bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreased expression of VLDLR is inversely correlated with miR‐200c in human colorectal cancer
Authors: Kim Bong‐Kyu , Yoo Hye‐In , Lee Ah‐Reum , Choi Keonwoo , Yoon Sungjoo Kim
Published: January 2017

Colorectal cancer (CRC) is one of the most common cancers and has a high rate of morbidity and mortality worldwide. Very‐low‐density‐lipoprotein receptor (VLDLR), a member of the low‐density‐lipoprotein receptor (LDLR) superfamily, is a multifunctional receptor that regulates cellular signaling by binding numerous ligands. Several studies reported the altered expression of VLDLR and suggested that VLDLR may play a critical role in tumor development by affecting cell proliferation and metastasis. However, the function of VLDLR and regulation of its expression by miRNAs have not been investigated in CRC. In the present study, we investigated the expression of VLDLR in CRC patients and found it to be significantly decreased in tumors in comparison with paired adjacent non‐tumor tissues. Moreover, VLDLR over‐expression inhibited the proliferation and migration of CRC cells. We also found that VLDLR expression was negatively regulated by miR‐200c in CRC cells and that their expression levels were inversely correlated in CRC patients. These data suggest that VLDLR down‐regulation mediated by the increased expression of miR‐200c may be involved in the development of CRC.
Communication versus Information Transparency in One‐Shot Interactions: A Labor Market Experiment
Authors: Işgın Ebru
Published: January 2017

This is an experimental study of communication and information transparency in one‐shot labor market relations with incomplete contracts. We find that communication in the form of non‐binding broadcast chat messages increases wages, effort levels, and overall efficiency regardless of the information regime. It serves as a negotiation platform and helps workers and firms learn how to cooperate. Communication outperforms information transparency in motivating trust and cooperative behavior in one‐shot interactions. Although transparency might be important in the long term, it does not improve any of the market outcomes in short‐term relations unless it is combined with communication. Copyright © 2017 John Wiley & Sons, Ltd.
Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study
Authors: Modak Shakeel , Kushner Brian H. , Basu Ellen , Roberts Stephen S. , Cheung Nai‐Kong V.
Published: January 2017

Background

The rationale for studying the combination of bevacizumab, irinotecan, and temozolomide (BIT) in neuroblastoma (NB) is based on the following: (i) vascular endothelial growth factor (VEGF) expression is associated with an aggressive phenotype, (ii) anti‐VEGF antibody bevacizumab enhances irinotecan‐mediated suppression of NB xenografts, (iii) bevacizumab safety has been established in pediatric phase I studies, and (iv) irinotecan + temozolomide (IT) is a standard salvage chemotherapy.

Procedure

We conducted a phase II study of BIT in patients with measurable/evaluable refractory or relapsed high‐risk NB (www.clinicaltrials.gov, NCT01114555). Each cycle consisted of bevacizumab (15 mg/kg intravenously [IV]) on days 1 and 15 plus irinotecan (50 mg/m2/day IV) and temozolomide (150 mg/m2/day orally) on days 4–8. Patients could have previously received, but not relapsed on, IT. An early stopping rule mandated continuing therapy only if more than five patients of 27 evaluable patients achieved partial response (PR) or complete response (CR) after four cycles.

Results

Thirty‐three heavily pretreated patients (nine primary refractory; 24 relapsed) received one to eight cycles of BIT. Toxicities were expected and transient. Grade 4 toxicities were neutropenia (30%) and thrombocytopenia (24%). Grade 3 toxicities included hepatic transaminitis (15%), proteinuria (9%), and diarrhea (3%). Overall responses were as follows: three CR (all in prior IT‐treated patients), 18 no response, and 12 progressive disease. Only one of 23 patients assessable for the early stopping rule regarding efficacy achieved PR/CR, so patient accrual was discontinued. Median progression‐free survival and overall survival was 7.7 ± 1.7 and 31.5 ± 5.6 months, respectively; all patients continued anti‐NB therapy post‐BIT.

Conclusions

BIT was well tolerated, but the addition of bevacizumab did not improve response rates in resistant NB compared to historical data for IT.
Concurrent myeloid sarcoma, atypical teratoid/rhabdoid tumor, and hypereosinophilia in an infant with a germline SMARCB1 mutation
Authors: Metts Jonathan L. , Park Sunita I. , Soares Bruno P. , Fong Cindy , Biegel Jaclyn A. , Goldsmith Kelly C.
Published: January 2017

We report a 1‐year‐old female child presenting with hypereosinophilia who was found to have concurrent myeloid sarcoma and a central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT). She was later found to have a germline mutation in SMARCB1. Concurrent hematologic malignancy and CNS AT/RT have not previously been described in the context of a SMARCB1 loss‐of‐function germline mutation.
Ge4+, Eu3+‐codoped Y2SiO5 as a novel red phosphor for white LED applications
Authors: Zhang Yan , Dong Yuanyuan , Xu Jiayue , Wei Bo
Published: January 2017

