bluuebunny/crossref_metadata_2025 huggingface dataset:
Correction: Corrigendum: Natural History of Non-Small-Cell Lung Cancer with Bone Metastases
Authors: Santini Daniele , Barni Sandro , Intagliata Salvatore , Falcone Alfredo , Ferraù Francesco , Galetta Domenico , Moscetti Luca , La Verde Nicla , Ibrahim Toni , Petrelli Fausto , Vasile Enrico , Ginocchi Laura , Ottaviani Davide , Longo Flavia , Ortega Cinzia , Russo Antonio , Badalamenti Giuseppe , Collovà Elena , Lanzetta Gaetano , Mansueto Giovanni , Adamo Vincenzo , De Marinis Filippo , Satolli Maria Antonietta , Cantile Flavia , Mancuso Andrea , Tanca Francesca Maria , Addeo Raffaele , Russano Marco , Sterpi Michelle , Pantano Francesco , Vincenzi Bruno , Tonini Giuseppe
Published: April 2016

Scientific Reports 5: Article number: 18670; published online: 22 December 2015; updated: 15 April 2016. The original version of this Article contained errors in the spelling of the authors Daniele Santini, Sandro Barni, Salvatore Intagliata, Alfredo Falcone, Francesco Ferraù, Domenico Galetta, LucaMoscetti, Nicla La Verde, Toni Ibrahim, Fausto Petrelli, Enrico Vasile, Laura Ginocchi, Davide Ottaviani, Flavia Longo, Cinzia Ortega, Antonio Russo, Giuseppe Badalamenti, Elena Collovà, Gaetano Lanzetta, Giovanni Mansueto, Vincenzo Adamo, Filippo De Marinis, Flavia Cantile, Andrea Mancuso, Raffaele Addeo, Marco Russano, Michelle Sterpi, Francesco Pantano, Bruno Vincenzi and Giuseppe Tonini which were incorrectly given as Santini Daniele, Barni Sandro, Intagliata Salvatore, Falcone Alfredo, Ferraù Francesco, Galetta Domenico, Moscetti Luca, La Verde Nicla, Ibrahim Toni, Petrelli Fausto, Vasile Enrico, Ginocchi Laura, Ottaviani Davide, Longo Flavia, Ortega Cinzia, Russo Antonio, Badalamenti Giuseppe, Collovà Elena, Lanzetta Gaetano, Mansueto Giovanni, Adamo Vincenzo, De Marinis Filippo, Cantile Flavia, Mancuso Andrea, Addeo Raffaele, Russano Marco, M Sterpi, Pantano Francesco, Vincenzi Bruno and Tonini Giuseppe respectively.
Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling
Authors: Zhou Chaoming , Ramaswamy Swarna S. , Johnson Derrick E. , Vitturi Dario A. , Schopfer Franciso J. , Freeman Bruce A. , Hudmon Andy , Levitan Edwin S.
Published: April 2016

Ca2+/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca2+-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca2+ independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO−) to mediate CaMKII activation and downstream Kv4.3 channel mRNA destabilization by Ang II. In vitro experiments show that ONOO− oxidizes and modestly activates pure CaMKII in the absence of Ca2+/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca2+-independent CaMKII activity. The role of ONOO− in cardiac and neuronal responses to Ang II was then tested by scavenging ONOO− and preventing its formation by inhibiting nitric oxide synthase. Both treatments blocked Ang II effects on Kv4.3, tyrosine nitration and CaMKIIδ oxidation and activation. Together, these data show that ONOO− participates in Ang II-CaMKII signaling. The requirement for ONOO− in transducing Ang II signaling identifies ONOO−, which has been viewed as a reactive damaging byproduct of superoxide and nitric oxide, as a mediator of GPCR-CaMKII signaling.
Comparisons of parallel potential biomarkers of 1H-MRS-measured hepatic lipid content in patients with non-alcoholic fatty liver disease
Authors: Shih Kai-Lun , Su Wei-Wen , Chang Chia-Chu , Kor Chew-Teng , Chou Chen-Te , Chen Ting-Yu , Wu Hung-Ming
Published: April 2016

Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease. This cross-sectional study aimed to evaluate whether parallel clinical features and serum markers are related to the severity of NAFLD. We enrolled 111 participants with different metabolic syndrome (MetS) scores (zero, n = 22; one, n = 19; two, n = 22; and ≥ three, n = 48) and used 1H-MRS to measure liver fat content. Biochemical profiles and potential biomarkers of NAFLD were measured in fasting plasma. We found that 1H-MRS-measured fat content was significantly associated with MetS score ≥1, endotoxin, and hs-CRP. Ordinal logistic regression analysis revealed that MetS score ≥2 and endotoxin were predictive of NAFLD (1H-MRS > 5%) and that endotoxin, hs-CRP, and malondialdehyde (MDA) were predictive of NAFLD with liver injury (1H-MRS > 9.67%). Endotoxin plus MetS score was shown to be the most accurate predictor of overall NAFLD (AUC = 0.854; (95% CI: 0.785–0.924), P < 0.001), and endotoxin plus hs-CRP and MDA was found to be predictive of NAFLD with liver injury (0.868; (0.801–0.936), P < 0.001). These results suggest that MetS score plus certain serum biomarkers with 1H-MRS findings may hold promise for developing an effective model for monitoring the severity of NAFLD.
Retinoic acid facilitates inactivated transmissible gastroenteritis virus induction of CD8+ T-cell migration to the porcine gut
Authors: Chen Xiaojuan , Tu Chongzhi , Qin Tao , Zhu Liqi , Yin Yinyan , Yang Qian
Published: April 2016

