bluuebunny/crossref_metadata_2025 huggingface dataset:
СУЗБИЈАЊЕ КОРУПЦИЈЕ У МЕЂУНАРОДНОМ КРИВИЧНОМ ПРАВУ
Authors: Симовић Миодраг , Јовашевић Драган
Published: September 2018

Иако се ради о давнашњој појави, која је присутна у свим правнимсистемима од најстаријих времена до данас, проблемом корупције се,поред националних кривичних законодавстава, бави и међународна зајед-ница. Тако је посљедњих деценија донијето више универзалних (у оквируОрганизације уједињених нација) и регионалних (у оквиру Европске унијеи Савјета Европе) међународних докумената којима се успоставља си-стем међународних стандарда за спречавање и сузбијање корупције насвим нивоима, укључујући и примјену кривичних санкција. Потписивањеммеђународних докумената поједина национална законодавства, па и за-конодавство Босне и Херцеговине, преузело је обавезу да пропише, измеђуосталог, и кривичну одговорност и систем кривичних санкција за учини-оце кривичних дјела корупције. О систему међународних стандарда заспречавање и сузбијање корупције говори се у овом раду.
Physical and chemical modification of lignocellulosic waste biomass-tool for improving sorption capacity
Authors: Lopičić Zorica , Šoštarić Tatjana , Milojković Jelena , Mihajlović Marija , Petrović Jelena , Antanasković Ivan , Stojanović Mirjana
Published: September 2018

The  main  constituents  of  ligno-cellulosic  (LC)  biomass  are  lignin,  celluloses  and  hemicelluloses,  complex polymers with  many  functional  groups,  which  can be modified with  the  purpose  to  improve the  sorption properties  of  the  starting  material.  This  paper  presents  several  physical  and  chemical  modifications applied  to  LC  biomass  of  peach  stones  (Prunus  persica  L.),  abundant  waste  from  food  industry.  These stones  were  firstly  mechanically  activated  in  two  mill  types,  and  then  by  different  chemicals.  Sorption experiments  were  performed  in  batch  reaction  system  with  stirring.  Cu(II)  sorption  kinetic  was  tested through three reaction kinetic models: pseudo-first order, pseudo-second order and Elovich equation. FT-IR analyses of chemically modified samples is alsopresented and discussed.
The Influence of Income Shifting Incentives towards The Tax Haven Country Utilization: Case Study on the Companies listed in Indonesian Stock Exchange
Authors: Nurhidayati Nurhidayati , Fuadillah Hendyga
Published: September 2018

This study aims to determine the association between a series of income shifting incentives, including multinationality, transfer pricing aggressiveness, thin capitalization, intangible assets, and tax haven country utilization. This study is based on a sample of 78 multinational companies listed on the Indonesia Stock Exchange over 2012–2016 period (390 firm-year). The results prove that, multinationality, thin capitalization, intangible asset are positively associated with tax haven utilization, while transfer pricing aggressiveness is not positively associated with tax haven utilization. Based on the additional analysis, basic and chemicals sectors have the highest association between a series of income shifting incentives and tax haven utilization among other industrial sectors and each industry sector has different ways of utilizing tax haven country. The findings of this study are expected to provide input to the Directorate General of Taxes the importance of reviewing debt to equity ratio rule which turned out to be one gap for the taxpayer and in making the proposed inspection plan and the potential thematic exploration related to profit shifting incentives more focused on basic industry and chemicals sector. The Directorate General of Taxes also needs to raise awareness of the taxpayers of agriculture, mining, basic and chemicals, and trade, service and investment, which has a growing number of subsidiaries in tax haven country. Increased supervision of intangible assets transfers in the agriculture and infra­structure, utilities & transportation sectors also needs to be done.
MARKETING ON POLITICS AND PUBLIC LEADERSHIP
Authors: Purwanto Purwanto , Sutanto Eddy Madiono , Indahingwati Asmara
Published: September 2018

This study examines the influence of political marketing and political will on public leadership and individual performance. The sample used is the people in Surabaya as many as 265 with a random sampling method. Amos 21 is used to test the indirect effect by using bootstrap test. The result of the research shows that political marketing and political will have a significant influence to the success of gaining public leadership, political marketing and marketing will have no significant effect on performance, and public le­a­dership has a significant effect on performance. For the indirect influence, political marketing and political will on individual performance are mediated by public leadership.
Targeting newly identified ERβ/TGF‐β1/SMAD3 signals with the FDA‐approved anti‐estrogen Faslodex or an ERβ selective antagonist in renal cell carcinoma
Authors: Song Wenbin , He Dalin , Chen Yule , Yeh Chiuan‐Ren , Hsu Iawen , Huang Qingbo , Zhang Xu , Chang Luke Sien‐Shih , Zuo Li , Chen Jiasheng , Doersch Karen M. , Chang Chawnshang , Li Lei , Yeh Shuyuan
Published: September 2018