The phosphors Y2SiO5: Ge4+, Eu3+ were synthesized by solid state reaction method assisted by flux, and have been characterized by X‐ray powder diffraction and fluorescence spectrometer. The results showed that the phosphors can be effectively excited by near‐UV (394 nm), and the major peak is located at 611 nm ascribed to the electric‐dipole 5D0 → 7F2 transition of Eu3+, the critical quenching concentration of Eu3+ in the phosphor is determined to be 15 mol% and the critical transfer distance is calculated as 8.90 Å. Co‐doping Y2SiO5: Eu3+ with Ge4+ helps to improve the luminescence intensity and color purity. The red emission of the phosphor under 394 nm excitation shows a good chromaticity index (0.652, 0.347) compared to commercial red phosphors Y2O2S: Eu3+ (0.631, 0.350). The quantum efficiency of the Y2Si0.97O5: 0.03Ge4+, 0.15Eu3+phosphor under 394 nm excitation is estimated to be 45.24%. It can be concluded that efficient red light emitting diodes were fabricated using Ge4+, Eu3+ co‐doped phosphor based on near ultraviolet(NUV) excited LED lights.
Tetrahedral DNA Nanostructure: A Potential Promoter for Cartilage Tissue Regeneration via Regulating Chondrocyte Phenotype and Proliferation
Authors: Shao Xiaoru , Lin Shiyu , Peng Qiang , Shi Sirong , Wei Xueqin , Zhang Tao , Lin Yunfeng
Published: January 2017

Utilizing biomaterials to regulate the phenotype and proliferation of chondrocytes is a promising approach for effective cartilage tissue regeneration. Recently, a significant amount of effort has been invested into directing chondrocytes toward a desired location and function by utilizing biomaterials to control the dedifferentiation and phenotypic loss of chondrocytes during in vitro monolayer culture. Here, the transmission signals resulting from tetrahedral DNA nanostructures (TDNs) in the regulation of chondrocyte phenotype and proliferation are exploited. TDNs, new DNA nanomaterials, have been considered as promising materials in biomedical fields. Upon exposure to TDNs, chondrocyte phenotype is significantly enhanced, accompanied by lower gene expression related to Notch signaling pathway and higher expression of type II collagen. In addition, the cell proliferation and morphology of chondrocytes are changed after exposure to TDNs. In conclusion, this work demonstrates that TDNs are potentially useful mechanism in cartilage tissue regeneration from chondrocytes, whereby chondrocyte phenotype and proliferation can be retained.
On analysis and redesign of bolted L‐flanged connections
Authors: Pedersen Niels Leergaard
Published: January 2017

In wind turbine towers, the preferred design is circular tubes that are connected by a bolted flange joint. The design is typically that of an L‐flange resulting in an eccentrically loaded bolted connection. The eccentricity results in a non‐linear relationship between external load on the tower and the tensile force in the bolt. In the literature and also in standards, different models are presented for this important non‐linear response. In the present paper, a simplified expression for the non‐linear force response is presented based on finite element calculations using contact analysis. The L‐flange connection is in essence a bad design because it leads to a non‐optimal ratio between external force and bolt force. Furthermore, bolt bending results in an even higher bolt stress resulting in a reduction of strength. The present paper presents simple modifications of the L‐flange design that considerably improves the connection strength. Copyright © 2017 John Wiley & Sons, Ltd.
Macrovascular and microvascular cerebral blood flow in adults at risk for Alzheimer's disease
Authors: Clark Lindsay R. , Berman Sara E. , Rivera‐Rivera Leonardo A. , Hoscheidt Siobhan M. , Darst Burcu F. , Engelman Corinne D. , Rowley Howard A. , Carlsson Cynthia M. , Asthana Sanjay , Turski Patrick , Wieben Oliver , Johnson Sterling C.
Published: January 2017

Introduction

Capillary hypoperfusion is reported in asymptomatic adults at‐risk for Alzheimer's disease (AD), but the extent that can be explained by reduced flow in intracranial arteries is unknown.

Methods

One hundred fifty‐five asymptomatic adults enriched for AD risk (mean age 61 years) completed arterial spin labeling (pcASL) and 4D‐flow MRI sequences. Voxel‐wise regression models investigated the relationship between mean flow in bilateral cerebral arteries and capillary perfusion, and tested potential moderators of this relationship.

Results

Mean arterial blood flow through middle cerebral arteries (MCAs) and internal carotid arteries was positively associated with perfusion in large cortical clusters (P < .05, false discovery rate corrected). Trends were observed for the interactions MCA flow × age and MCA flow × cardiovascular risk on cerebral perfusion (P < .001, uncorrected).

Discussion

These findings provide evidence that capillary perfusion measured via pseudocontinuous arterial spin labeling is strongly dependent on inflow from larger cerebral arteries. Further studies are warranted to investigate possible alterations between macrovascular and microvascular flow in advanced age and elevated cardiovascular risk in asymptomatic adults at risk for AD.
NONCLASSICAL SPECTRAL ASYMPTOTICS AND DIXMIER TRACES: FROM CIRCLES TO CONTACT MANIFOLDS
Authors: GIMPERLEIN HEIKO , GOFFENG MAGNUS
Published: January 2017

We consider the spectral behavior and noncommutative geometry of commutators$[P,f]$, where$P$is an operator of order 0 with geometric origin and$f$a multiplication operator by a function. When$f$is Hölder continuous, the spectral asymptotics is governed by singularities. We study precise spectral asymptotics through the computation of Dixmier traces; such computations have only been considered in less singular settings. Even though a Weyl law fails for these operators, and no pseudodifferential calculus is available, variations of Connes’ residue trace theorem and related integral formulas continue to hold. On the circle, a large class of nonmeasurable Hankel operators is obtained from Hölder continuous functions$f$, displaying a wide range of nonclassical spectral asymptotics beyond the Weyl law. The results extend from Riemannian manifolds to contact manifolds and noncommutative tori.
The relationship between organizational dissent and workplace freedom of speech: A cross-cultural analysis in Singapore
Authors: Croucher Stephen M , Zeng Cheng , Rahmani Diyako , Cui Xuejun
Published: January 2017