The digestive tract is the entry site for transmissible gastroenteritis virus (TGEV). TGEV transmission can be prevented if local immunity is established with increased lymphocytes. The current parenteral mode of vaccination stimulates systemic immunity well, but it does not induce sufficient mucosal immunity. Retinoic acid (RA) plays an important role in the induction of cells that imprint gut-homing molecules. We examined whether RA assist parenteral vaccination of pigs could improve mucosal immunity. We demonstrated that elevated numbers of gut-homing CD8+ T cells (which express α4β7 and CCR9 molecules) were presented in porcine inguinal lymph nodes and were recruited to the small intestine by RA. Intestinal mucosal immunity (IgA titre) and systemic immunity (serum IgG titre) were enhanced by RA. Therefore, we hypothesized that RA could induce DCs to form an immature mucosal phenotype and could recruit them to the small intestinal submucosa. Porcine T-cells expressed β7 integrin and CCR9 receptors and migrated to CCL25 by a mechanism that was dependent of activation by RA-pretreated DCs, rather than direct activation by RA. Together, our results provide powerful evidence that RA can assist whole inactivated TGEV (WI-TGEV) via subcutaneous (s.c.) immunization to generate intestinal immunity and offer new vaccination strategies against TGEV.
MHC-class-II are expressed in a subpopulation of human neural stem cells in vitro in an IFNγ–independent fashion and during development
Authors: Vagaska B. , New S. E. P. , Alvarez-Gonzalez C. , D’Acquisto F. , Gomez S. G. , Bulstrode N. W. , Madrigal A. , Ferretti P.
Published: April 2016

Expression of major histocompatibility antigens class-2 (MHC-II) under non-inflammatory conditions is not usually associated with the nervous system. Comparative analysis of immunogenicity of human embryonic/fetal brain-derived neural stem cells (hNSCs) and human mesenchymal stem cells with neurogenic potential from umbilical cord (UC-MSCs) and paediatric adipose tissue (ADSCs), while highlighting differences in their immunogenicity, led us to discover subsets of neural cells co-expressing the neural marker SOX2 and MHC-II antigen in vivo during human CNS development. MHC-II proteins in hNSCs are functional and differently regulated upon differentiation along different lineages. Mimicking an inflammatory response using the inflammatory cytokine IFNγ induced MHC-II up-regulation in both astrocytes and hNSCs, but not in UC-MSCs and ADSCs, either undifferentiated or differentiated, though IFNγ receptor expression was comparable. Together, hypoimmunogenicity of both UC-MSCs and ADSCs supports their suitability for allogeneic therapy, while significant immunogenicity of hNSCs and their progeny may at least in part underlie negative effects reported in some patients following embryonic neural cell grafts. Crucially, we show for the first time that MHC-II expression in developing human brains is not restricted to microglia as previously suggested, but is present in discrete subsets of neural progenitors and appears to be regulated independently of inflammatory stimuli.
Frequent mechanical stress suppresses proliferation of mesenchymal stem cells from human bone marrow without loss of multipotency
Authors: Frank Viktoria , Kaufmann Stefan , Wright Rebecca , Horn Patrick , Yoshikawa Hiroshi Y. , Wuchter Patrick , Madsen Jeppe , Lewis Andrew L. , Armes Steven P. , Ho Anthony D. , Tanaka Motomu
Published: April 2016

Mounting evidence indicated that human mesenchymal stem cells (hMSCs) are responsive not only to biochemical but also to physical cues, such as substrate topography and stiffness. To simulate the dynamic structures of extracellular environments of the marrow in vivo, we designed a novel surrogate substrate for marrow derived hMSCs based on physically cross-linked hydrogels whose elasticity can be adopted dynamically by chemical stimuli. Under frequent mechanical stress, hMSCs grown on our hydrogel substrates maintain the expression of STRO-1 over 20 d, irrespective of the substrate elasticity. On exposure to the corresponding induction media, these cultured hMSCs can undergo adipogenesis and osteogenesis without requiring cell transfer onto other substrates. Moreover, we demonstrated that our surrogate substrate suppresses the proliferation of hMSCs by up to 90% without any loss of multiple lineage potential by changing the substrate elasticity every 2nd days. Such “dynamic in vitro niche” can be used not only for a better understanding of the role of dynamic mechanical stresses on the fate of hMSCs but also for the synchronized differentiation of adult stem cells to a specific lineage.
Signatures of evanescent transport in ballistic suspended graphene-superconductor junctions
Authors: Kumaravadivel Piranavan , Du Xu
Published: April 2016

