bluuebunny/crossref_metadata_2025 huggingface dataset:
C. elegans maximum velocity correlates with healthspan and is maintained in worms with an insulin receptor mutation
Authors: Hahm Jeong-Hoon , Kim Sunhee , DiLoreto Race , Shi Cheng , Lee Seung-Jae V. , Murphy Coleen T. , Nam Hong Gil
Published: November 2015

Ageing is marked by physical decline. Caenorhabditis elegans is a valuable model for identifying genetic regulatory mechanisms of ageing and longevity. Here we report a simple method to assess C. elegans’ maximum physical ability based on the worms’ maximum movement velocity. We show maximum velocity declines with age, correlates well with longevity, accurately reports movement ability and, if measured in mid-adulthood, is predictive of maximal lifespan. Contrary to recent findings, we observe that maximum velocity of worm with mutations in daf-2(e1370) insulin/IGF-1 signalling scales with lifespan. Because of increased odorant receptor expression, daf-2(e1370) mutants prefer food over exploration, causing previous on-food motility assays to underestimate movement ability and, thus, worm health. Finally, a disease-burden analysis of published data reveals that the daf-2(e1370) mutation improves quality of life, and therefore combines lifespan extension with various signs of an increased healthspan.
Soil mulching significantly enhances yields and water and nitrogen use efficiencies of maize and wheat: a meta-analysis
Authors: Qin Wei , Hu Chunsheng , Oenema Oene
Published: November 2015

Global crop yields are limited by water and nutrient availability. Soil mulching (with plastic or straw) reduces evaporation, modifies soil temperature and thereby affects crop yields. Reported effects of mulching are sometimes contradictory, likely due to differences in climatic conditions, soil characteristics, crop species and also water and nitrogen (N) input levels. Here we report on a meta-analysis of the effects of mulching on wheat and maize, using 1310 yield observations from 74 studies conducted in 19 countries. Our results indicate that mulching significantly increased yields, WUE (yield per unit water) and NUE (yield per unit N) by up to 60%, compared with no-mulching. Effects were larger for maize than wheat and larger for plastic mulching than straw mulching. Interestingly, plastic mulching performed better at relatively low temperature while straw mulching showed the opposite trend. Effects of mulching also tended to decrease with increasing water input. Mulching effects were not related to soil organic matter content. In conclusion, soil mulching can significantly increase maize and wheat yields, WUE and NUE and thereby may contribute to closing the yield gap between attainable and actual yields, especially in dryland and low nutrient input agriculture. The management of soil mulching requires site-specific knowledge.
Nanoliposomal Nitroglycerin Exerts Potent Anti-Inflammatory Effects
Authors: Ardekani Soroush , Scott Harry A. , Gupta Sharad , Eum Shane , Yang Xiao , Brunelle Alexander R. , Wilson Sean M. , Mohideen Umar , Ghosh Kaustabh
Published: November 2015

Nitroglycerin (NTG) markedly enhances nitric oxide (NO) bioavailability. However, its ability to mimic the anti-inflammatory properties of NO remains unknown. Here, we examined whether NTG can suppress endothelial cell (EC) activation during inflammation and developed NTG nanoformulation to simultaneously amplify its anti-inflammatory effects and ameliorate adverse effects associated with high-dose NTG administration. Our findings reveal that NTG significantly inhibits human U937 cell adhesion to NO-deficient human microvascular ECs in vitro through an increase in endothelial NO and decrease in endothelial ICAM-1 clustering, as determined by NO analyzer, microfluorimetry and immunofluorescence staining. Nanoliposomal NTG (NTG-NL) was formulated by encapsulating NTG within unilamellar lipid vesicles (DPhPC, POPC, Cholesterol, DHPE-Texas Red at molar ratio of 6:2:2:0.2) that were ~155 nm in diameter and readily uptaken by ECs, as determined by dynamic light scattering and quantitative fluorescence microscopy, respectively. More importantly, NTG-NL produced a 70-fold increase in NTG therapeutic efficacy when compared with free NTG while preventing excessive mitochondrial superoxide production associated with high NTG doses. Thus, these findings, which are the first to reveal the superior therapeutic effects of an NTG nanoformulation, provide the rationale for their detailed investigation for potentially superior vascular normalization therapies.
Stiffness Enhancement in Nacre-Inspired Nanocomposites due to Nanoconfinement
Authors: Shao Chen , Keten Sinan
Published: November 2015

Layered assemblies of polymers and graphene derivatives employ nacre’s tested strategy of intercalating soft organic layers with hard crystalline domains. These layered systems commonly display elastic properties that exceed simple mixture rule predictions, but the molecular origins of this phenomenon are not well understood. Here we address this issue by quantifying the elastic behavior of nanoconfined polymer layers on a model layered graphene-polymer nanocomposite. Using a novel, validated coarse-grained molecular dynamics simulation approach, here we clearly show that the elastic properties of layered nanocomposites cannot be described by volume fraction considerations alone and depend strongly on both interfacial energy and nanostructure. We quantify the relative importance of polymer nanoconfinement and interfacial energy on polymer structure and elasticity and illustrate the validity of our model for two polymers with different intrinsic elastic properties. Our theoretical model culminates in phase diagrams that accurately predict the elastic response of nacre-inspired nanocomposites by accounting for all material design parameters. Our findings provide widely applicable prescriptive guidelines for utilizing nanoconfinement to improve the mechanical properties of layer-by-layer nanocomposites. Our findings also serve to explain why the elastic properties of organic layers in nacre exhibit multifold differences from the native and extracted states.
Highly Stretchable Electrodes on Wrinkled Polydimethylsiloxane Substrates
Authors: Tang Jun , Guo Hao , Zhao Miaomiao , Yang Jiangtao , Tsoukalas Dimitris , Zhang Binzhen , Liu Jun , Xue Chenyang , Zhang Wendong
Published: November 2015