This study is a test of the relationship between organizational dissent and the perception of workplace freedom of speech in Singapore. Through a quantitative analysis of 384 individuals in Singapore, the following was found: articulated dissent and latent dissent are positively correlated with workplace freedom of speech. In addition, multiple analysis of covariance analyses revealed nation of birth exerted considerable influence on articulated dissent, and latent dissent, but not on workplace freedom of speech. The results provide evidence of how nation of birth is related to an individual’s willingness to express dissent. Theoretical and practical implications for research into organizational behavior are discussed.
The same picture through different lenses: quantifying the effects of two preservation pathways on Green River Formation insects
Authors: Anderson Evan P. , Smith Dena M.
Published: January 2017

Insects in the fossil record are generally preserved in lacustrine shales or in amber. For those in lacustrine shales, preservation is usually via keroginization or mineralization. Given the extended period of microbial decay required to generate ions for mineralization, there is a predicted inherent bias toward lower preservation quality for this pathway by most taphonomic indices compared with keroginization. This study tests this hypothesis by comparing multiple measures of preservation quality between sites with similar sedimentology in the Eocene Green River Formation of Colorado. Here, insects are either mineralized in iron oxides (likely after pyrite) at the Paleoburn site or keroginized at the Anvil Points site.

Generally, the prediction that keroginization preserves soft-bodied fossils with higher preservational quality than mineralization is affirmed, but with some caveats. Beetles, known for their robust cuticles, are proportionately more abundant at the Paleoburn site, but eight of the nine orders recorded are shared between sites. As predicted, insects show lower preservation fidelity at the Paleoburn site, but they also show higher degrees of disarticulation. This second bias should be acquired primarily during the biostratinomy stage, and not early diagenesis. Nonetheless, higher-energy biostratinomic conditions may be compatible with taphonomic conditions that promote mineralization over keroginization.

Comparing the inherent taphonomic bias of different preservation pathways is often difficult, since fossil deposits may be preserved millions of years or thousands of kilometers apart. By studying two different preservation pathways of insects within the same formation, we can affirm that keroginization does indeed preserve recalcitrant organic matter with higher quality than pyritization or iron-oxide mineralization. Additionally, some guidelines can be proposed concerning the body parts and taxa that can be compared, and for what purpose, when contrasting mineralized and keroginized soft-bodied deposits.
Effect of dietary cholesterol and plant sterol consumption on plasma lipid responsiveness and cholesterol trafficking in healthy individuals
Authors: Alphonse Peter A. S. , Ramprasath Vanu , Jones Peter J. H.
Published: January 2017

Dietary cholesterol and plant sterols differentially modulate cholesterol kinetics and circulating cholesterol. Understanding how healthy individuals with their inherent variabilities in cholesterol trafficking respond to such dietary sterols will aid in improving strategies for effective cholesterol lowering and alleviation of CVD risk. The objectives of this study were to assess plasma lipid responsiveness to dietary cholesterolv. plant sterol consumption, and to determine the response in rates of cholesterol absorption and synthesis to each sterol using stable isotope approaches in healthy individuals. A randomised, double-blinded, crossover, placebo-controlled clinical trial (n49) with three treatment phases of 4-week duration were conducted in a Manitoba Hutterite population. During each phase, participants consumed one of the three treatments as a milkshake containing 600 mg/d dietary cholesterol, 2 g/d plant sterols or a control after breakfast meal. Plasma lipid profile was determined and cholesterol absorption and synthesis were measured by oral administration of [3, 4-13C] cholesterol and2H-labelled water, respectively. Dietary cholesterol consumption increased total (0·16 (sem0·06) mmol/l,P=0·0179) and HDL-cholesterol (0·08 (sem0·03) mmol/l,P=0·0216) concentrations with no changes in cholesterol absorption or synthesis. Plant sterol consumption failed to reduce LDL-cholesterol concentrations despite showing a reduction (6 %,P=0·0004) in cholesterol absorption. An over-compensatory reciprocal increase in cholesterol synthesis (36 %,P=0·0026) corresponding to a small reduction in absorption was observed with plant sterol consumption, possibly resulting in reduced LDL-cholesterol lowering efficacy of plant sterols. These data suggest that inter-individual variability in cholesterol trafficking mechanisms may profoundly impact plasma lipid responses to dietary sterols in healthy individuals.
THE DOUBLE CEILING ON UNJUST ENRICHMENT: OLD SOLUTIONS FOR OLD PROBLEMS
Authors: Trotter Andrew
Published: January 2017

Unjust enrichment is not calculated to strip defendants of gain at all costs, but rather to restore to the claimant the value or rights he has unjustly lost. It can therefore only justify restitution to the extent of the claimant's ultimate expense, or the defendant's ultimate enrichment, whichever is lesser. Although that “double ceiling” has not found favour (at least in England), this article defends it against perceived inconsistencies with principle and precedent, and proposes it as a solution to three unresolved doctrinal problems in the law of unjust enrichment: claims for improvements to property, subjective overvaluation and incidental benefits.
Parasitological versus molecular diagnosis of strongyloidiasis in serial stool samples: how many?
Authors: Dacal E. , Saugar J.M. , Soler T. , Azcárate J.M. , Jiménez M.S. , Merino F.J. , Rodríguez E.
Published: January 2017

