bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversible Multicolor Photochromism of Dihydroazulene Crystals
Authors: Liepuoniute Ieva , Commins Patrick , Karothu Durga Prasad , Schramm Stefan , Hara Hideyuki , Naumov Panče
Published: November 2018

The photochemical conversion of 1,8a‐dihydroazulene‐1,1‐dicarbonitrile (DHA) to vinylheptafulvene (VHF) is a positive T‐type photoswitch that is well understood in solution, but has not been explored in the solid state. Upon excitation with UV light, DHA is converted into VHF in the solid state, with a distinct color change from yellow to deep‐red, and retention of crystallinity. The structure of the ring‐opened product was assigned to syn‐VHF using variable‐temperature infrared spectroscopy, and determined by X‐ray photodiffraction in a crystal enriched with the product by two‐photon excitation. A radical pathway becomes an observable photoreaction channel at low temperatures, and includes a strongly colored, short‐lived diradical intermediate.
Thermally Reduced Graphene/MXene Film for Enhanced Li‐ion Storage
Authors: Xu Shuaikai , Dall'Agnese Yohan , Li Junzhi , Gogotsi Yury , Han Wei
Published: November 2018

Two‐dimensional transition‐metal carbides called MXenes are emerging electrode materials for energy storage due to their metallic electrical conductivity and low ion diffusion barrier. In this work, we combined Ti2CTx MXene with graphene oxide (GO) followed by a thermal treatment to fabricate flexible rGO/Ti2CTr film, in which electrochemically active rGO and Ti2CTr nanosheets impede the stacking of layers and synergistically interact producing ionically and electronically conducting electrodes. The effect of the thermal treatment on the electrochemical performance of Ti2CTx is evaluated. As anode for Li‐ion storage, the thermally treated Ti2CTr possesses a higher capacity in comparison to as‐prepared Ti2CTx. The freestanding hybrid rGO/Ti2CTr films exhibit excellent reversible capacity (700 mAh g−1 at 0.1 Ag−1), cycling stability and rate performance. Additionally, flexible rGO/Ti3C2Tr films are made using the same method and also present improved capacity. Therefore, this study provides a simple, yet effective, approach to combine rGO with different MXenes, which can enhance their electrochemical properties for Li‐ion batteries.
Deformylated Gramicidin A and Its Derivatives Showing High Antimicrobial Activity and Low Hemolytic Toxicity
Authors: Haoyang Wei‐Wei , Zhang Min , Hou Jun‐Li
Published: November 2018

Summary of main observation and conclusion

Gramicidin A is a natural peptide, which shows high antimicrobial activity to Gram‐positive bacteria. However, the hemolytic toxicity prevents its therapeutic usage. We demonstrated that by simply removing the formyl group at the N terminus, the hemolytic toxicity of the peptide could be obviously decreased. The deformylated gramicidin A (1) could efficiently insert into the lipid bilayer to form transmembrane channels. The peptide can also selectively insert into the membrane of Gram‐positive bacteria but not that of erythrocytes, leading to its high antimicrobial activity and very low hemolytic toxicity. The derivation of1could be achieved by decoration at the terminal NH2group, which also produced peptides showing high activity and low hemolytic toxicity. This derivation method provided us with an efficient strategy to build a library for future activity and cytotoxicity screeningin vitroandin vivo.
A geometric approach to harmonic color palette design
Authors: Lara‐Alvarez Carlos , Reyes Tania
Published: November 2018

We address the problem of finding harmonic colors, this problem has many applications, from fashion to industrial design. The proposed approach enables the evaluations and generation of color combinations incrementally. To solve this problem, we consider that colors follow normal distributions in tone (chroma and lightness) and hue. The proposed approach relies in the International Commission on Illumination standard for representing colors and evaluates proximity. Other approaches to this problem use a set of rules. Experimental results show that lines with specific parameters—angles of inclination and distance from the reference point—are preferred over others and that uncertain line patterns outperform nonlinear patterns.
High‐Throughput Analysis of Behavior Under the Control of Optogenetics in Caenorhabditis elegans
Authors: Yu Alex J. , McDiarmid Troy A. , Ardiel Evan L. , Rankin Catharine H.
Published: November 2018

In this unit, we describe an inexpensive and versatile method for optogenetic stimulation of a large population of genetically engineered Caenorhabditis elegans worms while quantitatively analyzing behavior. A custom light‐emitting diode light source is used to deliver blue‐light stimuli, causing direct depolarization of neurons expressing the light‐gated cation channel Channelrhodopsin‐2, which in turn evokes behavioral responses. The behavioral responses are recorded by a high‐throughput machine vision–based tracking system, the Multi‐Worm Tracker, for detailed analysis. This approach allows researchers to bypass technical obstacles to simultaneously deliver uniform stimuli to a large number of freely behaving animals and investigate the neural underpinnings of behavior. © 2018 by John Wiley & Sons, Inc.
An Industrial Applicable Method for the Synthesis of N‐alkylated Maleimides Based on Fatty Amines
Authors: Schmidt Philipp , Eschig Steven
Published: November 2018

A simple and economic two step synthesis of N‐alkylated maleimides with repeatable recycling of recovered starting materials from the second step is developed. In the first step, maleic anhydride is reacted with different natural mixtures of bio‐based fatty amines to give the corresponding maleic acid alkyl amides. The formation of the 5‐membered maleimide‐rings is achieved via acid‐catalyzed intramolecular condensation. However, in this step only 50–64% of the used alkyl amides are converted toward the required N‐alkylated maleimides. The novelty of our approach is the continuous recycling of recovered non‐converted amides for additional cyclization steps. These steps are repeated several times, whereby the yields of maleimides for each step leveled off at 46–50%.

