thymus of the knockout mouse. In addition, the spleen and lymph nodes of peripheral immune organs contained a lesser proportion of the mature T cells in the thymus specific BAP31 knockout mice. The BAP31 knockout T cells decreased the proliferation activated by TCR signal pathways. Further studies clarified that BAP31 affects the phosphorylation levels of both Zap70/Lck/Lat of the upstream members and Akt/GSK/Jnk/Erk of the downstream members of TCR signal pathways. Furthermore, BAP31 can regulate the expression of some markers such as CD3/TCRα/TCRβ and some cytokines like IL-2/IFN-γ/IL-6/TNF-α which are important for T cell activation. Taken together, these results demonstrate that BAP31 may play an important role in T cell activation by regulating TCR signaling.
New insights on the biomineralisation process developing in human lungs around inhaled asbestos fibres
Authors: Bardelli Fabrizio , Veronesi Giulia , Capella Silvana , Bellis Donata , Charlet Laurent , Cedola Alessia , Belluso Elena
Published: March 2017

Once penetrated into the lungs of exposed people, asbestos induces an in vivo biomineralisation process that leads to the formation of a ferruginous coating embedding the fibres. The ensemble of the fibre and the coating is referred to as asbestos body and is believed to be responsible for the high toxicological outcome of asbestos. Lung tissue of two individuals subjected to prolonged occupational exposure to crocidolite asbestos was investigated using synchrotron radiation micro-probe tools. The distribution of K and of elements heavier than Fe (Zn, Cu, As, and Ba) in the asbestos bodies was observed for the first time. Elemental quantification, also reported for the first time, confirmed that the coating is highly enriched in Fe (~20% w/w), and x-ray absorption spectroscopy indicated that Fe is in the 3+ oxidation state and that it is present in the form of ferritin or hemosiderin. Comparison of the results obtained studying the asbestos bodies upon removing the biological tissue by chemical digestion and those embedded in histological sections, allowed unambiguously distinguishing the composition of the asbestos bodies, and understanding to what extent the digestion procedure altered their chemical composition. A speculative model is proposed to explain the observed distribution of Fe.
Pupillary responses in non-proliferative diabetic retinopathy
Authors: Park Jason C. , Chen Yi-Fan , Blair Norman P. , Chau Felix Y. , Lim Jennifer I. , Leiderman Yannek I. , Shahidi Mahnaz , McAnany J. Jason
Published: March 2017

The goal of this study was to determine the extent of rod-, cone-, and melanopsin-mediated pupillary light reflex (PLR) abnormalities in diabetic patients who have non-proliferative diabetic retinopathy (NPDR). Fifty diabetic subjects who have different stages of NPDR and 25 age-equivalent, non-diabetic controls participated. PLRs were measured in response to full-field, brief-flash stimuli under conditions that target the rod, cone, and intrinsically-photosensitive (melanopsin) retinal ganglion cell pathways. Pupil responses were compared among the subjects groups using age-corrected linear mixed models. Compared to control, the mean baseline pupil diameters were significantly smaller for all patient groups in the dark (all p < 0.001) and for the moderate-severe NPDR group in the light (p = 0.003). Pairwise comparisons indicated: (1) the mean melanopsin-mediated PLR was significantly reduced in the mild and moderate-severe groups (both p < 0.001); (2) the mean cone-mediated PLR was reduced significantly in the moderate-severe group (p = 0.008); (3) no significant differences in the mean rod-mediated responses. The data indicate abnormalities in NPDR patients under conditions that separately assess pupil function driven by different photoreceptor classes. The results provide evidence for compromised neural function in these patients and provide a promising approach for quantifying their neural abnormalities.
LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway
Authors: Cuevas Eva P. , Eraso Pilar , Mazón María J. , Santos Vanesa , Moreno-Bueno Gema , Cano Amparo , Portillo Francisco
Published: March 2017