Strongyloidiasis is usually an asymptomatic disease in immunocompetent patients, caused by Strongyloides stercoralis. However, in immunocompromised patients it can produce a severe clinical profile. Therefore, a correct diagnosis is necessary in these cases and in those chronic asymptomatic patients. The low sensitivity of classical parasitological techniques requires the analysis of multiple serial stool samples. Molecular diagnostic techniques represent an improvement in the detection of the parasite. The objective of this study was to evaluate the minimum number of samples necessary to achieve maximum sensitivity by real-time polymerase chain reaction (PCR). A total of 116 stool samples from 39 patients were analysed by direct microscopic observation, agar culture, Harada–Mori and real-time PCR, in one, two, three and four or more consecutive samples. After two serial samples, 6 out of 39 patients were positive by parasitological and molecular techniques, while 16 of them were real-time PCR positive, and all the patients detected by parasitology were also detected by the molecular technique, reaching 100.00% sensitivity versus 83.00% when analysing a single sample. These data also reflect apparently low specificity (51.52%) and positive predictive value (PPV) (27.27 %) values, due to the high number of cases detected by real-time PCR and not by parasitological techniques. These cases were confirmed as true positives when analysing three, four or more samples from the same patient. In conclusion, the application of molecular techniques decreases the number of serial stool samples necessary to give a diagnosis with the maximum sensitivity.
Do cranial suture age and growth layer groups correlate in South American pinnipeds?
Authors: Audibert Priscila , Drehmer César Jaeger , Danilewicz Daniel , de Oliveira Larissa Rosa
Published: January 2017

Age is one of the most important life history parameters required to understand the dynamics of mammalian populations. Growth Layers Groups (GLGs) are incremental units of calcified tissue in the teeth (dentine and cementum), which represent a pattern of cyclical deposition that can be counted. However, the estimation of absolute age in GLGs demands a skull with teeth, the permission to destroy part of a tooth, equipment to cut the teeth, and experienced GLGs readers. In 1954 Sivertsen proposed an alternative method using cranial suture age (CSA) to establish age categories. However, there are no studies validating the CSA in relation to GLGs. Thus, this study examined whether there is a correlation between age categories proposed by the CSA and chronological age in years from GLGs of South American fur seals (Arctocephalus australis) (N = 52) and of South American sea lions (Otaria flavescens) (N = 37). 93% of the skulls ofA. australisand 83.8% ofO. flavescenscorresponded accurately to the age in years estimated by each cranial suture age range. These results indicated the existence of high correspondence between the CSA and the GLGs age (r: 0.491 forA. australisandr: 0.675 forO. flavescens). However, an adaptation to Sivertsen's method is recommended: using only eight sutures (excluding the premaxillary-maxillary suture for CSA analysis, due to its late fusion), and updating the intervals for cranial sutures, that correspond to 16–32 = adults, 11–15 = young and 8–10 = pups.
A TWO-CLASS RETRIAL SYSTEM WITH COUPLED ORBIT QUEUES
Authors: Dimitriou Ioannis
Published: January 2017

We consider a single server system accepting two types of retrial customers, which arrive according to two independent Poisson streams. The service station can handle at most one customer, and in case of blocking, typeicustomer,i=1, 2, is routed to a separate typeiorbit queue of infinite capacity. Customers from the orbits try to access the server according to the constant retrial policy. We consider coupled orbit queues, and thus, when both orbit queues are non-empty, the orbit queueitries to re-dispatch a blocked customer of typeito the main service station after an exponentially distributed time with rate μi. If an orbit queue empties, the other orbit queue changes its re-dispatch rate from μito$\mu_{i}^{\ast}$. We consider both exponential and arbitrary distributed service requirements, and show that the probability generating function of the joint stationary orbit queue length distribution can be determined using the theory of Riemann (–Hilbert) boundary value problems. For exponential service requirements, we also investigate the exact tail asymptotic behavior of the stationary joint probability distribution of the two orbits with either an idle or a busy server by using the kernel method. Performance metrics are obtained, computational issues are discussed and a simple numerical example is presented.
Trajectory modulated arc therapy using quasi-continuous couch motion layered on top of volumetric modulated arc therapy in left breast and chest wall irradiation: a feasibility study
Authors: Sarkar Biplab , Pradhan Anirudh
Published: January 2017

Aim

To investigate the dosimetric advantage of quasi-continuous couch motion-enabled trajectory modulated arc radiotherapy therapy (TMAT) over the coplanar tangential partial arcs volumetric modulated arc radiotherapy (VMAT) for treating left breast and chest wall patients.

Method

Treatment plans of 43 patients who received radiotherapy for left breast (17) or for left chest wall (26) using coplanar partial tangential arcs VMAT (reference plan) were considered for this study. For each patient, in addition to the treatment plan, a TMAT plan was also generated using quasi-continuous couch rotation. The TMAT plan consisted of original two 30° tangential arc beams and two supplementary beams having a couch rotation of ±10°, ±20° and ±30°, respectively. The difference in PTV volume coverage (PTV V95%) between TMAT plan and VMAT plan was calculated for all the cases and normalised to the plan’s prescription dose. Similarly, differences in PTV_V105% and several dose-volume parameters related to organs at risk (OAR) were also computed and tabulated.