Practical Applications: Click reactions have become more and more prominent in the field of material science. A relevant used example is the [4 + 2]‐cycloaddition of maleimides and furans, whereby both moieties can be attached to the polymer backbone. This is a promising approach for the introduction of new functionalities to a polymer by a simple addition reaction. For this purpose a polymer, which contains furan groups and a functionalized maleimide are needed. For example, the use of fatty acid based maleimides allows the introduction of hydrophobic properties to a furan‐functionalized polymer, due to their long alkyl chain. However, the functional group of the maleimide can be varied to introduce other properties, like antimicrobial, hydrophilic or combinations thereof. This technique is interesting for coatings and allows the adaption of surface properties in a wide range. Moreover, maleimides can be used as polymerizable monomers to synthesize high performance macromolecular systems like polymers with high thermal stability.

Synthesis of fatty acid based maleimides starting from maleic anhydride and fatty amines. This technique is interesting for coatings and allows the adaption of surface properties in a wide range. Moreover, maleimides can be used as polymerizable monomers to synthesize high performance macromolecular systems like polymers with high thermal stability.
Covalent Cages with Inwardly Directed Reactive Centers as Confined Metal and Organocatalysts
Authors: Yang Jian , Chatelet Bastien , Hérault Damien , Dutasta Jean‐Pierre , Martinez Alexandre
Published: November 2018

Covalent cages with a well‐defined cavity located close to a reactive center are of increasing interest because of their outstanding ability to mimic the catalytic properties of enzymatic systems. The size and shape of such synthetic nanosized reactors strongly affect the behavior of the trapped reaction partners, which can adopt specific conformations and orientations. In particular, the use of molecular cages with confined reactive functions strongly modifies the outcome of catalytic transformations that are carried out therein. This review article describes covalent molecular cages presenting an endohedral functionalization of their inner space and reports on their catalytic activities compared with those of model systems that lack cavity.
Synthesis of Nitriles from Aldehydes with Elongation of the Molecule with Two Carbon Atoms
Authors: Afanasyev Oleg I. , Zarochintsev Alexander , Petrushina Tatiana , Cherkasova Anastasia , Denisov Gleb , Cherkashchenko Ilia , Chusova Olga , Jinho Oh , Man‐Seog Chun , Usanov Dmitry L. , Semenov Sergei E. , Chusov Denis
Published: November 2018

A new protocol for the synthesis of nitriles from carbonyl compounds with elongation of the molecule with two carbon atoms was developed. It involves a reaction of ethyl cyanoacetate with different aldehydes in the presence of iron pentacarbonyl as a reducing agent. This protocol is very simple and requires only commonly available reagents, with no catalyst or complicated ligands being employed.
Mutagenic Activity of N‐Nitrosodiethylamine in Cell Lines Expressing Human CYP2E1—Adequacy of Dimethylsulfoxide as Solvent
Authors: Jin Guifang , Cai Lu , Hu Keqi , Luo Yuyi , Chen Yuting , Glatt Hansruedi , Liu Yungang
Published: November 2018

Human CYP2E1 metabolizes many xenobiotics of low‐molecular weight, thereby activating various promutagens/procarcinogens. In toxicological studies in vitro, dimethylsulfoxide (DMSO) is a common vehicle for organic compounds. However, it was observed to potently inhibit CYP2E1 activity. We were interested in whether it affects CYP2E1‐dependent mutagenic responses. In this study, N‐nitrosodiethylamine (NDEA), which is soluble in both water and DMSO, was used as a model promutagen. It induced Hprt gene mutations and micronuclei in a Chinese hamster V79‐derived cell line expressing both human CYP2E1 and sulfotransferase (SULT) 1A1 (V79‐hCYP2E1‐hSULT1A1) even at low‐micromolar concentrations, but was inactive in parental V79 cells. Mutagenicity of NDEA was also observed in a recombinant V79‐hCYP2E1 cell line that expresses human CYP2E1 at a lower level. NDEA induced micronuclei in human L‐02 hepatocytes which expressed CYP2E1 even more weakly. DMSO did not modify NDEA‐induced gene mutations or micronuclei, up to 0.2% (v:v, the highest noncytotoxic concentration) in V79‐hCYP2E1‐hSULT1A1 cells. In parental V79‐Mz cells, NDEA induced micronuclei with Aroclor 1254‐induced rat liver S9 mix, and this effect was unaffected by DMSO up to 0.2%. However, it inhibited the effect of NDEA in L‐02 (by 44%) and V79‐hCYP2E1 cells (by 70%) at 0.2%, with the effects of NDEA remaining statistically significant. No effect of DMSO was observed on CYP2E1 protein expression in V79‐hCYP2E1‐hSULT1A1 or its mRNA transcripts in each cell line. We conclude that DMSO may not significantly affect CYP2E1‐dependent mutagenic effects, at concentrations up to 0.2% in cells with relatively high CYP2E1 expression. Environ. Mol. Mutagen. 60:214–226, 2019. © 2018 Wiley Periodicals, Inc.
Variance and skew risk premiums for the volatility market: The VIX evidence
Authors: Da Fonseca José , Xu Yahua
Published: November 2018

We extract variance and skew risk premiums from volatility derivatives in a model‐free way and analyze their relationships along with volatility index and equity index returns. These risk premiums can be synthesized through option trading strategies. Using a time series of option prices on the VIX, we find that variance swap excess return can be partially explained by volatility index and equity index excess returns while these latter variables carry little information for the skew swap excess return. The results sharply contrast with those obtained for the equity index option market underlining very specific characteristics of the volatility derivative market.
Do country risk and ﬁnancial uncertainty matter for energy commodity futures?
Authors: Lee Chien‐Chiang , Lee Chi‐Chuan , Lien Donald
Published: November 2018