This paper demonstrates a fabrication technology of Ag wrinkled electrodes with application in highly stretchable wireless sensors. Ag wrinkled thin films that were formed by vacuum deposition on top of pre-strained and relaxed polydimethylsiloxane (PDMS) substrates which have been treated using an O2 plasma and a surface chemical functionalization process can reach a strain limit up to 200%, while surface adhesion area can reach 95%. The electrical characteristics of components such as resistors, inductors and capacitors made from such Ag conductors have remained stable under stretching exhibiting low temperature and humidity coefficients. This technology was then demonstrated for wireless wearable electronics using compatible processing with established micro/nano fabrication technology.
Giant optical enhancement of strain gradient in ferroelectric BiFeO3 thin films and its physical origin
Authors: Li Yuelin , Adamo Carolina , Chen Pice , Evans Paul G. , Nakhmanson Serge M. , Parker William , Rowland Clare E. , Schaller Richard D. , Schlom Darrell G. , Walko Donald A. , Wen Haidan , Zhang Qingteng
Published: November 2015

Through mapping of the spatiotemporal strain profile in ferroelectric BiFeO3 epitaxial thin films, we report an optically initiated dynamic enhancement of the strain gradient of 105–106 m−1 that lasts up to a few ns depending on the film thickness. Correlating with transient optical absorption measurements, the enhancement of the strain gradient is attributed to a piezoelectric effect driven by a transient screening field mediated by excitons. These findings not only demonstrate a new possible way of controlling the flexoelectric effect, but also reveal the important role of exciton dynamics in photostriction and photovoltaic effects in ferroelectrics.
Direct Depth- and Lateral- Imaging of Nanoscale Magnets Generated by Ion Impact
Authors: Röder Falk , Hlawacek Gregor , Wintz Sebastian , Hübner René , Bischoff Lothar , Lichte Hannes , Potzger Kay , Lindner Jürgen , Fassbender Jürgen , Bali Rantej
Published: November 2015

Nanomagnets form the building blocks for a variety of spin-transport, spin-wave and data storage devices. In this work we generated nanoscale magnets by exploiting the phenomenon of disorder-induced ferromagnetism; disorder was induced locally on a chemically ordered, initially non-ferromagnetic, Fe60Al40precursor film using "Equation missing" nm diameter beam of Ne+ions at 25 keV energy. The beam of energetic ions randomized the atomic arrangement locally, leading to the formation of ferromagnetism in the ion-affected regime. The interaction of a penetrating ion with host atoms is known to be spatially inhomogeneous, raising questions on the magnetic homogeneity of nanostructures caused by ion-induced collision cascades. Direct holographic observations of the flux-lines emergent from the disorder-induced magnetic nanostructures were made in order to measure the depth- and lateral- magnetization variation at ferromagnetic/non-ferromagnetic interfaces. Our results suggest that high-resolution nanomagnets of practically any desired 2-dimensional geometry can be directly written onto selected alloy thin films using a nano-focussed ion-beam stylus, thus enabling the rapid prototyping and testing of novel magnetization configurations for their magneto-coupling and spin-wave properties.
Efficient long-term survival of cell grafts after myocardial infarction with thick viable cardiac tissue entirely from pluripotent stem cells
Authors: Matsuo Takehiko , Masumoto Hidetoshi , Tajima Shuhei , Ikuno Takeshi , Katayama Shiori , Minakata Kenji , Ikeda Tadashi , Yamamizu Kohei , Tabata Yasuhiko , Sakata Ryuzo , Yamashita Jun K.
Published: November 2015

Poor engraftment of cells after transplantation to the heart is a common and unresolved problem in the cardiac cell therapies. We previously generated cardiovascular cell sheets entirely from pluripotent stem cells with cardiomyocytes, endothelial cells and vascular mural cells. Though sheet transplantation showed a better engraftment and improved cardiac function after myocardial infarction, stacking limitation (up to 3 sheets) by hypoxia hampered larger structure formation and long-term survival of the grafts. Here we report an efficient method to overcome the stacking limitation. Insertion of gelatin hydrogel microspheres (GHMs) between each cardiovascular cell sheet broke the viable limitation via appropriate spacing and fluid impregnation with GHMs. Fifteen sheets with GHMs (15-GHM construct; >1 mm thickness) were stacked within several hours and viable after 1 week in vitro. Transplantation of 5-GHM constructs (≈2 × 106 of total cells) to a rat myocardial infarction model showed rapid and sustained functional improvements. The grafts were efficiently engrafted as multiple layered cardiovascular cells accompanied by functional capillary networks. Large engrafted cardiac tissues (0.8 mm thickness with 40 cell layers) successfully survived 3 months after TX. We developed an efficient method to generate thicker viable tissue structures and achieve long-term survival of the cell graft to the heart.
Dexmedetomidine Inhibits TLR4/NF-κB Activation and Reduces Acute Kidney Injury after Orthotopic Autologous Liver Transplantation in Rats
Authors: Yao Hui , Chi Xinjin , Jin Yi , Wang Yiheng , Huang Pinjie , Wu Shan , Xia Zhengyuan , Cai Jun
Published: November 2015