Renal cell carcinoma (RCC) has the third highest mortality rate among urological tumors, and 20–30% of RCC patients present with metastatic RCC at the time of diagnosis. Although recent studies have indicated that estrogen receptor β (ERβ) could play promoting roles in RCC progression, the detailed mechanisms remain to be clarified. In the present study, we found that expression of ERβ, but not ERα, increases with tumor stage and grade, and also observed that modification of ERβ signals using estrogens/anti‐estrogens, shRNA knockdown of ERβ and overexpression of ERβ using ectopic cDNA affects RCC cell proliferation, migration and invasion. Mechanism analysis revealed that ERβ can promote RCC cell invasion via an increase in transforming growth factor β1 (TGF‐β1)/SMAD3 signals, and interrupting TGF‐β1/SMAD3 signals with a TGFβR1 inhibitor can reverse/block ERβ‐increased RCC cell migration. Importantly, preclinical analyses using in vivo mouse models of RCC revealed that targeting of this newly identified ERβ/TGF‐β1/SMAD3 pathway with either the FDA‐approved anti‐estrogen ICI182,780 (Faslodex) or a selective ERβ antagonist 4‐[2‐phenyl‐5,7 bis(trifluoromethyl)pyrazolo[1,5‐a]pyrimidin‐3‐yl]phenol can significantly reduce RCC tumor growth and invasion, which may be suitable as the basis for novel therapies to more effectively suppress metastatic RCC.
Trends in the Prevalence and Incidence of Psoriasis and Psoriatic Arthritis in Ontario, Canada: A Population‐Based Study
Authors: Eder Lihi , Widdifield Jessica , Rosen Cheryl F. , Cook Richard , Lee Ker‐Ai , Alhusayen Raed , Paterson Michael J. , Cheng Stephanie Y. , Jabbari Shirin , Campbell Willemina , Bernatsky Sasha , Gladman Dafna D. , Tu Karen
Published: September 2018

Objective

To estimate the prevalence and incidence of psoriasis and psoriatic arthritis (PsA) over time in Ontario, Canada.

Methods

We performed a population‐based study of Ontario health administrative data, using validated case definitions for psoriasis and PsA. We computed the crude and age‐ and sex‐standardized cumulative prevalence and incidence of psoriasis from 2000 to 2015.

Results

Among the 10,774,802 individuals ages ≥20 years residing in Ontario in 2015, we identified 273,238 patients with psoriasis and 18,655 patients with PsA, equating to cumulative prevalence estimates of 2.54% and 0.17%, respectively. Correcting the prevalence estimates for imperfect sensitivity and specificity resulted in similar estimates. The male:female ratio was approximately 1.0 for both conditions. For psoriasis, the age‐ and sex‐standardized cumulative prevalence increased from 1.74% in 2000 to 2.32% in 2015. For PsA, the age‐ and sex‐standardized cumulative prevalence increased from 0.09% in 2008 to 0.15% in 2015. Between 2008 and 2015, annual incidence rates for psoriasis decreased, whereas those for PsA remained relatively stable.

Conclusion

The prevalence and incidence of psoriasis and PsA in Ontario are similar to those observed in Europe and the US. The steady increase in the prevalence of psoriasis and PsA over the past decade may be due to a combination of population aging, population growth, and increasing life expectancy.
Development of thermoplastic films for ultrasonic manufacturing of printed circuit boards
Authors: Hopmann Christian , Höfs Christopher , Schomburg Werner Karl , Kosloh Julia , Sackmann Johannes
Published: September 2018

Conventional production processes of PCB involve a high amount of complex production steps and the use of hazardous chemicals. Furthermore, a great effort is required for their recycling. Ultrasonic hot embossing of coextruded films, filled with electrical conductive fillers, could be an economic and ecological alternative for the production of PCB. This study focuses on the identification of suitable filler–matrix combinations for the isotropic and anisotropic conductive film layers. Hence, monolayer films with different fillers and filler contents are extruded. Conductivities of 8.31 and 12 S/m were measured in cross and machine direction, respectively, for a polypropylene‐film with 10 wt.‐% of CNT. This is two magnitudes below the required 535 S/m. With 70 mS/m, the conductivity in thickness direction is 115–170 times lower. This is caused by process‐related surface layers with low filler content. For steel fibers, no electrical conductivity can be measured.
Iridium‐Catalyzed α‐Selective Arylation of Styrenes by Dual C−H Functionalization
Authors: Cooper Phillippa , Crisenza Giacomo E. M. , Feron Lyman J. , Bower John F.
Published: September 2018

An IrI‐system modified with a ferrocene derived bisphosphine ligand promotes α‐selective arylation of styrenes by dual C−H functionalization. These studies offer a regioisomeric alternative to the Pd‐catalyzed Fujiwara–Moritani reaction.
Micropatterned Ultrathin MOF Membranes with Enhanced Molecular Sieving Property
Authors: Huang Kang , Wang Bo , Guo Song , Li Kang
Published: September 2018

Metal–organic frameworks (MOFs) are attractive crystalline materials for membranes due to their diverse crystalline pore structures and molecular separation properties. However, the fabrication cost is relatively high compared to conventional polymeric membranes. The concern of the cost could be eased if they are part of a value‐added device, for example, as the key separation unit in a lab‐on‐a‐chip device. This study demonstrates the feasibility of miniaturization of MOF membranes by patterning the membrane surface, a necessary step for MOF membranes to be used in compact devices. Water‐stable ultrathin UiO‐66 membranes with a thickness down to 250 nm on a substrate with a complex pattern were grown. The patterned membranes showed a 100 % improvement in the apparent permeation flux over conventional flat‐UiO‐66 membranes without compromising the molecular separation property, indicating the complexity of a surface would not be a formidable obstacle to the MOF membrane fabrication.
A new frontier in digital activism: An exploration of digital feminism in Fiji
Authors: Brimacombe Tait , Kant Romitesh , Finau Glenn , Tarai Jope , Titifanue Jason
Published: September 2018

Social media has become a crucial feature of the Pacific islands in the 21st century, providing people with the means to demand greater accountability and transparency and offering an alternative platform through which to engage in policy processes, dialogue, and debate. Increasing social media access and use has altered the existing media and communications landscape, with implications for mainstream media reporting, censorship, and citizen voice. This paper explores this phenomenon through an examination of the digital activism practices of a group of women's rights activists in Fiji. In doing so, this paper explores how social media is being used as an online platform for information dissemination and debate, as well as the implications this is having “offline” as part of efforts to influence policymaking.
The Complex Interdependence of China's Belt and Road Initiative in the Philippines
Authors: Rabena Aaron Jed
Published: September 2018