Using an instrumental variable quantile regression technique, this paper assesses whether country risk and financial uncertainty exert an impact on energy commodity futures prices under different commodity conditional return distributions over the period from January 1994 to July 2017. We also discuss whether the correlations change with different dimensions of country risk, that is economic, financial, and political. The results reveal that country risk and financial stress do have a significant impact on energy commodity returns of futures contracts with different maturities, but their direction, intensity, and significance differ, caused by the distinct market situations and divergent channels of country risk.
Common fragile site instability in normal cells: Lessons and perspectives
Authors: Palumbo Elisa , Russo Antonella
Published: November 2018

Mechanisms and events related to common fragile site (CFS) instability are well known in cancer cells. Here, we argue that normal cells remain an important experimental model to address questions related to CFS instability in the absence of alterations in cell cycle and DNA damage repair pathways, which are common features acquired in cancer. Furthermore, a major gap of knowledge concerns the stability of CFSs during gametogenesis. CFS instability in meiotic or postmeiotic stages of the germ cell line could generate chromosome deletions or large rearrangements. This in turn can lead to the functional loss of the several CFS‐associated genes with tumor suppressor function. Our hypothesis is that such mutations can potentially result in genetic predisposition to develop cancer. Indirect evidence for CFS instability in human germ cells has been provided by genomic investigations in family pedigrees associated with genetic disease. The issue of CFS instability in the germ cell line should represent one of the future efforts, and may take advantage of the existence of sequence and functional conservation of CFSs between rodents and humans.
Reaction of arynes with trifluoroacetylated β‐diketones: Novel formation of isocoumarins and phenanthrenes
Authors: Okuma Kentaro , Tanabe Yukiko , Fukami Takuto , Ishibashi Yuto
Published: November 2018

Polysubstituted isocoumarins were synthesized by the reaction of substituted 2‐(trimethylsilyl)aryl triflates with trifluoromethylated β‐diketones in the presence of CsF. The reaction proceeded through carbon‐carbon bond insertion of aryne and intramolecular cyclization to form intermediates of alcohol anions, which extruded trifluoromethyl anion to afford isocoumarins. By using CuBr as a catalyst, 2 eq. of aryne reacted with β‐diketones to afford phenanthrenes and 1,2‐diarylethanones. Although reaction of 2‐(trimethylsilyl)phenyl triflate with 1,1,1‐trifluoro‐4′‐methylbenzoylacetone in the presence of CsF gave 3‐(4′‐methylphenyl)isocoumarin in 67% yield, addition of 0.2 eq. of CuCN resulted in the formation of 9‐(4‐methylbenzoyl)‐10‐trifluoromethylphenanthrene in 35% yield.
Surgical resection of carotid body tumors with versus without preoperative embolization: Retrospective case‐control study
Authors: Liu Jianlin , Li Yanzi , Yang Lin , Cai Hui
Published: November 2018

Background

The purpose of this study was to investigate the outcomes of surgical resection of carotid body tumors with and without preoperative embolization.

Methods

There were 31 patients who underwent surgical resection combined with preoperative embolization (SRE group), and 27 patients who underwent conventional surgical resection (SR group); all clinical data were included and reviewed.

Results

There was no difference in the approach for carotid reconstruction in either group (P > .05). The mean surgical time (110.65 ± 35.77 minutes vs 188.33 ± 66.44 minutes) and intraoperative blood loss (140.32 ± 57.12 mL vs 396.43 ± 272.82 mL) were significantly less in the SRE group (P < .05). The volume of blood transfusions required (475 ± 301.18 mL vs 0 mL) and incidence rate of total complications (33.3% vs 9.7%) were higher in the SR group (P < .05). However, the length of hospital stay was similar in both groups (P > .05).

Conclusion

Our results demonstrate that preoperative embolization of a carotid body tumor can reduce blood loss and complications and improve tumor excision.
Oral and pharyngeal cancer risk associated with occupational carcinogenic substances: Systematic review
Authors: Awan Kamran Habib , Hegde Rachana , Cheever Val J , Carroll William , Khan Shahrukh , Patil Shankargouda , Warnakulasuriya Saman
Published: November 2018

Background

Oral and pharyngeal cancers (OPC) represent the seventh most common type of cancer and the seventh leading cause of deaths by cancer worldwide. Few studies have assessed the occupational exposure risks associated with OPC and in many cases the results are conflicting. The aim of this study was to determine, through a systematic review, the association of OPC and exposure to different occupational carcinogenic substances.

Methods

The addressed focused question was “Is there an association of occupational carcinogenic substances with OPC?” PubMed, MEDLINE, EMBASE, and ISI Web of Science databases were searched between January 1995 up to and including July 2016 using the keywords “oral cancer,” “pharyngeal cancer,” “pharyngeal neoplasms,” “oral neoplasms,” “occupational disease,” “occupational exposure,” and “occupational risk factor” in various combinations. Letters to the Editor, review articles, case reports, and unpublished articles were excluded.

Results

Fourteen original articles were included. Majority of the studies were conducted in European countries and used a case‐control design. The results showed a significant association between formaldehyde, wood dust, coal dust, asbestos, welding fumes, and risk of developing OPC, while marginal association was observed with metal and leather dust. No associated risk was observed for textile fibers.

