bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioinspired Synthesis of Cu2+‐Modified Covalent Triazine Framework: A New Highly Efficient and Promising Peroxidase Mimic
Authors: Xiong Yuhao , Qin Yuemei , Su Linjing , Ye Fanggui
Published: May 2017

Artificial enzymes is an emerging field of research owing to the remarkable advantages of enzyme mimics over their natural counterpart, including tunable catalytic efficiencies, lower cost, ease of preparation, and excellent tolerance to variations of the reaction system. Herein, we report an efficient peroxidase mimic based on a copper‐modified covalent triazine framework (CCTF). Owing to its unique specific surface area, atomically dispersed active Cu sites, efficient electron transfer, and enhanced photo‐assisted enzyme‐like activity, the CCTF showed enhanced peroxidase‐like enzyme activity. Therefore, copper modification represents an effective route to tailor the peroxidase‐like activity of the covalent triazine frameworks. Furthermore, the mechanism of the enhanced peroxidase‐like activity and stability of the CCTF were investigated. As a proof of concept, the CCTF was used for the colorimetric detection of H2O2 and decomposition of organic pollutants. This work provides a new strategy for the design of enzyme mimics with a broad range of potential applications.
Primary Human Lung Alveolus‐on‐a‐chip Model of Intravascular Thrombosis for Assessment of Therapeutics
Authors: Jain A , Barrile R , van der Meer AD , Mammoto A , Mammoto T , De Ceunynck K , Aisiku O , Otieno MA , Louden CS , Hamilton GA , Flaumenhaft R , Ingber DE
Published: May 2017

Pulmonary thrombosis is a significant cause of patient mortality; however, there are no effective in vitro models of thrombi formation in human lung microvessels that could also assess therapeutics and toxicology of antithrombotic drugs. Here, we show that a microfluidic lung alveolus‐on‐a‐chip lined by human primary alveolar epithelium interfaced with endothelium and cultured under flowing whole blood can be used to perform quantitative analysis of organ‐level contributions to inflammation‐induced thrombosis. This microfluidic chip recapitulates in vivo responses, including platelet‐endothelial dynamics and revealed that lipopolysaccharide (LPS) endotoxin indirectly stimulates intravascular thrombosis by activating the alveolar epithelium, rather than acting directly on endothelium. This model is also used to analyze inhibition of endothelial activation and thrombosis due to a protease activated receptor‐1 (PAR‐1) antagonist, demonstrating its ability to dissect complex responses and identify antithrombotic therapeutics. Thus, this methodology offers a new approach to study human pathophysiology of pulmonary thrombosis and advance drug development.
Effect of withdrawal rate transition on microstructural features of a single crystal Ni‐based superalloy
Authors: Sadeghi Fazlollah , Kermanpur Ahmad , Heydari Davoud , Bahmani Majid
Published: May 2017

The effect of withdrawal rate transition during Bridgman directional solidification on microstructural aspects of a single crystal Ni‐based superalloy was investigated under both constant and changing withdrawal regimes. Variations of primary and secondary dendrite arm spacing (PDAS and SDAS, respectively) and crystal orientation were investigated using optical microscopy and electron backscattered diffraction (EBSD) techniques. The results showed a gradual decreasing trend in PDAS and SDAS by sudden increasing of withdrawal rate. Changes on PDAS was quantified as history‐dependent such that for a given secondary withdrawal rate, a higher PDAS was found for a lower initial withdrawal rate. The withdrawal rate transition showed a direct influence on crystal orientation.
Evolution of microstructure of niobium carbide NbC0.77 powders
Authors: Kurlov A. S. , Gusev A. I. , Rempel A. A. , Kuznetsov V. S. , Bobrikov I. A. , Balagurov A. M.
Published: May 2017

The microstructural evolution of annealed nonstoichiometric niobium carbide NbC0.77 powders subjected to high‐energy ball milling has been investigated by time‐of‐flight (TOF) high resolution neutron diffraction. The diffraction patterns have been collected with the high resolution Fourier diffractometer HRFD by using the TOF mode of data acquisition. The nanocrystalline powders produced by high‐energy milling have an inhomogeneous microstructure, in which two fractions with different particle size and composition can be identified. The average sizes of the coherent scattering regions and microstrains in nanocrystallites with allowance for the anisotropy of the deformation distortions have been estimated. It is shown that TOF neutron diffraction patterns can provide the very accurate data for microstructure analysis of nanocrystalline powders. No superstructure has been observed in the annealed NbC0.77 carbide.
Prognostic potential of midregional pro‐adrenomedullin following decompensation for systolic heart failure: comparison with cardiac natriuretic peptides
Authors: Morbach Caroline , Marx Almuth , Kaspar Mathias , Güder Gülmisal , Brenner Susanne , Feldmann Carolin , Störk Stefan , Vollert Jörn O. , Ertl Georg , Angermann Christiane E. ,   on behalf of the INH Study Group and the Competence Network Heart Failure
Published: May 2017

Aims

Whereas guidelines recommend the routine use of natriuretic peptides (NPs) in heart failure (HF) care, the clinical relevance and prognostic potential of midregional pro‐adrenomedullin (MR‐proADM) is less well established. We aimed to compare the prognostic potential of MR‐proADM after acute decompensation for systolic HF with that of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and midregional pro‐atrial NP (MR‐proANP), to investigate the significance of high/rising MR‐proADM, and to evaluate the incremental prognostic yield of repeat measurements.