Complex interdependence refers to the multiple channels of interaction and agenda in interstate relations, which involve domestic (public and private) stakeholders and nonmilitary issues. Since the Belt and Road Initiative (BRI) came into being, most analyses have largely focused on infrastructure development. The BRI not only has the potential to impact a host government's socioeconomic agenda but also its overall bilateral relationship with China. It is therefore imperative to measure the progress and prospects of China's Belt and Road projects in the Philippines, in line with Beijing's strategic goal to deepen complex interdependence with partner‐states, against the BRI's five major dimensions of cooperation: (a) policy coordination, (b) infrastructure development and connectivity, (c) trade and investment facilitation, (d) financial coordination and integration, and (e) people‐to‐people ties and connectivity. These, together with the examination of China's BRI projects in other Asian countries as modes of comparison, are crucial in assessing probable outcomes in the Philippines. The paper includes policy recommendations based on possible pitfalls and risks that may hamper the advancement of the Belt and Road projects in the Philippines and Sino‐Philippine bilateral interaction.
CYP3A but not P‐gp plays a relevant role in the in vivo intestinal and hepatic clearance of the delta‐specific phosphoinositide‐3 kinase inhibitor leniolisib
Authors: De Buck Stefan , Kucher Klaus , Hara Hisanori , Gray Cathy , Woessner Ralph
Published: September 2018

This study investigated the effect of itraconazole, a strong dual inhibitor of cytochrome P450 (CYP) 3A4 and P‐glycoprotein (P‐gp), on the single dose pharmacokinetics of leniolisib. In order to differentiate the specific contribution of CYP3A from P‐gp, the potential interaction with quinidine, a strong inhibitor of P‐gp but not CYP3A, was studied as well. Using a fixed‐sequence, 3‐way crossover design, 20 healthy male subjects received single oral doses of 10 mg leniolisib during three phases separated by a washout: (1) leniolisib alone, (2) 200 mg itraconazole once daily for 9 days plus leniolisib on day 5, and (3) 300 mg quinidine administered 1 h before and 3 h after leniolisib. Itraconazole increased the leniolisib oral drug exposure (AUCinf) by on average 2.1‐fold, whereas the peak drug concentration (Cmax) was less impacted (1.25‐fold). The terminal elimination half‐life (T1/2) of leniolisib was also increased by ~2‐fold. Neither oral AUCinf nor Cmax or T1/2 was found to be altered by quinidine. These findings suggest that the interaction with itraconazole occurred mainly systemically through inhibition of CYP3A, and corroborate our in vitro findings that leniolisib is neither a sensitive CYP3A substrate nor a relevant in vivo substrate for intestinal or hepatic P‐gp. Assuming itraconazole levels achieved complete inhibition of CYP3A, the fractional contribution of CYP3A to the overall disposition of leniolisib is estimated to be about 50%. The concomitant use of leniolisib with strong inhibitors of CYP3A as well as strong and moderate inducers of CYP3A is best avoided.
Synthesis and assembly of human vault particles in yeast
Authors: Wang Meng , Kickhoefer Valerie A. , Rome Leonard H. , Foellmer Oliver K. , Mahendra Shaily
Published: September 2018

Vault particles are the largest naturally occurring ribonucleoprotein complexes found in the cytoplasm. In all 78 copies of major vault protein (MVP) assemble on polyribosome templates, forming recombinant vault particles, which are of great interest as encapsulation carriers for therapeutics delivery and enzyme stabilization. Baculovirus‐insect cell expression is the only system that has been developed for recombinant vault synthesis, but it has low scalability and slow production rate. In this study, we demonstrated the first use of yeast cells for the production of vault particles with full integrity and functionality solely by expressing the complementary DNA (cDNA) encoding MVP. Vaults synthesized in Pichia pastoris yeast cells are morphologically indistinguishable from recombinant vault particles produced in insect cells, and are able to package and stabilize enzymes resulting in improved longevity and catalytic efficiency. Thus, our results imply that the yeast system is an economical alternative to insect cells for the production of recombinant vaults. The consistency of vault morphology between yeast and insect cell systems also underlines that polyribosome templating may be conserved among eukaryotes, which promises the synthesis and assembly of recombinant human vault particles in other eukaryotic organisms.
Model‐based identification of cell‐cycle‐dependent metabolism and putative autocrine effects in antibody producing CHO cell culture
Authors: Möller Johannes , Korte Katrin , Pörtner Ralf , Zeng An‐Ping , Jandt Uwe
Published: September 2018

The understanding of cell‐cycle‐dependent population heterogeneities in mammalian cell culture and their influence on production rates is still limited. Furthermore, metabolic regulations arising from self‐expressed signaling factors (autocrine/autoinhibitory factors) have been postulated in the past, but no determination of such effects have been made so far for fast‐growing production Chinese hamster ovary (CHO) cells in chemically defined media. In this study, a novel approach combining near‐physiological treatment of cells (including synchronization), population resolved mechanistic modeling and statistical analysis was developed to identify population inhomogeneities. Cell‐cycle‐dependent population dynamics and metabolic regulations due to a putative autocrine factor were examined and their impact on the metabolic rates and antibody production of near‐physiologically synchronized CHO DP‐12 cell cultures was determined. To achieve this, a population resolved model was extended to describe putative autocrine‐dependentt and cell‐cycle‐related metabolic rates for glucose, glutamine, lactate, ammonia, and antibody production. The model parameters were estimated based on data of two repeated batch cultivations (three batches each), with main substrates in excess and potentially inhibiting waste products (lactate and ammonium) controlled within narrow ranges. Significant changes, due to a putative autocrine factor, were identified for lactate and ammonia formation and antibody production. The cell growth and the uptake of glucose and glutamine were only partially affected by the putative autocrine under the given conditions. The results indicate the presence of a self‐expressed autocrine factor and its strong impact on the metabolism of CHO DP‐12 cells. Furthermore, glucose and glutamine uptake, as well as the formation of ammonium and antibody were found to be significantly cell‐cycle‐dependent. The combined approach has a strong potential to improve the understanding of the interplay of population heterogeneities and signal factors in mammalian cell culture.
Electrochemical Impedance Spectroscopy Based Biosensors: Mechanistic Principles, Analytical Examples and Challenges towards Commercialization for Assays of Protein Cancer Biomarkers
Authors: Bertok Tomas , Lorencova Lenka , Chocholova Erika , Jane Eduard , Vikartovska Alica , Kasak Peter , Tkac Jan
Published: September 2018