Epithelial-to-Mesenchymal Transition (EMT) is a key process contributing to the aggressiveness of cancer cells. EMT is triggered by activation of different transcription factors collectively known as EMT-TFs. Different cellular cues and cell signalling networks activate EMT at transcriptional and posttranscriptional level in different biological and pathological situations. Among them, overexpression of LOXL2 (lysyl oxidase-like 2) induces EMT independent of its catalytic activity. Remarkably, perinuclear/cytoplasmic accumulation of LOXL2 is a poor prognosis marker of squamous cell carcinomas and is associated to basal breast cancer metastasis by mechanisms no yet fully understood. Here, we report that overexpression of LOXL2 promotes its accumulation in the Endoplasmic Reticulum where it interacts with HSPA5 leading to activation of the IRE1-XBP1 signalling pathway of the ER-stress response. LOXL2-dependent IRE1-XBP1 activation induces the expression of several EMT-TFs: SNAI1, SNAI2, ZEB2 and TCF3 that are direct transcriptional targets of XBP1. Remarkably, inhibition of IRE1 blocks LOXL2-dependent upregulation of EMT-TFs thus hindering EMT induction.
Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer
Authors: Hsu Hsien-Yeh , Lin Tung-Yi , Lu Mei-Kuang , Leng Pei-Ju , Tsao Shu-Ming , Wu Yu-Chung
Published: March 2017

Fucoidan, a sulfated polysaccharide extracted from brown algae, exhibits anti-cancer activity. However, the effects and mechanism of fucoidan-induced apoptosis via endoplasmic reticulum (ER) stress is unclear. In this study, we demonstrated that fucoidan prevents tumorigenesis and reduces tumor size in LLC1-xenograft male C57BL/6 mice. Fucoidan induces an ER stress response by activating the PERK-ATF4-CHOP pathway, resulting in apoptotic cell death in vitro and in vivo. Furthermore, ATF4 knockdown abolishes fucoidan-induced CHOP expression and rescues cell viability. Specifically, fucoidan increases intracellular reactive oxygen species (ROS), which increase ATF4 and CHOP in lung cancer cells. Using the ROS scavenger N-acetyl-l-cysteine (NAC), we found that ROS generation is involved in fucoidan-induced ER stress-mediated apoptosis. Moreover, via Toll-like receptor 4 (TLR4) knockdown, we demonstrated that fucoidan-induced ROS and CHOP expression were attenuated. Our study is the first to identify a novel mechanism for the antitumor activity of fucoidan. We showed that fucoidan inhibits tumor viability by activating the TLR4/ROS/ER stress axis and the downstream PERK-ATF4-CHOP pathway, leading to apoptosis and suppression of lung cancer cell progression. Together, these results indicate that fucoidan is a potential preventive and therapeutic agent for lung cancer that acts via activation of ROS-dependent ER stress pathways.
Differential effects of face-realism and emotion on event-related brain potentials and their implications for the uncanny valley theory
Authors: Schindler Sebastian , Zell Eduard , Botsch Mario , Kissler Johanna
Published: March 2017

Cartoon characters are omnipresent in popular media. While few studies have scientifically investigated their processing, in computer graphics, efforts are made to increase realism. Yet, close approximations of reality have been suggested to evoke sometimes a feeling of eeriness, the “uncanny valley” effect. Here, we used high-density electroencephalography to investigate brain responses to professionally stylized happy, angry, and neutral character faces. We employed six face-stylization levels varying from abstract to realistic and investigated the N170, early posterior negativity (EPN), and late positive potential (LPP) event-related components. The face-specific N170 showed a u-shaped modulation, with stronger reactions towards both most abstract and most realistic compared to medium-stylized faces. For abstract faces, N170 was generated more occipitally than for real faces, implying stronger reliance on structural processing. Although emotional faces elicited highest amplitudes on both N170 and EPN, on the N170 realism and expression interacted. Finally, LPP increased linearly with face realism, reflecting activity increase in visual and parietal cortex for more realistic faces. Results reveal differential effects of face stylization on distinct face processing stages and suggest a perceptual basis to the uncanny valley hypothesis. They are discussed in relation to face perception, media design, and computer graphics.
Superhydrophobic hBN-Regulated Sponges with Excellent Absorbency Fabricated Using a Green and Facile Method
Authors: Zhou Ying , Wang Yao , Liu Tengfei , Xu Gang , Chen Guangming , Li Huayi , Liu Lichun , Zhuo Qiqi , Zhang Jiaoxia , Yan Chao
Published: March 2017