Conclusion

There is some evidence to suggest associations of occupational substances with OPC, particularly in the pharynx. Future well‐designed studies are required to confirm or rule out with confidence the associated exposure risk of these substances.
EGFR‐TKIs plus local therapy demonstrated survival benefit than EGFR‐TKIs alone in EGFR‐mutant NSCLC patients with oligometastatic or oligoprogressive liver metastases
Authors: Jiang Tao , Chu Qian , Wang Huijuan , Zhou Fei , Gao Guanghui , Chen Xiaoxia , Li Xuefei , Zhao Chao , Xu Qinghua , Li Wei , Wu Fengying , Xiong Anwen , Zhao Jing , Xu Yaping , Su Chunxia , Ren Shengxiang , Zhou Caicun , Hirsch Fred R.
Published: November 2018

To investigate whether addition of local therapy to EGFR‐TKIs could provide survival benefit than EGFR‐TKIs alone in EGFR‐mutant NSCLC patients with oligometastatic or oligoprogressive liver metastases (LM). Patients with EGFR‐mutant NSCLC and oligometastatic or oligoprogressive LM who met inclusion criteria were retrospectively identified. The primary endpoint was progression‐free survival (PFS); secondary endpoints included overall survival (OS) and patterns of failure. Addition of local therapy was associated with a significantly longer PFS (13.8 vs. 8.6 m, p <0.001) and OS (31.2 vs. 18.5 m, p <0.001) in whole group. In oligometastatic cohort, 20 patients received EGFR‐TKIs and 23 received EGFR‐TKIs plus local therapy as first‐line treatment. Addition of local therapy showed a significantly longer PFS (12.9 vs. 7.9 m, p = 0.041) and OS (36.8 vs. 21.3 m, p = 0.034) than EGFR‐TKIs alone. In oligoprogressive cohort, 24 patients received continuation of EGFR‐TKIs plus local therapy and 25 received switching chemotherapy. Median PFS2 (13.9 vs. 9.2 m, p = 0.007) and OS (28.3 vs. 17.1 m, p = 0.011) was significantly longer in combined group than in switching chemotherapy group. Distant metastatic sites progression was the major pattern of failure in combined group while locoregional recurrence was the major reason in monotherapy or switching chemotherapy group. Our study suggested that EGFR‐TKIs plus local therapy showed prolonged survival benefit than EGFR‐TKIs alone in EGFR‐mutant NSCLC patients with oligometastatic or oligoprogressive LM, indicating addition of local therapy would be alternative choice in this clinical scenario.
Clinical guidelines—the challenges and opportunities: What we have learned from the case of misoprostol for postpartum hemorrhage
Authors: Morris Jessica L. , Khatun Samia
Published: November 2018

Objective

To establish whether national guidelines for postpartum hemorrhage (PPH) reflect new scientific evidence on misoprostol, and determine the challenges faced in their implementation.

Methods

A web‐based survey was sent by email to 130 national societies of obstetrics and gynecology (FIGO Member Associations) in 2016. The survey, composed of 18 questions, covered national guidelines on PPH with particular reference to misoprostol, the creation of national guidelines, and challenges to implementation.

Results

Completed surveys were received from 69 societies, for a 53% response rate. The key findings were that many countries lacked comprehensive, up‐to‐date, evidence‐based national guidelines providing guidance on misoprostol use; recommended regimens were very different in the national guidelines as well as between international and regional guidelines that are most often used as referencing documents; and there are a variety of challenges to implementation of guidelines.

Conclusion

There is a need, especially in countries with high maternal mortality, to establish mechanisms that ensure the existence of up‐to‐date, comprehensive, evidence‐based guidelines on PPH. This can be difficult given conflicting guidance at the international level. Regional and international societies should prioritize clinical updates and ensure their dissemination and implementation.
Indwelling ports for prophylactic RBC exchanges in sickle cell patients: Comparison of bard and vortex ports
Authors: Lawicki Shaun , Craig‐Owens Laura , Bream Peter R. , Eichbaum Quentin
Published: November 2018

Introduction

Red blood cell exchange (RCE) procedures are commonly used for stroke prevention in sickle cell disease (SCD) patients. We compared two different dual lumen ports used for RCE because differences between the port and catheter design may lead to functional variance.

Methods

We reviewed the RCE parameters of SCD patients following implantable port placement encountered at a single institution. Five Vortex and four Bard ports were used and compared. Patients were followed for 1‐24 exchange procedures over 3‐26 months performed between 2013 and 2015.

Results

Nine patients underwent 124 RCE procedures with no failures. A total of 74 exchanges used Vortex ports with a mean flow rate of 45.2 mL/min while 50 exchanges used Bard ports with a mean flow rate of 42.1 mL/min which was a significant difference (P = .002). A total of 85 exchanges with tPA administration preprocedure had a mean flow rate of 43.8 mL/min while 39 exchanges without had a mean flow rate of 45.4 mL/min which was not a significant difference (P = .19).

Conclusion

Both the Bard and Vortex ports functioned well during our study period with no treatment failures, no significant complications requiring removal or replacement, and adequate mean flow rates. While the difference in mean flow rates was statistically significant between Vortex and Bard ports, there may not be a practical difference in performance. There also does not appear to be a significant benefit in flow rates with preprocedure tPA. We conclude that both ports may be a satisfactory choice for vascular access in SCD patients expected to undergo regularly scheduled RCE.
Single‐needle: an effective alternative to dual‐needle peripheral access in therapeutic plasma exchange
Authors: Doggett Betty M. , Session‐Augustine Nellie , Roig Joseph , Strunk Matthew , Valiyaparambil Shiney , Sarode Ravi , De Simone Nicole
Published: November 2018

Apheresis treatments, which involve the removal of a component of blood, generally require one access and one return line to continuously draw and return blood into the extracorporeal circuit. At our center, we prefer to use peripheral venous access to avoid central line‐related complications, especially infection. Motivated by patient‐centered care, the single‐needle (SN) option for therapeutic plasma exchange (TPE) offered on the Spectra Optia (Terumo BCT, Lakewood, CO) was evaluated. Five patients underwent procedures using both SN and dual‐needle (DN) plasma exchange procedures using the Spectra Optia. TPE procedures ran a median of 51 (range:10‐102) minutes longer using the SN‐TPE option. Inlet flow rates, plasma removal efficiency, and incidence of citrate reactions were similar between SN‐ and DN‐procedures. Patients reported great satisfaction with SN‐TPE.
TLR2 protects cisplatin‐induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway
Authors: Shen Qing , Zhang Xi , Li Qiuying , Zhang Jing , Lai Heng , Gan Hua , Du Xiaogang , Li Manli
Published: November 2018