Methods and results

The Interdisciplinary Network Heart Failure (INH) programme enrolled patients hospitalized for acute systolic HF and followed them for 18 months (100% complete). Of 1022 INH participants, 917 (68 ± 12 years, 28% female) who had biomaterials available were enrolled. High MR‐proADM was associated with more impaired left ventricular function, higher comorbidity burden, lower doses of HF medications, and lower likelihood of left ventricular reverse remodelling. Compared with NPs, MR‐proADM had superior prognostic significance (concordance index 0.72 for all‐cause mortality), improved Cox regression models including NPs (P < 0.001), and was the only biomarker also predicting non‐cardiac death (hazard ratio 1.8 vs. 1.0). In the setting of low NPs, patients with high MR‐proADM experienced non‐cardiac death more often. Six month MR‐proADM enhanced models including baseline MR‐proADM (P < 0.001) for prediction of all‐cause death (net reclassification index: 0.48, 95% confidence interval 0.19–0.78).

Conclusion

MR‐proADM was found to correlate with the global disease burden in HF and proved a potent prognostic indicator, capturing the risk for both cardiac and non‐cardiac death. Serial MR‐proADM measurements further enhanced risk assessment, thus facilitating substantial reclassification.
New insights on the relative contributions of coastal processes and tectonics to shore platform development following the Kaikōura earthquake
Authors: Stephenson Wayne J. , Dickson Mark E. , Denys Paul H.
Published: May 2017

We describe the immediate impact of the 14 November 2016 Kaikōura magnitude 7.8 (Mw) earthquake on shore platforms and cliffs around Kaikōura Peninsula. The earthquake caused an instantaneous uplift of ~1.01 m of the peninsula. We resurveyed seven profiles previously used for erosion monitoring and observed changes in the configuration of the shoreline. The coseismic uplift has fundamentally changed the process regime operating on the platforms and altered the future trajectory of shore platform and cliff development. Our observations highlight the interplay of waves, weathering, biology and tectonics. At this location tectonism strongly modulates the process regime, driving instantaneous changes in morphology and altering rates and patterns of erosion. Finally, the uplift of the Kaikōura coast has implications for changing resilience to climate change and sea level rise. Copyright © 2017 John Wiley & Sons, Ltd.
Toward solving the etiological mystery of primary biliary cholangitis
Authors: Tanaka Atsushi , Leung Patrick S.C. , Young Howard A. , Gershwin M. Eric
Published: May 2017

Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature anti‐mitochondrial antibody (AMA) autoantibody, female predominance, and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens recognized by AMA have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relatively high concordance rate in identical twins, genome‐wide association studies have not proven clinically useful and have led to suggestions of epigenetic events. To understand the natural history and etiology of PBC, several murine models have been developed, including spontaneous models, models induced by chemical xenobiotic immunization, and by “designer” mice with altered interferon metabolism. Herein, we describe five such models, including 1) NOD.c3c4 mice, 2) dominant negative form of transforming growth factor receptor type II mice, 3) interleukin‐2R α−/− mice, 4) adenylate‐uridylate‐rich element Del−/− mice, and 5) 2‐octynoic acid‐conjugated bovine serum albumin immunized mice. Individually there is no perfect murine model, but collectively the models point to loss of tolerance to PDC‐E2, the major mitochondrial autoantigen, as the earliest event that occurs before clinical disease is manifest. Although there is no direct association of AMA titer and PBC disease progression, it is noteworthy that the triad of PBC monocytes, biliary apotopes, and AMA leads to an intense proinflammatory cytokine burst. Further, the recurrence of PBC after liver transplantation indicates that, due to major histocompatibility complex restriction, disease activity must include not only adaptive immunity but also innate immune mechanisms. We postulate that successful treatment of PBC may require a personalized approach with therapies designed for different stages of disease. (Hepatology Communications 2017;1:275–287)
Genie in a blotter: A comparative study of LSD and LSD analogues' effects and user profile
Authors: Coney Leigh D. , Maier Larissa J. , Ferris Jason A. , Winstock Adam R. , Barratt Monica J.
Published: May 2017

Objective

This study aimed to describe self‐reported patterns of use and effects of lysergic acid diethylamide (LSD) analogues (AL‐LAD, 1P‐LSD, and ETH‐LAD) and the characteristics of those who use them.

Methods

An anonymous self‐selected online survey of people who use drugs (Global Drug Survey 2016; N = 96,894), which measured perceived drug effects of LSD and its analogues.

Results

Most LSD analogue users (91%) had also tried LSD. The proportion of U.K. and U.S. respondents reporting LSD analogue use in the last 12 months was higher than for LSD only. LSD analogue users described the effects as psychedelic (93%), over half (55%) obtained it online, and almost all (99%) reported an oral route of administration. The modal duration (8 hr) and time to peak (2 hr) of LSD analogues were not significantly different from LSD. Ratings for pleasurable high, strength of effect, comedown, urge to use more drugs, value for money, and risk of harm following use were significantly lower for LSD analogues compared with LSD.