Impedimetric affinity biosensors are, without any doubt, among the most sensitive analytical devices available, offering low limits of detection and wide linear response ranges. There are, however, only a few papers detailing the application of impedimetric biosensors for the analysis of clinically relevant samples with due clinical performance. The fact that these devices have not found their way to any commercial or clinical use to date might be surprising, since an electrochemical assay platform based on portable potentiostats is a success story for monitoring a range of clinical parameters such as ions, haematological indicators and glucose. This review discusses the reasons behind this discrepancy and addresses the barriers to be overcome in order to achieve the point‐of‐care diagnostics using such devices for detection of protein oncomarkers approved by FDA. The final part of the review covers the most recent progress in the area.
Deciphering the Influence of Meridional versus Facial Isomers in Spin Crossover Complexes
Authors: Lathion Timothée , Guénée Laure , Besnard Céline , Bousseksou Azzedine , Piguet Claude
Published: September 2018

Chelate coordination of non‐symmetrical didentate pyrazine‐benzimidazole (L1) or pyridine‐benzimidazole (L2) N‐donor ligands around divalent iron in acetonitrile produces stable homoleptic triple‐helical spin crossover [Fe(Lk)3]2+ complexes existing as mixtures of meridional (C1‐symmetry) and facial (C3‐symmetry) isomers in slow exchange on the NMR timescale. The speciation deviates from the expected statistical ratio mer/fac=3:1, a trend assigned to the thermodynamic trans‐influence, combined with solvation effects. Consequently, the observed spin state FeIIlow‐spin↔FeIIhigh‐spin equilibria occurring in [Fe(Lk)3]2+ refer to mixtures of complexes in solution, an issue usually not considered in this field, but which limits rational structure‐properties correlations. Taking advantage of the selective and quantitative formation of isostructural facial isomers in non‐constrained related spin crossover d‐f helicates (HHH)‐[LnFe(Lk)3]5+ (Ln is a trivalent lanthanide, Lk=L5, L6), we propose a novel strategy for assigning pertinent thermodynamic driving forces to each spin crossover triple‐helical isomer. The different enthalpic contributions to the spin state equilibrium found in mer‐[Fe(Lk)3]2+ and fac‐[Fe(Lk)3]2+ reflect the Fe−N bond strengths dictated by the trans‐influence, whereas a concomitant solvent‐based entropic contribution reinforces the latter effect and results in systematic shifts of the spin crossover transitions toward higher temperature in the facial isomers.
Prognostic value of autonomous and controlled motivation in outpatient eating‐disorder treatment
Authors: Sansfaçon Jeanne , Gauvin Lise , Fletcher Émilie , Cottier Danaëlle , Rossi Erika , Kahan Esther , Israël Mimi , Steiger Howard
Published: September 2018

According to Self‐Determination Theory, when motivation to reach an objective is fully internal, it is said to be “autonomous”; when driven by external incentives, it is said to be “controlled”. Previous research has indicated that autonomously motivated individuals show better response to treatments for eating disorders.

Objective

In individuals undergoing different intensities of outpatient treatment for an eating disorder, we sought to assess associations between autonomous and controlled motivations and response to treatment on the one hand, and likelihood of dropping out of treatment, on the other.

Method

Seven hundred seventy adults meeting DSM‐5 criteria for an eating disorder (216 with Anorexia Nervosa, 282 with Bulimia Nervosa, and 272 with Other Specified Feeding or Eating Disorder) were included in this study. Before an interval of outpatient treatment, individuals completed the Eating Disorder Examination Questionnaire and the Autonomous and Controlled Motivations for Treatment Questionnaire. Participants completed the Eating Disorder Examination Questionnaire again at one or two subsequent timepoints.

Results

After controlling for diagnosis, treatment intensity, and number of previous treatments, analyses showed that higher autonomous motivation was associated with better response on eating‐disorder overall symptoms and lower likelihood of dropping out of treatment. In contrast, controlled motivation was not associated with response to treatment.

Discussion

Our results suggest that autonomous motivation has trans‐diagnostic influence upon response to various intensities of treatment for an eating disorder. In support of an autonomy supportive approach to treatment, findings link autonomous motivation with more favorable outcome.
The outcome and characteristics of patients with relapsed adult T cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation
Authors: Kato Koji , Uike Naokuni , Wake Atsushi , Yoshimitsu Makoto , Tobai Tomomi , Sawayama Yasushi , Takatsuka Yoshifusa , Fukuda Takahiro , Uchida Naoyuki , Eto Tetsuya , Nakashima Yasuhiro , Kondo Tadakazu , Taguchi Jun , Miyamoto Toshihiro , Nakamae Hirohisa , Ichinohe Tatsuo , Kato Koji , Suzuki Ritsuro , Utsunomiya Atae ,   ATL Working Group of the Japan Society for Hematopoietic Cell Transplantation
Published: September 2018

