bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of slow economic growth on health sector reform: a cross-national perspective
Authors: Saltman Richard B. 
Published: January 2018

AbstractThis paper assesses recent health sector reform strategies across Europe adopted since the onset of the 2008 financial crisis. It begins with a brief overview of the continued economic pressure on public funding for health care services, particularly in tax-funded Northern European health care systems. While economic growth rates across Europe have risen a bit in the last year, they remain below the level necessary to provide the needed expansion of public health sector revenues. This continued public revenue shortage has become the central challenge that policymakers in these health systems confront, and increasingly constrains their potential range of policy options. The paper then examines the types of targeted reforms that various European governments have introduced in response to this increased fiscal stringency. Particularly in tax-funded health systems, these efforts have been focused on two types of changes on the production side of their health systems: consolidating and/or centralizing administrative authority over public hospitals, and revamping secondary and primary health services as well as social services to reduce the volume, cost and less-than-optimal outcomes of existing public elderly care programs. While revamping elderly care services also was pursued in the social health insurance (SHI) system in the Netherlands, both the Dutch and the German health systems also made important changes on the financing side of their health systems. Both types of targeted reforms are illustrated through short country case studies. Each of these country assessments flags up new mechanisms that have been introduced and which potentially could be reshaped and applied in other national health sector contexts. Reflecting the tax-funded structure of the Canadian health system, the preponderance of cases discussed focus on tax-funded countries (Norway, Denmark, Sweden, Finland, England, Ireland), with additional brief assessments of recent changes in the SHI-funded health systems in the Netherlands and Germany. The paper concludes that post-2008 European reforms have helped stretch existing public funds more effectively, but seem unlikely to resolve the core problem of inadequate overall public funding, particularly in tax-based health systems. This observation suggests that ongoing Canadian efforts to consolidate and better integrate its health care providers, while important, may not eliminate long-term health sector-funding dilemmas.
The efficacy of life insurance company general account equity asset allocations: a safety-first perspective using vine copulas
Authors: Timmer Ryan , Broussard John Paul , Booth G. Geoffrey 
Published: January 2018

AbstractWe study the asset allocation decision of a life insurance company’s general account with respect to the possibility of large negative economic shocks and examine how this account is affected by policyholder investment decisions in the company’s separate account. This is accomplished using a performance metric that incorporates downside risk measured using univariate and multivariate extreme value distributions. Because of its well-known price volatility, diversification attributes, and significant weight in the combined general and separate accounts, our primary focus is the company’s equity investments. Although industry asset allocations have varied over the past two decades, we find that the actual allocations to equity in the general account are close to the allocation percentages suggested by our extreme value metrics and both are far below the maximum values indicated by the relevant regulatory bodies.
Living apart together—bacterial volatiles influence methanotrophic growth and activity
Authors: Veraart A J , Garbeva P , van Beersum F , Ho A , Hordijk C A , Meima-Franke M , Zweers A J , Bodelier P L E 
Published: January 2018

Abstract
Volatile organic compounds play an important role in microbial interactions. However, little is known about how volatile-mediated interactions modulate biogeochemical processes. In this study, we show the effect of volatile-mediated interaction on growth and functioning of aerobic methane-oxidizing bacteria, grown in co-culture with five different heterotrophs. Both growth and methane oxidation of Methylobacter luteus were stimulated by interaction with specific heterotrophs. In Methylocystis parvus, we observed significant growth promotion, while methane oxidation was inhibited. Volatolomics of the interaction of each of the methanotrophs with Pseudomonas mandelii, revealed presence of a complex blend of volatiles, including dimethylsulfide, dimethyldisulfide, and bicyclic sesquiterpenes. Although the ecological role of the detected compounds remains to be elucidated, our results provide unprecedented insights into interspecific relations and associated volatiles for stimulating methanotroph functioning, which is of substantial environmental and biotechnological significance.
Multifunctional viral protein γ34.5 manipulates nucleolar protein NOP53 for optimal viral replication of HSV-1
Authors: Meng Wen , Han Shi-Chong , Li Cui-Cui , Dong Hui-Jun , Wang Xiao-Jia 
Published: January 2018

