bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging the antimicrobial mechanism(s) of cathelicidin-2
Authors: Schneider Viktoria A. F. , Coorens Maarten , Ordonez Soledad R. , Tjeerdsma-van Bokhoven Johanna L. M. , Posthuma George , van Dijk Albert , Haagsman Henk P. , Veldhuizen Edwin J. A. 
Published: September 2016

AbstractHost defence peptides (HDPs) have the potential to become alternatives to conventional antibiotics in human and veterinary medicine. The HDP chicken cathelicidin-2 (CATH-2) has immunomodulatory and direct killing activities at micromolar concentrations. In this study the mechanism of action of CATH-2 against Escherichia coli (E. coli) was investigated in great detail using a unique combination of imaging and biophysical techniques. Live-imaging with confocal fluorescence microscopy demonstrated that FITC-labelled CATH-2 mainly localized at the membrane of E. coli. Upon binding, the bacterial membrane was readily permeabilized as was shown by propidium iodide influx into the cell. Concentration- and time-dependent effects of the peptide on E. coli cells were examined by transmission electron microscopy (TEM). CATH-2 treatment was found to induce dose-dependent morphological changes in E. coli. At sub-minimal inhibitory concentrations (sub-MIC), intracellular granulation, enhanced vesicle release and wrinkled membranes were observed, while membrane breakage and cell lysis occurred at MIC values. These effects were visible within 1–5 minute of peptide exposure. Immuno-gold TEM showed CATH-2 binding to bacterial membranes. At sub-MIC values the peptide rapidly localized intracellularly without visible membrane permeabilization. It is concluded that CATH-2 has detrimental effects on E. coli at concentrations that do not immediately kill the bacteria.
TRPM4-mediated control of FcεRI-evoked Ca2+ elevation comprises enhanced plasmalemmal trafficking of TRPM4 channels in connective tissue type mast cells
Authors: Rixecker Torben , Mathar Ilka , Medert Rebekka , Mannebach Stefanie , Pfeifer Alexander , Lipp Peter , Tsvilovskyy Volodymyr , Freichel Marc 
Published: September 2016

AbstractTRPM4 proteins form Ca2+-activated non selective cation (CAN) channels that affect transmembrane Ca2+-influx by determining the membrane potential. Tight control of the intracellular Ca2+ concentration is essential for mast cell responses. In this study, we analyzed the expression of TRPM4 in peritoneal mast cells (PCMC) as a model for connective tissue type mast cells with respect to FcεRI-evoked calcium changes and the subcellular localization of fluorescently labeled TRPM4 using two viral transduction systems before and following antigen stimulation. Our results show that TRPM4 is expressed in PCMCs, is an essential constituent of the endogenous CAN channels in PCMCs and regulates antigen-evoked increases in intracellular calcium that are significantly enhanced in TRPM4-deficient PCMCs. Compared to PCMCs analyzed before antigen stimulation, the cells depict a substantially increased localization of TRPM4 proteins towards the plasma membrane after FcεRI stimulation. Thus, TRPM4 functions as a limiting factor for antigen evoked calcium rise in connective tissue type mast cells and concurrent translocation of TRPM4 into the plasma membrane is part of this mechanism.
Multipolar, time-dynamical model for the loss compensation and lasing of a spherical plasmonic nanoparticle spaser immersed in an active gain medium
Authors: Veltri Alessandro , Chipouline Arkadi , Aradian Ashod 
Published: September 2016