Toll‐like receptors (TLRs), which are essential components of the innate immune response, play an important role in acute kidney injury (AKI). Toll‐like receptor 2 (TLR2) is constitutively expressed in tubular epithelial cells of the kidney and participates in cisplatin‐induced AKI. The autophagy is a dynamic catabolic process that maintains intracellular homeostasis, which is involved in the pathogenesis of AKI. Recent studies demonstrate that PI3K/Akt signaling pathway regulates autophagy in response to various stimuli. Therefore, we propose that cisplatin might activate TLR2, which subsequently phosphorylates PI3K/Akt, leading to enhanced autophagy of renal tubular epithelial cells and protecting cisplatin‐induced AKI. We found that TLR2 expression was significantly increased in the kidney after the cisplatin treatment. TLR2‐deficient mice exacerbated renal injury in cisplatin‐induced AKI, with higher serum creatinine and blood urea nitrogen, more severe morphological injury compared with that of wild‐type mice. In vitro, we found that inhibition of TLR2 reduced tubular epithelial cell autophagy after the cisplatin treatment. Mechanistically, TLR2 inhibited autophagy via activating PI3K/Akt signaling pathway in renal tubular epithelial cells after the cisplatin treatment. Take together, these results suggest that TLR2 may protect cisplatin‐induced AKI by activating autophagy via PI3K/Akt signaling pathway.
P65‐mediated miR‐590 inhibition modulates the chemoresistance of osteosarcoma to doxorubicin through targeting wild‐type p53‐induced phosphatase 1
Authors: Long Xiao , Lin Xiang‐Jin
Published: November 2018

Osteosarcoma (OS) is a primary malignant bone tumor with high morbidity. Developing new therapeutic approaches with neoadjuvant is of great interest in OS treatment. Reportedly, ataxia telangiectasia mutated (ATM)/ataxia telangiectasia and radiation resistance gene 3 related (ATR)‐p53 signaling is considered as a critical DNA damage signaling pathway sensitizing cancer cells to chemotherapies; while wild‐type p53‐induced phosphatase 1 (WIP1), an oncogene overexpressed in diverse cancers, has been regarded as a critical inhibitor in the ATM/ATR‐p53 DNA damage signaling pathway. Herein, the expression of WIP1 in OS tissues and cell lines was examined; to investigate the mechanism of WIP1 abnormal upregulation, online tools were used to predict the upstream regulatory microRNAs (miRNAs) targeting WIP1. Among the candidate miRNAs, the expression and detailed function of miR‐590 were validated. Through binding to the 3′‐untranslated region of WIP1, miR‐590 inhibited WIP1 expression and, therefore, enhanced the effect of Dox on OS cell proliferation and apoptosis through downstream ATM‐p53 signaling. Moreover, RELA could bind to the promoter region of miR‐590 to inhibit its expression, thereby affecting downstream WIP1 and ATM‐p53 signaling. The expression of p65 was upregulated in OS tissues, indicating that the effect of p65 inhibition on cell viability, apoptosis, and related mechanisms could be partially restored by miR‐590 inhibition. Taken together, these results showed that p65‐mediated miR‐590/WIP1/ATM‐p53 modulation might be a novel target to enhance the cellular effect of Dox on OS cell lines.
Structural and functional analysis of single‐nucleotide polymorphic variants of purine‐rich element‐binding protein B
Authors: Ferris Lauren A. , Kelm Robert J.
Published: November 2018

Purine‐rich element‐binding protein B (Purβ) inhibits myofibroblast differentiation by repressing the expression of the smooth muscle α‐actin gene (Acta2). Several reports have identified the structural domains in Purβ that enable its characteristic interaction with purine‐rich single‐stranded DNA (ssDNA) sequences in the Acta2 promoter. However, little is known about the physical and functional effects of single‐nucleotide polymorphisms that alter individual amino acid residues in Purβ. This study evaluated seven rare single amino acid variants of human PURB engineered into the homologous mouse Purβ protein. Mapping the location of variant residues on a homology model of the Purβ homodimer suggested that most of the altered residues are remote from the predicted ssDNA‐binding regions of the protein. The repressor activity of each Purβ variant was assessed in transfected fibroblasts and smooth muscle cells via Acta2 promoter‐reporter assays. A Q64* nonsense variant was completely inactive while missense variants exhibited repressor activity that ranged from ~1.5‐fold greater to ~2‐fold less than wild‐type Purβ. Lower activity variants P223L and R297Q were expressed in bacteria and purified to homogeneity. Each variant was physically indistinguishable from wild‐type Purβ in terms of quaternary structure and thermostability. Results of DNA and protein‐binding assays indicated that the P223L and R297Q variants retained high affinity and specificity for purine‐rich ssDNA sequences but differed in their interaction with other Acta2 regulatory proteins. These findings suggest that the presence of certain variant residues affects the Acta2 repressor activity of Purβ by altering its interaction with other transcription factors but not with ssDNA.
Increased CDKL3 expression predicts poor prognosis and enhances malignant phenotypes in esophageal squamous cell carcinoma
Authors: Ye Wenguang , Zhu Jian , He Dongjie , Yu Dequan , Yang Haihua , Wang Wei , Zhang Mingxin , Zhou Suna
Published: November 2018

Background

Cyclin‐dependent kinase‐like 3 (CDKL3) is a putative protein serine kinase and plays an important role in the regulation of cell growth and/or differentiation. However, studies on the function of CDKL3 in esophageal squamous cell carcinoma (ESCC) is limited. In our study, we explored the role and prognosis of CDKL3 in ESCC and underlying mechanism.