AbstractTo ensure efficient virus replication, herpes simplex virus type 1 (HSV-1) encodes several viral proteins to counter host defense response upon infection. Among these proteins, the multifunctional viral protein γ34.5 crucially interferes with or disrupts several antiviral pathways at multiple levels. The current study shows that γ34.5 utilizes nucleolar protein NOP53 to facilitate the dephosphorylation of eukaryotic initiation factor eIF2α for efficient viral translation. Our study shows that: (1) ectopic expression of NOP53 greatly increases the intracellular and extracellular viral yields of HSV-1 (wild strain F) in type I interferon-deficient Vero cells, and more subtly promotes viral replication of γ34.5 deletion mutant virus HSV-1/Δγ34.5. (2) NOP53 is migrated from nuclei in HSV-1/F infected cells, but is redistributed incompletely after infection by either HSV-1/Δγ34.5 or ICP4 deletion mutant virus HSV-1/d120 (replication inadequate). Ectopic expression of γ34.5, consequently, induces cytoplasmic translocation of NOP53 in response to HSV-1/Δγ34.5 infection. (3) Increase of NOP53, in two forms of transient transfection and in vitro expression, attenuates the phosphorylation level of eIF2α in HSV-1/F infected cells, but fails to affect eIF2α phosphorylation induced by HSV-1/Δγ34.5 infection. (4) Knockdown of NOP53, which impairs the specific interaction between γ34.5 and protein phosphatase PP1α, disrupts the ability of γ34.5 to maintain HSV-1 virulence. (5) NOP53 knockdown also significantly reduces tissue damage and decreases viral yield in livers of HSV-1 infected mice. Our findings expand the understanding of the underlying mechanism by which viral protein γ34.5 induces NOP53 redistribution; cytoplasmic NOP53 facilitates γ34.5 recruitment of PP1α to dephosphorylate eIF2α, for optimal viral replication. This paper also demonstrates that blocking the specific interaction between γ34.5 and PP1α would be a useful approach for the development of antiviral agents.
Rosmarinic acid attenuates cardiac fibrosis following long-term pressure overload via AMPKα/Smad3 signaling
Authors: Zhang Xin , Ma Zhen-Guo , Yuan Yu-Pei , Xu Si-Chi , Wei Wen-Ying , Song Peng , Kong Chun-Yan , Deng Wei , Tang Qi-Zhu 
Published: January 2018

AbstractAgonists of peroxisome proliferator-activated receptor gamma (PPAR-γ) can activate 5′ AMP-activated protein kinase alpha (AMPKα) and exert cardioprotective effects. A previous study has demonstrated that rosmarinic acid (RA) can activate PPAR-γ, but its effect on cardiac remodeling remains largely unknown. Our study aimed to investigate the effect of RA on cardiac remodeling and to clarify the underlying mechanism. Mice were subjected to aortic banding to generate pressure overload induced cardiac remodeling and then were orally administered RA (100 mg/kg/day) for 7 weeks beginning 1 week after surgery. The morphological examination, echocardiography, and molecular markers were used to evaluate the effects of RA. To ascertain whether the beneficial effect of RA on cardiac fibrosis was mediated by AMPKα, AMPKα2 knockout mice were used. Neonatal rat cardiomyocytes and fibroblasts were separated and cultured to validate the protective effect of RA in vitro. RA-treated mice exhibited a similar hypertrophic response as mice without RA treatment, but had an attenuated fibrotic response and improved cardiac function after pressure overload. Activated AMPKα was essential for the anti-fibrotic effect of RA via inhibiting the phosphorylation and nuclear translocation of Smad3 in vivo and in vitro, and AMPKα deficiency abolished RA-mediated protective effects. Small interfering RNA against Ppar-γ (siPpar-γ) and GW9662, a specific antagonist of PPAR-γ, abolished RA-mediated AMPKα phosphorylation and alleviation of fibrotic response in vitro. RA attenuated cardiac fibrosis following long-term pressure overload via AMPKα/Smad3 signaling and PPAR-γ was required for the activation of AMPKα. RA might be a promising therapeutic agent against cardiac fibrosis.
Non-alcoholic fatty liver disease phenotypes in patients with inflammatory bowel disease
Authors: Sartini Alessandro , Gitto Stefano , Bianchini Marcello , Verga Maria Chiara , Di Girolamo Maria , Bertani Angela , Del Buono Mariagrazia , Schepis Filippo , Lei Barbara , De Maria Nicola , Villa Erica 
Published: January 2018