In Dirac materials, the low energy excitations behave like ultra-relativistic massless particles with linear energy dispersion. A particularly intriguing phenomenon arises with the intrinsic charge transport behavior at the Dirac point where the charge density approaches zero. In graphene, a 2-D Dirac fermion gas system, it was predicted that charge transport near the Dirac point is carried by evanescent modes, resulting in unconventional “pseudo-diffusive” charge transport even in the absence of disorder. In the past decade, experimental observation of this phenomenon remained challenging due to the presence of strong disorder in graphene devices which limits the accessibility of the low carrier density regime close enough to the Dirac point. Here we report transport measurements on ballistic suspended graphene-Niobium Josephson weak links that demonstrate a transition from ballistic to pseudo-diffusive like evanescent transport below a carrier density of ~1010 cm−2. Approaching the Dirac point, the sub-harmonic gap structures due to multiple Andreev reflections display a strong Fermi energy-dependence and become increasingly pronounced, while the normalized excess current through the superconductor-graphene interface decreases sharply. Our observations are in qualitative agreement with the long standing theoretical prediction for the emergence of evanescent transport mediated pseudo-diffusive transport in graphene.
Differential tolerance capacity to unfavourable low and high temperatures between two invasive whiteflies
Authors: Xiao Na , Pan Li-Long , Zhang Chang-Rong , Shan Hong-Wei , Liu Shu-Sheng
Published: April 2016

Thermal response and tolerance to ambient temperature play important roles in determining the geographic distribution and seasonal abundance of insects. We examined the survival and performance, as well as expression of three heat shock protein related genes, of two species of invasive whiteflies, Middle East-Asia Minor 1 (MEAM1) and Mediterranean (MED), of the Bemisia tabaci species complex following exposure to a range of low and high temperatures. Our data demonstrated that the MED species was more tolerant to high temperatures than the MEAM1 species, especially in the adult stage, and this difference in thermal responses may be related to the heat shock protein related genes hsp90 and hsp70. These findings may assist in understanding and predicting the distribution and abundance of the two invasive whiteflies in the field.
Anatomy of Indian heatwaves
Authors: Ratnam J. V. , Behera Swadhin K. , Ratna Satyaban B. , Rajeevan M. , Yamagata Toshio
Published: April 2016

India suffers from major heatwaves during March-June. The rising trend of number of intense heatwaves in recent decades has been vaguely attributed to global warming. Since the heat waves have a serious effect on human mortality, root causes of these heatwaves need to be clarified. Based on the observed patterns and statistical analyses of the maximum temperature variability, we identified two types of heatwaves. The first-type of heatwave over the north-central India is found to be associated with blocking over the North Atlantic. The blocking over North Atlantic results in a cyclonic anomaly west of North Africa at upper levels. The stretching of vorticity generates a Rossby wave source of anomalous Rossby waves near the entrance of the African Jet. The resulting quasi-stationary Rossby wave-train along the Jet has a positive phase over Indian subcontinent causing anomalous sinking motion and thereby heatwave conditions over India. On the other hand, the second-type of heatwave over the coastal eastern India is found to be due to the anomalous Matsuno-Gill response to the anomalous cooling in the Pacific. The Matsuno-Gill response is such that it generates northwesterly anomalies over the landmass reducing the land-sea breeze, resulting in heatwaves.
Recombinant soluble gp130 protein reduces DEN-induced primary hepatocellular carcinoma in mice
Authors: Hong Jing , Wang Hang , Shen Guoying , Lin Da , Lin Yanxue , Ye Nanhui , Guo Yashan , Li Qiaoling , Ye Nanhui , Deng Chengjun , Meng Chun
Published: April 2016

IL-6 (interleukin 6) plays an important role in the development and growth of hepatocellular carcinoma (HCC) via both classic signaling and trans-signaling pathways. Soluble gp130 (sgp130) is known to be a natural inhibitor of the trans-signaling pathway. In the present study, our goal was to investigate whether recombinant sgp130 could suppress the initiation and progression of HCC in mouse models. Our results demonstrate that sgp130 induced an apoptosis of HepG2 cells and inhibited the clonogenicity of HepG2 in vitro. Moreover, the IL-6 trans-signaling pathway is significantly suppressed by sgp130 as reflected by the decrease in the level of STAT3 phosphorylation and other inflammatory factors both in vitro and in vivo. In the DEN-induced HCC mouse model, intravenous injection of sgp130 attenuated hepatic fibrosis at 16 weeks and reduced the initiation and progression of primary HCC at 36 weeks. Furthermore, our results also demonstrate that intravenous administration of sgp130 significantly suppressed the growth and metastasis of xenograft human HCC in NOD/SCID mice.
Strong Antibacterial Polydopamine Coatings Prepared by a Shaking-assisted Method
Authors: Su Lei , Yu Yang , Zhao Yanshuang , Liang Feng , Zhang Xueji
Published: April 2016

Strong antibacterial polydopamine (PDA) coatings prepared by a facile shaking-assisted method is reported for the first time. It was found that a minor modification made to the conventional synthesis procedure of PDA coatings, viz. replacing the static solution condition with a shaking solution condition by using a mechanical shaker, can produce the roughened polydopamine (rPDA) coatings at different substrates, e.g., glass, stainless steel, plastic and gauze. The resulting rPDA coatings were characterized with Raman spectrum, zeta-potential analysis and contact angle measurement. The antibacterial activity of the rPDA coatings was evaluated by a shake flask test with gram-positive Staphylococcus aureus and gram-negative Escherichia coli and Pseudomonas aeruginosa as bacteria models. Testing results revealed that, in the absence of any other antibacterial agents, the rPDA coatings exhibited remarkably enhanced antibacterial activities. In addition, such enhanced antibacterial activities of the rPDA coatings were found to be unimpaired by steam sterilization treatments.
Mathematical Modeling of Yarn Dynamics in a Generalized Twisting System
Authors: Yin R. , Tao X. M. , Xu B. G.
Published: April 2016