AbstractThe plasmonic response of a metal nanoparticle in the presence of surrounding gain elements is studied, using a space and time-dependent model, which integrates a quantum formalism to describe the gain and a classical treatment for the metal. Our model fully takes into account the influence of the system geometry (nanosphere) and offers for the first time, the possibility to describe the temporal evolution of the fields and the coupling among the multipolar modes of the particle. We calculate the lasing threshold value for all multipoles of the spaser, and demonstrate that the dipolar one is lowest. The onset of the lasing instability, in the linear regime, is then studied both with and without external field forcing. We also study the behaviour of the system below the lasing threshold, with the external field, demonstrating the existence of an amplification regime where the nanoparticle’s plasmon is strongly enhanced as the threshold is approached. Finally, a qualitative discussion is provided on later, non-linear stages of the dynamics and the approach to the steady-state of the spaser; in particular, it is shown that, for the considered geometry, the spasing is necessarily multi-modal and multipolar modes are always activated.
Attention induced neural response trade-off in retinotopic cortex under load
Authors: Torralbo Ana , Kelley Todd A. , Rees Geraint , Lavie Nilli 
Published: September 2016

AbstractThe effects of perceptual load on visual cortex response to distractors are well established and various phenomena of ‘inattentional blindness’ associated with elimination of visual cortex response to unattended distractors, have been documented in tasks of high load. Here we tested an account for these effects in terms of a load-induced trade-off between target and distractor processing in retinotopic visual cortex. Participants were scanned using fMRI while performing a visual-search task and ignoring distractor checkerboards in the periphery. Retinotopic responses to target and distractors were assessed as a function of search load (comparing search set-sizes two, three and five). We found that increased load not only increased activity in frontoparietal network, but also had opposite effects on retinotopic responses to target and distractors. Target-related signals in areas V2–V3 linearly increased, while distractor response linearly decreased, with increased load. Critically, the slopes were equivalent for both load functions, thus demonstrating resource trade-off. Load effects were also found in displays with the same item number in the distractor hemisphere across different set sizes, thus ruling out local intrahemispheric interactions as the cause. Our findings provide new evidence for load theory proposals of attention resource sharing between target and distractor leading to inattentional blindness.
An integrative study identifies KCNC2 as a novel predisposing factor for childhood obesity and the risk of diabetes in the Korean population
Authors: Hwang Joo-Yeon , Lee Hyo Jung , Go Min Jin , Jang Han Byul , Park Sang Ick , Kim Bong-Jo , Lee Hye-Ja 
Published: September 2016

AbstractObesity is a major risk factor for type 2 diabetes. To unravel the genetic determinants of obesity-associated diabetes, we performed a genome-wide study using the 1,000 Genomes-based imputation in a Korean childhood cohort (KoCAS-1, n = 484) and carried out de novo replication in an independent population (KoCAS-2, n = 1,548). A novel variant (rs10879834) with multiple diverse associations for obesity-related traits was also found to be replicated in an adult cohort (KARE, n = 8,842). Functional annotations using integrative epigenetic analyses identified biological significance and regulatory effects with an inverse methylation-expression correlation (cg27154343 in the 5′-UTR of the KCNC2 gene), tissue-specific enhancer mark (H3K4me1), and pathway enrichment (insulin signaling). Further functional studies in cellular and mouse models demonstrated that KCNC2 is associated with anti-obesogenic effects in the regulation of obesity-induced insulin resistance. KCNC2 shRNA transfection induced endoplasmic reticulum (ER) stress and hepatic gluconeogenesis. Overproduction of KCNC2 decreased ER stress, and treatment with metformin enhanced KCNC2 expression. Taken together, these data suggest that reduction of KCNC2 is associated with modified hepatic gluconeogenesis and increased ER stress on obesity-mediated diabetic risk. An integrative multi-omics analysis might reveal new functional and clinical implications related to the control of energy and metabolic homeostasis in humans.
Doped Graphene for DNA Analysis: the Electrochemical Signal is Strongly Influenced by the Kind of Dopant and the Nucleobase Structure
Authors: Tian Huidi , Wang Lu , Sofer Zdenek , Pumera Martin , Bonanni Alessandra 
Published: September 2016