Result

TMAT shows an increment in the PTV dose coverage V95% with respect to reference plan by 4·7±2·5% when averaged overall prescription dose levels. Mean PTV dose (averaged overall prescription levels) for reference and TMAT plan was 4638·6±423·8 and 4793·5±447·2 cGy, respectively, and statistically insignificant (p=0·06). However mean PTV_V105% values for TMAT and for reference plans were 6·7±4·8 and 7·2±5·2%, respectively, and were not statistically different (p=0·85). Mean heart dose in TMAT was less than in VMAT plans, but not significantly. As regarding D1% to heart, TMAT plan was again found to be better with a mean difference of 137·1 cGy over VMAT plan. Other parameters evaluated were: mean dose and D1% to contralateral breast, and V20 Gy and V5 Gy for lung.

Conclusion

TMAT plans were found to be better than VMAT plans in terms of PTV coverage and D1% for heart. For evaluated dose parameters apart from PTV coverage and D1% to the heart, no significant differences were observed. Thus, TMAT plans yielded better dose distribution in terms of PTV dose coverage, hot spots and OAR doses.
Evaluation of the dose received by ovaries in the treatment of a desmoid tumour presenting in the lower extremity using intensity-modulated radiotherapy tomotherapy
Authors: Barlaz Us Songül , Temelli Öztun
Published: January 2017

Background

Desmoid tumour is a rare neoplasm occurring intra- and extra-abdominally.

Method

In this study, a lower extremity desmoid tumour located close to the ovaries was irradiated with tomotherapy after surgery in a 16-year-old female patient. 30 fractions defined for delivery of 54 Gy were administered to the patient.

Result

The planning target volume and organs at risk doses were evaluated and the ovary doses were discussed for fertility.

Conclusion

The patient tolerated the radiotherapy well. During radiotherapy, only grade 1 skin toxicity occurred.
POINT-FREE GEOMETRY, OVALS, AND HALF-PLANES
Authors: GERLA GIANGIACOMO , GRUSZCZYŃSKI RAFAŁ
Published: January 2017

In this paper we develop a point-free system of geometry based on the notions of region, parthood, and ovality, the last one being a region-based counterpart of the notion of convex set. In order to show that the system we propose is sufficient to reconstruct an affine geometry we make use of a theory of a Polish mathematician Aleksander Śniatycki from [15], in which the concept of half-plane is assumed as basic.
The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process
Authors: Baxter Amy A , Poon Ivan KH , Hulett Mark D
Published: January 2017

Cationic anti-microbial peptides (CAPs) have an important role in host innate defense against pathogens such as bacteria and fungi. Many CAPs including defensins also exhibit selective cytotoxic activity towards mammalian cells via both apoptotic and non-apoptotic processes, and are being investigated as potential anticancer agents. The anti-fungal plant defensin from ornamental tobacco, Nicotiana alata Defensin 1 (NaD1), was recently shown to induce necrotic-like cell death in a number of tumor cell types within 30 min of treatment, at a concentration of 10 μM. NaD1-mediated cell killing within these experimental parameters has been shown to occur via binding to the plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) in target cells to facilitate membrane destabilization and subsequent lysis. Whether NaD1 is also capable of inducing apoptosis in tumor cells has not been reported previously. In this study, treatment of MM170 (melanoma) and Jurkat T (leukemia) cells with subacute (<10 μM) concentrations of NaD1 over 6–24 h was investigated to determine whether NaD1 could induce cell death via apoptosis. At subacute concentrations, NaD1 did not efficiently induce membrane permeabilization within 30 min, but markedly reduced cell viability over 24 h. In contrast to other CAPs that have been shown to induce apoptosis through caspase activation, dying cells were not sensitive to a pancaspase inhibitor nor did they display caspase activity or DNA fragmentation over the 24 h treatment time. Furthermore, over the 24 h period, cells exhibited necrotic phenotypes and succumbed to membrane permeabilization. These results indicate that the cytotoxic mechanism of NaD1 at subacute concentrations is membranolytic rather than apoptotic and is also likely to be mediated through a PIP2-targeting cell lytic pathway.
Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites
Authors: Braig David , Nero Tracy L. , Koch Hans-Georg , Kaiser Benedict , Wang Xiaowei , Thiele Jan R. , Morton Craig J. , Zeller Johannes , Kiefer Jurij , Potempa Lawrence A. , Mellett Natalie A. , Miles Luke A. , Du Xiao-Jun , Meikle Peter J. , Huber-Lang Markus , Stark G. Björn , Parker Michael W. , Peter Karlheinz , Eisenhardt Steffen U.
Published: January 2017

C-reactive protein (CRP) concentrations rise in response to tissue injury or infection. Circulating pentameric CRP (pCRP) localizes to damaged tissue where it leads to complement activation and further tissue damage. In-depth knowledge of the pCRP activation mechanism is essential to develop therapeutic strategies to minimize tissue injury. Here we demonstrate that pCRP by binding to cell-derived microvesicles undergoes a structural change without disrupting the pentameric symmetry (pCRP*). pCRP* constitutes the major CRP species in human-inflamed tissue and allows binding of complement factor 1q (C1q) and activation of the classical complement pathway. pCRP*–microvesicle complexes lead to enhanced recruitment of leukocytes to inflamed tissue. A small-molecule inhibitor of pCRP (1,6-bis(phosphocholine)-hexane), which blocks the pCRP–microvesicle interactions, abrogates these proinflammatory effects. Reducing inflammation-mediated tissue injury by therapeutic inhibition might improve the outcome of myocardial infarction, stroke and other inflammatory conditions.
MicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes
Authors: Liu Can , Liu Ruifang , Zhang Dingxiao , Deng Qu , Liu Bigang , Chao Hsueh-Ping , Rycaj Kiera , Takata Yoko , Lin Kevin , Lu Yue , Zhong Yi , Krolewski John , Shen Jianjun , Tang Dean G.
Published: January 2017