Twisting is an important process to form a continuous yarn from short fibres and to determine the structure and properties of the resultant yarn. This paper proposes a new theoretical model of yarn dynamics in a generalized twisting system, which deals with two important phenomena simultaneously, that is, twist generation and twist propagation. Equations of yarn motion are established and the boundary value problems are numerically solved by Newton-Raphson method. The simulation results are validated by experiments and a good agreement has been demonstrated for the system with a moving rigid cylinder as the twisting element. For the first time, influences of several parameters on the twisting process have been revealed in terms of twist efficiency of the moving rigid cylinder, propagation coefficients of twist trapping and congestion. It was found that the wrap angle and yarn tension have large influence on the twisting process, and the yarn torsional rigidity varies with the twisting parameters.
Growth, collapse and self-organized criticality in complex networks
Authors: Wang Yafeng , Fan Huawei , Lin Weijie , Lai Ying-Cheng , Wang Xingang
Published: April 2016

Network growth is ubiquitous in nature (e.g., biological networks) and technological systems (e.g., modern infrastructures). To understand how certain dynamical behaviors can or cannot persist as the underlying network grows is a problem of increasing importance in complex dynamical systems as well as sustainability science and engineering. We address the question of whether a complex network of nonlinear oscillators can maintain its synchronization stability as it expands. We find that a large scale avalanche over the entire network can be triggered in the sense that the individual nodal dynamics diverges from the synchronous state in a cascading manner within a relatively short time period. In particular, after an initial stage of linear growth, the network typically evolves into a critical state where the addition of a single new node can cause a group of nodes to lose synchronization, leading to synchronization collapse for the entire network. A statistical analysis reveals that the collapse size is approximately algebraically distributed, indicating the emergence of self-organized criticality. We demonstrate the generality of the phenomenon of synchronization collapse using a variety of complex network models and uncover the underlying dynamical mechanism through an eigenvector analysis.
High-order spoof localized surface plasmons supported on a complementary metallic spiral structure
Authors: Gao Zhen , Gao Fei , Zhang Baile
Published: April 2016

We experimentally demonstrate that multiple high-order spoof localized surface plasmons (spoof-LSPs) modes can be supported on a complementary metallic spiral structure, which were absent in the previously reported spoof-LSPs modes. Through exact numerical simulations and near-field imaging experiments, we directly observe these high-order spoof-LSPs modes at microwave frequencies. We also show that these higher-order spoof-LSPs modes exhibit larger frequency shifts caused by the local environmental refractive index change than the previously reported low-order spoof-LSPs modes. Hence the complementary MSS may find potential applications as plasmonic sensor in the microwave and terahertz frequencies.
Computer-Aided Diagnosis with Deep Learning Architecture: Applications to Breast Lesions in US Images and Pulmonary Nodules in CT Scans
Authors: Cheng Jie-Zhi , Ni Dong , Chou Yi-Hong , Qin Jing , Tiu Chui-Mei , Chang Yeun-Chung , Huang Chiun-Sheng , Shen Dinggang , Chen Chung-Ming
Published: April 2016

This paper performs a comprehensive study on the deep-learning-based computer-aided diagnosis (CADx) for the differential diagnosis of benign and malignant nodules/lesions by avoiding the potential errors caused by inaccurate image processing results (e.g., boundary segmentation), as well as the classification bias resulting from a less robust feature set, as involved in most conventional CADx algorithms. Specifically, the stacked denoising auto-encoder (SDAE) is exploited on the two CADx applications for the differentiation of breast ultrasound lesions and lung CT nodules. The SDAE architecture is well equipped with the automatic feature exploration mechanism and noise tolerance advantage, and hence may be suitable to deal with the intrinsically noisy property of medical image data from various imaging modalities. To show the outperformance of SDAE-based CADx over the conventional scheme, two latest conventional CADx algorithms are implemented for comparison. 10 times of 10-fold cross-validations are conducted to illustrate the efficacy of the SDAE-based CADx algorithm. The experimental results show the significant performance boost by the SDAE-based CADx algorithm over the two conventional methods, suggesting that deep learning techniques can potentially change the design paradigm of the CADx systems without the need of explicit design and selection of problem-oriented features.
Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents
Authors: Aziz Marwa A. , Serya Rabah A. T. , Lasheen Deena S. , Abdel-Aziz Amal Kamal , Esmat Ahmed , Mansour Ahmed M. , Singab Abdel Nasser B. , Abouzid Khaled A. M.
Published: April 2016

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase enzyme. Seven compounds (15b, 16c, 16e, 21a, 21b, 21c and 21e) demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range, of which the thieno[2,3-d]pyrimidine based-derivatives (21b, 21c and 21e) exhibited IC50 values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3-d]pyrimidine-based derivative (15b) showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 μM concentration. Consistent with our in vitro findings, compounds (21b and 21e) orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects in vivo. Intriguingly, such compounds showed no obvious toxicity.
An enhanced chemiluminescence bioplatform by confining glucose oxidase in hollow calcium carbonate particles
Authors: Wang Congmin , Zhou Cuisong , Long Yuyin , Cai Honglian , Yin Cuiyun , Yang Qiufang , Xiao Dan
Published: April 2016