The world faces severe environmental, human and ecological problems when major oil spills and organic discharges are released into the environment. And so it is imperative to develop tools and high performance innovative materials that can efficiently absorb these organic discharges. Furthermore, green, facile methods to produce these advanced materials are also needed. In this paper, we demonstrate a novel porous supersponge based on melamine coated with hBN. This superhydrophobic sponge (with a contact angle >150°) exhibits excellent absorption performance for oils and organic solvents, including good selectivity, high capacity (up to 175 g·g−1) and extraordinary recyclability (less than 20% decline after 30 cycles of absorption/squeezing). The synthetic procedure required only ultrasonication and immersion of the sponge in aqueous hBN solution, being a green, cost-effective and scalable production methodology. By virtue of the straightforward and cost-effective fabrication method, along with the excellent absorption performance, hBN-decorated sponges have great promise for real world practical application in the field of oil spills and organic leakage cleanup.
Evaluation of the Immunomodulatory Activity of the Chicken NK-Lysin-Derived Peptide cNK-2
Authors: Kim Woo H. , Lillehoj Hyun S. , Min Wongi
Published: March 2017

Chicken NK-lysin (cNK-lysin), the chicken homologue of human granulysin, is a cationic amphiphilic antimicrobial peptide (AMP) that is produced by cytotoxic T cells and natural killer cells. We previously demonstrated that cNK-lysin and cNK-2, a synthetic peptide incorporating the core α-helical region of cNK-lysin, have antimicrobial activity against apicomplexan parasites such as Eimeria spp., via membrane disruption. In addition to the antimicrobial activity of AMPs, the immunomodulatory activity of AMPs mediated by their interactions with host cells is increasingly recognized. Thus, in this study, we investigated whether cNK-lysin derived peptides modulate the immune response in the chicken macrophage cell line HD11 and in chicken primary monocytes by evaluating the induction of chemokines, anti-inflammatory properties, and activation of signalling pathways. cNK-2 induced the expression of CCL4, CCL5 and interleukin(IL)-1β in HD11 cells and CCL4 and CCL5 in primary monocytes. We also determined that cNK-2 suppresses the lipopolysaccharide-induced inflammatory response by abrogating IL-1β expression. The immunomodulatory activity of cNK-2 involves the mitogen-activated protein kinases-mediated signalling pathway, including p38, extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinases, as well as the internalization of cNK-2 into the cells. These results indicate that cNK-2 is a potential novel immunomodulating agent rather than an antimicrobial agent.
Integrative variants, haplotypes and diplotypes of the CAPN3 and FRMD5 genes and several environmental exposures associate with serum lipid variables
Authors: Guo Tao , Yin Rui-Xing , Pan Ling , Yang Shuo , Miao Liu , Huang Feng
Published: March 2017

To determine whether the integrative variants, haplotypes and diplotypes of the calpain 3 (CAPN3) and the FERM domain containing 5 genes (FRMD5) and several environmental exposures are associated with an implication in lipid homeostasis, which are associated with cardiovascular risk. Genotyping of the CAPN3 rs4344713 and FRMD5 rs524908 was performed by Sanger sequencing in 1,640 subjects (Jing, 819 and Han, 821). Multivariate analyses of covariance models that adjusted by age, gender, body mass index (BMI), blood pressure and lifestyle (smoking and drinking), were constructed using variants, haplotypes and diplotypes of the CAPN3 rs4344713 and FRMD5 rs524908 as predictors and changes in lipid variables. Significant associations with low-density lipoprotein cholesterol and apolipoprotein (Apo) B were found. Linkage disequilibrium with each other showed the haplotype-phenotype associations with triglyceride and ApoA1. This study also suggested pleiotropic associations of the CAPN3-FRMD5 diplotypes with lipid variables. As potential confounders, diastolic blood pressure (DBP) and BMI were significantly associated with lipid variables. We conclude that integrative variants, haplotypes and diplotypes of the CAPN3 rs4344713 and FRMD5 rs524908, as well as DBP and BMI are associated with serum lipid variables in the Jing and Han populations.
Lumican effectively regulates the estrogen receptors-associated functional properties of breast cancer cells, expression of matrix effectors and epithelial-to-mesenchymal transition
Authors: Karamanou Konstantina , Franchi Marco , Piperigkou Zoi , Perreau Corinne , Maquart Francois-Xavier , Vynios Demitrios H. , Brézillon Stéphane
Published: March 2017

