bluuebunny/crossref_metadata_2025 huggingface dataset:
Mre11-Rad50–dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1
Authors: Limbo Oliver , Yamada Yoshiki , Russell Paul
Published: May 2018

The Mre11-Rad50-Nbs1 (MRN) protein complex and ATM/Tel1 kinase protect genome integrity through their functions in DNA double-strand break (DSB) repair, checkpoint signaling, and telomere maintenance. Nbs1 has a conserved C-terminal motif that binds ATM/Tel1, but the full extent and significance of ATM/Tel1 interactions with MRN are unknown. Here, we show that Tel1 overexpression bypasses the requirement for Nbs1 in DNA damage signaling and telomere maintenance. These activities require Mre11-Rad50, which localizes to DSBs and bind Tel1 in the absence of Nbs1. Fusion of the Tel1-binding motif of Nbs1 to Mre11 is sufficient to restore Tel1 signaling in nbs1Δ cells. Tel1 overexpression does not restore Tel1 signaling in cells carrying the rad50-I1192W mutation, which impairs the ability of Mre11-Rad50 to form the ATP-bound closed conformation. From these findings, we propose that Tel1 has a high-affinity interaction with the C-terminus of Nbs1 and a low-affinity association with Mre11-Rad50, which together accomplish efficient localization and activation of Tel1 at DSBs and telomeres.
The effects of mechanical strain on mouse eye lens capsule and cellular microstructure
Authors: Parreno Justin , Cheng Catherine , Nowak Roberta B. , Fowler Velia M.
Published: May 2018

The mouse eye lens was used as a model for multiscale transfer of loads. In the lens, compressive strain is distributed across specific lens tissue microstructures, including the extracellular capsule, as well as the epithelial and fiber cells. The removal of high loads resulted in complete recovery of most, but not all, microstructures.
Toric Contact Geometry in Arbitrary Codimension
Authors: Apostolov Vestislav , Calderbank David M J , Gauduchon Paul , Legendre Eveline
Published: May 2018

We define toric contact manifolds in arbitrary codimension and give a description of such manifolds in terms of a kind of labelled polytope embedded into a grassmannian, analogous to the Delzant polytope of a toric symplectic manifold.
A Union Default: A Policy to Raise Union Membership, Promote the Freedom to Associate, Protect the Freedom not to Associate and Progress Union Representation
Authors: Harcourt Mark , Gall Gregor , Vimal Kumar Rinu , Croucher Richard
Published: May 2018

Workers are defaulted to being non-union in employment relationships across the world. A non-union default likely has substantial negative effects, consistent with the empirical literature reviewed, on union membership levels, because of switching costs, inertia, social norms and loss aversion. A union default would likely have positive effects on union membership, and has the additional virtues of partially internalising the public goods externalities of unions, improving the freedom to associate (the right to join a union) and preserving the freedom not to associate (the right not to join a union). A union default would also strengthen the extent and effectiveness of union representation.
Mass-invariance of the iron enrichment in the hot haloes of massive ellipticals, groups, and clusters of galaxies
Authors: Mernier F , de Plaa J , Werner N , Kaastra J S , Raassen A J J , Gu L , Mao J , Urdampilleta I , Truong N , Simionescu A
Published: May 2018

X-ray measurements find systematically lower Fe abundances in the X-ray emitting haloes pervading groups (kT ≲ 1.7 keV) than in clusters of galaxies. These results have been difficult to reconcile with theoretical predictions. However, models using incomplete atomic data or the assumption of isothermal plasmas may have biased the best-fitting Fe abundance in groups and giant elliptical galaxies low. In this work, we take advantage of a major update of the atomic code in the spectral fitting package spex to re-evaluate the Fe abundance in 43 clusters, groups, and elliptical galaxies (the CHEERS sample) in a self-consistent analysis and within a common radius of 0.1r500. For the first time, we report a remarkably similar average Fe enrichment in all these systems. Unlike previous results, this strongly suggests that metals are synthesized and transported in these haloes with the same average efficiency across two orders of magnitude in total mass. We show that the previous metallicity measurements in low-temperature systems were biased low due to incomplete atomic data in the spectral fitting codes. The reasons for such a code-related Fe bias, also implying previously unconsidered biases in the emission measure and temperature structure, are discussed.
The first VLBI detection of a spiral DRAGN core
Authors: Mao Minnie Y , Blanchard Jay M , Owen Frazer , Sjouwerman Loránt O , Singh Vikram , Scaife Anna , Paragi Zsolt , Norris Ray P , Momjian Emmanuel , Johnson Gia , Browne Ian
Published: May 2018

We present the first observation of 0313−192, the archetypal spiral DRAGN, at very long baseline interferometry (VLBI) resolutions. Spiral DRAGNs are Double-lobed Radio sources Associated with Galactic Nuclei (DRAGNs) that are hosted by spiral galaxies. 0313−192 is an edge-on spiral galaxy that appears to host a 360 kpc double-lobed radio source. The core of this galaxy is clearly detected at L, S, and X bands using the Very Long Baseline Array, signifying an ongoing active nucleus in the galaxy. This rules out the possibility that the spiral DRAGN is merely a chance alignment. The radio core has L1.4 GHz ∼ 3.0 × 1023 W Hz−1. Radio components are detected to the south-west of the core, but there are no detections of a counterjet. Assuming a symmetric, relativistic jet, we estimate an upper limit to the inclination angle of θ ≲ 72 deg. The VLBI-detected radio jet components are extremely well aligned with the larger scale radio source suggesting little to no jet disruption or interaction with the interstellar medium of the host galaxy.
Systematic Review of Bilateral Independent Periodic Discharges Written for Topical Journal Subject on Periodic Discharges
Authors: Freund Brin , Kaplan Peter W.
Published: May 2018