A chemiluminescence (CL) amplification platform based on HCC/Lucigenin&GOx (HLG) film was developed. Hollow structural calcium carbonate (HCC) particles were used as alternative materials for carrying both enzyme and CL reagent. The model enzyme (GOx), immobilized in confined space of HCC particles, exhibited an improved biocatalysis. The Michaelis constant (Km) and the enzymatic rate constant (kcat) were determined to be 0.209 μM and 2.21 s−1, respectively, which are much better than those of either free GOx in aqueous solution or the GOx immobilized on common nanomaterials. Based on the HLG platform, CL signal was effectively amplified and visualized after adding trace glucose, which could be attributed to the HCC particles’ high biocompatibility, large specific surface area, attractive interfacial properties and efficient interaction with analyses. The visual CL bioplatform showed an excellent performance with high selectivity, wide linear range and low detection limit for sensing trace glucose. Because it eliminates the need of complicated assembly procedure and enables visualization by the naked eye, the sensitive and selective CL bioplatform would provide wide potential applications in disease diagnosis and food safety.
Integrative Phosphoproteomics Links IL-23R Signaling with Metabolic Adaptation in Lymphocytes
Authors: Lochmatter Corinne , Fischer Roman , Charles Philip D. , Yu Zhanru , Powrie Fiona , Kessler Benedikt M.
Published: April 2016

Interleukin (IL)-23 mediated signal transduction represents a major molecular mechanism underlying the pathology of inflammatory bowel disease, Crohn’s disease and ulcerative colitis. In addition, emerging evidence supports the role of IL-23-driven Th17 cells in inflammation. Components of the IL-23 signaling pathway, such as IL-23R, JAK2 and STAT3, have been characterized, but elements unique to this network as compared to other interleukins have not been readily explored. In this study, we have undertaken an integrative phosphoproteomics approach to better characterise downstream signaling events. To this end, we performed and compared phosphopeptide and phosphoprotein enrichment methodologies after activation of T lymphocytes by IL-23. We demonstrate the complementary nature of the two phosphoenrichment approaches by maximizing the capture of phosphorylation events. A total of 8202 unique phosphopeptides and 4317 unique proteins were identified, amongst which STAT3, PKM2, CDK6 and LASP-1 showed induction of specific phosphorylation not readily observed after IL-2 stimulation. Interestingly, quantitative analysis revealed predominant phosphorylation of pre-existing STAT3 nuclear subsets in addition to translocation of phosphorylated STAT3 within 30 min after IL-23 stimulation. After IL-23R activation, a small subset of PKM2 also translocates to the nucleus and may contribute to STAT3 phosphorylation, suggesting multiple cellular responses including metabolic adaptation.
Titin stiffness modifies the force-generating region of muscle sarcomeres
Authors: Li Yong , Lang Patrick , Linke Wolfgang A.
Published: April 2016

The contractile units of striated muscle, the sarcomeres, comprise the thick (myosin) and thin (actin) filaments mediating active contraction and the titin filaments determining “passive” elasticity. We hypothesized that titin may be more active in muscle contraction by directly modulating thick-filament properties. We used single-myofibril mechanical measurements and atomic force microscopy of individual sarcomeres to quantify the effects of sarcomere strain and titin spring length on both the inter-filament lattice spacing and the lateral stiffness of the actin-myosin overlap zone (A-band). We found that strain reduced the lattice spacing similarly in sarcomeres with stiff (rabbit psoas) or compliant titin (rabbit diaphragm), but increased A-band lateral stiffness much more in psoas than in diaphragm. The strain-induced alterations in A-band stiffness that occur independently of lattice spacing effects may be due to titin stiffness-sensing by A-band proteins. This mechanosensitivity could play a role in the physiologically important phenomenon of length-dependent activation of striated muscle.
A Network of Splice Isoforms for the Mouse
Authors: Li Hong-Dong , Menon Rajasree , Eksi Ridvan , Guerler Aysam , Zhang Yang , Omenn Gilbert S. , Guan Yuanfang
Published: April 2016

The laboratory mouse is the primary mammalian species used for studying alternative splicing events. Recent studies have generated computational models to predict functions for splice isoforms in the mouse. However, the functional relationship network, describing the probability of splice isoforms participating in the same biological process or pathway, has not yet been studied in the mouse. Here we describe a rich genome-wide resource of mouse networks at the isoform level, which was generated using a unique framework that was originally developed to infer isoform functions. This network was built through integrating heterogeneous genomic and protein data, including RNA-seq, exon array, protein docking and pseudo-amino acid composition. Through simulation and cross-validation studies, we demonstrated the accuracy of the algorithm in predicting isoform-level functional relationships. We showed that this network enables the users to reveal functional differences of the isoforms of the same gene, as illustrated by literature evidence withAnxa6(annexin a6) as an example. We expect this work will become a useful resource for the mouse genetics community to understand gene functions. The network is publicly available at:http://guanlab.ccmb.med.umich.edu/isoformnetwork.
Characterization of the 5′-flanking region of the human DNA helicase B (HELB) gene and its response to trans-Resveratrol
Authors: Uchiumi Fumiaki , Arakawa Jun , Iwakoshi Keiko , Ishibashi Sayaka , Tanuma Sei-ichi
Published: April 2016

