bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors
Authors: Chen Yunching , Liu Ya-Chi , Sung Yun-Chieh , Ramjiawan Rakesh R. , Lin Ts-Ting , Chang Chih-Chun , Jeng Kuo-Shyang , Chang Chiung-Fang , Liu Chun-Hung , Gao Dong-Yu , Hsu Fu-Fei , Duyverman Annique M. , Kitahara Shuji , Huang Peigen , Dima Simona , Popescu Irinel , Flaherty Keith T. , Zhu Andrew X. , Bardeesy Nabeel , Jain Rakesh K. , Benes Cyril H. , Duda Dan G. 
Published: March 2017

AbstractSorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent “paradoxical” upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether “paradoxical” ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC.
The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: a systematic review and meta-analysis
Authors: Chen Jiao , Fan Fang , Wang J. Y. , Long Yang , Gao C. L. , Stanton R. C. , Xu Yong 
Published: March 2017

AbstractTo assess the efficacy and safety of the SGLT-2 inhibitors as adjunct therapy to insulin in T1DM, clinical trials indexed in PubMed, Cochrane Library, EMbase from inception through April 5, 2016. A meta-analysis was conducted on trials of SGLT-2 inhibitors in patients with T1DM on insulin therapy using RevMan 5.3 software. Of the 371 articles identified, ten met eligibility criteria. Seven clinical trials including four randomized controlled trials and 581 patients were included. Compared with the control group, SGLT-2 inhibitors group had significantly reduced fasting plasma glucose by 0.69 mmol/L [1.32; 0.07], glycosylated hemoglobin A1C by 0.37% [0.54; 0.20], body weight by 2.54 kg [3.48; 1.60] and total daily insulin dose by 6.22 IU [8.04; 4.40]. The total incidence of adverse events (AEs), hypoglycemia, and genital and urinary infections were also similar to placebo, while an increased incidence of diabetic ketoacidosis (DKA) (n = 16) was seen in SGLT-2 inhibitors group. The present study demonstrates that SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, heralding improved glycemic control, reduced body weight and total daily insulin dose without an increase in total AEs, hypoglycemia, or genital and urinary infections. However, the risk of DKA should be carefully monitored in future clinical trials.
Electrochemical tuning of the optical properties of nanoporous gold
Authors: Jalas D. , Shao L.-H. , Canchi R. , Okuma T. , Lang S. , Petrov A. , Weissmüller J. , Eich M. 
Published: March 2017

AbstractUsing optical in-situ measurements in an electrochemical environment, we study the electrochemical tuning of the transmission spectrum of films from the nanoporous gold (NPG) based optical metamaterial, including the effect of the ligament size. The long wavelength part of the transmission spectrum around 800 nm can be reversibly tuned via the applied electrode potential. The NPG behaves as diluted metal with its transition from dielectric to metallic response shifted to longer wavelengths. We find that the applied potential alters the charge carrier density to a comparable extent as in experiments on gold nanoparticles. However, compared to nanoparticles, a NPG optical metamaterial, due to its connected structure, shows a much stronger and more broadband change in optical transmission for the same change in charge carrier density. We were able to tune the transmission through an only 200 nm thin sample by 30%. In combination with an electrolyte the tunable NPG based optical metamaterial, which employs a very large surface-to-volume ratio is expected to play an important role in sensor applications, for photoelectrochemical water splitting into hydrogen and oxygen and for solar water purification.
Biotic and abiotic factors predicting the global distribution and population density of an invasive large mammal
Authors: Lewis Jesse S. , Farnsworth Matthew L. , Burdett Chris L. , Theobald David M. , Gray Miranda , Miller Ryan S. 
Published: March 2017