Periodic discharges (PDs) are EEG patterns that may have important clinical and prognostic implications. There are different subtypes of PDs that are delineated by their location, and each type may have different meaning regarding prognosis and clinical associations. Bilateral independent PDs are a subtype that have not been analyzed recently and remain poorly understood. In this article, we systematically review the literature to better describe bilateral independent PDs regarding underlying neuropathology, neuroimaging, and neuroexamination correlates, seizure incidence, EEG characteristics, their comparison with other PD subtypes, and prognostic meaning.
Organometallic gold(III) [Au(Hdamp)(L14)]Cl (L1 =SNS-donating thiosemicarbazone) complex protects mice against acuteT. cruziinfection
Authors: Lopes Carla Duque , Gaspari Ana Paula S. , Oliveira Ronaldo J. , Abram Ulrich , Almeida José P. A. , Maia Pedro v. S. , da Silva João S. , de Albuquerque Sérgio , Carneiro Zumira A.
Published: May 2018

Chagas disease remains a serious public health concern with unsatisfactory treatment outcomes due to strain-specific drug resistance and various side effects. To identify new therapeutic drugs againstTrypanosoma cruzi, we evaluated both thein vitroandin vivoactivity of the organometallic gold(III) complex [Au(Hdamp)(L14)]Cl (L1 =SNS- donating thiosemicarbazone), which was denoted 4-Cl. Our results demonstrated that 4- Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and the intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In very-low-dosein vivoassays, 4-Cl reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage. All these changes resulted in the survival of 100% of the mice treated with 4-Cl during the acute phase. We hypothesised that 4-Cl can act directly on the parasite and may participate in the modulation of IFN-γ production at the acute stage of the disease. Molecular docking simulations showed that the compound may interact with cruzain, a thiol protease considered a possible antiparasitic drug target, primarily by hydrophobic interactions. These analyses predicted that the Cys25 residue in the cruzain binding site is approximately 3.0 Å away from the S and Au atoms of the gold compound, which could suggest formation of a possible covalent bond between cruzain and the inhibitor. Overall, we confirmed the potential of 4-Cl as a new candidate for Chagas disease treatment.
Nonmuscle myosin II shRNA inhibit migration and contraction in rat hepatic stellate cells through regulating AKT/mTOR/S6K/4EBP1 signaling pathway
Authors: Li Zhenghong , Feng Yun , Zhang Ruling , Wang Peiwen , Lu Lungen , Dong Yuwei
Published: May 2018

Migration and contraction of activated hepatic stellate cell (HSC) are essential factors for cirrhosis formation and development. It has been demonstrated that blebbistatin, a nonmuscle myosin II (NMMII) inhibitor, can inhibit the migration and contraction of HSC, whereas the main cell signaling pathway is still unknown. Mammalian target of rapamycin (mTOR) signaling pathway may be involved in many cells migration and contraction, whether NMMII and mTOR have any crosslinks draw our attention. In the currently study, we used LV-RNAi to specifically attenuate mTOR and NMMII in rat HSC. We aimed to examine the effect of mTOR LV-RNAi on the migration and contraction of HSC and explore the crosslink between mTOR cell signal and NMMII. Using real-time PCR and western blot, we found that mTOR and the downstream factors including S6K and 4EBP1 all up-regulated with the activation of HSC, mTOR and NMMII LV-RNAi was transfected into activated HSC using lipofectamine 2000. The levels of mRNA and proteins were also examined using real-time PCR and western blot respectively. The expression of mTOR can be down-regulated by NMMII LV-RNAi significantly, as well as the expression of S6K, 4EBP1, α-SMA and collagen I, but the level of AKT was up-regulated. Then we used Transwell system and collagen lattices to examine the NMMII and mTOR LV-RNAi efficiency on HSC migration and contraction, as we hypothesized, both of the LV-RNAi could inhibit HSC migration and contraction significantly. These results indicated that nonmuscle myosin II shRNA inhibit migration and contraction in rat hepatic stellate cells through the regulation of mTOR/S6K/4EBP1 signaling pathway
Anti-BP180 Autoantibodies Are Present in Stroke and Recognize Human Cutaneous BP180 and BP180-NC16A
Authors: Wang Yanan , Mao Xuming , Wang Di , Hammers Christoph M. , Payne Aimee S. , Wang Yiman , Jin Hongzhong , Peng Bin , Li Li
Published: May 2018

Background

Current evidence has revealed a significant association between bullous pemphigoid (BP) and neurological diseases (ND), including stroke, but the incidence of BP autoantibodies in patients with stroke has not previously been investigated.

Objective

Our study aims to assess BP antigen-specific antibodies in stroke patients.