Conclusions

LSD analogues were reported as similar in time to peak and duration as LSD but weaker in strength, pleasurable high, and comedown. Future studies should seek to replicate these findings with chemical confirmation and dose measurement.
Long Noncoding RNA GAS5 Suppresses Cell Growth and Epithelial–Mesenchymal Transition in Osteosarcoma by Regulating the miR‐221/ARHI Pathway
Authors: Ye Kaishan , Wang Shuanke , Zhang Haihong , Han Hua , Ma Bing , Nan Wei
Published: May 2017

Dysregulated long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play key roles in the development of human cancers. The lncRNA growth arrest‐specific 5 (GAS5) is reported to be a tumor suppressor in multiple cancers. However, the roles of GAS5 and its related miRNAs in osteosarcoma are poorly understood. This study explored the potential functions and mechanisms of GAS5 in the tumorigenesis of osteosarcoma. Here, the expression of GAS5, miR‐221 and aplasia Ras homologue member I (ARHI) was determined in osteosarcoma tissues and cells by Real‐time PCR (RT‐qPCR). The underlying mechanism of GAS5 in osteosarcoma growth was analyzed via MTT, Transwell, RT‐qPCR, Western blot, dual‐luciferase reporter assay, RNA immunoprecipitation, and xenograft models after GAS5 overexpression. GAS5 and ARHI levels were significantly reduced, while miR‐221 increased, both in osteosarcoma tissues and cells. Overexpression of GAS5 suppressed the proliferation, migration, and epithelial–mesenchymal transition (EMT) of osteosarcoma cells. GAS5 could directly bind to miR‐221 to decrease miR‐221 expression and enhance ARHI expression. The effect of GAS5 overexpression on the proliferation, migration and EMT was reversed by miR‐221 mimics or ARHI siRNA in osteosarcoma cells. Additionally, GAS5 suppressed tumor volume, Ki‐67 and PCNA staining, and EMT process in the development of osteosarcoma in vivo. Taken together, lncRNA GAS5 functions as a competing endogenous RNA for miR‐221 to suppress cell growth and EMT in osteosarcoma by regulating the miR‐221/ARHI pathway. J. Cell. Biochem. 118: 4772–4781, 2017. © 2017 Wiley Periodicals, Inc.
S‐Adenosylmethionine‐mediated apoptosis is potentiated by autophagy inhibition induced by chloroquine in human breast cancer cells
Authors: Cave Donatella Delle , Desiderio Vincenzo , Mosca Laura , Ilisso Concetta P. , Mele Luigi , Caraglia Michele , Cacciapuoti Giovanna , Porcelli Marina
Published: May 2017

The naturally occurring sulfonium compound S‐adenosyl‐L‐methionine (AdoMet) is an ubiquitous sulfur‐nucleoside that represents the main methyl donor in numerous methylation reactions. In recent years, it has been shown that AdoMet possesses antiproliferative properties in various cancer cells, but the molecular mechanisms at the basis of the effect induced by AdoMet have been only in part investigated. In the present study, we found that AdoMet strongly inhibited the proliferation of breast cancer cells MCF‐7 by inducing both autophagy and apoptosis. AdoMet consistently enhanced the levels of the autophagy markers beclin‐1 and LC3B‐II, and caused a significant increase of pro‐apoptotic Bax/Bcl‐2 ratio paralleled by poly (ADP ribose) polymerase (PARP) and caspase 9, and 6 cleavage. Notably, AdoMet, already at low doses, raised the percentage of cells in G2/M phase of cell cycle by down‐regulating the expression of cell cycle‐regulatory proteins cyclin B and cyclin E with a remarkable increase of p53, p27, and p21. We also evaluated the combination of AdoMet and the autophagy inhibitor chloroquine (CLC) showing that autophagy block is synergistic in inducing both growth inhibition and apoptosis. These effects were paralleled by a strong inhibition of the activity of AKT and of the downstream effector mTOR and by an increased cleavage of caspase‐6 and PARP. These data suggest, for the first time, that autophagy can act as an escape mechanism from the apoptotic activity of AdoMet, and that AdoMet could be used in combination with CLC or its analogs in the treatment of breast cancer.
Intercentrum versus pleurocentrum growth in early tetrapods: A paleohistological approach
Authors: Danto Marylène , Witzmann Florian , Pierce Stephanie E. , Fröbisch Nadia B.
Published: May 2017

A variety of vertebral centrum morphologies have evolved within early tetrapods which range from multipartite centra consisting of intercentra and pleurocentra in stem‐tetrapods, temnospondyls, seymouriamorphs, and anthracosaurs up to monospondylous centra in lepospondyls. With the present study, we aim to determine the formation of both intercentrum and pleurocentrum and asked whether these can be homologized based on their bone histology. Both intercentra and pleurocentra ossified endochondrally and periosteal bone was subsequently deposited on the outer surface of the centra. Our observations indicate low histological variation between intercentrum and pleurocentrum in microstructural organization and growth which inhibits the determination of homologies. However, intercentrum and pleurocentrum development differs during ontogeny. As previously assumed, the intercentrum arises from ventrally located and initially paired ossification centers that fuse ventromedially to form the typical, crescentic, rhachitomous intercentrum. In contrast, presacral pleurocentra may be ancestrally represented by four ossification centers: a ventral and a dorsal pair. Subsequently, two divergent developmental patterns are observed: In stem‐tetrapods and temnospondyls, the pleurocentrum evolves from the two dorsally located ossification centers which may occasionally fuse to form a dorsal crescent. In some dvinosaurian temnospondyls, the pleurocentrum may even ossify to full rings. In comparison, the pleurocentrum of stem‐amniotes (anthracosaurs, chroniosuchids, seymouriamorphs, and lepospondyls) arises from the two ventrally located ossification centers whereby the ossification pattern is almost identical to that of temnospondyls but mirror‐inverted. Thus, the ring‐shaped pleurocentrum of Discosauriscus ossifies from ventral to dorsal. We also propose that the ossified portions of the intercentrum and pleurocentrum continued as cartilaginous rings or discs that surrounded the notochord in the living animals.
Proteomic analysis of Lupinus angustifolius (var. Zeus and Bojar) and Lupinus luteus (var. Lord and Parys) seed proteins and their hydrolysates
Authors: Czubinski Jaroslaw , Montowska Magdalena , Pospiech Edward , Lampart‐Szczapa Eleonora
Published: May 2017