AbstractBiotic and abiotic factors are increasingly acknowledged to synergistically shape broad-scale species distributions. However, the relative importance of biotic and abiotic factors in predicting species distributions is unclear. In particular, biotic factors, such as predation and vegetation, including those resulting from anthropogenic land-use change, are underrepresented in species distribution modeling, but could improve model predictions. Using generalized linear models and model selection techniques, we used 129 estimates of population density of wild pigs (Sus scrofa) from 5 continents to evaluate the relative importance, magnitude, and direction of biotic and abiotic factors in predicting population density of an invasive large mammal with a global distribution. Incorporating diverse biotic factors, including agriculture, vegetation cover, and large carnivore richness, into species distribution modeling substantially improved model fit and predictions. Abiotic factors, including precipitation and potential evapotranspiration, were also important predictors. The predictive map of population density revealed wide-ranging potential for an invasive large mammal to expand its distribution globally. This information can be used to proactively create conservation/management plans to control future invasions. Our study demonstrates that the ongoing paradigm shift, which recognizes that both biotic and abiotic factors shape species distributions across broad scales, can be advanced by incorporating diverse biotic factors.
Regulation of molecular clock oscillations and phagocytic activity via muscarinic Ca2+ signaling in human retinal pigment epithelial cells
Authors: Ikarashi Rina , Akechi Honami , Kanda Yuzuki , Ahmad Alsawaf , Takeuchi Kouhei , Morioka Eri , Sugiyama Takashi , Ebisawa Takashi , Ikeda Masaaki , Ikeda Masayuki 
Published: March 2017

AbstractVertebrate eyes are known to contain circadian clocks, however, the intracellular mechanisms regulating the retinal clockwork remain largely unknown. To address this, we generated a cell line (hRPE-YC) from human retinal pigmental epithelium, which stably co-expressed reporters for molecular clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). The hRPE-YC cells demonstrated circadian rhythms in Bmal1 transcription. Also, these cells represented circadian rhythms in Ca2+-spiking frequencies, which were canceled by dominant-negative Bmal1 transfections. The muscarinic agonist carbachol, but not photic stimulation, phase-shifted Bmal1 transcriptional rhythms with a type-1 phase response curve. This is consistent with significant M3 muscarinic receptor expression and little photo-sensor (Cry2 and Opn4) expression in these cells. Moreover, forskolin phase-shifted Bmal1 transcriptional rhythm with a type-0 phase response curve, in accordance with long-lasting CREB phosphorylation levels after forskolin exposure. Interestingly, the hRPE-YC cells demonstrated apparent circadian rhythms in phagocytic activities, which were abolished by carbachol or dominant-negative Bmal1 transfection. Because phagocytosis in RPE cells determines photoreceptor disc shedding, molecular clock oscillations and cytosolic Ca2+ signaling may be the driving forces for disc-shedding rhythms known in various vertebrates. In conclusion, the present study provides a cellular model to understand molecular and intracellular signaling mechanisms underlying human retinal circadian clocks.
Microwave Study of Field-Effect Devices Based on Graphene/Aluminum Nitride/Graphene Structures
Authors: Adabi Mohammad , Lischner Johannes , Hanham Stephen M. , Mihai Andrei P. , Shaforost Olena , Wang Rui , Hao Ling , Petrov Peter K. , Klein Norbert 
Published: March 2017

AbstractMetallic gate electrodes are often employed to control the conductivity of graphene based field effect devices. The lack of transparency of such electrodes in many optical applications is a key limiting factor. We demonstrate a working concept of a double layer graphene field effect device that utilizes a thin film of sputtered aluminum nitride as dielectric gate material. For this system, we show that the graphene resistance can be modified by a voltage between the two graphene layers. We study how a second gate voltage applied to the silicon back gate modifies the measured microwave transport data at around 8.7 GHz. As confirmed by numerical simulations based on the Boltzmann equation, this system resembles a parallel circuit of two graphene layers with different intrinsic doping levels. The obtained experimental results indicate that the graphene-aluminum nitride-graphene device concept presents a promising technology platform for terahertz- to- optical devices as well as radio-frequency acoustic devices where piezoelectricity in aluminum nitride can also be exploited.
The impact of the RBM4-initiated splicing cascade on modulating the carcinogenic signature of colorectal cancer cells
Authors: Lin Jung-Chun , Lee Yuan-Chii , Liang Yu-Chih , Fann Yang C. , Johnson Kory R. , Lin Ying-Ju 
Published: March 2017