Methods

100 patients with stroke and 100 healthy controls were randomly selected to measure anti-BP180/230 IgG autoantibodies by enzyme-linked immunosorbent assay (ELISA), salt split indirect immunofluorescence (IIF) and immunoblotting against human cutaneous BP180 and BP180-NC16A.

Results

Anti-BP180 autoantibodies were found in 14(14.0%) patients with stroke and 5(5.0 %) of controls by ELISA (p<0.05). Sera from 13(13.0%) patients with stroke and 3(3.0 %) controls reacted with 180-kDa proteins from human cutis extract (p<0.05). 11(11.0%) of stroke and 2(2.0 %) of control sera recognized the human recombinant full length BP180 and NC16A (p<0.05). The anti-BP180-positive patients were significantly younger than the negative patients in stroke (p<0.001).

Limitations

Longitudinal changes in antibody titers and long-term clinical outcome for a long duration were not fully investigated.

Conclusion

Development of anti-BP180 autoantibodies occur at a higher frequency after stroke, suggesting BP180 as a shared autoantigen in stroke with BP and providing novel insights into BP pathogenesis in aging.
Dominant negative FADD/MORT1 inhibits the development of intestinal intraepithelial lymphocytes with a marked defect on CD8αα+TCRγδ+ T cells
Authors: Zhang Xuerui , Huo Lina , Song Lulu , Hu Zhaoqing , Wang Xinran , Han Yuheng , Wang Ying , Xu Peipei , Zhang Jing , Hua Zi-Chun
Published: May 2018

Intestinal intraepithelial lymphocytes are considered to be distinct from thymus-derived cells and are thought to derive locally from cryptopatch (CP) precursors. Although the development and homing of IELs have been studied in some details, the factors controlling their homeostasis are incompletely understood. Here, we demonstrate that FADD, a classic adaptor protein required for death-receptor-induced apoptosis, is a critical regulator of the intestinal IEL development. The mice with a dominant negative mutant of FADD (FADD-DN) display a defective localized intestinal IELs with a marked defect on CD8αα+TCRγδ+T cells. Since Lin-LPLs have been identified as precursors CP cells for CD8αα+development, we analyzed lamina propria lymphocytes (LPLs) and found the massive accumulation of IL-7R-lin-LPLs in FADD-DN mice. IL-7 plays a differentiation inducing role in the development of intestinal IELs and its receptor IL-7R is a transcriptional target of Notch1. The level of Notch1 expression also showed very low in Lin-LPLs cells from FADD-DN mice compared with normal mice, indicating a possible molecular mechanism of FADD in the early IEL development. In addition, loss of γδ T-IELs induced by FADD-DN results in a worsening inflammation in murine DSS-induced colitis model, suggesting a protective role of FADD in the intestinal homeostasis.
Loading of piperlongumine to liposomes after complexation with ß- cyclodextrin and its effect on viability of colon and prostate cancer cells
Authors: Jayawardana Kalana W. , Jyotsana Nidhi , Zhang Zhenjiang , King Michael R.
Published: May 2018

Use of nano carriers to treat cancer is attractive due to their advantages such as the sustained release of drugs and ability to target specific regions of the body where treatment is needed. However, loading water insoluble chemotherapeutic drugs into liposomes is challenging. In this study, we developed a method to encapsulate water-insoluble drug (piperlongumine) in liposomes by complexing piperlongumine with ß-Cyclodextrin. Liposomes encapsulated with piperlongumine incubated with COLO 205 and PC-3 cell lines and demonstrated that viability of COLO 205 and PC-3 cells decreases to 7% and 41% respectively when the piperlongumine concentration is at 20 μM.
Modeling critical leadership competences for junior high school principals
Authors: Tang Hui-Wen Vivian
Published: May 2018

Purpose

Based on generic reviews of research on school leadership, this study aims to conceptualize an emerging leadership competence model for further prioritizing school leadership training needs by decision-making trial and evaluation laboratory (DEMATEL)-based analytic network process (ANP). Targeting at a specific group of junior high school principals in Taiwan, the synthesized prioritization of core competences and competence indicators computed by DEMATEL-based ANP can be used as a blueprint for systematically developing school principal preparation programs elsewhere based on contextually specific needs and concerns.

Design/methodology/approach

For the purpose of detecting the priority of competences extracted from a plethora of literature in relation to school leaders’ skills, abilities and knowledge, a hybrid MCDM model, known as DEMATEL-based ANP, is used to snapshot critical leadership competences for tailoring the intended junior high school principal preparation program.

Findings

Results of global weight computations by DEMATEL-based ANP show that the overall prioritization of the five dimensions in ranking order are “Redesigning the organization,” “Related leadership practices,” “Setting Directions,” “Personal Characteristics” and “Developing People.” Factor-level analysis indicated that “Legality,” “Consensus Building,” “Shared Vision,” “Strategic Management,” “Authoritarianism,” “Modeling Behavior” and “High Performance Emphasis” were prioritized factors to be included in developing the intended school principal preparation program.

Research limitations/implications

Contextually based findings yielded from DEMATEL-based ANP would only be applicable to the target context under investigation. Generalizing the findings to junior high school principals elsewhere might not be appropriate. Methods introduced in this study are extensible to further studies aiming at shaping leadership trainings in other school settings to achieve maximum impact based on contextually specific needs. Limitations associated with sophisticated mathematical computations involved in performing high-leverage MCDM models would shed light on the importance of interdisciplinary collaborations between scholars, practitioners and methodologists.