BACKGROUND

Proteins enzymatic digestion is a very complex process, during which some components are degraded, whereas others remain in an unchanged form. Moreover, enzymatic hydrolysis is one of the most popular methods used to reduce the allergenicity of food proteins. In the present study, the efficiency of enzymatic hydrolysis of lupin seed proteins was assessed by proteomic analysis as performed by two‐dimensional gel electrophoresis (2‐DE) coupled with mass spectrometry identification. Two digestion systems were used: oriented digestion carried out by trypsin and model in vitro digestion mimicking the conditions present in the gastrointestinal tract.

RESULTS

The comparisons of 2‐DE maps of proteins isolated form different lupin seed species revealed that the differences in proteins expression were observed mainly in the central parts of gels (i.e. in the molecular weight range from 20 to 70 kDa, and the pH range 5–7). In total, 27 differentially expressed proteins spots were successfully identified by mass spectrometry analysis. An important reduction in the number of proteins spots on 2‐DE maps was observed when trypsin and the in vitro digestion model were applied. The protein spot insensitive to digestion in both hydrolysis systems was identified as β‐conglutin.

CONCLUSIONS

The results of the present study provide insight into the nature of the digestion process that may take place after lupin seed protein intake and highlight the important fact that some of the proteins are insensitive to digestive enzyme activity. Moreover, evaluation of digestion activity of trypsin towards lupin seed proteins may be used for the development of specific processes with respect to hypoallergenic food production. © 2017 Society of Chemical Industry
Predation on Atlantic herring (Clupea harengus) eggs by the resident predator community in coastal transitional waters
Authors: Kotterba Paul , Moll Dorothee , Hammer Cornelius , Peck Myron A. , Oesterwind Daniel , Polte Patrick
Published: May 2017

Atlantic herring (Clupea harengus) migrates from offshore to coastal areas to spawn and their eggs and larvae may substantially increase prey resources for resident predators. We combined an in situ predator exclusion experiment using eggs naturally spawned on submerged aquatic vegetation and field observations of predator abundance to estimate the magnitude of predation mortality of herring eggs. During our predator exclusion experiment, performed in an important spawning ground in the southwest Baltic Sea, 20% of the herring eggs were consumed resulting in an extrapolated predation of 42% of all eggs between spawning and hatch. Abundance and stomach content analyses indicated that one predator (threespine stickleback, Gasterosteus aculeatus) was responsible for the majority of the predation impact. Predation mortality estimates from this in situ study were more than 10‐fold higher than those of an empirical egg predation model for the same predator in the same region. Our findings highlight the potential of resident predators to regulate the survival of early life stages of ocean‐going fishes that rely on the nursery functions of inshore transitional waters.
Stress, deflection, and frequency analysis of CNT reinforced graded sandwich plate under uniform and linear thermal environment: A finite element approach
Authors: Mehar Kulmani , Panda Subrata Kumar , Patle Bhumesh K.
Published: May 2017

The frequency, deflection, and stress values of carbon nanotube reinforced sandwich plate structure is investigated numerically under the influence of the mechanical loading and thermal field. The effective properties of individual components of sandwich structure (face sheet and core layer) are assumed to be temperature‐dependent and modeled via thermoelastic constitutive relations. In addition, the distribution of carbon nanotube through the thickness of the face sheets are assumed to follow the rule based grading pattern. Further, the sandwich structural panel modeled using the extant high‐order shear deformation kinematic theory for the mathematical purpose. The desired structural responses (frequency, deflection and stress) obtained numerically through a generic finite element based computer code developed in MATLAB. The convergence criteria and the accuracy of the current high‐order finite element solutions have been assessed by solving a sufficient number of numerical examples. Lastly, the influences of structural parameters (core to face thickness ratios, carbon nanotube fractions, type of loading, aspect ratios, end constraints, length to thickness ratios, type of carbon nanotube gradings, and type of temperature gradings) on the transverse deflection and frequencies of carbon nanotube‐reinforced sandwich structure are obtained under the elevated thermal field and the subsequent conclusions discussed accordingly. POLYM. COMPOS., 39:3792–3809, 2018. © 2017 Society of Plastics Engineers
Development of an alginate hydrogel to deliver aqueous bait for pest ant management
Authors: Tay Jia‐Wei , Hoddle Mark S , Mulchandani Ashok , Choe Dong‐Hwan
Published: May 2017

BACKGROUND

Insecticide sprays used for ant control cause environmental contamination. Liquid bait is a safe and effective alternative, but it requires bait stations to dispense the toxicant. We developed a biodegradable hydrogel to deliver liquid bait obviating the need for bait stations.