AbstractA growing body of studies has demonstrated that dysregulated splicing profiles constitute pivotal mechanisms for carcinogenesis. In this study, we identified discriminative splicing profiles of colorectal cancer (CRC) cells compared to adjacent normal tissues using deep RNA-sequencing (RNA-seq). The RNA-seq results and cohort studies indicated a relatively high ratio of exon 4-excluded neuro-oncological ventral antigen 1 (Nova1−4) and intron 2-retained SRSF6 (SRSF6+intron 2) transcripts in CRC tissues and cell lines. Nova1 variants exhibited differential effects on eliminating SRSF6 expression in CRC cells by inducing SRSF6+intron 2 transcripts which were considered to be the putative target of alternative splicing-coupled nonsense-mediated decay mechanism. Moreover, the splicing profile of vascular endothelial growth factor (VEGF)165/VEGF165b transcripts was relevant to SRSF6 expression, which manipulates the progression of CRC calls. These results highlight the novel and hierarchical role of an alternative splicing cascade that is involved in the development of CRC.
Ultrasensitive colorimetric detection of circulating tumor DNA using hybridization chain reaction and the pivot of triplex DNA
Authors: Li Ruimin , Zou Li , Luo Yanwei , Zhang Manjun , Ling Liansheng 
Published: March 2017

AbstractThis work presents an amplified colorimetric biosensor for circulating tumor DNA (ctDNA), which associates the hybridization chain reaction (HCR) amplification with G-Quadruplex DNAzymes activity through triplex DNA formation. In the presence of ctDNA, HCR occurs. The resulting HCR products are specially recognized by one sequence to include one GGG repeat and the other containing three GGG repeats, through the synergetic effect of triplex DNA and asymmetrically split G-Quadruplex forming. Such design takes advantage of the amplification property of HCR and the high peroxidase-like catalytic activity of asymmetrically split G-Quadruplex DNAzymes by means of triplex DNA formation, which produces color signals in the presence of ctDNA. Nevertheless, in the absence of ctDNA, no HCR happens. Thus, no triplex DNA and G-Quadruplex structure is formed, producing a negligible background. The colorimetric sensing platform is successfully applied in complex biological environments such as human blood plasma for ctDNA detection, with a detection limit corresponding to 0.1 pM. This study unambiguously uses triplex DNA forming as the pivot to integrate nucleic acid amplification and DNAzymes for producing a highly sensitive signal with low background.
Genetic interactions and functional analyses of the fission yeast gsk3 and amk2 single and double mutants defective in TORC1-dependent processes
Authors: Rallis Charalampos , Townsend StJohn , Bähler Jürg 
Published: March 2017

AbstractThe Target of Rapamycin (TOR) signalling network plays important roles in aging and disease. The AMP-activated protein kinase (AMPK) and the Gsk3 kinase inhibit TOR during stress. We performed genetic interaction screens using synthetic genetic arrays (SGA) with gsk3 and amk2 as query mutants, the latter encoding the regulatory subunit of AMPK. We identified 69 negative and 82 positive common genetic interactors, with functions related to cellular growth and stress. The 120 gsk3-specific negative interactors included genes functioning in translation and ribosomes. The 215 amk2-specific negative interactors included genes functioning in chromatin silencing and DNA damage repair. Both amk2- and gsk3-specific interactors were enriched in phenotype categories related to abnormal cell size and shape. We also performed SGA screen with the amk2 gsk3 double mutant as a query. Mutants sensitive to 5-fluorouracil, an anticancer drug are under-represented within the 305 positive interactors specific for the amk2 gsk3 query. The triple-mutant SGA screen showed higher number of negative interactions than the double mutant SGA screens and uncovered additional genetic network information. These results reveal common and specialized roles of AMPK and Gsk3 in mediating TOR-dependent processes, indicating that AMPK and Gsk3 act in parallel to inhibit TOR function in fission yeast.
Mutagenesis and redox partners analysis of the P450 fatty acid decarboxylase OleTJE
Authors: Fang Bo , Xu Huifang , Liu Yi , Qi Fengxia , Zhang Wei , Chen Hui , Wang Cong , Wang Yilin , Yang Wenxia , Li Shengying 
Published: March 2017