Patients who undergo orthotopic liver transplantation often sustain acute kidney injury(AKI). The toll-like receptor 4(TLR4)/Nuclear factor-кB(NF-кB) pathway plays a role in AKI. Dexmedetomidine(Dex) has been shown to attenuate AKI. The current study aimed to determine whether liver transplantation-induced AKI is associated with inflammatory response and to assess the effects of dexmedetomidine pretreatment on kidneys in rats following orthotopic autologous liver transplantation(OALT). Seventy-seven adult male rats were randomized into 11 groups. Kidney tissue histopathology and levels of blood urea nitrogen(BUN) and serum creatinine(SCr) were evaluated. Levels of TLR4, NF-κB, tumor necrosis factor-α and interleukin-1β levels were measured in kidney tissues. OALT resulted in significant kidney functional impairment and tissue injury. Pre-treatment with dexmedetomidine decreased BUN and SCr levels and reduced kidney pathological injury, TLR4 expression, translocation of NF-κB and cytokine production. The effects of dexmedetomidine were reversed by pre-treatment with atipamezole and BRL44408, but not ARC239. These results were confirmed by using α2A-adrenergic receptor siRNA which reversed the protective effect of dexmedetomidine on attenuating NRK-52E cells injury induced by hypoxia reoxygenation. In conclusion, Dexmedetomidine-pretreatment attenuates OALT-induced AKI in rats which may be contributable to its inhibition of TLR4/MyD88/NF-κB pathway activation. The renoprotective effects are related to α2A-adrenergic receptor subtypes.
Repetitive transcranial magnetic stimulation induces long-lasting changes in protein expression and histone acetylation
Authors: Etiévant Adeline , Manta Stella , Latapy Camille , Magno Luiz Alexandre V. , Fecteau Shirley , Beaulieu Jean-Martin
Published: November 2015

The use of non-invasive brain stimulation like repetitive transcranial magnetic stimulation (rTMS) is an increasingly popular set of methods with promising results for the treatment of neurological and psychiatric disorders. Despite great enthusiasm, the impact of non-invasive brain stimulation on its neuronal substrates remains largely unknown. Here we show that rTMS applied over the frontal cortex of awaken mice induces dopamine D2 receptor dependent persistent changes of CDK5 and PSD-95 protein levels specifically within the stimulated brain area. Importantly, these modifications were associated with changes of histone acetylation at the promoter of these genes and prevented by administration of the histone deacetylase inhibitor MS-275. These findings show that, like several other psychoactive treatments, repeated rTMS sessions can exert long-lasting effects on neuronal substrates. This underscores the need of understanding these effects in the development of future clinical applications as well as in the establishment of improved guidelines to use rTMS in non-medical settings.
The structural neural substrate of subjective happiness
Authors: Sato Wataru , Kochiyama Takanori , Uono Shota , Kubota Yasutaka , Sawada Reiko , Yoshimura Sayaka , Toichi Motomi
Published: November 2015

Happiness is a subjective experience that is an ultimate goal for humans. Psychological studies have shown that subjective happiness can be measured reliably and consists of emotional and cognitive components. However, the neural substrates of subjective happiness remain unclear. To investigate this issue, we used structural magnetic resonance imaging and questionnaires that assessed subjective happiness, the intensity of positive and negative emotional experiences and purpose in life. We found a positive relationship between the subjective happiness score and gray matter volume in the right precuneus. Moreover, the same region showed an association with the combined positive and negative emotional intensity and purpose in life scores. Our findings suggest that the precuneus mediates subjective happiness by integrating the emotional and cognitive components of happiness.
Osteoarthritis-like pathologic changes in the knee joint induced by environmental disruption of circadian rhythms is potentiated by a high-fat diet
Authors: Kc Ranjan , Li Xin , Forsyth Christopher B. , Voigt Robin M. , Summa Keith C. , Vitaterna Martha Hotz , Tryniszewska Beata , Keshavarzian Ali , Turek Fred W. , Meng Qing-Jun , Im Hee-Jeong
Published: November 2015

A variety of environmental factors contribute to progressive development of osteoarthritis (OA). Environmental factors that upset circadian rhythms have been linked to various diseases. Our recent work establishes chronic environmental circadian disruption - analogous to rotating shiftwork-associated disruption of circadian rhythms in humans - as a novel risk factor for the development of OA. Evidence suggests shift workers are prone to obesity and also show altered eating habits (i.e., increased preference for high-fat containing food). In the present study, we investigated the impact of chronic circadian rhythm disruption in combination with a high-fat diet (HFD) on progression of OA in a mouse model. Our study demonstrates that when mice with chronically circadian rhythms were fed a HFD, there was a significant proteoglycan (PG) loss and fibrillation in knee joint as well as increased activation of the expression of the catabolic mediators involved in cartilage homeostasis. Our results, for the first time, provide the evidence that environmental disruption of circadian rhythms plus HFD potentiate OA-like pathological changes in the mouse joints. Thus, our findings may open new perspectives on the interactions of chronic circadian rhythms disruption with diet in the development of OA and may have potential clinical implications.
Ultrathin W space layer-enabled thermal stability enhancement in a perpendicular MgO/CoFeB/W/CoFeB/MgO recording frame
Authors: Kim Jae-Hong , Lee Ja-Bin , An Gwang-Guk , Yang Seung-Mo , Chung Woo-Seong , Park Hae-Soo , Hong Jin-Pyo
Published: November 2015