Treatment options for patients with adult T cell leukemia/lymphoma (ATLL) who have relapsed disease after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) are limited. To clarify which patients with ATLL are likely to benefit from these treatment options and to define patient populations for novel treatments, we performed a nationwide retrospective analysis of 252 Japanese patients who had relapsed ATLL after allo‐HSCT. Some long‐term survivors remained after tapering and withdrawal of immunosuppressive agents. Thirty‐six patients who received donor lymphocyte infusion had a better overall survival (OS) in comparison to those who did not [hazard ratio (HR), 0.63; 95% confidence interval (CI), 0.43‐0.93; P = .02], suggesting the efficacy of a graft‐versus‐ATLL (GvATLL) effect even after relapse. Multivariate analysis demonstrated that skin lesions at initial relapse of ATLL were independently associated with higher OS (HR, 0.41; 95% CI, 0.22‐0.74; P = .003), indicating that the skin is a susceptible target organ of GvATLL. This study suggested that enhancement of a GvATLL effect is a potential therapeutic option for relapsed disease after allo‐HSCT. Further investigations of incorporation of immune‐based approaches with new molecular target drugs into the therapeutic options of patients with ATLL before and after transplantation are warranted.
A high‐fat diet impairs mitochondrial biogenesis, mitochondrial dynamics, and the respiratory chain complex in rat myocardial tissues
Authors: Chen Dan , Li Xia , Zhang LiTing , Zhu Mei , Gao Ling
Published: September 2018

A high‐fat diet (HFD) has been associated with heart failure and arrhythmias; however, the molecular mechanisms underlying these associations are poorly understood. The mitochondria play an essential role in optimal heart performance, most of the energy for which is obtained from the oxidation of fatty acids. As such, chronic exposure to excess fatty acids may cause mitochondrial dysfunction and heart failure. To investigate the effects of a HFD on the mitochondrial function in the myocardium, 40 male rats were randomly divided into two groups and fed with either a normal diet or a HFD for 28 weeks. The myocardial lipid content, cardiac parameters and function, and mitochondrial morphology and function were evaluated. The expression of a number of genes involved in mitochondrial dynamics was measured using quantitative polymerase chain reaction and Western blot analyses. Proteomic analysis was also performed to identify the proteins affected by HFD treatment. Significant fat deposition in the myocardia, cardiac hypertrophy, and cardiac dysfunction were all observed in HFD‐treated rats. Electron microscopy showed abnormal mitochondrial density and morphology. In addition, abnormal expression of genes involved in mitochondrial dynamics, decreased mitochondrial DNA copy numbers, reduced complex I‐III and citrate synthase activities, and decreased mitochondrial respiration were observed in HFD‐treated rats. High performance liquid chromatography showed downregulated adenosine triphosphate (ATP) and adenosine diphosphate levels and an increased adenosine monophosphate (AMP)/ATP ratio. Proteomic analysis confirmed the alteration of mitochondrial function and impaired expression of proteins involved in mitochondrial dynamics in HFD‐treated rats. Mitochondrial dysfunction and impaired mitochondrial dynamics play an important role in heart dysfunction induced by a HFD, thus presenting a potential therapeutic target for the treatment of heart disease.
Opening of the CLC‐3 chloride channel induced by dihydroartemisinin contributed to early apoptotic events in human poorly differentiated nasopharyngeal carcinoma cells
Authors: Zhou Congran , Tang Xinwei , Xu Jingkui , Wang Jiajia , Yang Yaping , Chen Yehui , Chen Lixin , Wang Liwei , Zhu Linyan , Yang Haifeng
Published: September 2018

Nasopharyngeal carcinoma (NPC) is a specific type of head and neck cancer that is prevalent in Southeast Asia. Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has specific anticancer activity. Here, we aimed to investigate the role of the CLC‐3 chloride channel in the anticancer effect of DHA in poorly differentiated NPC CNE‐2Z cells. First, we observed that DHA could specifically inhibit the proliferation, induce apoptosis, and increase cleaved caspase‐3 expression in the CNE‐2Z cells. Then, we found that DHA could activate chloride channels, which led to Cl− efflux and apoptotic volume decrease (AVD) in the early stage in the CNE‐2Z cells. DHA also specifically increased CLC‐3 chloride channel protein expression in the CNE‐2Z cells. Silencing of the CLC‐3 protein expression depleted the Cl− currents, and decreased the AVD capacity and cell apoptosis induced by DHA. Finally, we revealed that the [Ca2+]i increased after around 6 hours of treatment with DHA, which was also inhibited by silencing of the CLC‐3 protein expression. Our data demonstrated that the selective antitumor activities of DHA in NPC may occur through the specific activation of the CLC‐3 Cl− channel, leading to Cl− efflux, and induced AVD, then led to [Ca2+]i accumulation and caspase‐3 activation, and finally induced apoptosis. The activation of the CLC‐3 chloride channel played an essential and proximal upstream role in the antitumor activities of DHA.
Genomic integrity of ground‐state pluripotency
Authors: Jafari Narges , Giehr Pascal , Hesaraki Mahdi , Baas Roy , de Graaf Petra , Timmers H. T. Marc , Walter Jörn , Baharvand Hossein , Totonchi Mehdi
Published: September 2018