Practical implications

To efficiently deliver training for junior high school principals, the prioritization of core competences and competence indicators solicited by DEMATEL-based ANP can be used as a scenario-based reference for planning the intended school principal preparation program planning, as well as a mechanism for selecting and evaluating potential and incumbent school principals with desired leadership competences.

Originality/value

This study has used DELATEL-based ANP as a decision-making tool to disclose a plethora of competences extracted from different threads in the literature into a prioritized competence framework that differs from past one-size-fit-all approach to design and plan school principal preparation programs.
Mainland Chinese cruise passengers’ perceptions of Western service
Authors: Li Na , Fairley Sheranne
Published: May 2018

Purpose

The purpose of this paper is to empirically examine the service perceptions of mainland Chinese passengers on three international cruise ships.

Design/methodology/approach

Participant observation and casual conversations were conducted on three international cruise ships departing from Shanghai. Additionally, semi-structured in-depth interviews were conducted with 76 mainland Chinese cruise passengers over the three cruise trips.

Findings

The results suggest that mainland Chinese cruise passengers continually made cultural comparisons between Eastern and Western service. A preference for Western service was expressed, which passengers likened to luxury service that one would receive in China. In contrast to what they would expect to experience in China, passengers viewed cruise staff as polite and attentive, egalitarian, sincere and patient, interactive and engaged with the passengers, and committed to cleanliness. Although some passengers believed that the provision of more Chinese-speaking staff would improve the experience, most passengers did not perceive the ratio of Chinese-speaking staff to passengers to be an issue and were satisfied with the efforts of non-Chinese-speaking staff to provide high-quality service.

Practical implications

Understanding the service perceptions of mainland Chinese cruise passengers provides insights to cruise companies and travel agencies that service Chinese passengers.

Originality/value

Limited research has examined how mainland Chinese cruise passengers perceive Western service on cruise ships. This study provides insight into how to improve the service experience and enhance satisfaction of cruise passengers from mainland China.
Rethinking the tenant eviction process in Harare, Zimbabwe
Authors: Gambe Tazviona Richman
Published: May 2018

Purpose

The purpose of this paper is to explore the lessee eviction process in Zimbabwe in order to suggest possible ways of improving this process that has become a rutted road characterised by a litany of hiccups.

Design/methodology/approach

The study is guided by the qualitative methodology. Data were mainly collected from property managers operating in the real property market in Harare using in-depth interviews. Analysis of data was done through content analysis.

Findings

It emerged from the study that the eviction process in Zimbabwe is fraught with impediments and expenses that are sometimes exasperating to property owners and investors. The current eviction regulations favour the lessees at the expense of lessors thus niggling lessees have aggravated the already protracted process by unnecessary appeals.

Research limitations/implications

The paper only focuses on residential property management and eviction of legal lessees due to non-payment of rentals.

Practical implications

The rent regulations should be reviewed in order to create a fair legal system that protects the rights of both the lessors and lessees in Zimbabwe.

Originality/value

The perpetual decline of the economy in Zimbabwe has crippled lessees’ ability to pay rentals. Yet, it has also become intricate to evict defaulting lessees thereby causing loss of income to rental housing investors. Thus, the paper challenges the protracted eviction processes in the real property industry that have prejudiced property owners and scared away potential rental housing investors that are greatly needed to boost the rental market.
Symposium Introduction: Anthony Atkinson's ‘The Case for a Participation Income’
Authors: Stirton Lindsay
Published: May 2018

This article introduces the published proceedings of a symposium into Anthony Atkinson's proposal for a participation income. Just one of his many intellectual contributions, Atkinson famously argued for a scheme that gave up on the ambition of an unconditional scheme in order to press the case for a universal and non‐means tested income support scheme. The 'participation requirement' was a response to criticisms of basic income based on the absence of reciprocity. The contributions represent a range of responses and includes critics of participation income as well as those who are sympathetic to the goal of a participation income. All of them demonstrate the continuing relevance of Atkinson's proposal to ongoing debates on the reform of the welfare state.
“All that appears possible now is to mitigate as much as possible the trials of their closing years”1: Alfred Deakin's Attitudes to Aboriginal Affairs
Authors: Cahir Fred , Tout Dan
Published: May 2018