Perpendicularly magnetized tunnel junctions (p-MTJs) show promise as reliable candidates for next-generation memory due to their outstanding features. However, several key challenges remain that affect CoFeB/MgO-based p-MTJ performance. One significant issue is the low thermal stability (Δ) due to the rapid perpendicular magnetic anisotropy (PMA) degradation during annealing at temperatures greater than 300 °C. Thus, the ability to provide thermally robust PMA characteristics is a key steps towards extending the use of these materials. Here, we examine the influence of a W spacer on double MgO/CoFeB/W/CoFeB/MgO frames as a generic alternative layer to ensure thermally-robust PMAs at temperatures up to 425 °C. The thickness-dependent magnetic features of the W layer were evaluated at various annealing temperatures to confirm the presence of strong ferromagnetic interlayer coupling at an optimized 0.55 nm W spacer thickness. Using this W layer we achieved a higher Δ of 78 for an approximately circular 20 nm diameter free layer device.
Shape-Dependent Skin Penetration of Silver Nanoparticles: Does It Really Matter?
Authors: Tak Yu Kyung , Pal Sukdeb , Naoghare Pravin K. , Rangasamy Sabarinathan , Song Joon Myong
Published: November 2015

Advancements in nano-structured materials have facilitated several applications of nanoparticles (NPs). Skin penetration of NPs is a crucial factor for designing suitable topical antibacterial agents with low systemic toxicity. Available reports focus on size-dependent skin penetration of NPs, mainly through follicular pathways. Herein, for the first time, we demonstrate a proof-of-concept study that entails variations in skin permeability and diffusion coefficients, penetration rates and depth-of-penetration of differently shaped silver NPs (AgNPs) via intercellular pathways using both in vitro and in vivo models. The antimicrobial activity of AgNPs is known. Different shapes of AgNPs may exhibit diverse antimicrobial activities and skin penetration capabilities depending upon their active metallic facets. Consideration of the shape dependency of AgNPs in antimicrobial formulations could help developing an ideal topical agent with the highest efficacy and low systemic toxicity.
Chelator-Free Labeling of Layered Double Hydroxide Nanoparticles for in Vivo PET Imaging
Authors: Shi Sixiang , Fliss Brianne C. , Gu Zi , Zhu Yian , Hong Hao , Valdovinos Hector F. , Hernandez Reinier , Goel Shreya , Luo Haiming , Chen Feng , Barnhart Todd E. , Nickles Robert J. , Xu Zhi Ping , Cai Weibo
Published: November 2015

Layered double hydroxide (LDH) nanomaterial has emerged as a novel delivery agent for biomedical applications due to its unique structure and properties. However, in vivo positron emission tomography (PET) imaging with LDH nanoparticles has not been achieved. The aim of this study is to explore chelator-free labeling of LDH nanoparticles with radioisotopes for in vivo PET imaging. Bivalent cation 64Cu2+ and trivalent cation 44Sc3+ were found to readily label LDH nanoparticles with excellent labeling efficiency and stability, whereas tetravalent cation 89Zr4+ could not label LDH since it does not fit into the LDH crystal structure. PET imaging shows that prominent tumor uptake was achieved in 4T1 breast cancer with 64Cu-LDH-BSA via passive targeting alone (7.7 ± 0.1%ID/g at 16 h post-injection; n = 3). These results support that LDH is a versatile platform that can be labeled with various bivalent and trivalent radiometals without comprising the native properties, highly desirable for PET image-guided drug delivery.
Mesenchymal Stem Cells Induce Directional Migration of Invasive Breast Cancer Cells through TGF-β
Authors: McAndrews Kathleen M. , McGrail Daniel J. , Ravikumar Nithin , Dawson Michelle R.
Published: November 2015

Mesenchymal stem cells (MSCs) are recruited to the tumor microenvironment and influence tumor progression; however, how MSCs induce the invasion of cancer cells is not completely understood. Here, we used a 3D coculture model to determine how MSCs affect the migration of invasive breast cancer cells. Coculture with MSCs increases the elongation, directional migration and traction generation of breast cancer cells. MSC-induced directional migration directly correlates with traction generation and is mediated by transforming growth factor β (TGF-β) and the migratory proteins rho-associated kinase, focal adhesion kinase and matrix metalloproteinases. Treatment with MSC conditioned media or recombinant TGF-β1 elicits a similar migration response to coculture. Taken together, this work suggests TGF-β is secreted by MSCs, leading to force-dependent directional migration of invasive breast cancer cells. These pathways may be potential targets for blocking cancer cell invasion and subsequent metastasis.
Position-specific automated processing of V3 env ultra-deep pyrosequencing data for predicting HIV-1 tropism
Authors: Jeanne Nicolas , Saliou Adrien , Carcenac Romain , Lefebvre Caroline , Dubois Martine , Cazabat Michelle , Nicot Florence , Loiseau Claire , Raymond Stéphanie , Izopet Jacques , Delobel Pierre
Published: November 2015