MicroRNAs play important roles in regulating tumour development, progression and metastasis. Here we show that one of the miR-200 family members, miR-141, is under-expressed in several prostate cancer (PCa) stem/progenitor cell populations in both xenograft and primary patient tumours. Enforced expression of miR-141 in CD44+ and bulk PCa cells inhibits cancer stem cell properties including holoclone and sphere formation, as well as invasion, and suppresses tumour regeneration and metastasis. Moreover, miR-141 expression enforces a strong epithelial phenotype with a partial loss of mesenchymal phenotype. Whole-genome RNA sequencing uncovers novel miR-141-regulated molecular targets in PCa cells including the Rho GTPase family members (for example, CDC42, CDC42EP3, RAC1 and ARPC5) and stem cell molecules CD44 and EZH2, all of which are validated as direct and functionally relevant targets of miR-141. Our results suggest that miR-141 employs multiple mechanisms to obstruct tumour growth and metastasis.
Combined immunotherapy with “anti-insulin resistance” therapy as a novel therapeutic strategy against neurodegenerative diseases
Authors: Takamatsu Yoshiki , Ho Gilbert , Koike Wakako , Sugama Shuei , Takenouchi Takato , Waragai Masaaki , Wei Jianshe , Sekiyama Kazunari , Hashimoto Makoto
Published: January 2017

Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid β and α-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid β immunotherapy has been extensively investigated in Alzheimer’s disease, followed by similar studies of α-synuclein in Parkinson’s disease. Notably, a recent study of solanezumab, an amyloid β monoclonal antibody, raises hope for the further therapeutic potential of immunotherapy, not only in Alzheimer’s disease, but also for other neurodegenerative disorders, including Parkinson’s disease. Thus, it is expected that further refinement of immunotherapy against neurodegenerative diseases may lead to increasing efficacy. Meanwhile, type II diabetes mellitus has been associated with an increased risk of neurodegenerative disease, such as Alzheimer’s disease and Parkinson’s disease, and studies have shown that metabolic dysfunction and abnormalities surrounding insulin signaling may underlie disease progression. Naturally, “anti-insulin resistance” therapy has emerged as a novel paradigm in the therapy of neurodegenerative diseases. Indeed, incretin agonists, which stimulate pancreatic insulin secretion, reduce dopaminergic neuronal loss and suppress Parkinson’s disease disease progression in clinical trials. Similar studies are ongoing also in Alzheimer’s disease. This paper focuses on critical issues in “immunotherapy” and “anti-insulin resistance” therapy in relation to therapeutic strategies against neurodegenerative disease, and more importantly, how they might merge mechanistically at the point of suppression of protein aggregation, raising the possibility that combined immunotherapy and “anti-insulin resistance” therapy may be superior to either monotherapy.
An algorithm recommendation for the pharmacological management of allergic rhinitis in the UK: a consensus statement from an expert panel
Authors: Lipworth Brian , Newton Jon , Ram Bhaskar , Small Iain , Schwarze Jürgen
Published: January 2017

Allergic rhinitis is a frequent presenting problem in primary care in the UK, and has increased in prevalence over the last 30 years. When symptomatic, patients report significant reduction in their quality of life and impairment in school and work performance. Achieving adequate symptom control is pivotal to successful allergic rhinitis management, and relies mostly on pharmacotherapy. While it is recognised that most mild-moderate allergic rhinitis symptoms can be managed successfully in primary care, important gaps in general practitioner training in relation to allergic rhinitis have been identified. With the availability of new effective combination therapies, such as the novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in a single device (Dymista®; Meda), the majority of allergic rhinitis symptoms can be treated in the primary care setting. The primary objective of this consensus statement is to improve diagnosis and treatment of allergic rhinitis in primary care, and offer guidance on appropriate referral of difficult-to-treat patients into secondary care. The guidance provided herein outlines a sequential treatment pathway for allergic rhinitis in primary care that incorporates a considered approach to improve the management of allergic rhinitis symptoms and improve compliance and patient satisfaction with therapy. Adherence with this care pathway has the potential to limit the cost of providing effective allergic rhinitis management in the UK by avoiding unnecessary treatments and investigations, and avoiding the need for costly referrals to secondary care in the majority of allergic rhinitis cases. The fundamentals presented in this consensus article should apply in most health-care settings.
Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity
Authors: Stephen J. , Scales H. E. , Benson R. A. , Erben D. , Garside P. , Brewer J. M.
Published: January 2017

There are over 6 billion vaccine doses administered each year, most containing aluminium-based adjuvants, yet we still do not have a complete understanding of their mechanisms of action. Recent evidence has identified host DNA and downstream sensing as playing a significant role in aluminium adjuvant (aluminium hydroxide) activity. However, the cellular source of this DNA, how it is sensed by the immune system and the consequences of this for vaccination remains unclear. Here we show that the very early injection site reaction is characterised by inflammatory chemokine production and neutrophil recruitment. Intravital imaging demonstrates that the Alum injection site is a focus of neutrophil swarms and extracellular DNA strands. These strands were confirmed as neutrophil extracellular traps due to their sensitivity to DNAse and absence in mice deficient in peptidylarginine deiminase 4. Further studies in PAD4−/− mice confirmed a significant role for neutrophil extracellular trap formation in the adjuvant activity of Alum. By revealing neutrophils recruited to the site of Alum injection as a source of the DNA that is detected by the immune system this study provides the missing link between Alum injection and the activation of DNA sensors that enhance adjuvant activity, elucidating a key mechanism of action for this important vaccine component.
Correction: Corrigendum: Gammaproteobacteria as essential primary symbionts in the striped shield bug, Graphosoma Lineatum (Hemiptera: Pentatomidae)
Authors: Karamipour Naeime , Fathipour Yaghoub , Mehrabadi Mohammad
Published: January 2017