Materials and methods

The expression of CDKL3 was investigated by quantitative reverse transcription polymerase chain reaction and immunohistochemical staining. CDKL3 expression was downregulated by the RNAi‐mediated knockdown. The functions of CDKL3 on cell growth were assessed by Celigo image cytometry, MTT assay, cell‐cycle analysis, Annexin V assay, and caspase‐3/7 activity analysis. The effect of CDKL3 on cellular invasive was investigated by the Transwell assay. Pathscan Stress Signaling Antibody Array was used to study the underlying mechanism. Additionally, the association between the survival and CDKL3 expression in ESCC were evaluated based on the TCGA data.

Results

CDKL3 was highly expressed in ESCC tissues and cell lines. TE‐1 cells transfected with CDKL3‐shRNA‐lentivirus significantly decreased CDKL3 expression and resulted in inhibiting cell proliferation, inducing the S‐phase cell‐cycle arrest, attenuating cellular invasive and increasing cell apoptosis. The expression of pERK1/2, p‐Akt, p‐Smad2, p‐p38 mitogen‐activated protein kinase, cleaved caspase‐7, and phospho‐Chk1 were significantly decreased by CDKL3 knockdown. In addition, high expression of CDKL3 was associated with shorter overall survival.

Conclusion

Our findings suggest that higher expression of CDKL3 is correlated with poor prognosis in patients with ESCC and play a vital role in the malignant phenotype of ESCC cell lines, which indicating that CDKL3 may be as a new therapeutic target in ESCC.
Epigallocatechin‐3‐gallate regulates mitofusin 2 expression through the peroxisome proliferator‐activated receptor‐γ coactivator‐1α and estrogen‐related receptor‐α pathway
Authors: Shu ZhouWu , Zhang XiaoCong , Zheng Li , Zeng GuoNing , Mo You , Yu Min , Zhang Xin , Tan XueRui
Published: November 2018

Our previous study showed that epigallocatechin‐3‐gallate (EGCG) inhibition of human aortic smooth muscle cell (HASMC) proliferation might be mediated via upregulation of mitofusin 2 (Mfn‐2). Studies on the mechanism of Mfn‐2 inhibition of cell proliferation have mainly focused on downstream signaling. However, it is still not clear how upstream signaling molecules regulate Mfn‐2. The promoter region of the Mfn‐2 gene contains cis‐acting elements of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) and estrogen‐related receptor‐α (ERR‐α), suggesting a possible link between EGCG, Mfn‐2, and PGC‐1α/ERR‐α. However, the effect of EGCG on PGC‐1α/ERR‐α remains unknown. In this study, we investigated the role of PGC‐1α/ERR‐α in the regulation of Mfn‐2 induced by EGCG and assessed the underlying mechanisms. The effects of EGCG on cell proliferation of cultured HASMCs were observed by a cell counting kit‐8 (CCK8) and 5‐ethynyl‐2‐deoxyuridine (EdU) incorporation assay. Mfn‐2, PGC‐1α, and ERR‐α gene and protein levels were determined by quantitative real‐time polymerase chain reaction (PCR) and Western blot analysis. PGC‐1α gene‐silencing (PGC‐1α small interfering RNA [siRNA]) was achieved by RNA interference and Mfn‐2 promoter and peroxisome proliferator response element (PPRE) functional activity was achieved by a luciferase transfection assay. The results showed that the ERR‐α‐specific antagonist XCT‐790 and PGC‐1α siRNA decreased the expression of Mfn‐2, thus antagonizing the inhibition of HASMC proliferation induced by EGCG. EGCG enhanced Mfn‐2 promoter (−352 to 459) activity, while XCT‐790 and PGC‐1α siRNA abrogated this effect. PGC‐1α stimulating Mfn‐2 expression was dependent on intact ERR‐α binding in the Mfn‐2 promoter. The transcriptional effect of PGC‐1α on the Mfn‐2 promoter required the integrity of the −432 to 459 region and supported that Mfn‐2 was a key target gene of PGC‐1α. These results imply that PGC‐1α/ERR‐α played important physiological roles in inhibiting the proliferation of HASMCs by modulating Mfn‐2 gene expression. Hence, EGCG regulated Mfn‐2 expression likely through the PGC‐1α/ERR‐α pathway.
Diallyl disulfide suppresses FOXM1‐mediated proliferation and invasion in osteosarcoma by upregulating miR‐134
Authors: Li Yonggang , Wang Zhiyong , Li Jianmin , Sang Xiguang
Published: November 2018

Diallyl disulfide (DADS), a volatile component of garlic oil, exerts anticancer activity in various types of cancers, while its anticancer effects against osteosarcoma (OS) have not been previously explored. This study aimed to investigate the anticancer potential of DADS in OS and to explore the underlying mechanisms. DADS reduced the cell viability and increased the expression of miR‐134 in OS cell lines, and this effect was in a time‐ and concentration‐dependent manner. Furthermore, in vitro functional assays revealed that DADS significantly inhibited the proliferation and invasion of human OS U2OS and MG‐63 cells, which was partially reversed by miR‐134 inhibitor transfection. DADS exhibited in vivo antitumor activity and upregulated miR‐134 expression in xenograft tumors. Downregulation of miR‐134 attenuated DADS‐induced antitumor capacity. Further bioinformatics prediction analysis revealed that the 3′‐untranslated region (3′‐UTR) of Forkhead Box M1 (FOXM1) harbored miR‐134‐binding sites, and overexpression of miR‐134 repressed the luciferase activity of the reporting vector containing FOXM1 3′‐UTR. Both miR‐134 overexpression and DADS inhibited FOXM1 expression in U2OS cells, while enforced expression of FOXM1 suppressed DADS‐induced antiproliferation and anti‐invasion capacity in U2OS cells. Furthermore, DADS treatment led to significant downregulation of cyclin D1, c‐myc, and lymphoid enhancer‐binding factor 1 expression, but the remarkably upregulated p21 level in U2OS cells. Collectively, DADS could be a promising anticancer agent for OS, and the underlying mechanisms might be associated with the antiproliferation and anti‐invasion properties through upregulating miR‐134 expression.
Rs6265 polymorphism in brain‐derived neurotrophic factor (Val/Val and Val/Met) promotes proliferation of bladder cancer cells by suppressing microRNA‐205 and enhancing expression of cyclin J
Authors: Zhang Jin , Song Ni , Duan Zhongqi
Published: November 2018

Background

In this study, we evaluated the effect of rs6265 polymorphism on the expression of brain‐derived neurotrophic factor (BDNF) and relevant downstream targets, as well as the involvement of this polymorphism in bladder cancer.