RESULTS

Alginate hydrogel beads with preferred rigidity and maximum hydration in 25% sucrose solution were engineered by optimizing a crosslinking process. The moisture content of the substrate on which the beads were placed and the relative atmospheric humidity significantly influenced water loss dynamics of the hydrated hydrogel beads. Laboratory choice studies indicated that hydrated hydrogel beads had reduced palatability to foraging ants when they lost ≥50% water. An enzyme‐linked immunosorbent assay (ELISA) indicated that the insecticide thiamethoxam added to sucrose solution was absorbed into the hydrogel beads. Hydrogel beads conditioned in sucrose solution with 1 mg L–1 thiamethoxam provided complete control of all castes of Argentine ant Linepithema humile (Mayr) colony by 14 days post treatment in the laboratory trial and provided a 79% reduction in ant activity after 8 weeks in the field trial.

CONCLUSION

Alginate hydrogel beads provided an effective delivery system for liquid baits laced with low concentrations of insecticide to control Argentine ants. © 2017 Society of Chemical Industry
Birefringence in GaN epitaxial layers and GaN microrods
Authors: Trenkmann Ines , Uhlig Lukas , Wachs Matthias , Mounir Christian , Schwarz Ulrich T.
Published: May 2017

Light propagating through a birefringent material undergoes a change of the state of polarization. In this article, we demonstrate the application of the non‐invasive method of conoscopy to analyze the birefringence of c‐plane GaN. For thick GaN bulk layers, the difference Δn between the ordinary and extraordinary refractive index results in a modification of the state of polarization from linear to elliptical to circular and back to orthogonally linear polarization within a few degree variation of the internal angle propagation. Measurements of thin epitaxial GaN layers on c‐plane sapphire show the strong influence of the sapphire substrate to the observed changes of the state of polarization.
Size selection from fishways and potential evolutionary responses in a threatened Atlantic salmon population
Authors: Maynard G. A. , Kinnison M. T. , Zydlewski J. D.
Published: May 2017

The evolutionary effects of harvest on wild fish populations have been documented around the world; however, sublethal selective pressures can also cause evolutionary changes in phenotypes. For migratory fishes, passage facilities may represent instances of nonlethal selective pressure. Our analysis of 6 years of passage data suggests that certain fish passage facilities on the Penobscot River have been exerting selective pressure against large‐bodied, anadromous Atlantic salmon (Salmo salar). At the second and third dams in the river, a 91‐cm salmon was 21%–27% and 12%–16% less likely to pass than a 45‐cm salmon, respectively. Fish size positively influences egg survival and number and is a heritable trait. Therefore, in a wild‐reproducing population, exclusion of large fish from spawning areas may have population‐level impacts. In the Penobscot River, most returning adults derive from a hatchery program that collects its broodstock after passing the first dam in the river. Analysis of fork lengths of salmon returning to the Penobscot River from 1978 to 2012 provided mixed support for evolution of size at maturity in different age classes in a pattern that may be expected from interactions with conservation hatchery operations. Additionally, slow‐maturing and iteroparous individuals that represent the largest salmon size classes were essentially lost from the population during that time, and Penobscot River fish have shorter fork lengths at maturity than Atlantic salmon in undammed systems.
Elevated expression of CST1 promotes breast cancer progression and predicts a poor prognosis
Authors: Dai Da-nian , Li Yan , Chen Bo , Du Yong , Li Shi-bing , Lu Shi-xun , Zhao Zhi-ping , Zhou Ai-jun , Xue Ning , Xia Tian-liang , Zeng Mu-sheng , Zhong Qian , Wei Wei-dong
Published: May 2017

Cystatin SN (CST1) belongs to the type 2 cystatin (CST) superfamily, which restricts the proteolytic activities of cysteine proteases. CST1 has been recently considered to be involved in the development of several human cancers. However, the prognostic significance and function of CST1 in breast cancer remains unknown. In the current study, we found that CST1 was generally upregulated in breast cancer at both mRNA and protein level. Furthermore, overall survival (OS) and disease-free survival (DFS) in the low CST1 expression subgroup were significantly superior to the high CST1 expression subgroup (OS, p < 0.001; DFS, p < 0.001), which indicated that CST1 expression level was closely correlated to the survival risk of these patients. Univariate and multivariate analyses demonstrated that CST1 expression was an independent prognostic factor, the same as ER status and nodal status. Next, CST1 overexpression promoted breast cancer cell proliferation, clonogenicity, migration, and invasion abilities. By contrast, knockdown of CST1 attenuated these malignant characteristics in breast cancer cells. Collectively, our study indicates that CST1 cannot only serve as a significant prognostic indicator but also as a potential therapeutic target for breast cancer.

Key messages

High CST1 expression is negatively correlated with survival of breast cancer patients.

CST1 promotes cell proliferation, clone formation, and metastasis in breast cancer cells.

CST1 is a novel potential prognostic biomarker and therapeutic target for breast cancer.
Extracellular low‐n oligomers of tau cause selective synaptotoxicity without affecting cell viability
Authors: Kaniyappan Senthilvelrajan , Chandupatla Ram Reddy , Mandelkow Eva‐Maria , Mandelkow Eckhard
Published: May 2017

Introduction

Tau‐mediated toxicity in Alzheimer's disease is thought to operate through low‐n oligomers, rather than filamentous aggregates. However, the nature of oligomers and pathways of toxicity are poorly understood. Therefore, we investigated structural and functional aspects of highly purified oligomers of a pro‐aggregant tau species.