AbstractDoping graphene with heteroatoms can alter the electronic and electrochemical properties of the starting material. Contrasting properties should be expected when the doping is carried out with electron donating species (n-type dopants) or with electron withdrawing species (p-type dopants). This in turn can have a profound influence on the electroanalytical performance of the doped material being used for the detection of specific probes. Here we investigate the electrochemical oxidation of DNA bases adenine, guanine, thymine and cytosine on two heteroatom-doped graphene platforms namely boron-doped graphene (p-type dopant) and nitrogen-doped graphene (n-type dopant). We found that overall, boron–doped graphene provided the best response in terms of electrochemical signal sensitivity for all bases. This is due to the electron deficiency of boron-doped graphene, which can promote the oxidation of DNA bases, as opposed to nitrogen-doped graphene which possesses an excess of electrons. Moreover, also the structure of the nucleobase was found to have significant influence on the obtained signal. Our study may open new frontiers in the electrochemical detection of DNA bases which is the first step for label-free DNA analysis.
Gene deleted live attenuated Leishmania vaccine candidates against visceral leishmaniasis elicit pro-inflammatory cytokines response in human PBMCs
Authors: Avishek Kumar , Kaushal Himanshu , Gannavaram Sreenivas , Dey Ranadhir , Selvapandiyan Angamuthu , Ramesh V. , Negi Narender Singh , Dubey Uma S. , Nakhasi Hira L. , Salotra Poonam 
Published: September 2016

AbstractCurrently no effective vaccine is available for human visceral leishmaniasis(VL) caused by Leishmania donovani. Previously, we showed that centrin1 and p27gene deleted live attenuated Leishmania parasites (LdCen1−/− and Ldp27−/−) are safe, immunogenic and protective in animal models. Here, to assess the correlates of protection, we evaluated immune responses induced by LdCen1−/− and Ldp27−/− in human blood samples obtained from healthy, healed VL (HVL), post kala-azar dermal leishmaniasis(PKDL) and VL subjects. Both parasites infected human macrophages, as effectively as the wild type parasites. Further, LdCen1−/− and Ldp27−/− strongly stimulated production of pro-inflammatory cytokines including, IL-12, IFN-γ, TNF-α, IL-2, IL-6 and IL-17 in the PBMCs obtained from individuals with a prior exposure to Leishmania (HVL and PKDL). There was no significant stimulation of anti-inflammatory cytokines (IL-4 and IL-10). Induction of Th1 biased immune responses was supported by a remarkable increase in IFN-γ secreting CD4+ and CD8+ T cells and IL-17 secreting CD4+ cells in PBMCs from HVL cases with no increase in IL-10 secreting T cells. Hence, LdCen1−/− and Ldp27−/− are promising as live vaccine candidates against VL since they elicit strong protective immune response in human PBMCs from HVL, similar to the wild type parasite infection, mimicking a naturally acquired protection following cure.
The enhanced atorvastatin hepatotoxicity in diabetic rats was partly attributed to the upregulated hepatic Cyp3a and SLCO1B1
Authors: Shu Nan , Hu Mengyue , Ling Zhaoli , Liu Peihua , Wang Fan , Xu Ping , Zhong Zeyu , Sun Binbin , Zhang Mian , Li Feng , Xie Qiushi , Liu Xiaodong , Liu Li 
Published: September 2016

AbstractLiver injury is a common adverse effect of atorvastatin. This study aimed to investigate atorvastatin-induced hepatotoxicity in diabetic rats induced by high-fat diet combined with streptozotocin. The results showed that 40 mg/kg atorvastatin was lethal to diabetic rats, whose mean survival time was 6.2 days. Severe liver injury also occurred in diabetic rats treated with 10 mg/kg and 20 mg/kg atorvastatin. The in vitro results indicated that atorvastatin cytotoxicity in hepatocytes of diabetic rats was more severe than normal and high-fat diet feeding rats. Expressions and activities of hepatic Cyp3a and SLCO1B1 were increased in diabetic rats, which were highly correlated with hepatotoxicity. Antioxidants (glutathione and N-Acetylcysteine), Cyp3a inhibitor ketoconazole and SLCO1B1 inhibitor gemfibrozil suppressed cytotoxicity and ROS formation in primary hepatocytes of diabetic rats. In HepG2 cells, up-regulations of CYP3A4 and SLCO1B1 potentiated hepatotoxicity and ROS generation, whereas knockdowns of CYP3A4 and SLCO1B1 as well as CYP3A4/SLCO1B1 inhibitions showed the opposite effects. Phenobarbital pretreatment was used to induce hepatic Cyp3a and SLCO1B1 in rats. Phenobarbital aggravated atorvastatin-induced hepatotoxicity, while decreased plasma exposure of atorvastatin. All these findings demonstrated that the upregulations of hepatic Cyp3a and SLCO1B1 in diabetic rats potentiated atorvastatin-induced hepatotoxicity via increasing ROS formation.
Allergy-specific Phenome-Wide Association Study for Immunogenes in Turkish Children
Authors: Karaca Sefayet , Civelek Ersoy , Karaca Mehmet , Sahiner Umit M. , Ozgul Riza K. , Kocabas Can N. , Polimanti Renato , Sekerel Bülent E. 
Published: September 2016