Method

A computational analysis and luciferase assays were used to explore the interaction among BDNF, miR‐205, and cyclin J (CCNJ). Real‐time polymerase chain reaction (RT‐PCR) and Western blot analysis were carried out to determine the effect of rs6265 polymorphism on the expression of BDNF and relevant downstream genes.

Result

BDNF directly inhibited miR‐205 expression but enhanced the expression of CCNJ, which was identified as a virtual target gene of miR‐205. Furthermore, the inhibitory effect of BDNF carrying the Val genotype, defined as BDNF (Val), on miR‐205 expression was much stronger than that of BDNF (Met), while the inductive effect of BDNF (Val) on CCNJ expression was much weaker than that of BDNF (Met). miR‐205 and CCNJ small interfering RNA (siRNA) were found to reduce cell proliferation and arrest the cells in G0/G1 phase. In addition, miR‐205 expression in patients carrying BDNF genotyped as Met/Met (defined as Met/Met group) was much higher than patients carrying BDNF genotyped as Val/Val and Val/Met (defined as Val/Val group and Val/Met group). As an inhibitor of CCNJ expression, the inhibitory effect of miR‐205 was much higher in the Met/Met group than that in the Val/Val and Val/Met groups.

Conclusion

In summary, we suggested that the rs6265 polymorphism in BDNF upregulates the expression of CCNJ in bladder cancer via the inhibition of miR‐205 expression, which leads to the promoted proliferation of bladder cancer cells.
Stabilization of hypoxia‐inducible factor 1α by cobalt chloride impairs podocyte morphology and slit‐diaphragm function
Authors: Nakuluri Krishnamurthy , Mukhi Dhanunjay , Mungamuri Sathish Kumar , Pasupulati Anil Kumar
Published: November 2018

Glomerular podocytes are the major components of the renal filtration barrier, and altered podocyte permselectivity is a key event in the pathogenesis of proteinuric conditions. Clinical conditions such as ischemia and sleep apnea and extreme physiological conditions such as high‐altitude sickness are presented with renal hypoxia and are associated with significant proteinuria. Hypoxia is considered as an etiological factor in the progression of acute renal injury. A sustained increase in hypoxia‐inducible factor 1α (HIF1α) is a major adaptive stimulus to the hypoxic conditions. Although the temporal association between hypoxia and proteinuria is known, the mechanism by which hypoxia elicits proteinuria remains to be investigated. Furthermore, stabilization of HIF1α is being considered as a therapeutic option to treat anemia in patients with chronic kidney disease. Therefore, in this study, we induced stabilization of HIF1α in glomerular regions in vivo and in podocytes in vitro upon exposure to cobalt chloride. The elevated HIF1α expression is concurrence with diminished expression of nephrin and podocin, podocyte foot‐processes effacement, and significant proteinuria. Podocytes exposed to cobalt chloride lost their arborized morphology and cell‐cell connections and also displayed cytoskeletal derangements. Elevation in expression of HIF1α is in concomitance with loss of nephrin and podocin in patients with diabetic nephropathy and chronic kidney disease. In summary, the current study suggests that HIF1α stabilization impairs podocyte function vis‐à‐vis glomerular permselectivity.
The antiproliferative effects of cold atmospheric plasma‐activated media on different cancer cell lines, the implication of ozone as a possible underlying mechanism
Authors: Mokhtari Hesam , Farahmand Leila , Yaserian Kiomars , Jalili Neda , Majidzadeh‐A Keivan
Published: November 2018

Recent studies have proven several promising anticancer activities for cold atmospheric plasma (CAP) against a wide range of cancer cells in vitro. Recently, media treated with CAP have also found to effectively eradicate cancer cells similar to the CAP. Based on advantages, many researchers prefer to apply CAP‐activated media (PAM) as an alternative to cap in the treatment of cancer. However, less has been achieved regarding the anticancer effects and anticancer mechanisms of PAM. Investigating the selective anticancerous activities of PAM, the viability of SKBR3, MCF7, ASPC‐1, A‐549, G‐292, and SW742 cancer cell lines, as well as normal human skin fibroblasts (FMGB‐1) and MCF10A cells in relation to the media activation time, and the length of exposure was studied. Also, we examined the concentration of ozone in media as a function to CAP activation time since recent studies have proposed ozone as a pivotal reactive species in the induction of cell death. Based on the result, both increasing the duration of media activation time and the length of exposure to PAM could significantly increase the anticancer activity. Nevertheless, the cytotoxicity on normal cells was either not affected or slightly increased. Among the six tested cancer cell lines, SW742 was the most resistant and SKBR3 the most susceptible cancer cell lines to PAM. Also, increasing duration of treatment with CAP resulted in a significant rise in O3 concentration levels in media. Overall, these results suggest PAM, as a promising tool in the treatment of different cancers and O
3 formation as a probable underlying mechanism.
Knockdown of TRPV4 suppresses osteoclast differentiation and osteoporosis by inhibiting autophagy through Ca2+–calcineurin–NFATc1 pathway
Authors: Cao Boran , Dai Xin , Wang Wenbo
Published: November 2018