Methods

Purified oligomers of the tau repeat domain were characterized by biophysical and structural methods. Functional aspects were investigated by cellular assays ((3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay of cell viability, lactate dehydrogenase release assay [for cell toxicity], reactive oxygen species production, and calcium assay), combined with analysis of neuronal dendritic spines exposed to oligomers.

Results

Purified low‐n oligomers are roughly globular, with sizes around 1.6 to 5.4 nm, exhibit an altered conformation, but do not have substantial β‐structure. Treatment of primary neurons with oligomers impairs spine morphology and density, accompanied by increased reactive oxygen species and intracellular calcium, but without affecting cell viability (by (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay of cell viability and lactate dehydrogenase release assay [for cell toxicity]).

Discussion

Tau oligomers are toxic to synapses but not lethal to cells.
Electronic Health Record Transition Considerations
Authors: Penrod Louis E.
Published: May 2017

After an initial phase of electronic health record (EHR) solutions for both independent practices and larger health care organizations, we are now entering a period in which transitioning between EHRs is becoming more common. Many of the decisions and implementation processes for an EHR transition are similar to those encountered during the transition from paper records to an EHR. Detailed project planning and management are essential to keep the effort on track and within budget to a successful conclusion. One major difference between the 2 situations is the possibility of migrating patient data by using automation. Understanding the implications of structured and unstructured data to manage the data migration between EHR systems is important to ensure success of the effort. Access to legacy data after the transition for both patient care and release of information to external parties is also critical to understand and manage proactively.
New technology in nutrition research and practice
Authors: Brennan Lorraine , McNulty Breige
Published: May 2017

Recent technology advancements are aiding the development of scientific discoveries and changing the methods by which we perform research. In order to gain full benefits for human health, it will be important to embrace these new technologies in nutrition research while also acknowledging their limitations. The present issue covers a range of technological approaches that impact on public health nutrition and molecular nutrition. The critical appraisal of these approaches in the context of nutrition research makes this issue a timely and pertinent addition to the scientific literature.
Negotiating Positive Non-interventionism: Regulating Hong Kong's Finance Companies, 1976–1986
Authors: Schenk Catherine R.
Published: May 2017

Since colonial times to the present day, Hong Kong's position as a global financial centre is one of the enduring economic strengths of the territory. This success is often attributed to the distinctive role of the state, coined in the 1970s by the-then financial secretary, Sir Philip Haddon-Cave, as “positive non-interventionism.” The relationship between the market and the state has also been characterized as a form of corporatism, particularly in the financial sector as bankers were able to influence policy. However, closer examination of the behind-the-scenes relations between bankers and the state reveals a much more complex relationship, with the banks seeking protection that the government was not willing to provide. Moreover, the reluctance to regulate financial markets resulted in piecemeal interventions and weak implementation that undermined the stability of this sector and of the economy as a whole. This paper demonstrates the confusion over the concept and practicalities of positive non-interventionism, even for Haddon-Cave, and how the concept evolved towards a policy of “when in doubt, do nothing” during a period of financial instability. Along the way, the paper presents new evidence about the origins of Hong Kong's current banking structure.
Key drivers of patient experience in ambulatory paediatric cardiology
Authors: Allam Shalini D. , Mehta Mary , Ben Khallouq Bertha , Burrows James F. , Rosen Paul
Published: May 2017

Patient experience is becoming a central focus of healthcare. A broad range of studies on how to increase patient satisfaction ratings exists; however, they lack the specificity to adequately guide physicians and hospitals on how to improve patient experience. The objective of this study was to define the aspects of patient experience within paediatric cardiologist practices that can serve as predictors of excellent patient satisfaction. From 1 January, 2013 to 28 February, 2015 (26 months), outpatients who visited paediatric cardiologists were asked to complete a 39-question patient satisfaction survey regarding their experience. Surveys were collected over a 26-month period by Press Ganey, an independent provider of patient satisfaction surveys. Participants were asked to rate their experience on a 1–5 Likert-scale: a score of 1 demonstrated a “poor” experience, whereas a score of 5 demonstrated a “very good” experience. This retrospective study of 2468 responses determined that cheerfulness of the practice (r=0.85, p<0.001), a cohesive staff (r=0.83, p<0.001), and a care provider explaining problems and conditions (r=0.81, p<0.001) were key aspects of a paediatric cardiologist’s practice that can be used as predictors of overall patient satisfaction. Awareness of how doctors can personalise a patient’s experience is vital to achieve greater patient satisfaction and, ultimately, better patient outcomes.
Cross-cultural adaptation and validation of the Newest Vital Sign (NVS) health literacy instrument in general population and highly educated samples of Brazilian adults
Authors: Rodrigues Renne , de Andrade Selma Maffei , González Alberto Durán , Birolim Marcela Maria , Mesas Arthur Eumann
Published: May 2017

Objective

The present work aimed at cross-cultural adaptation and validation of the health literacy assessment tool Newest Vital Sign (NVS) in general population (GP) and highly educated (HE) samples of Brazilian adults.

Design

An expert committee reviewed the translation and back-translation processes and the cultural adaptation. The construct validity was analysed with confirmatory factor analysis and via associations with features of the study population.

Setting

The final validation test was performed in two different populations from Londrina, a large town in southern Brazil.

Subjects

Brazilian adults: GP (adult clients of community pharmacies;n189) and HE (public school teachers;n301).