AbstractTo dissect the role of immunogenetics in allergy and asthma, we performed a phenome-wide association study in 974 Turkish children selected from a cross-sectional study conducted using ISAAC (International Study of Asthma and Allergies in Children) Phase II tools. We investigated 9 loci involved in different immune functions (ADAM33, ADRB2, CD14, IL13, IL4, IL4R, MS4A2, SERPINE1, and TNF) with respect to 116 traits assessed through blood tests, hypertonic saline challenge tests, questionnaires, and skin prick tests. Multiple associations were observed for ADAM33: rs2280090 was associated with reduced MEF240% (i.e., the ratio of Mean Expiratory Flow after 240s of hypertonic saline inhalation with respect to the age- and ancestry-matched reference value) and with an increased risk of allergic bronchitis (p = 1.77*10−4 and p = 7.94*10−4, respectively); rs3918396 was associated with wheezing and eczema comorbidity (p = 3.41*10−4). IL4 rs2243250 was associated with increased FEV240 (Forced Expiratory Flow Volume after 240s of hypertonic saline inhalation; p = 4.81*10−4) and CD14 rs2569190 was associated with asthma diagnosis (p = 1.36*10−3). ADAM33 and IL4 appeared to play a role in the processes linked to allergic airway inflammation and lung function. Due to its association with wheezing and eczema comorbidity, ADAM33 may also be involved in the atopic march.
Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization
Authors: Smith Caren E. , Coltell Oscar , Sorlí Jose V. , Estruch Ramón , Martínez-González Miguel Ángel , Salas-Salvadó Jordi , Fitó Montserrat , Arós Fernando , Dashti Hassan S. , Lai Chao Q. , Miró Leticia , Serra-Majem Lluís , Gómez-Gracia Enrique , Fiol Miquel , Ros Emilio , Aslibekyan Stella , Hidalgo Bertha , Neuhouser Marian L. , Di Chongzhi , Tucker Katherine L. , Arnett Donna K. , Ordovás José M. , Corella Dolores 
Published: September 2016

AbstractControversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n ≤ 20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations. Moreover, we analyzed longitudinal associations with milk, CVD and mortality in PREDIMED), a randomized Mediterranean diet (MedDiet) intervention trial (n = 7185). The MCM6-rs3754686/MCM6-rs309180 (as proxy), LP-allele (T) was strongly associated with higher milk intake, but inconsistently associated with glucose and lipids, and not associated with CVD or total mortality in the whole population. Heterogeneity analyses suggested some sex-specific associations. The T-allele was associated with higher CVD and mortality risk in women but not in men (P-sex interaction:0.005 and 0.032, respectively), mainly in the MedDiet group. However, milk intake was not associated with CVD biomarkers, CVD or mortality either generally or in sub-groups. Although MCM6-rs3754686 is a good milk intake proxy in these populations, attributing its associations with CVD and mortality in Mediterranean women to milk is unwarranted, as other factors limiting the assumption of causality in Mendelian randomization may exist.
Topological phase transition and quantum spin Hall edge states of antimony few layers
Authors: Kim Sung Hwan , Jin Kyung-Hwan , Park Joonbum , Kim Jun Sung , Jhi Seung-Hoon , Yeom Han Woong 
Published: September 2016