This article examines Alfred Deakin's attitudes towards, and impacts upon, Aboriginal people during the period 1880–1910, drawing on newspaper articles and parliamentary debates as principal source materials. The discussion begins by charting the long, influential and often positive relationships Deakin had with several Aboriginal communities during a period as a Victorian MLA between 1881 and 1884. It then proceeds to document Deakin's extraordinary descent into paternalism and racially‐based fatalism which pervaded his later association with Aboriginal affairs whilst Victoria's Chief Secretary (1886–1890), Victorian MLA for Essendon and delegate to Federal conventions (1890–1900), as the Federation debates took shape. And finally, the article outlines the attitudes Deakin expressed towards Aboriginal people in his various post‐Federation political roles, including Attorney‐General, Prime Minister and Minister for External Affairs. In doing so, the discussion draws out the connections between Deakin's advocacy of a white Australia and his attitudes towards Aboriginal Australia, and demonstrates the extent to which the creation of a new nation both informed and responded to socio‐racial ideologies that mandated the exclusion of non‐white identities from the nation‐to‐come.
High efficacy of direct‐acting anti‐viral agents in hepatitis C virus‐infected cirrhotic patients with successfully treated hepatocellular carcinoma
Authors: Persico M. , Aglitti A. , Aghemo A. , Rendina M. , Lleo A. , Ciancio A. , Di Marco V. , Lampertico P. , Brunetto M. R. , Zuin M. , Andreone P. , Villa E. , Troshina G. , Calvaruso V. , Degasperi E. , Coco B. , Giorgini A. , Conti F. , Di Leo A. , Marzi L. , Boccaccio V. , Bollani S. , Maisonneuve P. , Bruno S.
Published: May 2018

Background

The efficacy of direct‐acting anti‐viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown.

Aim

We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real‐life cohort of cirrhotic patients.

Methods

From January to December 2015 all consecutive HCV mono‐infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon‐based regimen.

Results

The sustained virologic response (SVR) rate at intention‐to‐treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class.

Conclusion

This large real‐life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.
Systematic review: safety of mesalazine in ulcerative colitis
Authors: Sehgal P. , Colombel J.‐F. , Aboubakr A. , Narula N.
Published: May 2018

Background

Mesalazine is the most commonly prescribed medication for mild to moderate ulcerative colitis. It is generally well tolerated with some reported side effects.

Aim

To summarise adverse drug events to mesalazine and recommend techniques for management. Furthermore, to determine if there is a dose‐dependent relationship between high (>2.4 g/day) vs low dosing (≤2.4 g/day) and occurrence of adverse drug events.

Methods

A literature search for relevant studies from inception to 1 December 2017 of the MEDLINE database was conducted. Two reviewers screened all titles identified. Data obtained from randomised controlled trials was used to estimate incidence rates of each adverse event. Two reviewers independently assessed methodological risk of bias and performed data extraction.

Results

3581 articles were initially considered. Of these, 3573 were screened, 622 reviewed and 91 included. Adverse events attributed to mesalazine included inflammatory reactions, pancreatitis, cardiotoxicity, hepatotoxicity, musculoskeletal complaints, respiratory symptoms, nephropathies and sexual dysfunction. There does not appear to be a dose‐dependent relationship of mesalazine and occurrence of adverse events.

Conclusion

Patients on mesalazine should be monitored for worsening of ulcerative colitis and development of new onset organ dysfunction. High‐dose mesalazine appears to have similar safety profile as low dose, and is not associated with greater risk of adverse events. Prior to placing a patient on mesalazine, baseline liver and renal function should be evaluated. Renal function should be periodically assessed, whereas other testing should be performed depending on development of symptoms.
The Evidence of Crucifixion on the Shroud of Turin Through the Anatomical Traits of the Lower Limbs and Feet
Authors: Caja V. L. , Boi M.
Published: May 2018

The imprint of the feet and lower limbs, as well as the blood and rivulets, present on the Shroud of Turin were analysed with regard to anatomical and pathological characteristics. In the dorsal image of the cloth, the crucifixion position shows the left foot on top of the right one; in the frontal view, the feet are almost parallel. The nail used in the crucifixion was driven through the foot. In the frontal image, the knees, the tibiae and the ankles seem to be parallel with different varus–valgus angles; the left one is straighter than the right one, which shows a greater angle. Because of this parallelism, both ankles show a plantar flexion that is dissimilar in the dorsal images. We describe for the first time the anatomical study of the image of the Shroud through modern concepts. At the level of biomechanics and anatomy, the image on the Shroud of Turin does not comply with modern knowledge; in fact, the image fails with regard to some aspects that we cannot interpret yet.
Productive and economic parameters of pigs supplemented from weaning to finishing with prebiotic and probiotic feed additives
Authors: Méndez‐Palacios Néstor , Méndez‐Mendoza Maximino , Vázquez‐Flores Felicitas , Castro‐Colombres José G. , Ramírez‐Bribiesca J. Efrén
Published: May 2018

Practical evidence suggests possible beneficial effects with the combined use of prebiotics and probiotics which can improve production parameters. The objective of the study was to investigate the addition of Saccharomyces cerevisiae (SC) as prebiotic and the combination of Lactobacillus spp. (L), Bacillus spp. (B) as probiotics on productive parameters and economic feasibility. Four hundred male pigs, hybrids of commercial genetic lines (Pietrain), were used: T1 = control group, T2 = 4 kg/tonne SC, T3 = 0.8 kg/tonne feed L and B, T4 = 4 kg/tonne SC + 0.8 kg/tonne L and B. Productive parameters were recorded in the treatment groups for four periods. Then, the viscera of five pigs per treatment were collected after slaughter to evaluate the histological changes and cytokine concentrations in the ileum. The weight gains of groups at 70–100, 100–125 and 125–150 days in the T4 group showed statistically increases (p < .05). Feed intake had a significant difference (p < .05) in T3 versus T1. The feed‐conversion ratio improved for all periods in the T4 group (p < .05). The eosinophil, mononuclear infiltration and cytokines (tumor necrosis factor‐α and interleukin‐6) in the mucosa were lower for treatments with probiotics. In conclusion, there was an economic benefit when using both prebiotics and probiotics in the diet of pigs from weaning to finishing.
Effect of ABCB1 C3435T Polymorphism on Pharmacokinetics of Antipsychotics and Antidepressants
Authors: Saiz‐Rodríguez Miriam , Belmonte Carmen , Román Manuel , Ochoa Dolores , Jiang‐Zheng Carolina , Koller Dora , Mejía Gina , Zubiaur Pablo , Wojnicz Aneta , Abad‐Santos Francisco
Published: May 2018