The aim of this study is to evaluate the effect of transient receptor potential vanilloid 4 (TRPV4) on osteoclast differentiation and osteoporosis, and to investigate the underlying mechanism. The results showed that TRPV4 expression and intracellular Ca2+ concentration were significantly upregulated in macrophage colony‐stimulating factor (M‐CSF)‐stimulated and receptor activator of nuclear factor κΒ ligand (RANKL)‐stimulated RAW264.7 cells. Furthermore, TRPV4 overexpression further increased the M‐CSF‐ and RANKL‐induced number of tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclasts and expression of osteoclastogenesis‐related genes (TRAP, c‐Fos, and nuclear factor of activated T cells [NFATc1]), activated the Ca
2+–calcineurin–NFATc1 signaling and increased autophagy‐related proteins (light chain [LC] 3II and Beclin‐1) during osteoclast differentiation. In contrast, TRPV4 knockdown exerted the opposite effects. Mechanically, inhibition of Ca
2+–calcineurin–NFATc1 signaling by FK506 or 11R‐VIVIT abrogated the TRPV4 overexpression‐induced osteoclast differentiation and autophagy induction. Moreover, suppression of autophagy by 3‐methyladenine attenuated the TRPV4‐induced osteoclast differentiation. In addition, short hairpin RNA TRPV4‐lentivirus administration significantly diminished the increased levels of several osteoclastogenesis‐related genes (RANKL, TRAP, and tumor necrosis factor‐α), alleviated the disturbed microarchitecture of lumbar vertebrae, restored the decreased bone mineral density, ratio of bone volume to total tissue volume, trabecular thickness, and trabecular number, and diminished the increased trabecular separation, in ovariectomy (OVX)‐induced osteoporosis mice. Consistent with the in vitro data, TRPV4 knockdown significantly decreased the induced number of TRAP‐positive osteoclasts, the increased LC3 and NFATc1 expression in the lumbar vertebrae of OVX mice. In conclusion, TRPV4 knockdown suppresses osteoclast differentiation and osteoporosis by inhibiting autophagy through Ca
2+–calcineurin–NFATc1 pathway.
Laurus nobilis leaf extract controls inflammation by suppressing NLRP3 inflammasome activation
Authors: Lee Eun Hye , Shin Jin Hak , Kim Seon Sook , Lee Hanbyeol , Yang Se‐Ran , Seo Su Ryeon
Published: November 2018

Laurus nobilis Linn. (Lauraceae), commonly known as Bay, has been used as a traditional medicine in the Mediterranean and Europe to treat diverse immunological disorders. Although the effects of L. nobilis on immunosuppression have been reported, the detailed underlying mechanism remains unclear. In this study, to elucidate the anti‐inflammatory mechanism of L. nobilis, we examined the effect of L. nobilis leaf extract on inflammasome activation in mouse bone marrow‐derived macrophages. L. nobilis leaf extract inhibited NOD‐like receptor pyrin domain‐containing 3 (NLRP3) inflammasome activation, which was associated with caspase‐1 activation, interleukin‐1β secretion, and apoptosis‐associated speck‐like protein containing a CARD (ASC) pyroptosome complex formation. We also observed that 1,8‐cineole, the major component of L. nobilis extract, consistently suppressed NLRP3 inflammasome activation. Furthermore, L. nobilis leaf extract attenuated the in vivo expression of proinflammatory cytokines in an acute lung injury mouse model. Our results provide the first evidence that L. nobilis leaf extract modulates inflammatory signaling by suppressing inflammasome activation.
Repression of TXNIP–NLRP3 axis restores intestinal barrier function via inhibition of myeloperoxidase activity and oxidative stress in nonalcoholic steatohepatitis
Authors: Bai Ru‐Xue , Xu Ying‐Ying , Qin Geng , Chen Yan‐Ming , Wang Hui‐Fen , Wang Miao , Du Shi‐Yu
Published: November 2018

Dysfunction of the intestinal barrier function occurs in hepatic injury, but the specific mechanisms responsible are largely unknown. Recently, NOD‐like receptor 3 (NLRP3) inflammasome functions in impairing endothelial barrier function. In this study, we test the hypothesis that TXNIP–NLRP3 axis repression prevents against intestinal barrier function disruption in nonalcoholic steatohepatitis (NASH). First, lipopolysaccharide (LPS)‐induced alterations in expression of ZO‐1 and occludin, myeloperoxidase (MPO) activity, reactive oxygen species (ROS) level, and transepithelial electric resistance (TEER) in intestinal epithelial cells (IECs) isolated from C57BL/6 wild‐type (WT) and TXNIP−/− mice were evaluated. The underlying regulatory mechanisms of TXNIP knockout in vivo were investigated with the detection of expressions of TXNIP, NLRP3 and ZO‐1, and occludin, the interaction of TXNIP–NLRP3, MPO activity, ROS level, permeability of intestinal mucosa, levels of inflammatory factors in serum, and LPS concentration. We identified that TXNIP knockout promoted ZO‐1 and occludin expression, yet reduced MPO activity, ROS level, and cell permeability in IECs, indicating restored the intestinal barrier function. However, LPS upregulated TXNIP and NLRP3 expression, as well as contributed to the interaction between TXNIP and NLRP3 in vitro. Furthermore, TXNIP was significantly upregulated in the intestinal mucosa of NASH mice and its knockout repaired the intestinal barrier disrupt, inhibited expression of inflammatory factors, and reduced LPS concentration as well as hepatic injury in vivo. Taken together, our findings demonstrated that inhibited the activation of the TXNIP–NLRP3 axis reduced MPO activity and oxidative stress and thus restoring the intestinal barrier function in NASH. TXNIP–NLRP3 axis may be a promising therapeutic strategy for the NASH treatment.