Scientific Reports 6: Article number: 33168; published online: 09 September 2016; updated: 23 January 2017 The original version of this Article contained an error in the order of author names, which were incorrectly given as ‘Naeime Karamipour, Mohammad Mehrabadi & Yaghoub Fathipour’. These errors have now been corrected in the HTML and PDF versions of this Article.
Dynamics of Bemisia tabaci biotypes and insecticide resistance in Fujian province in China during 2005–2014
Authors: Yao Feng-Luan , Zheng Yu , Huang Xiao-Yan , Ding Xue-Ling , Zhao Jian-Wei , Desneux Nicolas , He Yu-Xian , Weng Qi-Yong
Published: January 2017

The whitefly Bemisia tabaci (Gennadius) is an important agricultural insect pest worldwide. The B and Q biotypes are the two most predominant and devastating biotypes prevalent across China. However, there are few studies regarding the occurrence of the Q biotype in Fujian Province, China, where high insecticide resistance has been reported in the B biotype. Differences in some biological characteristics between the B and Q biotypes, especially insecticide resistance, are considered to affect the outcome of their competition. Extensive surveys in Fujian revealed that the B biotype was predominant during 2005–2014, whereas the Q biotype was first detected in some locations in 2013 and widely detected throughout the province in 2014. Resistance to neonicotinoids (that have been used for more than 10 years) exhibited fluctuations in open fields, but showed a continual increasing trend in protected areas. Resistance to lambda-cyhalothrin, chlorpyrifos, and abamectin exhibited a declining trend. Resistance to novel insecticides, such as nitenpyram, pymetrozine, sulfoxaflor, and cyantraniliprole, in 2014 was generally below a moderate level. A decline in insecticide resistance in the B biotype and the rapid buildup of protected crops under global temperature increase may have promoted the establishment of the Q biotype in Fujian.
Hypoxia inducible factors are dispensable for myeloid cell migration into the inflamed mouse eye
Authors: Gardner Peter J. , Liyanage Sidath E. , Cristante Enrico , Sampson Robert D. , Dick Andrew D. , Ali Robin R. , Bainbridge James W.
Published: January 2017

Hypoxia inducible factors (HIFs) are ubiquitously expressed transcription factors important for cell homeostasis during dynamic oxygen levels. Myeloid specific HIFs are crucial for aspects of myeloid cell function, including their ability to migrate into inflamed tissues during autoimmune disease. This contrasts with the concept that accumulation of myeloid cells at ischemic and hypoxic sites results from a lack of chemotactic responsiveness. Here we seek to address the role of HIFs in myeloid trafficking during inflammation in a mouse model of human uveitis. We show using mice with myeloid-specific Cre-deletion of HIFs that myeloid HIFs are dispensable for leukocyte migration into the inflamed eye. Myeloid-specific deletion of Hif1a, Epas1, or both together, had no impact on the number of myeloid cells migrating into the eye. Additionally, stabilization of HIF pathways via deletion of Vhl in myeloid cells had no impact on myeloid trafficking into the inflamed eye. Finally, we chemically induce hypoxemia via hemolytic anemia resulting in HIF stabilization within circulating leukocytes to demonstrate the dispensable role of HIFs in myeloid cell migration into the inflamed eye. These data suggest, contrary to previous reports, that HIF pathways in myeloid cells during inflammation and hypoxia are dispensable for myeloid cell tissue trafficking.
Electronic State of Sodium trans-[Tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) in Tumor, Liver and Kidney Tissue of a SW480-bearing Mouse
Authors: Blazevic Amir , Hummer Alfred A. , Heffeter Petra , Berger Walter , Filipits Martin , Cibin Giannantonio , Keppler Bernhard K. , Rompel Annette
Published: January 2017

Ruthenium complexes are promising candidates for anticancer agents, especially NKP-1339 (sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]), which is on the edge to clinical applications. The anticancer mechanism seems to be tightly linked to the redox chemistry but despite progress in human clinical trials the in vivo Ru oxidation state and the coordination of Ru remains unclear. The Ru-based anticancer drug NKP-1339 was studied applying XANES (Cl K- and Ru L2,3-edges) in tumor, kidney and liver tissue of a SW480 bearing mouse. Based on coordination charge and 3D XANES plots containing a series of model compounds as well as pre-edge analysis of the ligand Cl K-edge it is suggested that NKP-1339 remains in its +III oxidation state after 24 hours and at least one of the four chlorido ligands remain covalently bound to the Ru ion showing a biotransformation from RuIIIN2Cl4 to RuIIIClx(N/O)6−x (X = 1 or 2).
Cyclin I-like (CCNI2) is a cyclin-dependent kinase 5 (CDK5) activator and is involved in cell cycle regulation
Authors: Liu Chengcheng , Zhai Xiaoyan , Zhao Bin , Wang Yanfei , Xu Zhigang
Published: January 2017