HIV-1 coreceptor usage must be accurately determined before starting CCR5 antagonist-based treatment as the presence of undetected minor CXCR4-using variants can cause subsequent virological failure. Ultra-deep pyrosequencing of HIV-1 V3 env allows to detect low levels of CXCR4-using variants that current genotypic approaches miss. However, the computation of the mass of sequence data and the need to identify true minor variants while excluding artifactual sequences generated during amplification and ultra-deep pyrosequencing is rate-limiting. Arbitrary fixed cut-offs below which minor variants are discarded are currently used but the errors generated during ultra-deep pyrosequencing are sequence-dependant rather than random. We have developed an automated processing of HIV-1 V3 env ultra-deep pyrosequencing data that uses biological filters to discard artifactual or non-functional V3 sequences followed by statistical filters to determine position-specific sensitivity thresholds, rather than arbitrary fixed cut-offs. It allows to retain authentic sequences with point mutations at V3 positions of interest and discard artifactual ones with accurate sensitivity thresholds.
Adipose-derived Stem Cell Conditioned Media Extends Survival time of a mouse model of Amyotrophic Lateral Sclerosis
Authors: Fontanilla Christine V. , Gu Huiying , Liu Qingpeng , Zhu Timothy Z. , Zhou Changwei , Johnstone Brian H. , March Keith L. , Pascuzzi Robert M. , Farlow Martin R. , Du Yansheng
Published: November 2015

Adipose stromal cells (ASC) secrete various trophic factors that assist in the protection of neurons in a variety of neuronal death models. In this study, we tested the effects of human ASC conditional medium (ASC-CM) in human amyotrophic lateral sclerosis (ALS) transgenic mouse model expressing mutant superoxide dismutase (SOD1G93A). Treating symptomatic SOD1G93A mice with ASC-CM significantly increased post-onset survival time and lifespan. Moreover, SOD1G93A mice given ASC-CM treatment showed high motor neuron counts, less activation of microglia and astrocytes at an early symptomatic stage in the spinal cords under immunohistochemical analysis. SOD1G93A mice treated with ASC-CM for 7 days showed reduced levels of phosphorylated p38 (pp38) in the spinal cord, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death. Additionally, the levels of α-II spectrin in spinal cords were also inhibited in SOD1G93A mice treated with ASC-CM for 3 days. Interestingly, nerve growth factor (NGF), a neurotrophic factor found in ASC-CM, played a significant role in the protection of neurodegeneration inSOD1G93A mouse. These results indicate that ASC-CM has the potential to develop into a novel and effective therapeutic treatment for ALS.
Antitumor potential of a synthetic interferon-alpha/PLGF-2 positive charge peptide hybrid molecule in pancreatic cancer cells
Authors: Yin Hongmei , Chen Naifei , Guo Rui , Wang Hong , Li Wei , Wang Guanjun , Cui Jiuwei , Jin Haofan , Hu Ji-Fan
Published: November 2015

Pancreatic cancer is the most aggressive malignant disease, ranking as the fourth leading cause of cancer-related death among men and women in the United States. Interferon alpha (IFNα) has been used to treat pancreatic cancer, but its clinical application has been significantly hindered due to the low antitumor activity. We used a “cDNA in-frame fragment library” screening approach to identify short peptides that potentiate the antitumor activity of interferons. A short positively charged peptide derived from the C-terminus of placental growth factor-2 (PLGF-2) was selected to enhance the activity of IFNα. For this, we constructed a synthetic interferon hybrid molecule (SIFα) by fusing the positively charged PLGF-2 peptide to the C-terminus of the human IFNα. Using human pancreatic cell lines (ASPC and CFPAC1) as a model system, we found that SIFα exhibited a significantly higher activity than did the wild-type IFNα in inhibiting the tumor cell growth. The enhanced activity of the synthetic SIFα was associated with the activation of interferon pathway target genes and the increased binding of cell membrane receptor. This study demonstrates the potential of a synthetic SIFα as a novel antitumor agent.
Substrate-based inhibitors exhibiting excellent protective and therapeutic effects against Botulinum Neurotoxin A intoxication
Authors: Guo Jiubiao , Wang Jinglin , Gao Shan , Ji Bin , Waichi Chan Edward , Chen Sheng
Published: November 2015

Potent inhibitors to reverse Botulinum neurotoxins (BoNTs) activity in neuronal cells are currently not available. A better understanding of the substrate recognition mechanism of BoNTs enabled us to design a novel class of peptide inhibitors which were derivatives of the BoNT/A substrate, SNAP25. Through a combination of in vitro, cellular based and in vivo mouse assays, several potent inhibitors of approximately one nanomolar inhibitory strength both in vitro and in vivo have been identified. These compounds represent the first set of inhibitors that exhibited full protection against BoNT/A intoxication in mice model with undetectable toxicity. Our findings validated the hypothesis that a peptide inhibitor targeting the two BoNT structural regions which were responsible for substrate recognition and cleavage respectively could exhibit excellent inhibitory effect, thereby providing insight on future development of more potent inhibitors against BoNTs.
High-frequency and high-quality silicon carbide optomechanical microresonators
Authors: Lu Xiyuan , Lee Jonathan Y. , Lin Qiang
Published: November 2015

Silicon carbide (SiC) exhibits excellent material properties attractive for broad applications. We demonstrate the first SiC optomechanical microresonators that integrate high mechanical frequency, high mechanical quality and high optical quality into a single device. The radial-breathing mechanical mode has a mechanical frequency up to 1.69 GHz with a mechanical Q around 5500 in atmosphere, which corresponds to a fm · Qm product as high as 9.47 × 1012 Hz. The strong optomechanical coupling allows us to efficiently excite and probe the coherent mechanical oscillation by optical waves. The demonstrated devices, in combination with the superior thermal property, chemical inertness and defect characteristics of SiC, show great potential for applications in metrology, sensing, and quantum photonics, particularly in harsh environments that are challenging for other device platforms.
Evolution of the statistical distribution in a topological defect network
Authors: Xue Fei , Wang Xueyun , socolenco Ion , Gu Yijia , Chen Long-Qing , Cheong Sang-Wook
Published: November 2015