Human DNA helicase B (HELB/HDHB) regulates DNA replication through association with human DNA polymerase α-primase. In the present study, an 866-base pair (bp) of the 5′-flanking region of the human HELB gene-containing Luciferase (Luc) reporter plasmid, pHDHB-Luc was transfected into various cell lines and Luc activity was analyzed. Deletion analyses revealed that a 121-bp containing the major transcription start site (TSS) was essential for the basal promoter activity in all tested cells. TF-SEARCH analysis indicated that GC-box/Sp1 and duplicated GGAA-motifs containing putative STAT-x and c-ETS binding sites are located close to the TSS. Furthermore, chromatin immunoprecipitation (ChIP) analysis showed that PU.1 and Sp1 bind to the 121-bp region. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analyses showed the HELB gene and protein expression was up-regulated by trans-Resveratrol (Rsv) treatment in HeLa S3 cells. Moreover, transfection experiment indicated that mutations on the GC-boxes and the duplicated GGAA-motif greatly reduced promoter activity and the response to Rsv in HeLa S3 cells. These results suggest that Rsv, which is a natural compound that has been found to elongate the lifespan of various organisms, regulates HELB promoter activity through co-operation of the GC-boxes and the duplicated GGAA-motif in the 121-bp.
Inhibition of miR-21 in glioma cells using catalytic nucleic acids
Authors: Belter Agnieszka , Rolle Katarzyna , Piwecka Monika , Fedoruk-Wyszomirska Agnieszka , Naskręt-Barciszewska Mirosława Z. , Barciszewski Jan
Published: April 2016

Despite tremendous efforts worldwide, glioblastoma multiforme (GBM) remains a deadly disease for which no cure is available and prognosis is very bad. Recently, miR-21 has emerged as a key omnipotent player in carcinogenesis, including brain tumors. It is recognized as an indicator of glioma prognosis and a prosperous target for anti-tumor therapy. Here we show that rationally designed hammerhead ribozymes and DNAzymes can target miR-21 and/or its precursors. They decrease miR-21 level and thus silence this oncomiR functions. We demonstrated that anti-miRNA catalytic nucleic acids show a novel terrific arsenal for specific and effective combat against diseases with elevated cellular miR-21 content, such as brain tumors.
A novel anesthesia regime enables neurofunctional studies and imaging genetics across mouse strains
Authors: Petrinovic Marija M. , Hankov Georges , Schroeter Aileen , Bruns Andreas , Rudin Markus , von Kienlin Markus , Künnecke Basil , Mueggler Thomas
Published: April 2016

Functional magnetic resonance imaging (fMRI) has revolutionized neuroscience by opening a unique window that allows neurocircuitry function and pathological alterations to be probed non-invasively across brain disorders. Here we report a novel sustainable anesthesia procedure for small animal neuroimaging that overcomes shortcomings of anesthetics commonly used in rodent fMRI. The significantly improved preservation of cerebrovascular dynamics enhances sensitivity to neural activity changes for which it serves as a proxy in fMRI readouts. Excellent cross-species/strain applicability provides coherence among preclinical findings and is expected to improve translation to clinical fMRI investigations. The novel anesthesia procedure based on the GABAergic anesthetic etomidate was extensively validated in fMRI studies conducted in a range of genetically engineered rodent models of autism and strains commonly used for transgenic manipulations. Etomidate proved effective, yielded long-term stable physiology with basal cerebral blood flow of ~0.5 ml/g/min and full recovery. Cerebrovascular responsiveness of up to 180% was maintained as demonstrated with perfusion- and BOLD-based fMRI upon hypercapnic, pharmacological and sensory stimulation. Hence, etomidate lends itself as an anesthetic-of-choice for translational neuroimaging studies across rodent models of brain disorders.
Therapeutic hypothermia attenuates tissue damage and cytokine expression after traumatic brain injury by inhibiting necroptosis in the rat
Authors: Liu Tao , Zhao Dong-xu , Cui Hua , Chen Lei , Bao Ying-hui , Wang Yong , Jiang Ji-yao
Published: April 2016

Necroptosis has been shown as an alternative form of cell death in many diseases, but the detailed mechanisms of the neuron loss after traumatic brain injury (TBI) in rodents remain unclear. To investigate whether necroptosis is induced after TBI and gets involved in the neuroprotecton of therapeutic hypothermia on the TBI, we observed the pathological and biochemical change of the necroptosis in the fluid percussion brain injury (FPI) model of the rats. We found that receptor-interacting protein (RIP) 1 and 3 and mixed lineage kinase domain-like protein (MLKL), the critical downstream mediators of necroptosis recently identified in vivo, as well as HMGB1 and the pro-inflammation cytokines TNF-α, IL-6 and IL-18, were increased at an early phase (6 h) in cortex after TBI. Posttraumatic hypothermia (33 °C) led to the decreases in the necroptosis regulators, inflammatory factors and brain tissue damage in rats compared with normothermia-treated TBI animals. Immunohistochemistry studies showed that posttraumatic hypothermia also decreased the necroptosis-associated proteins staining in injured cortex and hippocampal CA1. Therefore, we conclude that the RIP1/RIP3-MLKL-mediated necroptosis occurs after experimental TBI and therapeutic hypothermia may protect the injured central nervous system from tissue damage and the inflammatory responses by targeting the necroptosis signaling after TBI.
β2-adrenoceptor signaling reduction in dendritic cells is involved in the inflammatory response in adjuvant-induced arthritic rats
Authors: Wu Huaxun , Chen Jingyu , Song Shasha , Yuan Pingfan , Liu Lihua , Zhang Yunfang , Zhou Aiwu , Chang Yan , Zhang Lingling , Wei Wei
Published: April 2016