Pluripotent cells appear to be in a transient state during early development. These cells have the capability to transition into embryonic stem cells (ESCs). It has been reported that mouse pluripotent cells cultivated in chemically defined media sustain the ground state of pluripotency. Because the epigenetic pattern of pluripotent cells reflects their environment, culture under different conditions causes epigenetic changes, which could lead to genomic instability. This study focused on the DNA methylation pattern of repetitive elements (REs) and their activation levels under two ground‐state conditions and assessed the genomic integrity of ESCs. We measured the methylation and expression level of REs in different media. The results indicated that although the ground‐state conditions show higher REs activity, they did not lead to DNA damage; therefore, the level of genomic instability is lower under the ground‐state compared with the conventional condition. Our results indicated that when choosing an optimum condition, different features of the condition must be considered to have epigenetically and genomically stable stem cells.
Decreased miR‐200a‐3p is a key regulator of renal carcinoma growth and migration by directly targeting CBL
Authors: Ding Meng , Sun Xinlei , Zhong Jinsha , Zhang Cuiping , Tian Yaping , Ge Jingping , Zhang Chen‐Yu , Zen Ke , Wang Jun‐Jun , Zhang Chunni , Wang Cheng
Published: September 2018

Although emerging evidence has revealed that microRNAs (miRNAs) dysregulation contribute to carcinogenesis, the mechanism underlying their roles in renal cell carcinoma (RCC) is unclear. The purpose of the current study was to analyze the association of miR‐200a‐3p expression with RCC and to understand potential novel target genes, functions and mechanisms of miR‐200a‐3p in RCC. MiR‐200a‐3p expression levels were first measured by quantitative real‐time polymerase chain reaction and in situ hybridization in pairs of RCC tissue samples. Next, the potential miR‐200a‐3p target gene was analyzed using a combination of computer‐aided algorithms, luciferase reporter assays and Western blot analysis. Finally, the biological roles of miR‐200a‐3p in RCC tumorigenesis were investigated both in vitro by 5‐ethynyl‐20‐deoxyuridine, apoptosis assay and transwell assay, as well as in vivo using a xenograft mouse model. Our results demonstrated that miR‐200a‐3p was remarkably downregulated in RCC tissues compared with normal adjacent tissue, and CBL is a direct target of miR‐200a‐3p. An inverse correlation between miR‐200a‐3p and CBL was observed in RCC tissue samples. Mechanistic investigations revealed that ectopic expression of miR‐200a‐3p in RCC cell lines suppressed cell proliferation and migration and enforced cell apoptosis by directly inhibiting CBL in vitro and in vivo, whereas silencing miR‐200a‐3p resulted in the opposite effects. Additionally, overexpressing CBL abolished the effects induced by miR‐200a‐3p overexpression. Taken together, our results show that the miR‐200a‐3p/CBL regulation axis is a novel mechanism underlying RCC pathogenesis and may serve as a candidate biomarker and therapeutic target in RCC.
Developing DNA methylation‐based prognostic biomarkers of acute myeloid leukemia
Authors: Gao Chundi , Zhuang Jing , Zhou Chao , Liu Lijuan , Liu Cun , Li Huayao , Zhao Minzhang , Liu Gongxi , Sun Changgang
Published: September 2018

Acute myeloid leukemia (AML) is a heterogeneous clonal neoplasm characterized by complex genomic alterations. The incidence of AML increases with age, and most cases experience serious illness and poor prognosis. To explore the relationship between abnormal DNA methylation and the occurrence and development of AML based on the Gene Expression Database (GEO), this study extracted data related to methylation in AML and identified a methylated CpG site that was significantly different in terms of expression and distribution between the primary cells of AML patients, and hematopoietic stem/progenitor cells from normal bone marrow. To further investigate the differences caused by the dysfunction of methylation sites, bioinformatics analysis was used to screen methylation‐related biomarkers, and the potential prognostic genes were selected by univariate and multivariate Cox proportional hazards regressions. Finally, five independent prognostic indicators were identified. In addition, these results provide new insight into the molecular mechanisms of methylation.
Evaluation of IL‐17A, IL‐17F, IL‐23R, VDR, CCL2, CCL5, CCR2, and CCR5 gene polymorphisms and expression in Chinese individuals with syphilis
Authors: Hu Wen‐Long , Ren Hong , Xu Bu‐Fang , Zhang Jing‐Ping , Zhang Rui‐Li , Wang Qian‐Qiu , Zhang Ting‐Ting
Published: September 2018

Syphilis is a sexually transmitted disease caused by the infection of Treponema pallidum subspecies pallidum. T‐helper type 17–related genes, vitamin D receptor (VDR) gene, and chemokine/chemokine receptor genes are crucial in microbial infection. A total of 16 single‐nucleotide polymorphisms (SNPs) in eight genes (interleukin [IL]‐17A, IL‐17F, IL‐23R, VDR, C‐C motif chemokine ligand [CCL] 2, CCL5, C‐C chemokine receptor [CCR] 2, and CCR5) were analyzed in 188 patients with syphilis and 216 healthy controls. The results showed a strong correlation of IL‐17A rs2275913 (AA vs AG + GG: odds ratio [OR], 1.78; 95% confidence interval [CI], 1.09 to 2.92; P = 0.020; A vs G: OR, 1.33; 95% CI, 1.01 to 1.76; P = 0.043) and rs3819024 (GG vs AA + GA: OR, 1.76; 95% CI, 1.06 to 2.91; P = 0.028; G vs A: OR, 1.36; 95% CI, 1.03 to 1.80; P = 0.030) with syphilis. In haplotype analysis, IL‐17A rs2275913A/rs3819024G showed a risk effect (OR, 1.38; 95% CI, 1.04 to 1.82; P = 0.026), whereas IL‐17A rs2275913G/rs3819024A showed a protective effect (OR, 0.76; 95% CI, 0.57 to 0.998; P = 0.048). The expression levels of IL‐17A messenger RNA (mRNA) in peripheral blood mononuclear cells and IL‐17A secretion in plasma were further examined. No significant differences were found between patients with syphilis and healthy controls. The study also explored whether IL‐17A rs2275913 and rs3819024 were associated with the expression of IL‐17A mRNA and IL‐17A secretion in patients with syphilis. Similar negative results were found. In conclusion, the polymorphisms of IL‐17A rs2275913 and rs3819024 and the haplotype containing these two SNPs influenced the susceptibility to syphilis in a Han Chinese population.
Perillaldehyde prevents the formations of atherosclerotic plaques through recoupling endothelial nitric oxide synthase
Authors: Yu Li , Liu Hua
Published: September 2018

Backgrounds

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is essential for cardiovascular homeostasis owing to its anti‐inflammatory, antithrombotic, antiproliferative, and antioxidant effects. Perillaldehyde (PAH), one of the major oil components in Perilla frutescens, has anti‐inflammatory effects.