The complex networks of numerous topological defects in hexagonal manganites are highly relevant to vastly different phenomena from the birth of our cosmos to superfluidity transition. The topological defects in hexagonal manganites form two types of domain networks: type-I without and type-II with electric self-poling. A combined phase-field simulations and experimental study shows that the frequencies of domains with N-sides, i.e. of N-gons, in a type-I network are fitted by a lognormal distribution, whereas those in type-II display a scale-free power-law distribution with exponent ∼2. A preferential attachment process that N-gons with a larger N have higher probability of coalescence is responsible for the emergence of the scale-free networks. Since the domain networks can be observed, analyzed and manipulated at room temperature, hexagonal manganites provide a unique opportunity to explore how the statistical distribution of a topological defect network evolves with an external electric field.
Catalytic Hydrogenation of Sugars
Authors: Murzin Dmitry Yu , Duque Angela , Arve Kalle , Sifontes Victor , Aho Atte , Eränen Kari , Salmi Tapio
Published: November 2015

Heterogeneous catalytic hydrogenation of various sugars over a range of catalysts was historically done mainly using sponge nickel catalysts, while more recently ruthenium based catalysts started to be applied since Ru affords good activity and excellent selectivity in addition to being void of the toxic properties of Ni. The chapter covers various aspects of catalytic sugar hydrogenations, such as catalyst selection, reaction kinetics, sugar structure influence, structure sensitivity and reactor design.
Advances in Sugar-based Polymers: Xylan and its Derivatives for Surface Modification of Pulp Fibres
Authors: Vega Beatriz , Grigoray Olga , Gustafsson Jan , Fardim Pedro
Published: November 2015

Xylans are one of the most common hemicellulose polysaccharides and natural polymers in plants. The utilization of xylan as a polymer has great potential for functional materials in different applications. In this chapter, different processes for the extraction of xylans from biomass are evaluated, due to their influence on the final properties of the extracted polymers such as molar mass and purity. Pressured hot water extraction (PHWE), a very common but versatile method for extracting xylans from hard wood, is described in detail. Cold caustic extraction (CCE) of xylans from bleached hard wood pulps is discussed as an alternative route for obtaining extremely pure xylan polymers. Derivatisation of the extracted xylans by incorporation of functional groups such as ethers and esters to the xylan backbone is a toolbox that allows the incorporation of a huge range of tailor-made new features for the polymer. Fibre engineering with sorption of xylans and xylan derivatives through self-assembly gives the perfect opportunity for incorporation of brand new functionalities to fibre-based products, which results in improved performance and helps to broaden the application areas for these materials.
Non-fuel Applications of Sugars in Brazil
Authors: Seidl Peter R. , Freire Estevão , Borschiver Suzana
Published: November 2015

The use of biomass for the production of fuels and chemicals can mitigate several of the problems involving greenhouse gas emissions and the depletion of the world's non-renewable resources. High value, lower volume biobased chemicals may also increase the return on investments in biofuels-only operations thus contributing to overcome a significant barrier to realizing a biorefinery's economic goals. Recent evaluations of structures most easily obtained from a given conversion process have the advantage of tailoring broad-based processes to the building blocks available from certain biorefinery operations. Selected structures available from chemical and biological transformations of sugar cane and its residues are discussed in terms of their integration into biorefinery operations. Those structures currently under investigation by Brazilian groups that appear to be the most promising for production by the chemical industry are discussed.
Lake Ecology and Chemistry
Authors: Bartoli Marco , Viaroli Pierluigi
Published: November 2015

We present an overview of the main physical, chemical and ecological features of lake ecosystems. The main aim is to briefly address the complexity of this subject. The solute composition of lake water depends upon a number of interplaying factors, including the watershed geology, land uses, climate, pollution sources, thermal regime and biota. Excess nutrients (N and P) from diffuse or point sources may trigger eutrophication processes, resulting in algal blooms and oxygen shortage. For this reason, a great wealth of studies has been performed on the causal factors and effects of eutrophication and possible remedial measures. In recent decades, P loadings from point sources decreased due to the enforcement of strong environmental policies, e.g. the implementation of wastewater treatment plants. Nonetheless, the restoration of pristine conditions has not yet been achieved because P may be recycled in large amounts from anoxic sediments, thus providing an internal source. Nitrogen loadings decreased proportionally less, mostly due to land use and diffuse pollution from agriculture and livestock, leading to new and challenging issues, e.g. the combined stoichiometry of N, P and Si as a driving factor of lake productivity and the food web. In the last two decades, studies on dissolved organic carbon have assumed a growing importance. This source of organic carbon fuels microbial communities and heterotrophic activity, with side effects on carbon dioxide emissions. The bulk of dissolved molecules composing this organic pool may also support planktonic production. Finally, they have optical properties, which are largely unexplored for their effects on lake ecology.
Phototransformation Induced by HO• Radicals
Authors: Mostofa Khan M. G. , Liu Cong-Qiang , Sakugawa Hiroshi , Fu Pingqing , Minella Marco , Vione Davide , Minakata Daisuke , Wu Feng-Chang , Zhai Lin , Mortuza M. Golam , Al-Misned Fahad A. , Chen Jingwen , Yuan Jie , Si-liang Li
Published: November 2015