AbstractWhile two-dimensional (2D) topological insulators (TI’s) initiated the field of topological materials, only very few materials were discovered to date and the direct access to their quantum spin Hall edge states has been challenging due to material issues. Here, we introduce a new 2D TI material, Sb few layer films. Electronic structures of ultrathin Sb islands grown on Bi2Te2Se are investigated by scanning tunneling microscopy. The maps of local density of states clearly identify robust edge electronic states over the thickness of three bilayers in clear contrast to thinner islands. This indicates that topological edge states emerge through a 2D topological phase transition predicted between three and four bilayer films in recent theory. The non-trivial phase transition and edge states are confirmed for epitaxial films by extensive density-functional-theory calculations. This work provides an important material platform to exploit microscopic aspects of the quantum spin Hall phase and its quantum phase transition.
Synthesis and mechanisms of action of novel harmine derivatives as potential antitumor agents
Authors: Zhang Xiao-Fei , Sun Rong-qin , Jia Yi-fan , Chen Qing , Tu Rong-Fu , Li Ke-ke , Zhang Xiao-Dong , Du Run-Lei , Cao Ri-hui 
Published: September 2016

AbstractA series of novel harmine derivatives bearing a benzylindine substituent in position-1 of β-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated β-carboline derivatives 3a–g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment.
Residue Geometry Networks: A Rigidity-Based Approach to the Amino Acid Network and Evolutionary Rate Analysis
Authors: Fokas Alexander S. , Cole Daniel J. , Ahnert Sebastian E. , Chin Alex W. 
Published: September 2016

AbstractAmino acid networks (AANs) abstract the protein structure by recording the amino acid contacts and can provide insight into protein function. Herein, we describe a novel AAN construction technique that employs the rigidity analysis tool, FIRST, to build the AAN, which we refer to as the residue geometry network (RGN). We show that this new construction can be combined with network theory methods to include the effects of allowed conformal motions and local chemical environments. Importantly, this is done without costly molecular dynamics simulations required by other AAN-related methods, which allows us to analyse large proteins and/or data sets. We have calculated the centrality of the residues belonging to 795 proteins. The results display a strong, negative correlation between residue centrality and the evolutionary rate. Furthermore, among residues with high closeness, those with low degree were particularly strongly conserved. Random walk simulations using the RGN were also successful in identifying allosteric residues in proteins involved in GPCR signalling. The dynamic function of these residues largely remain hidden in the traditional distance-cutoff construction technique. Despite being constructed from only the crystal structure, the results in this paper suggests that the RGN can identify residues that fulfil a dynamical function.
Ultra-strong and damage tolerant metallic bulk materials: A lesson from nanostructured pearlitic steel wires
Authors: Hohenwarter A. , Völker B. , Kapp M. W. , Li Y. , Goto S. , Raabe D. , Pippan R. 
Published: September 2016

AbstractStructural materials used for safety critical applications require high strength and simultaneously high resistance against crack growth, referred to as damage tolerance. However, the two properties typically exclude each other and research efforts towards ever stronger materials are hampered by drastic loss of fracture resistance. Therefore, future development of novel ultra-strong bulk materials requires a fundamental understanding of the toughness determining mechanisms. As model material we use today’s strongest metallic bulk material, namely, a nanostructured pearlitic steel wire, and measured the fracture toughness on micron-sized specimens in different crack growth directions and found an unexpected strong anisotropy in the fracture resistance. Along the wire axis the material reveals ultra-high strength combined with so far unprecedented damage tolerance. We attribute this excellent property combination to the anisotropy in the fracture toughness inducing a high propensity for micro-crack formation parallel to the wire axis. This effect causes a local crack tip stress relaxation and enables the high fracture toughness without being detrimental to the material’s strength.