Aim

This study was designed to explore whether PAH prevents atherosclerosis through normalizing eNOS functions.

Methods

The model of atherosclerosis was induced by feeding rats and mice with high‐fat diet or plus balloon injury. Oil red and hematoxylin‐eosin (HE) stainings were used to assess the atherosclerotic plaque.

Results

Pretreatment of PAH for 30 minutes concentration‐dependently increased tetrahydrobiopterin (BH4) levels, NO generations, and improved cell viabilities in cultured human umbilicus vessel endothelial cells (HUVEC) incubated with oxidized (OX) low‐density lipoprotein (LDL), in which all protective effects of PAH were abolished by guanosinetriphosphate (GTP) cyclohydrolase 1 inhibitor 2,4‐Diamino‐6‐hydroxypyrimidine (DAHP) or eNOS inhibitor L‐NAME in those cells. In rats, high‐fat diet plus balloon injury induced the formation of atherosclerotic plaque in carotid arteries. Administration of PAH or lovastatin reduced the size of atherosclerotic plaque in rats and improved the responses of aortic rings to acetylcholine isolated from rats, accompanied with increased BH4 content and NO generations. In Apoe
−/− mice feeding with normal diet or high‐fat diet, PAH (150 mg/kg) reduced the size of atherosclerotic plaque in aortic arteries, prevented endothelial dysfunctions, and increased both BH4 and NO generations in carotid arteries.

Conclusion

PAH prevents the growth of atherosclerosis through increasing BH4 generation and subsequent eNOS recouping. Clinically, PAH should be considered as a new medicine to treat patients with atherosclerosis.
Effect of scrotal heating on sperm quality, seminal biochemical substances, and reproductive hormones in human fertile men
Authors: Zhang Mei‐Hua , Zhai Li‐Ping , Fang Zhen‐Ya , Li An‐Na , Xiao Wei , Qiu Yi
Published: September 2018

At present, male contraceptive methods are only vasectomy and condoms, so it is necessary to research on male contraceptive techniques. The aim of this study is to observe the effects of scrotal heating (SH) on semen parameters, seminal l‐carnitine (LC), epidermal growth factor (EGF), macrophage migration inhibitory factor (MIF), reproductive hormones and sperm chromosome numbers of adult healthy men, and to provide the experimental data for male contraception. The scrotums of 30 healthy male volunteers were exposed to the condition of 40 to 43°C SH belt warming 40 minutes each day for successive 2 days per week. The course of SH was continuous for 3 months. Computer‐assisted semen analysis and hypo‐osmotic swelling test, sperm DNA integrity, l‐carnitine, MIF and EGF, and sperm fluorescence in situ hybridization were performed before, during, and after SH. The serum level of follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) were measured by chemiluminescent immunoassay. The mean parameters of sperm concentration, vitality, and normal morphological sperm were significantly decreased in groups with sperms being collected during 1, 2, and 3 months of SH when compared with those in groups of pre‐SH (P < 0.01). Statistically significant differences of sperm DNA fragmentation, normal sperm membrane functionality, levels of LC and MIF in semen, and LH, FSH, and T in serum were observed between the groups of before SH and after SH 3 months and the groups of during SH 1, 2, and 3 months (P < 0.001). The total rate of chromosome number for 13, 18, 21, X, and Y in the 3 months of SH was 13.7‐fold greater (13.72%/1.69%) than before SH (P < 0.001). The constant SH can impact the semen quality, sperm DNA integrity, sperm chromosome, LC and MIF, and LH, FSH, and T in serum. Transient SH may be a new method for male contraception.
Characterization of potential TRPP2 regulating proteins in early Xenopus embryos
Authors: Futel Mélinée , Le Bouffant Ronan , Buisson Isabelle , Umbhauer Muriel , Riou Jean‐François
Published: September 2018

Transient receptor potential cation channel‐2 (TRPP2) is a nonspecific Ca2+‐dependent cation channel with versatile functions including control of extracellular calcium entry at the plasma membrane, release of intracellular calcium ([Ca2+]i) from internal stores of endoplasmic reticulum, and calcium‐dependent mechanosensation in the primary cilium. In early Xenopus embryos, TRPP2 is expressed in cilia of the gastrocoel roof plate (GRP) involved in the establishment of left‐right asymmetry, and in nonciliated kidney field (KF) cells, where it plays a central role in early specification of nephron tubule cells dependent on [Ca2+]i signaling. Identification of proteins binding to TRPP2 in embryo cells can provide interesting clues about the mechanisms involved in its regulation during these various processes. Using mass spectrometry, we have therefore characterized proteins from late gastrula/early neurula stage embryos coimmunoprecipitating with TRPP2. Binding of three of these proteins, golgin A2, protein kinase‐D1, and disheveled‐2 has been confirmed by immunoblotting analysis of TRPP2‐coprecipitated proteins. Expression analysis of the genes, respectively, encoding these proteins, golga2, prkd1, and dvl2 indicates that they are likely to play a role in these two regions. Golga2 and prkd1 are expressed at later stage in the developing pronephric tubule where golgin A2 and protein kinase‐D1 might also interact with TRPP2. Colocalization experiments using exogenously expressed fluorescent versions of TRPP2 and dvl2 in GRP and KF reveal that these two proteins are generally not coexpressed, and only colocalized in discrete region of cells. This was observed in KF cells, but does not appear to occur in the apical ciliated region of GRP cells.
MiR‐874 alleviates renal injury and inflammatory response in diabetic nephropathy through targeting toll‐like receptor‐4
Authors: Yao Tao , Zha Dongqing , Gao Ping , Shui Hua , Wu Xiaoyan
Published: September 2018