Lumican is a small leucine-rich proteoglycan that has been shown to contribute in several physiological processes, but also to exert anticancer activity. On the other hand, it has been recently shown that knockdown of the estrogen receptor α (ERα) in low invasive MCF-7 (ERα+) breast cancer cells and the suppression of ERβ in highly aggressive MDA-MB-231 (ERβ+) cells significantly alter the functional properties of breast cancer cells and the gene expression profile of matrix macromolecules related to cancer progression and cell morphology. In this report, we evaluated the effects of lumican in respect to the ERs-associated breast cancer cell behaviour, before and after suppression of ERs, using scanning electron and confocal microscopies, qPCR and functional assays. Our data pinpointed that lumican significantly attenuated cell functional properties, including proliferation, migration and invasion. Furthermore, it modified cell morphology, inducing cell-cell junctions, evoked EMT/MET reprogramming and suppressed the expression of major matrix effectors (matrix metalloproteinases and EGFR) implicated in breast cancer progression. The effects of lumican were found to be related to the type of breast cancer cells and the ERα/β type. These data support the anticancer activity of lumican and open a new area for the pharmacological targeting of the invasive breast cancer.
Improved lysis efficiency and immunogenicity of Salmonella ghosts mediated by co-expression of λ phage holin-endolysin and ɸX174 gene E
Authors: Won Gayeon , Hajam Irshad Ahmed , Lee John Hwa
Published: March 2017

Bacterial ghosts (BGs) are empty cell envelopes derived from Gram-negative bacteria by bacteriophage ɸX174 gene E mediated lysis. They represent a novel inactivated vaccine platform; however, the practical application of BGs for human vaccines seems to be limited due to the safety concerns on the presence of viable cells in BGs. Therefore, to improve the lysis efficiency of the gene E, we exploited the peptidoglycan hydrolyzing ability of the λ phage holin-endolysins to expedite the process of current BG production system. In this report, we constructed a novel ghost plasmid encoding protein E and holin-endolysins in tandem. We observed that sequential expressions of the gene E and the holin-endolysins elicited rapid and highly efficient Salmonella lysis compared to the lysis mediated by gene E only. These lysed BGs displayed improved immunogenicity in mice compared to the gene E mediated BGs. Consequently, seventy percent of the mice immunized with these novel ghosts survived against a lethal challenge while all the mice vaccinated with gene E mediated ghosts died by day 9 post-infection. We conclude that this novel strategy has the potential to generate highly efficient inactivated candidate vaccines that could replace the currently available bacterial vaccines.
Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents
Authors: Wang Jinfeng , Zhang Lin , Pan Xiaoyan , Dai Bingling , Sun Ying , Li Chuansheng , Zhang Jie
Published: March 2017

Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents with BPS-7 as lead compound through combining diarylureas with N-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate that N-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis.
Hierarchical meso/macro-porous carbon fabricated from dual MgO templates for direct electron transfer enzymatic electrodes
Authors: Funabashi Hiroto , Takeuchi Satoshi , Tsujimura Seiya
Published: March 2017

We designed a three-dimensional (3D) hierarchical pore structure to improve the current production efficiency and stability of direct electron transfer-type biocathodes. The 3D hierarchical electrode structure was fabricated using a MgO-templated porous carbon framework produced from two MgO templates with sizes of 40 and 150 nm. The results revealed that the optimal pore composition for a bilirubin oxidase-catalysed oxygen reduction cathode was a mixture of 33% macropores and 67% mesopores (MgOC33). The macropores improve mass transfer inside the carbon material, and the mesopores improve the electron transfer efficiency of the enzyme by surrounding the enzyme with carbon.