Results

The tool under validation showed good cross-cultural adaptation and internal consistency, with Cronbach’sαof 0·75 for GP and 0·74 for HE. Confirmatory factor analysis showed acceptable models and identified two independent factors according to the relationship between components and numeracy for both GP and HE data. According to the Brazilian Portuguese version of the NVS instrument (NVS-BR), 48·7 % of GP and 33·5 % of HE presented adequate health literacy; this condition was inversely associated with age for both populations and directly correlated with educational level for GP.

Conclusions

The NVS-BR showed good validity in two different populations of Brazilian adults and can be considered an alternative in screening for inadequate health literacy.
How Gullible are We? A Review of the Evidence from Psychology and Social Science
Authors: Mercier Hugo
Published: May 2017

A long tradition of scholarship, from ancient Greece to Marxism or some contemporary social psychology, portrays humans as strongly gullible—wont to accept harmful messages by being unduly deferent. However, if humans are reasonably well adapted, they should not be strongly gullible: they should be vigilant toward communicated information. Evidence from experimental psychology reveals that humans are equipped with well-functioning mechanisms of epistemic vigilance. They check the plausibility of messages against their background beliefs, calibrate their trust as a function of the source's competence and benevolence, and critically evaluate arguments offered to them. Even if humans are equipped with well-functioning mechanisms of epistemic vigilance, an adaptive lag might render them gullible in the face of new challenges, from clever marketing to omnipresent propaganda. I review evidence from different cultural domains often taken as proof of strong gullibility: religion, demagoguery, propaganda, political campaigns, advertising, erroneous medical beliefs, and rumors. Converging evidence reveals that communication is much less influential than often believed—that religious proselytizing, propaganda, advertising, and so forth are generally not very effective at changing people's minds. Beliefs that lead to costly behavior are even less likely to be accepted. Finally, it is also argued that most cases of acceptance of misguided communicated information do not stem from undue deference, but from a fit between the communicated information and the audience's preexisting beliefs.
MiR-130a-3p attenuates activation and induces apoptosis of hepatic stellate cells in nonalcoholic fibrosing steatohepatitis by directly targeting TGFBR1 and TGFBR2
Authors: Wang Yang , Du Jinghua , Niu Xuemin , Fu Na , Wang Rongqi , Zhang Yuguo , Zhao Suxian , Sun Dianxing , Nan Yuemin
Published: May 2017

Nonalcoholic fibrosing steatohepatitis is a uniform process that occurs throughout nonalcoholic fatty liver disease (NAFLD). MicroRNAs (miRNAs) have been shown to be involved in the biological processes, but the role and molecular mechanism of miRNAs in NAFLD are not entirely clear. In this study, we observed a significant reduction in the expression of miR-130a-3p in livers of a mouse model with fibrosis induced by a methionine–choline-deficient diet, of NAFLD patients, and in activated hepatic stellate cells (HSCs). A dual-luciferase activity assay confirmed that transforming growth factor-beta receptors (TGFBRs) 1 and 2 were both the target genes of miR-130a-3p. The hepatic expression of TGFBR1 and TGFBR2 was significantly increased. Moreover, the overexpression of miR-130a-3p in HSCs inhibited HSC activation and proliferation, concomitant with the decreased expression of TGFBR1, TGFBR2, Smad2, Smad3, matrix metalloproteinase-2 (MMP-2), MMP-9, type I collagen (Col-1), and Col-4. In addition, the overexpression of miR-130a-3p promoted HSC apoptosis by inducing the expression of caspase-dependent apoptosis genes. Transfection with si-TGFBR1 and si-TGFBR2 revealed effects on HSC function that were consistent with those of miR-130a-3p. TGFBR1 and TGFBR2 rescued the miR-130a-3p-mediated reductions in the mRNA and protein expression levels of Smad2, Smad3, Col-1, and Col-4. In conclusion, our findings suggest that miR-130a-3p might play a critical role in negatively regulating HSC activation and proliferation in the progression of nonalcoholic fibrosing steatohepatitis by directly targeting TGFBR1 and TGFBR2 via the TGF-β/SMAD signaling pathway.
MiR-106b and miR-93 regulate cell progression by suppression of PTEN via PI3K/Akt pathway in breast cancer
Authors: Li Nana , Miao Yuan , Shan Yujia , Liu Bing , Li Yang , Zhao Lifen , Jia Li
Published: May 2017

Accumulating evidences have revealed that dysregulated microRNAs (miRNAs) involve in the tumorigenesis, progression and even lead to poor prognosis of various carcinomas, including breast cancer. MiRNA-106b-5p (miR-106b) and miRNA-93-5p (miR-93) levels were confirmed to be significantly upregulated in breast cancer clinical samples (n=36) and metastatic cell line (MDA-MB-231) compared with those in the paired adjacent tissues and normal breast epithelial cell line (MCF-10A). Moreover, further research stated that the capability of migration, invasion and proliferation changed along with the altered expression of miR-106b and miR-93 in breast cancer. PTEN, the tumor-suppressor gene, was discovered to be reduced in breast cancer tissues or MDA-MB-231 cells with high levels of miR-106b and miR-93, which were inversely expressed in PTEN overexpression tissues or cells. Based on the investigation, miR-106b and miR-93 induced the migration, invasion and proliferation and simultaneously enhanced the activity of phosphatidylinositol-3 kinase (PI3K)/Akt pathway of MCF-7 cells, which could be blocked by upregulation of PTEN. Furthermore, suppression of PTEN reversed the function induced by anti-miR-106b and anti-miR-93 in MDA-MB-231 cells, indicating that PTEN was directly targeted by these miRNAs and acted as the potential therapeutic target for breast cancer therapy. In short, reductive PTEN mediated by miR-106b and miR-93 promoted cell progression through PI3K/Akt pathway in breast cancer.
Acyl-CoA thioesterase 7 is involved in cell cycle progression via regulation of PKCζ–p53–p21 signaling pathway
Authors: Jung Seung Hee , Lee Hyung Chul , Hwang Hyun Jung , Park Hyun A , Moon Young-Ah , Kim Bong Cho , Lee Hyeong Min , Kim Kwang Pyo , Kim Yong-Nyun , Lee Byung Lan , Lee Jae Cheol , Ko Young-Gyu , Park Heon Joo , Lee Jae-Seon
Published: May 2017