Diabetic nephropathy (DN) is a kind of diabetic complication with capillary damage, and its pathogenesis remains obscure. Recently, microRNAs have been identified as diagnostic biomarkers in various diseases including DN. Toll‐like receptor 4 (TLR4) contributes to inflammation, and it has been implicated in diabetes pathophysiology. This study was designed to investigate the role of miR‐874 and TLR4 in a streptozotocin (STZ)‐induced DN rat model and glucose‐induced mouse podocyte model. In the current study, we reported that miR‐874 was markedly downregulated in DN rats and glucose‐induced mouse podocytes compared with the corresponding control groups with the activation of TLR4. In addition, we observed that overexpression of miR‐874 was able to alleviate renal injury in DN rats. The cell counting kit (CCK‐8) assay and 5‐Ethynyl‐2′‐deoxyuridine (EdU) assay demonstrated that glucose simulation significantly inhibited podocyte proliferation and induced cell apoptosis, which can be reversed by miR‐874 mimics significantly. Notably, miR‐874 overexpression dramatically attenuated the inflammatory response, indicated by the decreased levels of interleukin‐6, L‐1β, and tumor necrosis factor α (TNF‐α). Finally, the binding correlation between miR‐874 and TLR4 was confirmed by carrying out dual‐luciferase reporter assay in our study. It was found that overexpression of miR‐874 depressed TLR4 levels in podocytes. These findings implied for the first time that the overexpression of miR‐874 repressed glucose‐triggered podocyte injury through targeting TLR4 and suggested that miR‐874/TLR4 axis might represent a pathological mechanism of DN.
Irisin promotes cardiac progenitor cell‐induced myocardial repair and functional improvement in infarcted heart
Authors: Zhao Yu Tina , Wang Jianguo , Yano Naohiro , Zhang Ling X. , Wang Hao , Zhang Shouyan , Qin Gangjian , Dubielecka Patrycja M. , Zhuang Shougang , Liu Paul Y. , Chin Y. Eugene , Zhao Ting C.
Published: September 2018

Irisin, a newly identified hormone and cardiokine, is critical for modulating body metabolism. New evidence indicates that irisin protects the heart against myocardial ischemic injury. However, whether irisin enhances cardiac progenitor cell (CPC)‐induced cardiac repair remains unknown. This study examines the effect of irisin on CPC‐induced cardiac repair when these cells are introduced into the infarcted myocardium. Nkx2.5+ CPC stable cells were isolated from mouse embryonic stem cells. Nkx2.5
+ CPCs (0.5 × 10
6) were reintroduced into the infarcted myocardium using PEGlylated fibrin delivery. The mouse myocardial infarction model was created by permanent ligation of the left anterior descending (LAD) artery. Nkx2.5
+ CPCs were pretreated with irisin at a concentration of 5 ng/ml in vitro for 24 hr before transplantation. Myocardial functions were evaluated by echocardiographic measurement. Eight weeks after engraftment, Nkx2.5
+ CPCs improved ventricular function as evident by an increase in ejection fraction and fractional shortening. These findings are concomitant with the suppression of cardiac hypertrophy and attenuation of myocardial interstitial fibrosis. Transplantation of Nkx2.5
+ CPCs promoted cardiac regeneration and neovascularization, which were increased with the pretreatment of Nkx2.5
+ CPCs with irisin. Furthermore, irisin treatment promoted myocyte proliferation as indicated by proliferative markers Ki67 and phosphorylated histone 3 and decreased apoptosis. Additionally, irisin resulted in a marked reduction of histone deacetylase 4 and increased p38 acetylation in cultured CPCs. These results indicate that irisin promoted Nkx2.5
+ CPC‐induced cardiac regeneration and functional improvement and that irisin serves as a novel therapeutic approach for stem cells in cardiac repair.
GlyRS is a new mediator of amino acid‐induced milk synthesis in bovine mammary epithelial cells
Authors: Luo Chaochao , Qi Hao , Huang Xin , Li Meng , Zhang Li , Lin Ye , Gao Xuejun
Published: September 2018

Amino acids are required for the mammalian target of rapamycin (mTOR) signaling pathway and milk synthesis in bovine mammary epithelial cells (BMECs). However, the mechanism through which amino acids activate this pathway is largely unknown. Here we show that glycyl‐tRNA synthetase (GlyRS) mediates amino acid‐induced activation of the mTOR‐S6K1/4EBP1 pathway, and milk protein and fat synthesis in BMECs. Among 19 aminoacyl‐tRNA synthetases, only the mRNA expression of GlyRS and Leucyl‐tRNA synthetase (LeuRS) were significantly increased by several amino acids including Met and Leu. We then observed that GlyRS knockdown abolished the stimulation of Met on milk protein and fat synthesis in BMECs, whereas GlyRS overexpression led to more significantly increased milk synthesis in cells treated with Met. By western blotting and qualitative real time‐polymerase chain reaction analysis (qRT‐PCR) analysis, we next revealed that GlyRS is required for amino acid‐induced activation of the mTOR‐S6K1/4EBP1 pathway. Thus, this study establishes that GlyRS mediates amino acid‐induced activation of the mTOR pathway, thereby regulating milk protein and fat synthesis.