AbstractThe cytochrome P450 enzyme OleTJE from Jeotgalicoccus sp. ATCC 8456 is capable of converting free long-chain fatty acids into α-alkenes via one-step oxidative decarboxylation in presence of H2O2 as cofactor or using redox partner systems. This enzyme has attracted much attention due to its intriguing but unclear catalytic mechanism and potential application in biofuel production. Here, we investigated the functionality of a select group of residues (Arg245, Cys365, His85, and Ile170) in the active site of OleTJE through extensive mutagenesis analysis. The key roles of these residues for catalytic activity and reaction type selectivity were identified. In addition, a range of heterologous redox partners were found to be able to efficiently support the decarboxylation activity of OleTJE. The best combination turned out to be SeFdx-6 (ferredoxin) from Synechococcus elongatus PCC 7942 and CgFdR-2 (ferredoxin reductase) from Corynebacterium glutamicum ATCC 13032, which gave the highest myristic acid conversion rate of 94.4%. Moreover, Michaelis-Menton kinetic parameters of OleTJE towards myristic acid were determined.
Myocardial oxidative damage is induced by cardiac Fas-dependent and mitochondria-dependent apoptotic pathways in human cocaine-related overdose
Authors: Turillazzi Emanuela , Cerretani Daniela , Cantatore Santina , Fiaschi Anna Ida , Frati Paola , Micheli Lucia , Neri Margherita , Cipolloni Luigi , Di Paolo Marco , Pinchi Enrica , Riezzo Irene , Santurro Alessandro , Vullo Annamaria , Fineschi Vittorio 
Published: March 2017

AbstractThe aim of this study is to analyse cardiac specimens from human cocaine-related overdose, to verify the hypothesis that cardiac toxicity by acute exposure to high dosage of cocaine could be mediated by unbalanced myocardial oxidative stress, and to evaluate the apoptotic response. To address these issues, biochemical and immunohistological markers of oxidative/nitrosative stress were evaluated. We found that i-NOS, NOX2 and nitrotyrosine expression were significantly higher in the hearts of subjects who had died from high doses of cocaine, compared to the control group. Increase of these markers was associated with a dramatic increase in 8-OHdG, another marker of oxidative stress. A high number of TUNEL-positive apoptotic myocells was observed in the study group compared to the control group. The immunoexpression of TNF-α was significantly higher in the cocaine group compared to the control group. Furthermore, we detected a significantly stronger immunoresponse to anti-SMAC/DIABLO in our study group compared to control cases. Both cardiac Fas-dependent and mitochondria-dependent apoptotic pathways appeared to be activated to a greater extent in the cocaine group than in the control group. Our results highlight the central role of oxidative stress in cocaine toxicity. High levels of NOS can promote the oxidation process and lead to apoptosis.
Pathologic Roles of Receptor-Associated Prorenin System in Idiopathic Epiretinal Membrane
Authors: Dong Yoko , Kanda Atsuhiro , Noda Kousuke , Saito Wataru , Ishida Susumu 
Published: March 2017

AbstractReceptor-associated prorenin system (RAPS) refers to the pathogenic mechanism whereby prorenin binding to (pro)renin receptor [(P)RR] dually activates tissue renin-angiotensin system (RAS) and RAS-independent signaling via (P)RR. The aim of this study is to determine the association of RAPS with idiopathic epiretinal membrane (iERM). Reverse transcription-PCR indicated the expression of RAPS components, including (P)RR and Ang II type 1 receptor (AT1R), in iERM tissues and human Müller glial cell line. Double-labeling analyses demonstrated that (P)RR and AT1R were detected in cells positive for glial fibrillary acidic protein, a marker for glial cells, and co-localized with prorenin and angiotensinogen, respectively. Administration of prorenin to Müller glial cells enhanced mRNA expression of fibroblast growth factor 2, while Ang II application stimulated the expression of glial cell line-derived neurotrophic factor, nerve growth factor, and transforming growth factor-β1. These expression levels induced by prorenin or Ang II were reversed by (P)RR or AT1R blockade, respectively. Immunofluorescence revealed tissue co-localization of (P)RR and AT1R with the products of the upregulated genes in vitro. The present findings suggest the involvement of RAPS in the pathogenesis of iERM.
Revealing new insights into different phosphorus-starving responses between two maize (Zea mays) inbred lines by transcriptomic and proteomic studies
Authors: Jiang Huimin , Zhang Jianfeng , Han Zhuo , Yang Juncheng , Ge Cailin , Wu Qingyu 
Published: March 2017