P‐glycoprotein, encoded by ABCB1, is an ATP‐dependent drug efflux pump which exports substances outside the cell. Some studies described connections between C3435T polymorphism T allele and lower P‐glycoprotein expression; therefore, homozygous T/T could show higher plasma levels. Our aim was to evaluate the effect of C3435T on pharmacokinetics of 4 antipsychotics (olanzapine, quetiapine, risperidone and aripiprazole) and 4 antidepressants (trazodone, sertraline, agomelatine and citalopram). The study included 473 healthy volunteers receiving a single oral dose of one of these drugs, genotyped by real‐time PCR. Multivariate analysis was performed to adjust the effect of sex and genotype of the main cytochrome P450 enzymes. C3435T polymorphism had an effect on olanzapine pharmacokinetics, as T/T individuals showed lower clearance and volume of distribution. T/T individuals showed lower T1/2 of 9‐OH‐risperidone, but this difference disappeared after multivariate correction. T/T homozygous individuals showed lower dehydro‐aripiprazole and trazodone area under the concentration‐time curve, along with lower half‐life and higher clearance of trazodone. C/T genotype was associated to higher citalopram maximum concentration. C3435T had no effect on quetiapine, sertraline or agomelatine pharmacokinetics. C3435T can affect the elimination of some drugs in different ways. Regarding risperidone, trazodone and dehydro‐aripiprazole, we observed enhanced elimination while it was reduced in olanzapine and citalopram. However, in quetiapine, aripiprazole, sertraline and agomelatine, no changes were detected. These results suggest that P‐glycoprotein polymorphisms could affect CNS drugs disposition, but the genetic factor that alters its activity is still unknown. This fact leads to consider the analysis of ABCB1 haplotypes instead of individual variants.
Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice
Authors: Song Lu , Wang Hao , Wang Ying‐Jie , Wang Jin‐Liang , Zhu Qing , Wu Feng , Zhang Wei , Jiang Bo
Published: May 2018

Background and Purpose

Developing novel pharmacological targets beyond the monoaminergic system is now a popular strategy for treating depression. PPARα is a nuclear receptor protein that functions as a transcription factor,‐regulating gene expression. We have previously reported that both WY14643 and fenofibrate, two pharmacological agonists of PPARα, have antidepressant‐like effects in mice, implying that PPARα is a potential antidepressant target.

Experimental Approach

We first used various biotechnological methods to evaluate the effects of chronic stress and fluoxetine on hippocampal PPARα. The viral‐mediated genetic approach was then employed to explore whether hippocampal PPARα was an antidepressant target. PPARα inhibitors, PPARα‐knockout (KO) mice and PPARα‐knockdown (KD) mice were further used to determine the role of PPARα in the antidepressant effects of fluoxetine.

Key Results

Chronic stress significantly decreased mRNA and protein levels of PPARα in the hippocampus, but not other regions, and also fully reduced the recruitment of hippocampal PPARα to the cAMP response element‐binding (CREB) promoter. Genetic overexpression of hippocampal PPARα induced significant antidepressant‐like actions in mice by promoting CREB‐mediated biosynthesis of brain‐derived neurotrophic factor. Moreover, fluoxetine notably restored the stress‐induced negative effects on hippocampal PPARα. Using PPARα antagonists fully blocked the antidepressant effects of fluoxetine in mice, and similarly, both PPARα‐KO and PPARα‐KD abolished the effects of fluoxetine. Besides, PPARα‐KO and PPARα‐KD aggravated depression in mice.

Conclusions and Implications

Hippocampal PPARα is a potential novel antidepressant target that mediates the antidepressant actions of fluoxetine in mice.
PEP06 polypeptide 30 exerts antitumour effect in colorectal carcinoma via inhibiting epithelial–mesenchymal transition
Authors: Yu Siming , Li Linna , Tian Wei , Nie Dan , Mu Wei , Qiu Fang , Liu Yu , Liu Xinghan , Wang Xiaofeng , Du Zhimin , Chu Wen‐Feng , Yang Baofeng
Published: May 2018

Background and Purpose

PEP06, a polypeptide modified from endostatin, was investigated for its antitumour effects on colorectal cancer (CRC) and the possible mechanisms of this antitumour activity were examined in in vitro and in vivo models.

Experimental Approach

After PEP06 treatment, cell proliferation and migration assays were performed in CRC cells. Epithelial–mesenchymal transition (EMT) progression was determined by Western blotting, immunofluorescent staining and immunohistochemistry in vitro and in a residual xenograft model. MiRNAs regulated by PEP06 were identified by miRNA microarray and verified by in situ hybridization and quantitative real‐time PCR. The interactions between PEP06 and integrin αvβ3 were determined with Biacore SA biochips. The cellular function of miR‐146b‐5p was validated by gain‐of‐function and loss‐of‐function approaches. A mouse model of lung metastasis was used to determine the effect of PEP06 on metastatic growth.