The hydroxyl radical (HO•) is a strong oxidizing agent that can transform dissolved organic matter (DOM) into many intermediate photoproducts and byproducts, which include low molecular weight (LMW) DOM, hydrogen peroxide (H2O2), CO2, dissolved inorganic carbon (DIC: dissolved CO2, H2CO3, HCO3−, and CO32−), NO3−, NH4+, and so on, in surface waters. Furthermore, HO• has a prominent role in the transformation of recalcitrant pollutants into more biodegradable compounds. This chapter discusses the key sources of HO• in natural waters and elucidates the phototransformation pathways of high molecular weight (HMW) and low molecular weight (LMW) DOM induced by HO•. As an example, the photooxidation of methylmercury chloride (MeHgCl) by hydroxyl radicals is discussed along with its reaction mechanism. Among the possible indicators of DOM transformation, the decrease in the fluorescence intensity of autochthonous fulvic acid is discussed based on field observations. The presented results suggest that HO• may be involved in the photooxidation of both HMW and LMW DOM in surface waters.
The Role of Singlet Oxygen in Surface Water Photochemistry
Authors: Latch Douglas E.
Published: November 2015

Singlet oxygen, (1O2, 1Δg), is a selective oxidant produced in sunlit surface waters. It is an electrophile produced from the quenching of excited state triplet natural organic matter (3NOM) by dissolved oxygen and it reacts with electron-rich alkenes, sulfides, and phenols. The concentration of 1O2 is high near the NOM molecules that sensitize its production and significantly decreases moving away from the NOM source. This chapter discusses the formation, quenching, reactivity, and detection of 1O2 and includes examples of surface water contaminants that react with 1O2.
Stem Cells and Drug Metabolism
Authors: Kelly Edward J. , Voellinger Jenna L.
Published: November 2015

Stem cells have a high self-renewal capability and can give rise to any cell in the body making them a very attractive target for researchers in regenerative medicine, as well as drug discovery and development. Preclinical screening of drug metabolism is a fundamental component of drug development and is used to aid in predicting drug bioavailability, drug–drug interactions, and toxicity. The main tissues responsible for drug metabolism are the liver, intestine, and kidney. Tissue specific cells generated from pluripotent stem cells for all three of these organs have vast potential to aid in drug metabolism screens. In this chapter we provide an overview of the current state of stem cell technologies regarding their use in drug metabolism screening, with an emphasis on stem cell derived hepatocytes.
Drug–Drug Interactions: Computational Approaches
Authors: Rowland-Yeo Karen , Tucker Geoffrey T.
Published: November 2015

The background to computational methods for the prediction of the extent of drug–drug interactions mediated by enzyme and transporter inhibition and induction, using both static and dynamic [physiologically based pharmacokinetic (PBPK)] modelling is reviewed. Four case studies are described to illustrate the application of the latter models in understanding and predicting complex interactions, especially when more than one drug is co-administered with the ‘victim’ compound and when the outcome is also dependent on a concomitant disease or genotype. The impact of PBPK modelling of drug–drug interactions with regard to regulation and labelling is considered, and future developments with regard to using such modelling as a basis for ‘personalised’/‘stratified’ drug dosage at the point of care are predicted.
Epigenetics – What it is and Why it Matters
Authors: Nightingale Karl P.
Published: November 2015

Over the last decade there has been a revolution in our understanding of gene regulation, and how patterns of gene expression are established and maintained in eukaryotic cells. We now know that many factors – including the chemical modification of chromatin, many of the proteins involved in packaging DNA, and even where a gene is located in the nucleus – will influence transcriptional activity. These ‘epigenetic’ mechanisms are essential in ensuring short-term gene activity is appropriate for a cell's environment, and that cell-type specific patterns of gene expression are maintained over the longer term. As these are integral aspects of gene regulation, epigenetic mechanisms are inevitably involved in the misregulation of genes in disease, and occasionally act as the initiating step. As such, the promise of ‘epigenetic therapies’, based on drugs that target these processes, is huge. This chapter is aimed at a non-expert reader, and acts as an introduction to: (i) broadly define epigenetic phenomena; (ii) discuss how genes are regulated in higher organisms, and how epigenetic mechanisms play a crucial role in this, including their deregulation in disease; and (iii) explain how epigenetic processes represent an important new class of targets for clinical intervention.
Progress in Targeting Epigenetic Readers
Authors: Chung Chun-wa
Published: November 2015

Histone modifications are ‘read’ by protein modules which recognise defined modification states and act as scaffolds to attract protein complexes that further alter the epigenetic architecture at a specific location. This leads to enhanced or repressed gene expression. The dogma that it would be impossible to target these protein–protein interactions has recently been overturned, first by the discovery of potent small molecule inhibitors of bromodomains, the readers of acetylated histones, and more recently by inhibitors of methyl-lysine reader proteins of the ‘Royal’ and WD40r families. This chapter will present case studies of how these inhibitors have emerged from, and the merits of, a variety of hit discovery approaches including phenotypic screening, structure and fragment-based drug design and peptide mimicry. A view of the therapeutic value and biological challenges of targeting reader domains, as well as the utility of emerging biological and chemical tools will also be given.
Who will Benefit from Epigenetic Drugs?
Authors: Verhelle Dominique , Shields David J.
Published: November 2015

