bluuebunny/crossref_metadata_2025_split 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

AbstractSince 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

AbstractRecent 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

AbstractToday, 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

AbstractGlobal 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

AbstractTumor 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

AbstractThe 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

AbstractThe 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

AbstractHow 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

AbstractAlthough 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

AbstractProblematic 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

AbstractGenomic 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

AbstractMolecular 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.
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

AbstractTeleconnections 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.