Key Results

PEP06 did not affect cell viability but reduced migration and EMT in SW620 and HCT116 cells. PEP06 significantly repressed the expression of miR‐146b‐5p in these two cell lines through binding to integrin αvβ3. MiR‐146b‐5p was shown to increase EMT by targeting Smad4, and the miR‐146b‐5p‐Smad4 cascade regulated EMT in CRC. PEP06 also suppressed CRC pulmonary metastasis, increased survival of mice and hampered residual tumour growth by inhibiting EMT through down‐regulating miR‐146b‐5p.

Conclusions and Implications

PEP06 is a polypeptide that inhibits the growth and metastasis of colon cancer through its RGD motif binding to integrin αvβ3, thereby down‐regulating miR‐146b‐5p to inhibit EMT in vitro and in vivo. It might have potential as a therapeutic for CRC.
High‐frequency autonomic modulation: a new model for analysis of autonomic cardiac control
Authors: Champéroux Pascal , Fesler Pierre , Judé Sebastien , Richard Serge , Le Guennec Jean‐Yves , Thireau Jérôme
Published: May 2018

Background and Purpose

Increase in high‐frequency beat‐to‐beat heart rate oscillations by torsadogenic hERG blockers appears to be associated with signs of parasympathetic and sympathetic co‐activation which cannot be assessed directly using classic methods of heart rate variability analysis. The present work aimed to find a translational model that would allow this particular state of the autonomic control of heart rate to be assessed.

Experimental Approach

High‐frequency heart rate and heart period oscillations were analysed within discrete 10 s intervals in a cohort of 200 healthy human subjects. Results were compared to data collected in non‐human primates and beagle dogs during pharmacological challenges and torsadogenic hERG blockers exposure, in 127 genotyped LQT1 patients on/off β‐blocker treatment and in subgroups of smoking and non‐smoking subjects.

Key Results

Three states of autonomic modulation, S1 (parasympathetic predominance) to S3 (reciprocal parasympathetic withdrawal/sympathetic activation), were differentiated to build a new model of heart rate variability referred to as high‐frequency autonomic modulation. The S2 state corresponded to a specific state during which both parasympathetic and sympathetic systems were coexisting or co‐activated. S2 oscillations were proportionally increased by torsadogenic hERG‐blocking drugs, whereas smoking caused an increase in S3 oscillations.

Conclusions and Implications

The combined analysis of the magnitude of high‐frequency heart rate and high‐frequency heart period oscillations allows a refined assessment of heart rate autonomic modulation applicable to long‐term ECG recordings and offers new approaches to assessment of the risk of sudden death both in terms of underlying mechanisms and sensitivity.
Government loan guarantees and the credit decision‐making structure
Authors: Ben‐Yashar Ruth , Krausz Miriam , Nitzan Shmuel
Published: May 2018

Governments can alleviate the problem of banks denying credit to high risk borrowers and excluding weaker sectors from borrowing by introducing state‐guaranteed loan programs. The main contribution of this paper is the elucidation of the importance of the bank's credit decision‐making structure in ensuring overall effectiveness of loan guarantees. In particular, the government can use the guarantee as an instrument for credit inducement and for affecting the bank's decision‐making system, i.e., its degree of centralization, bias towards approval of loans and reliance on objective loan‐specific information.

Les garanties gouvernementales de prêts et la structure de la prise de décision en ce qui a trait au crédit. Les gouvernements peuvent soulager le problème des banques qui refusent de faire crédit à des emprunteurs à hauts risques et excluent certains secteurs plus faibles d’accès au crédit, en introduisant des programmes de garantie de prêts. La contribution centrale de ce mémoire est l’élucidation de l’importance de la structure de prise de décision des banques en ce qui a trait au crédit pour assurer l’efficacité des garanties de prêts. En particulier, le gouvernement peut utiliser la garantie comme instrument d’incitation au crédit et pour influencer le système de prise de décision des banques, i.e., le degré de centralisation, la tendance à approuver les prêts, le recours à de l’information objective et spécifique au prêt.
Co‐administration of kla‐TAT peptide and iRGD to enhance the permeability on A549 3D multiple sphere cells and accumulation on xenograft mice
Authors: Hu Cuihua , Chen Xiaolong , Huang Yibing , Chen Yuxin
Published: May 2018