AbstractNon-alcoholic fatty liver disease (NAFLD) can be detected in up to 33.6% of inflammatory bowel disease (IBD) patients, often in absence of metabolic risk factors. Nevertheless, most of previous studies on such issue were conducted within the IBD population only. The primary aim of this study was to compare clinical and metabolic features of NAFLD in patients with and without IBD (w/o IBD) and to identify specific NAFLD phenotypes within the IBD population. Among 223 NAFLD patients, 78 patients with IBD were younger compared to 145 without (w/o) IBD, were less likely to have altered liver enzymes, had lower mean body weight, smaller waist circumference and lower body mass index (BMI); at the same time, MetS was more prevalent among patients w/o IBD (56.6 vs. 23.1%, p < 0.001). Within IBD population, patients with severe IBD showed more often severe steatosis (S3) at ultrasound (US) (32.1 vs. 16.6%, p = 0.01), compared to mild-to-moderate disease. Independent risk factors for S3 US steatosis in IBD patients at the multivariate logistic regression analysis were: more than 1 IBD relapse per year during disease history (OR 17.3, 95% CI 3.6–84), surgery for IBD (OR 15.1, 95% CI 3.1–73.7) and more extensive intestinal involvement (OR 19.4, 95% CI 3.4–110.9); the ongoing anti-Tumor Necrosis Factor alpha (antiTNFα) therapy was the only independent factor which protect toward the presence of altered liver enzymes (OR 0.15, 95% CI 0–0.8, p = 0.02). In conclusion, NAFLD in IBD patients is different from that in patients w/o IBD, who seem to develop different NAFLD phenotypes according to intestinal disease clinical course. More severe IBD seem to predict the presence of more severe steatosis. Therapy with antiTNFα antibodies could prevent alteration of liver enzymes in such population.
Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy
Authors: Chen Kehong , Dai Huanzi , Yuan Junjie , Chen Jia , Lin Lirong , Zhang Weiwei , Wang Limin , Zhang Jianguo , Li Kailong , He Yani 
Published: January 2018

AbstractPremature senescence is a key process in the progression of diabetic nephropathy (DN). Premature senescence of renal tubular epithelial cells (RTEC) in DN may result from the accumulation of damaged mitochondria. Mitophagy is the principal process that eliminates damaged mitochondria through PTEN-induced putative kinase 1 (PINK1)-mediated recruitment of optineurin (OPTN) to mitochondria. We aimed to examine the involvement of OPTN in mitophagy regulation of cellular senescence in RTEC in the context of DN. In vitro, the expression of senescence markers P16, P21, DcR2, SA-β-gal, SAHF, and insufficient mitophagic degradation marker (mitochondrial P62) in mouse RTECs increased after culture in 30 mM high-glucose (HG) conditions for 48 h. Mitochondrial fission/mitophagy inhibitor Mdivi-1 significantly enhanced RTEC senescence under HG conditions, whereas autophagy/mitophagy agonist Torin1 inhibited cell senescence. MitoTempo inhibited HG-induced mitochondrial reactive oxygen species and cell senescence with or without Mdivi-1. The expression of PINK1 and OPTN, two regulatory factors for mitophagosome formation, decreased significantly after HG stimulation. Overexpression of PINK1 did not enhance mitophagosome formation under HG conditions. OPTN silencing significantly inhibited HG-induced mitophagosome formation, and overexpression of OPTN relieved cellular senescence through promoting mitophagy. In clinical specimens, renal OPTN expression was gradually decreased with increased tubulointerstitial injury scores. OPTN-positive renal tubular cells did not express senescence marker P16. OPTN expression also negatively correlated with serum creatinine levels, and positively correlated with eGFR. Thus, OPTN-mediated mitophagy plays a crucial regulatory role in HG-induced RTEC senescence in DN. OPTN may, therefore, be a potential antisenescence factor in DN.
Long non-coding RNA and microRNA-675/let-7a mediates the protective effect of melatonin against early brain injury after subarachnoid hemorrhage via targeting TP53 and neural growth factor
Authors: Yang Song , Tang Wanzhong , He Yuchao , Wen Linbao , Sun Bin , Li Shengli 
Published: January 2018