Rheumatoid arthritis (RA) is characterized by inflammation of the synovium, which leads to the progressive destruction of cartilage and bone. Adrenoreceptor (AR) signaling may play an important role in modulating dendritic cell (DC), which may be involved in the pathogenesis of RA. We examined the effect of the β-AR agonist isoprenaline (ISO) on DC function, the impact of the β2-AR agonist salbutamol on adjuvant-induced arthritic (AA) rats and changes in β2-AR signaling in DCs during the course of AA. ISO inhibited the expression of the surface molecules CD86 and MHC-II, inhibited the stimulation of T lymphocyte proliferation by DC and TNF-α secretion and promoted DC antigen uptake and IL-10 secretion. The effects of ISO on MHC-II expression, DC stimulation of T lymphocyte proliferation and DC antigen uptake were mediated by β2-AR. Treatment with salbutamol ameliorated the severity of AA and histopathology of the joints and inhibited proliferation of thymus lymphocytes and FLS in vivo. β2-AR signaling was weaker in AA rats compared to the control. Elevated GRK2 and decreased β2-AR expression in DC cytomembranes were observed in AA and may have decreased the anti-inflammatory effect of β2-AR signaling. Decreased β2-AR signaling may be relevant to the exacerbation of arthritis inflammation.
Engineering of a novel cellulose-adherent cellulolytic Saccharomyces cerevisiae for cellulosic biofuel production
Authors: Liu Zhuo , Ho Shih-Hsin , Sasaki Kengo , den Haan Riaan , Inokuma Kentaro , Ogino Chiaki , van Zyl Willem H. , Hasunuma Tomohisa , Kondo Akihiko
Published: April 2016

Cellulosic biofuel is the subject of increasing attention. The main obstacle toward its economic feasibility is the recalcitrance of lignocellulose requiring large amount of enzyme to break. Several engineered yeast strains have been developed with cellulolytic activities to reduce the need for enzyme addition, but exhibiting limited effect. Here, we report the successful engineering of a cellulose-adherent Saccharomyces cerevisiae displaying four different synergistic cellulases on the cell surface. The cellulase-displaying yeast strain exhibited clear cell-to-cellulose adhesion and a “tearing” cellulose degradation pattern; the adhesion ability correlated with enhanced surface area and roughness of the target cellulose fibers, resulting in higher hydrolysis efficiency. The engineered yeast directly produced ethanol from rice straw despite a more than 40% decrease in the required enzyme dosage for high-density fermentation. Thus, improved cell-to-cellulose interactions provided a novel strategy for increasing cellulose hydrolysis, suggesting a mechanism for promoting the feasibility of cellulosic biofuel production.
The effect of temperature on the coupled slow and fast dynamics of an electrochemical oscillator
Authors: Zülke Alana A. , Varela Hamilton
Published: April 2016

The coupling among disparate time-scales is ubiquitous in many chemical and biological systems. We have recently investigated the effect of fast and, long-term, slow dynamics in surface processes underlying some electrocatalytic reactions. Herein we report on the effect of temperature on the coupled slow and fast dynamics of a model system, namely the electro-oxidation of formic acid on platinum studied at five temperatures between 5 and 45 °C. The main result was a turning point found at 25 °C, which clearly defines two regions for the temperature dependency on the overall kinetics. In addition, the long-term evolution allowed us to compare reaction steps related to fast and slow evolutions. Results were discussed in terms of the key role ofPtOspecies, which chemically couple slow and fast dynamics. In summary we were able to: (a) identify the competition between two reaction steps as responsible for the occurrence of two temperature domains; (b) compare the relative activation energies of these two steps; and (c) suggest the role of a given reaction step on the period-increasing set of reactions involved in the oscillatory dynamics. The introduced methodology could be applied to other systems to uncover the temperature dependence of complex chemical networks.
Abnormal Population Responses in the Somatosensory Cortex of Alzheimer’s Disease Model Mice
Authors: Maatuf Yossi , Stern Edward A. , Slovin Hamutal
Published: April 2016

Alzheimer’s disease (AD) is the most common form of dementia. One of the neuropathological hallmarks of AD is the accumulation of amyloid-β plaques. Overexpression of human amyloid precursor protein in transgenic mice induces hippocampal and neocortical amyloid-β accumulation and plaque deposition that increases with age. The impact of these effects on neuronal population responses and network activity in sensory cortex is not well understood. We used Voltage Sensitive Dye Imaging, to investigate at high spatial and temporal resolution, the sensory evoked population responses in the barrel cortex of aged transgenic (Tg) mice and of age-matched non-transgenic littermate controls (Ctrl) mice. We found that a whisker deflection evoked abnormal sensory responses in the barrel cortex of Tg mice. The response amplitude and the spatial spread of the cortical responses were significantly larger in Tg than in Ctrl mice. At the network level, spontaneous activity was less synchronized over cortical space than in Ctrl mice, however synchronization during evoked responses induced by whisker deflection did not differ between the two groups. Thus, the presence of elevated Aβ and plaques may alter population responses and disrupts neural synchronization in large-scale networks, leading to abnormalities in sensory processing.
Nanoparticle Self-Assembled Grain Like Curcumin Conjugated ZnO: Curcumin Conjugation Enhances Removal of Perylene, Fluoranthene and Chrysene by ZnO
Authors: Moussawi Rasha N. , Patra Digambara
Published: April 2016