AbstractPhosphorus (P) is an essential plant nutrient, and deficiency of P is one of the most important factors restricting maize yield. Therefore, it is necessary to develop a more efficient program of P fertilization and breeding crop varieties with enhanced Pi uptake and use efficiency, which required understanding how plants respond to Pi starvation. To understand how maize plants adapt to P-deficiency stress, we screened 116 inbred lines in the field and identified two lines, DSY2 and DSY79 that were extreme low-P resistant and sensitive, respectively. We further conducted physiological, transcriptomic, and proteomic studies using the roots of DSY2 and DSY79 under normal or low-P conditions. The results showed that the low-P resistant line, DSY2 had larger root length, surface area and volume, higher root vitality, as well as acid phosphatase activity as compared with the low-P sensitive line, DSY79 under the low-P condition. The transcriptomic and proteomic results suggest that dramatic more genes were induced in DSY2, including the plant hormone signaling, acid phosphatase, and metabolite genes, as compared with DSY79 after being challenged by low-P stress. The new insights generated in this study will be useful toward the improvement of P-utilize efficiency in maize.
Major shifts at the range edge of marine forests: the combined effects of climate changes and limited dispersal
Authors: Assis J. , Berecibar E. , Claro B. , Alberto F. , Reed D. , Raimondi P. , Serrão E. A. 
Published: March 2017

AbstractGlobal climate change is likely to constrain low latitude range edges across many taxa and habitats. Such is the case for NE Atlantic marine macroalgal forests, important ecosystems whose main structuring species is the annual kelpSaccorhiza polyschides. We coupled ecological niche modelling with simulations of potential dispersal and delayed development stages to infer the major forces shaping range edges and to predict their dynamics. Models indicated that the southern limit is set by high winter temperatures above the physiological tolerance of overwintering microscopic stages and reduced upwelling during recruitment. The best range predictions were achieved assuming low spatial dispersal (5 km) and delayed stages up to two years (temporal dispersal). Reconstructing distributions through time indicated losses of ~30% from 1986 to 2014, restrictingS. polyschidesto upwelling regions at the southern edge. Future predictions further restrict populations to a unique refugium in northwestern Iberia. Losses were dependent on the emissions scenario, with the most drastic one shifting ~38% of the current distribution by 2100. Such distributional changes might not be rescued by dispersal in space or time (as shown for the recent past) and are expected to drive major biodiversity loss and changes in ecosystem functioning.
Effects of silk fibroin in murine dry eye
Authors: Kim Chae Eun , Lee Ji Hyun , Yeon Yeung Kyu , Park Chan Hum , Yang JaeWook 
Published: March 2017

AbstractThe study aimed to investigate the effects of silk fibroin in a mouse model of dry eye. The experimental dry eye mouse model was developed using more than twelve-weeks-old NOD.B10.H2b mice exposing them to 30–40% ambient humidity and injecting them with scopolamine hydrobromide for 10 days. Tear production and corneal irregularity score were measured by the instillation of phosphate buffered saline or silk fibroin. Corneal detachment and conjunctival goblet cell density were observed by hematoxylin and eosin or periodic acid Schiff staining in the cornea or conjunctiva. The expression of inflammatory markers was detected by immunohistochemistry in the lacrimal gland. The silk group tear production was increased, and corneal smoothness was improved. The corneal epithelial cells and conjunctival goblet cells were recovered in the silk groups. The expression of inflammatory factors was inhibited in the lacrimal gland of the silk group. These results show that silk fibroin improved the cornea, conjunctiva, and lacrimal gland in the mouse model of dry eye. These findings suggest that silk fibroin has anti-inflammatory effects in the experimental models of dry eye.