AbstractThe objective of this study was to identify the protective effect of melatonin (MT) against early brain injury (EBI) following subarachnoid hemorrhage (SAH) and explore the underlying molecular mechanism. Real-time polymerase chain reaction (PCR) and luciferase assay were utilized to detect the effect of MT on H19 expression level, computation analysis and luciferase assay were conducted to the underlying mechanism of let-7a and miR-675. Real-time PCR, western blot analysis, immunohistochemistry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and flow cytometry analysis were performed to detect the effect of MT on H19, miR-675, let-7a, TP53, neural growth factor (NGF) levels, cell viability, and apoptosis status. Melatonin increased H19 expression level by enhancing H19 transcriptional efficiency in a concentration-dependent manner. MiR-675 and let-7a directly targeted P53 and NGF, respectively, and miR-675 reduced luciferase activity of wild-type but not mutant TP53 3′UTR. Meanwhile, let-7a suppressed luciferase activity of wild-type but not mutant NGF 3′UTR. H2O2 increased number of SA-b-gal, and while MT administration repressed the premature senescence. H2O2 obviously upregulated expressions of H19, miR-675, and NGF, and downregulated let-7a and TP53 levels; however, MT treatment reduced expressions of H19, miR-675, and NGF, and improved let-7a and TP53 levels. Treating with MT attenuated the neurological deficits and reduced the brain swelling. MT treatment repressed apoptosis of neurons caused by SAH. Levels of H19, miR-675, and NGF were much higher in the SAH +  MT group, while there were even higher levels of H19, miR-675, and NGF in the SAH group than in the sham group; levels of let-7a and TP53 were much lower in the SAH + MT group, while they were even lower in the SAH group than in the sham group. Our study revealed that treatment with MT protected against EBI after SAH by modulating the signaling pathways of H19-miR-675-P53-apoptosis and H19-let-7a-NGF-apoptosis.
MicroRNA-379-5p is associated with biochemical premature ovarian insufficiency through PARP1 and XRCC6
Authors: Dang Yujie , Wang Xiaoyan , Hao Yajing , Zhang Xinyue , Zhao Shidou , Ma Jinlong , Qin Yingying , Chen Zi-Jiang 
Published: January 2018

AbstractPremature ovarian insufficiency (POI) imposes great challenges on women’s fertility and lifelong health. POI is highly heterogeneous and encompasses occult, biochemical, and overt stages. MicroRNAs (miRNAs) are negative regulators of gene expression, whose roles in physiology and diseases like cancers and neurological disorders have been recognized, but little is known about the miRNAs profile and functional relevance in biochemical POI (bPOI). In this study, the expression of miRNAs and mRNAs in granulosa cells (GCs) of bPOI women was determined by two microarrays, respectively. MiR-379-5p, PARP1, and XRCC6 were differentially expressed in GCs of bPOI as revealed by microarrays. Subsequently, functional studies demonstrated that miR-379-5p overexpression inhibited granulosa cell proliferation and attenuated DNA repair efficiency. Furthermore, both PARP1 and XRCC6 showed lower levels in GCs from patients with bPOI and were identified as executives of miR-379-5p. Therefore, our data first uncovered potentially pathogenic miR-379-5p and two novel targets PARP1 and XRCC6 in bPOI, which corroborated the significance of DNA repair for POI, and brought up an epigenetic explanation for the disease.
Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor
Authors: Khandelwal Anuj , Kent Caitlin N. , Balch Maurie , Peng Shuxia , Mishra Sanket J. , Deng Junpeng , Day Victor W. , Liu Weiya , Subramanian Chitra , Cohen Mark , Holzbeierlein Jeffery M. , Matts Robert , Blagg Brian S. J. 
Published: January 2018

AbstractThe 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. pan-Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer that may limit some of the detriments. Described herein is a structure-based approach to design isoform-selective inhibitors of Hsp90β, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90β-selective inhibitors as a method to overcome the detriments associated with pan-inhibition.
A carbon nanotube tape for serial-section electron microscopy of brain ultrastructure
Authors: Kubota Yoshiyuki , Sohn Jaerin , Hatada Sayuri , Schurr Meike , Straehle Jakob , Gour Anjali , Neujahr Ralph , Miki Takafumi , Mikula Shawn , Kawaguchi Yasuo 
Published: January 2018