Acyl-CoA thioesterase 7 (ACOT7) is a major isoform of the ACOT family that catalyzes hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH. However, canonical and non-canonical functions of ACOT7 remain to be discovered. In this study, for the first time, ACOT7 was shown to be responsive to genotoxic stresses such as ionizing radiation (IR) and the anti-cancer drug doxorubicin in time- and dose-dependent manners. ACOT7 knockdown induced cytostasis via activation of the p53–p21 signaling pathway without a DNA damage response. PKCζ was specifically involved in ACOT7 depletion-mediated cell cycle arrest as an upstream molecule of the p53–p21 signaling pathway in MCF7 human breast carcinoma and A549 human lung carcinoma cells. Of the other members of the ACOT family, including ACOT1, 4, 8, 9, 11, 12, and 13 that were expressed in human, ACOT4, 8, and 12 were responsive to genotoxic stresses. However, none of those had a role in cytostasis via activation of the PKCζ–p53–p21 signaling pathway. Analysis of the ACOT7 prognostic value revealed that low ACOT7 levels prolonged overall survival periods in breast and lung cancer patients. Furthermore, ACOT7 mRNA levels were higher in lung cancer patient tissues compared to normal tissues. We also observed a synergistic effect of ACOT7 depletion in combination with either IR or doxorubicin on cell proliferation in breast and lung cancer cells. Together, our data suggest that a low level of ACOT7 may be involved, at least in part, in the prevention of human breast and lung cancer development via regulation of cell cycle progression.
Cycloheximide promotes paraptosis induced by inhibition of cyclophilins in glioblastoma multiforme
Authors: Wang Lin , Gundelach Justin H , Bram Richard J
Published: May 2017

Cancer is the second leading cause of death worldwide. Current treatment strategies based on multi-agent chemotherapy and/or radiation regimens have improved overall survival in some cases. However, resistance to apoptosis often develops in cancer cells, and its occurrence is thought to contribute to treatment failure. Non-apoptotic cell death mechanisms have become of great interest, therefore, in hopes that they would bypass tumor cell resistance. Glioblastoma multiforme (GBM), a grade IV astrocytic tumor is the most frequent brain tumor in adults, and has a high rate of mortality. We report that NIM811, a small molecule cyclophilin-binding inhibitor, induces catastrophic vacuolization and cell death in GBM cells. These unique features are distinct from many known cell death pathways, and are associated with an incompletely defined cell death mechanism known as paraptosis. We found that NIM811-induced paraptosis is due to unresolved ER stress. The abnormal upregulation of protein translation was responsible for the build-up of misfolded or unfolded proteins in ER, whereas pro-survival autophagy and UPR signals were shutdown during prolonged treatment with NIM811. Although cycloheximide has been claimed to suppress paraptosis, instead we find that it only temporarily delayed vacuole formation, but actually enhanced paraptotic cell death in the long term. On the other hand, mTOR inhibitors rescued cells from NIM811-induced paraptosis by sustaining autophagy and the UPR, while specifically restraining cap-dependent translation. These findings not only provide new insights into the mechanisms underlying paraptosis, but also shed light on a potential approach to enhance GBM treatment.
Molecular mechanism of Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif
Authors: de Opakua Alain Ibáñez , Parag-Sharma Kshitij , DiGiacomo Vincent , Merino Nekane , Leyme Anthony , Marivin Arthur , Villate Maider , Nguyen Lien T. , de la Cruz-Morcillo Miguel Angel , Blanco-Canosa Juan B. , Ramachandran Sekar , Baillie George S. , Cerione Richard A. , Blanco Francisco J. , Garcia-Marcos Mikel
Published: May 2017

Heterotrimeric G proteins are quintessential signalling switches activated by nucleotide exchange on Gα. Although activation is predominantly carried out by G-protein-coupled receptors (GPCRs), non-receptor guanine-nucleotide exchange factors (GEFs) have emerged as critical signalling molecules and therapeutic targets. Here we characterize the molecular mechanism of G-protein activation by a family of non-receptor GEFs containing a Gα-binding and -activating (GBA) motif. We combine NMR spectroscopy, computational modelling and biochemistry to map changes in Gα caused by binding of GBA proteins with residue-level resolution. We find that the GBA motif binds to the SwitchII/α3 cleft of Gα and induces changes in the G-1/P-loop and G-2 boxes (involved in phosphate binding), but not in the G-4/G-5 boxes (guanine binding). Our findings reveal that G-protein-binding and activation mechanisms are fundamentally different between GBA proteins and GPCRs, and that GEF-mediated perturbation of nucleotide phosphate binding is sufficient for Gα activation.