Recently targeted drug discovery effort in oncology has expanded its traditional focus on genetic lesions to epigenetic alterations that directly modulate tumour cell proliferation, survival, migration and differentiation. Both DNA methylation and histone modification regulation has been found dysregulated in cancer. In addition to hypomethylating agents and HDAC inhibitors which have been on the market for several years, additional epigenetic drugs affecting histone methylation and chromatin remodelling have recently entered in clinic. Most of them have been developed for selective patient populations and their indication is being expanded as single agent or combination therapy through a strong effort in translational medicine. Because tumour response to an epigenetic inhibitor may be independent of target expression, mutational status and substrate levels, different approaches may be required to identify responder patients. This chapter will focus on precision medicine approaches applied to epigenetic targets using EZH2, Dot1L and NSD2 as examples.
Histone Methyltransferase Activity Assays
Authors: Ma Haiching , Howitz Konrad T. , Horiuchi Kurumi Y. , Wang Yuren
Published: November 2015

Histone methyltransferases (HMTs) methylate either the lysine or arginine residues on histones and other proteins and play a crucial role in epigenetic regulation. Over 70 HMTs are encoded by the human genome, and many have been implicated in the aetiology of cancer, inflammatory diseases, neurodegenerative diseases and other conditions. There are currently about a dozen HMT activity assays available, and many of these assay formats are applicable to other epigenetic factors, such as histone acetyltransferases, histone deacetylases, and histone and DNA demethylases. Many factors need to be considered in selecting an HMT assay for drug discovery studies, including cost, adaptability to high-throughput screening, and rates of false positives and false negatives. This chapter describes the mechanisms of the major assay platforms available for HMT screening and profiling and presents the advantages and limitations associated with each.
Safety Considerations for Epigenetic Mechanisms as Drug Targets: Are Existing Toxicology Studies Fit for Purpose?
Authors: Butler Paul , Lawton Michael , Chapin Robert E. , Hollingshead Brett D. , Leach Karen , Nambiar Prashant R. , Pletcher Mathew , Yang Amy H.
Published: November 2015

Epigenetic mechanisms have emerged as attractive therapeutic targets because of their pleiotropic role in diseases processes and the ability to pharmacologically modulate their activities. One key question in the safety assessment of epigenetic drug targets is whether existing toxicity testing paradigms require modification to adequately characterize and address safety concerns, given the potential long-term consequences as a result of changes in gene expression. Currently approved epigenetic drugs are for the treatment of cancer, with additional disease indications now being explored outside of oncology. What can one learn about safety considerations from these recently marketed compounds as well as approved non-epigenetic drugs as epigenetic modulators? This chapter provides an overview of toxicological considerations for epigenetic therapeutics, outlines currently known and theoretical target organ toxicities, including the potential concerns for transgenerational transmission of epigenetic alterations, and offers recommendations for screening and risk mitigation strategies. Regulatory and risk–benefit considerations for epigenetic therapies are also discussed. Sharing knowledge and understanding around what comprises a comprehensive drug safety assessment should further increase confidence in advancing compounds that modulate epigenetic proteins to significantly improve lives by treating a wide variety of diseases.
Sensitive detection and glycoprofiling of a prostate specific antigen using impedimetric assays
Authors: Pihíková D. , Belicky Š. , Kasák P. , Bertok T. , Tkac J.
Published: November 2015

We develop an impedimetric biosensor for the detection of prostate specific antigen capable of sensitive glycoprofiling.
A novel biocompatible europium ligand for sensitive time-gated immunodetection
Authors: Sayyadi Nima , Connally Russell E. , Try Andrew
Published: November 2015

We describe the synthesis of a novel hydrophilic derivative of a tetradentate β-diketone europium ligand that was used to prepare an immunoconjugate probe against Giardia lamblia cysts. We used a Gated Autosynchronous Luminescence Detector (GALD) to obtain high quality delayed luminescence images of cells 30-fold faster than ever previously reported.
Intramolecular electron transfer reactions in meso-(4-nitrophenyl)-substituted subporphyrins
Authors: Copley Graeme , Oh Juwon , Yoshida Kota , Shimizu Daiki , Kim Dongho , Osuka Atsuhiro
Published: November 2015

A2B-type meso-(4-nitrophenyl)-substituted subporphyrins have been synthesized and shown to undergo very fast photoinduced intramolecular charge separation (CS) and charge recombination (CR) between the subporphyrin core and the meso-4-nitrophenyl group in CH2Cl2 as probed by femtosecond time-resolved transient absorption spectroscopy.
The culprit of gout: triggering factors and formation of monosodium urate monohydrate
Authors: Chih Meng Hsiu , Lee Hung Lin , Lee Tu
Published: November 2015

Triggering factors, proposed mechanism and self-sustaining cycle for the crystallization of MSUM and gout.
ZnO modified ZSM-5 and Y zeolites fabricated by atomic layer deposition for propane conversion
Authors: Gong Ting , Qin Lijun , Lu Jian , Feng Hao
Published: November 2015

Zeolite supported highly dispersed ZnO fabricated by ALD is an effective catalyst for conversion of propane to propylene and aromatics.
Facile synthesis of highly conductive sulfur-doped reduced graphene oxide sheets
Authors: Tian Zhengshan , Li Jitao , Zhu Gangyi , Lu Junfeng , Wang Yueyue , Shi Zengliang , Xu Chunxiang
Published: November 2015

A facile hydrothermal reaction process was designed to synthesize sulfur-doped RGO sheets with excellent conductivity.
Theoretical studies of energetics and binding isotope effects of binding a triazole-based inhibitor to HIV-1 reverse transcriptase
Authors: Krzemińska A. , Świderek K. P. , Paneth P.
Published: November 2015

The18O binding isotope effect allows us to distinguish the actual binding site of an inhibitor in HIV-1 reverse transcriptase.