In contrast to conventional cyclin-dependent kinases that are important for mitotic cell division, cyclin-dependent kinase 5 (CDK5) is predominantly activated in post-mitotic cells and is involved in various cellular events. The kinase activity of CDK5 is tightly regulated by specific activators including p35, p39, and cyclin I (CCNI). Here we show that cyclin I-like (CCNI2), a homolog of CCNI, interacts with CDK5 and activates the kinase activity of CDK5. Different from CCNI, which colocalizes with CDK5 in the nuclei in transfected cells, CCNI2 mainly retains CDK5 in the cytoplasm as well as on the cell membrane. Furthermore, although the expression level of CCNI2 mRNA and CCNI2 protein do not change significantly during cell cycle, depletion of CCNI2 with siRNA affects cell cycle progression as well as cell proliferation. In conclusion, our data strongly suggest that CCNI2 is a novel CDK5 activator and is involved in cell cycle regulation.
Serum vitamin D, intact parathyroid hormone, and Fetuin A concentrations were associated with geriatric sarcopenia and cardiac hypertrophy
Authors: Chang Wei-Ting , Wu Chih-Hsing , Hsu Ling-Wei , Chen Po-Wei , Yu Jia-Rong , Chang Chin-Sung , Tsai Wei-Chuan , Liu Ping-Yen
Published: January 2017

With aging, intact parathyroid hormone (iPTH) increases. It plays a crucial role in left ventricular hypertrophy (LVH). Also, 25-hydroxy vitamin D (Vit-D) and iPTH have been observed to be determinants of muscle wasting known as sarcopenia. Fetuin A (FetA), a systemic calcification inhibitor, involves in the development of diastolic heart failure. Hence, we hypothesized that the interplay among FetA, Vit-D and iPTH may contribute to sarcopenic LVH among the elders. We analyzed a database from the Tianliao Old People study with 541 elders (≥65 years) in a Taiwan’s suburban community. After excluding patients with renal function impairment, 120/449 (26.7%) patients were diagnosed with sarcopenia. Sarcopenic patients had lower serum Vit-D levels but higher FetA as well as iPTH. Notably, sarcopenic patients with LVH had significantly lower FetA and higher iPTH levels. In multivariate logistic regression analysis, only the increase in iPTH was independently associated with sarcopenic LVH (Odds ratio: 1.05; confidence interval: 1.03–1.08, p = 0.005). Using iPTH >52.3 ng/l as a cutoff point, the sensitivity and specificity was 66% and 84%, respectively. In conclusion, FetA, Vit-D, and iPTH levels were all associated with sarcopenia in this geriatric population. Among them, iPTH specifically indicates patients with sarcopenic LVH.
Neutron Radiation Tolerance of Two Benchmark Thiophene-Based Conjugated Polymers: the Importance of Crystallinity for Organic Avionics
Authors: Paternò G. M. , Robbiano V. , Fraser K. J. , Frost C. , García Sakai V. , Cacialli F.
Published: January 2017

Aviation and space applications can benefit significantly from lightweight organic electronics, now spanning from displays to logics, because of the vital importance of minimising payload (size and mass). It is thus crucial to assess the damage caused to such materials by cosmic rays and neutrons, which pose a variety of hazards through atomic displacements following neutron-nucleus collisions. Here we report the first study of the neutron radiation tolerance of two poly(thiophene)s-based organic semiconductors: poly(3-hexylthiophene-2,5-diyl), P3HT, and the liquid-crystalline poly(2,5-bis (3-tetradecylthiophen-2-yl)thieno[3,2-b]thiophene), PBTTT. We combine spectroscopic investigations with characterisation of intrinsic charge mobility to show that PBTTT exhibits significantly higher tolerance than P3HT. We explain this in terms of a superior chemical, structural and conformational stability of PBTTT, which can be ascribed to its higher crystallinity, in turn induced by a combination of molecular design features. Our approach can be used to develop design strategies for better neutron radiation-tolerant materials, thus paving the way for organic semiconductors to enter avionics and space applications.
Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy
Authors: Roeters Steven J. , Iyer Aditya , Pletikapić Galja , Kogan Vladimir , Subramaniam Vinod , Woutersen Sander
Published: January 2017

The aggregation of the intrinsically disordered protein alpha-synuclein (αS) into amyloid fibrils is thought to play a central role in the pathology of Parkinson’s disease. Using a combination of techniques (AFM, UV-CD, XRD, and amide-I 1D- and 2D-IR spectroscopy) we show that the structure of αS fibrils varies as a function of ionic strength: fibrils aggregated in low ionic-strength buffers ([NaCl] ≤ 25 mM) have a significantly different structure than fibrils grown in higher ionic-strength buffers. The observations for fibrils aggregated in low-salt buffers are consistent with an extended conformation of αS molecules, forming hydrogen-bonded intermolecular β-sheets that are loosely packed in a parallel fashion. For fibrils aggregated in high-salt buffers (including those prepared in buffers with a physiological salt concentration) the measurements are consistent with αS molecules in a more tightly-packed, antiparallel intramolecular conformation, and suggest a structure characterized by two twisting stacks of approximately five hydrogen-bonded intermolecular β-sheets each. We find evidence that the high-frequency peak in the amide-I spectrum of αS fibrils involves a normal mode that differs fundamentally from the canonical high-frequency antiparallel β-sheet mode. The high sensitivity of the fibril structure to the ionic strength might form the basis of differences in αS-related pathologies.