Curcumin conjugated ZnO, referred as Zn(cur)O, nanostructures have been successfully synthesized, these sub-micro grain-like structures are actually self-assemblies of individual needle-shaped nanoparticles. The nanostructures as synthesized possess the wurtzite hexagonal crystal structure of ZnO and exhibit very good crystalline quality. FT-Raman and TGA analysis establish that Zn(cur)O is different from curcumin anchored ZnO (ZnO@cur), which is prepared by physically adsorbing curcumin on ZnO surfaces. Chemically Zn(cur)O is more stable than ZnO@cur. Diffuse reflectance spectroscopy indicates Zn(cur)O have more impurities compared to ZnO@cur. The solid-state photoluminescence of Zn(cur)O has been investigated, which demonstrates that increase of curcumin concentration in Zn(cur)O suppresses visible emission of ZnO prepared through the same method, this implies filling ZnO defects by curcumin. However, at excitation wavelength 425 nm the emission is dominated by fluorescence from curcumin. The study reveals that Zn(cur)O can remove to a far extent high concentrations of perylene, fluoranthene and chrysene faster than ZnO. The removal depends on the extent of curcumin conjugation and is found to be faster for PAHs having smaller number of aromatic rings, particularly, it is exceptional for fluoranthene with 93% removal after 10 minutes in the present conditions. The high rate of removal is related to photo-degradation and a mechanism has been proposed.
Size Dependent Cellular Uptake of Rod-like Bionanoparticles with Different Aspect Ratios
Authors: Liu Xiangxiang , Wu Fengchi , Tian Ye , Wu Man , Zhou Quan , Jiang Shidong , Niu Zhongwei
Published: April 2016

Understanding the cellular internalization mechanism of nanoparticles is essential to study their biological fate. Especially, due to the anisotropic properties, rod-like nanoparticles have attracted growing interest for the enhanced internalization efficiency with respect to spherical nanoparticles. Here, to elucidate the effect of aspect ratio of rod-like nanoparticles on cellular uptake, tobacco mosaic virus (TMV), a typical rod-like bionanoparticle, is developed as a model. Nanorods with different aspect ratios can be obtained by ultrasound treatment and sucrose density gradient centrifugation. By incubating with epithelial and endothelial cells, we found that the rod-like bionanoparticles with various aspect ratios had different internalization pathways in different cell lines: microtubules transport in HeLa and clathrin-mediated uptake in HUVEC for TMV4 and TMV8; caveolae-mediated pathway and microtubules transport in HeLa and HUVEC for TMV17. Differently from most nanoparticles, for all the three TMV nano-rods with different aspect ratios, macropinocytosis takes no effect on the internalization in both cell types. This work provides a fundamental understanding of the influence of aspect ratio on cellular uptake decoupled from charge and material composition.
Uncovering disease mechanisms through network biology in the era of Next Generation Sequencing
Authors: Piñero Janet , Berenstein Ariel , Gonzalez-Perez Abel , Chernomoretz Ariel , Furlong Laura I.
Published: April 2016

Characterizing the behavior of disease genes in the context of biological networks has the potential to shed light on disease mechanisms, and to reveal both new candidate disease genes and therapeutic targets. Previous studies addressing the network properties of disease genes have produced contradictory results. Here we have explored the causes of these discrepancies and assessed the relationship between the network roles of disease genes and their tolerance to deleterious germline variants in human populations leveraging on: the abundance of interactome resources, a comprehensive catalog of disease genes and exome variation data. We found that the most salient network features of disease genes are driven by cancer genes and that genes related to different types of diseases play network roles whose centrality is inversely correlated to their tolerance to likely deleterious germline mutations. This proved to be a multiscale signature, including global, mesoscopic and local network centrality features. Cancer driver genes, the most sensitive to deleterious variants, occupy the most central positions, followed by dominant disease genes and then by recessive disease genes, which are tolerant to variants and isolated within their network modules.
Cerebral Spinal Fluid levels of Cytokines are elevated in Patients with Metachromatic Leukodystrophy
Authors: Thibert Kathryn A. , Raymond Gerald V. , Tolar Jakub , Miller Weston P. , Orchard Paul J. , Lund Troy C.
Published: April 2016

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulfatase A causing an accumulation of cerebroside sulfate, a lipid normally abundant in myelin. Sulfatide accumulation is associated with progressive demyelination and a clinical presentation in severe disease forms that is dominated by motor manifestations. Cerebral inflammation may contribute to the pathophysiology of MLD. To date, cytokine levels in the cerebral spinal fluid of MLD patients have not previously been reported. The objective of this study was to evaluate the concentration of inflammatory cytokines in the CSF of patients with MLD and to compare these levels to unaffected controls. Of 22 cytokines evaluated, we documented significant elevations of MCP-1, IL-1Ra, IL-8, MIP-1b and VEGF in the MLD patients compared to unaffected controls. The elevated cytokines identified in this study may play a significant role in the pathophysiology of MLD. Better understanding of the inflammatory and neurodegenerative process of MLD may lead to improved targeted therapies.