To enhance the anticancer activity, tumor penetration ability of the hybrid anticancer peptide, in this study, a TAT (RKKRRQRRR) peptide modified kla peptide (KLAKLAKKLAKLAK, with all D‐amino acids), named kla‐TAT, was co‐administrated with the homing/penetrating peptide iRGD which could enhance the permeability of chemical drug in solid tumor and tumor vessel by co‐administration. In this study, the nonsmall cell lung cancer A549 cell line with the iRGD targeting receptor neuropilin‐1 high expression was selected to establish the 2D monolayer cell, 3D multiple cell spheroids, and xenograft mice model. The co‐administration of iRGD strengthened the permeability of kla‐TAT peptide against A549 2D and 3D sphere model with the penetration improvement property of iRGD; more importantly, co‐administration with iRGD dramatically enhanced the accumulation of kla‐TAT peptide in tumor tissue on the xenograft mice model with the homing property of iRGD. The co‐administration of iRGD strategy confers targeting ability to the hybrid peptide kla‐TAT. We believe the chemical conjugation plus co‐administration approach may provide a promising way for cancer treatment in clinical practices.
Synthesis and antibacterial activities of novel pleuromutilin derivatives bearing an aminothiophenol moiety
Authors: Zhang Zhao‐Sheng , Huang Yun‐Zhen , Luo Jian , Jin Zhen , Liu Ya‐Hong , Tang You‐Zhi
Published: May 2018

We synthesized a series of novel thioether pleuromutilin derivatives incorporating 2‐aminothiophenol moieties into the C14 side chain via acylation reactions under mild conditions. We evaluated the in‐vitro antibacterial activities of the derivatives against methicillin‐resistant Staphylococcus aureus (MRSA, ATCC 43300), Staphylococcus aureus (ATCC 29213) and Escherichia coli (ATCC 25922). The majority of the synthesized derivatives possessed moderate antibacterial activities. Compound 8 was found to be the most active antibacterial derivative against MRSA. We conducted docking experiments to understand the possible mode of interactions between compounds 8, 9b, 11a and 50S ribosomal subunit. The docking results proved that there is a reasonable correlation between the binding free energy and the antibacterial activity. Compound 8 was evaluated for its in‐vivo antibacterial activity and showed higher efficacy than tiamulin against MRSA in mouse infection model.
Cerebrospinal fluid findings in reversible cerebral vasoconstriction syndrome: a way to differentiate from cerebral vasculitis?
Authors: Kraayvanger L , Berlit P , Albrecht P , Hartung H-P , Kraemer M
Published: May 2018

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by an acute onset of severe headache and multi-focal segmental vasoconstriction of cerebral arteries resolving within 12 weeks. Diagnostic criteria include normal or near-normal findings in cerebrospinal fluid (CSF) analysis, especially leucocyte levels < 10/mm³. Distinguishing RCVS from primary angiitis of the central nervous system (PACNS) is essential to avoid unnecessary and sometimes unfavourable immunosuppressive treatment. We reviewed retrospectively the clinical and diagnostic data of 10 RCVS patients who presented in our neurological department from 1 January 2013 to February 2017. The main purpose was to verify whether CSF leucocyte counts < 10/mm³ serve to discriminate RCVS from PACNS. Five of six patients who underwent lumbar puncture presented with CSF leucocyte levels ≥ 10/mm³. Two patients had a history of misinterpretation of CSF pleocytosis as cerebral vasculitis and of immunosuppressive treatment. A complete restitution of cerebral vasoconstriction was evident in all. No patient had further cerebral strokes or bleedings without immunosuppressive treatment over more than 12 weeks. Despite the established diagnostic criteria, RCVS can manifest with CSF leucocyte levels > 10/mm³. Careful anamnesis and the response of ‘vasculitis-like angiography’ to nimodipine given as a test during angiography and as oral medication are key to differentiate RCVS from cerebral vasculitis.
A novel PDE9 inhibitor WYQ‐C36D ameliorates corticosterone‐induced neurotoxicity and depression‐like behaviors by cGMP‐CREB‐related signaling
Authors: Huang Xian‐Feng , Jiang Wen‐Tao , Liu Li , Song Fang‐Chen , Zhu Xia , Shi Gui‐Lan , Ding Shu‐Ming , Ke Heng‐Ming , Wang Wei , O'Donnell James M. , Zhang Han‐Ting , Luo Hai‐Bin , Wan Yi‐Qian , Song Guo‐Qiang , Xu Ying
Published: May 2018

Background

Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated.

Methods

We examined the protective effects of WYQ‐C36D (C36D), a novel PDE9 inhibitor, against corticosterone‐induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT‐22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1 mg/kg on stress‐induced depression‐ and anxiety‐like behaviors and memory deficits were also examined in mice.

Results

C36D significantly protected HT‐22 cells against corticosterone‐induced cytotoxicity and rescued corticosterone‐induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp‐8‐Br‐PET‐cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant‐like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic‐like and memory‐enhancing effects in the elevated plus‐maze and novel object recognition tests.

Conclusion

Our results show that inhibition of PDE9 by C36D produces antidepressant‐ and anxiolytic‐like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD.
Ferrimagnetic wollastonite ceramics based on waste valorization
Authors: González‐Triviño Isabel , Benítez‐Guerrero Mónica , Moreno Belén , Pascual‐Cosp José
Published: May 2018

Industrial residues may be considered as an economic and environmentally friendly option for the manufacture of ceramic materials for civil and energy engineering. In this work, granite sludge, mussel shells and glass cullet were used to produce a ceramic material that presents high hardness (HV = 5.57 GPa) and fracture toughness values (KIC = 1.78 MPa·m1/2) as well as soft ferrimagnetic behavior. The presence of wollastonite confers characteristics typical of porcelain stoneware (σ = 64 N/mm2, WA = 0.361%) to the final products.