AbstractAutomated tape-collecting ultramicrotomy in conjunction with scanning electron microscopy (SEM) is a powerful approach for volume electron microscopy and three-dimensional neuronal circuit analysis. Current tapes are limited by section wrinkle formation, surface scratches and sample charging during imaging. Here we show that a plasma-hydrophilized carbon nanotube (CNT)-coated polyethylene terephthalate (PET) tape effectively resolves these issues and produces SEM images of comparable quality to those from transmission electron microscopy. CNT tape can withstand multiple rounds of imaging, offer low surface resistance across the entire tape length and generate no wrinkles during the collection of ultrathin sections. When combined with an enhanced en bloc staining protocol, CNT tape-processed brain sections reveal detailed synaptic ultrastructure. In addition, CNT tape is compatible with post-embedding immunostaining for light and electron microscopy. We conclude that CNT tape can enable high-resolution volume electron microscopy for brain ultrastructure analysis.
Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology
Authors: Fujita Kyota , Chen Xigui , Homma Hidenori , Tagawa Kazuhiko , Amano Mutsuki , Saito Ayumu , Imoto Seiya , Akatsu Hiroyasu , Hashizume Yoshio , Kaibuchi Kozo , Miyano Satoru , Okazawa Hitoshi 
Published: January 2018

AbstractMutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI). Phosphoproteomic analysis of this model revealed activation of signaling pathways connecting PKC and MAPK to tau prior to TDP43 aggregation and cognitive impairments, and identified PKCα as the kinase responsible for the early-stage tau phosphorylation at Ser203. Disinhibition of Gas6 binding to Tyro3 due to PGRN reduction results in activation of PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss. Administration of a PKC inhibitor, B-Raf inhibitor, or knockdown of molecules in the Gas6-Tyro3-tau axis rescues spine loss and cognitive impairment of PGRN-KI mice. Collectively, these results suggest that targeting of early-stage and aggregation-independent tau signaling represents a promising therapeutic strategy for this disease.
Bismuth antimicrobial drugs serve as broad-spectrum metallo-β-lactamase inhibitors
Authors: Wang Runming , Lai Tsz-Pui , Gao Peng , Zhang Hongmin , Ho Pak-Leung , Woo Patrick Chiu-Yat , Ma Guixing , Kao Richard Yi-Tsun , Li Hongyan , Sun Hongzhe 
Published: January 2018

AbstractDrug-resistant superbugs pose a huge threat to human health. Infections by Enterobacteriaceae producing metallo-β-lactamases (MBLs), e.g., New Delhi metallo-β-lactamase 1 (NDM-1) are very difficult to treat. Development of effective MBL inhibitors to revive the efficacy of existing antibiotics is highly desirable. However, such inhibitors are not clinically available till now. Here we show that an anti-Helicobacter pylori drug, colloidal bismuth subcitrate (CBS), and related Bi(III) compounds irreversibly inhibit different types of MBLs via the mechanism, with one Bi(III) displacing two Zn(II) ions as revealed by X-ray crystallography, leading to the release of Zn(II) cofactors. CBS restores meropenem (MER) efficacy against MBL-positive bacteria in vitro, and in mice infection model, importantly, also slows down the development of higher-level resistance in NDM-1-positive bacteria. This study demonstrates a high potential of Bi(III) compounds as the first broad-spectrum B1 MBL inhibitors to treat MBL-positive bacterial infection in conjunction with existing carbapenems.
A peak in the critical current for quantum critical superconductors
Authors: Jung Soon-Gil , Seo Soonbeom , Lee Sangyun , Bauer Eric D. , Lee Han-Oh , Park Tuson 
Published: January 2018

AbstractGenerally, studies of the critical current Ic are necessary if superconductors are to be of practical use, because Ic sets the current limit below which there is a zero-resistance state. Here, we report a peak in the pressure dependence of the zero-field Ic, Ic(0), at a hidden quantum critical point (QCP), where a continuous antiferromagnetic transition temperature is suppressed by pressure toward 0 K in CeRhIn5 and 4.4% Sn-doped CeRhIn5. The Ic(0)s of these Ce-based compounds under pressure exhibit a universal temperature dependence, underlining that the peak in zero-field Ic(P) is determined predominantly by critical fluctuations associated with the hidden QCP. The dc conductivity σdc is a minimum at the QCP, showing anti-correlation with Ic(0). These discoveries demonstrate that a quantum critical point hidden inside the superconducting phase in strongly correlated materials can be exposed by the zero-field Ic, therefore providing a direct link between a QCP and unconventional superconductivity.