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Advances in newly developing therapy for chronic hepatitis C virus infection

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Frontiers of Medicine 2014年第2期8卷 166-174页

作者： paul j. Pockros Division of Gastro/Hepatology Scripps Clinic 10666 N Torrey Pines Road N203 La Jolla CA 92067 USA

Chronic hepatitis C virus （HCV） infection afflicts a reported 170 million people worldwide and is often complicated by cirrhosis and hepatocellular carcinoma. Morbidity and mortality are decreased with the successful treatment of chronic HCV infection. Increased understanding of the HCV has allowed further development of new direct-acting antiviral （DAA） agents against the HCV and has also allowed the development of IFN-free oral treatment regimens. In late 2013 the first nucleotide polymerase inhibitor regimen with RBV alone for genotypes 2/3 and in combination with a 12-week regimen of PEG-IFN ＋ RBV for genotypes 1, 4 was approved for use in the US. A number of promising new DAA regimens which are IFN-free are in phase 3 development and the first will likely be approved for use in the US in 2014. The currently approved regimens are discussed in detail and currently available data on future regimens are reviewed herein.

关键词： direct-acting antiviral (DAA) nucleotide polymerase inhibitors protease inhibitors

A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

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Neural Regeneration Research 2025年第1期20卷 291-304页

作者： Simeon C.Daeschler Katelyn j.W.So Konstantin Feinberg Marina Manoraj.j.nny Cheung j.nnifer Zhang Kaveh Mirmoeini j.0} Santerre Tessa Gordon Gregory HBorschel SickKids Research Institute Neuroscience and Mental Health ProgramTorontoONCanada Institute of Biomaterials and Biomedical Engineering University of TorontoTorontoONCanada Indiana University School of Medicine IndianapolisINUSA Division of Plastic and Reconstructive Surgery the Hospital for Sick ChildrenTorontoONCanada Translational Biology and Engineering Program Ted Rogers Centre for Heart ResearchInstitute of Biomedical EngineeringFaculty of DentistryUniversity of TorontoTorontoONCanada

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong ***,there are no FDA-approved therapies available to promote nerve *** accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve *** authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug *** is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 *** and drug loading are adj.stable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible *** released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic *** its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

关键词： biodegradable local drug delivery nerve inj.ry nerve regeneration nerve wrap tacrolimus

Three-dimensional simulation of liquid inj.ction,film formation and transport,in fluidized beds

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Particuology 2009年第5期7卷 337-346页

作者： paul Zhao Peter j. O'Rourke Dale Snider CPFD Software LLCAlbuquerqueNM 87111USA CFD d'OR Software and Consulting LLCLos AlamosNM 87544USA

Liquid inj.ction, and film formation and transport in dense-phase gas-solids fluidized beds are numerically simulated in three dimensions using a collisional exchange model that is based on the mechanism that collisions cause transfer of liquid mass, momentum, and energy between particles. In the model, each of the particles is represented by a solid core and a liquid film surrounding the core. The model is incorporated in the framework of the commercial code Barracuda developed by CPFD Software. The commercial software is an advanced CFD-based computational tool where the particles are treated as discrete entities, calculated by the MP-PIC method, and tracked using the Lagrangian method. Details of the collisional liquid transfer model have been previously presented in O＇Rourke, Zhao, and Snider （2009）; this paper presents new capabilities and proof-testing of the collision model and a new method to better quantify the penetration length. Example calculations of a fluidized bed without liquid inj.ction show the expected effect of collisions on the reduction of granular temperature （fluctuational kinetic energy） of the bed. When applied to liquid inj.ction into a dense-phase fluidized bed under different conditions, the model predicts liquid penetration lengths comparable to the experiments. In addition, the simulation reveals for the first time the dynamic mixing of the liquid droplets with the bed particles and the transient distribution of the droplets inside the bed.

关键词： MP-PIC Liquid inj.ction Fluidized bed Particle collisions CPFD j.t penetration

Cell Wall Microstructure Analysis Implicates Hemicellulose Polysaccharides in Cell Adhesion in Tomato Fruit Pericarp Parenchyma

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Molecular Plant 2009年第5期2卷 910-921页

作者： j.se j. Ordaz-Ortiz Susan E. Marcus j. paul Knox Centre for Plant Sciences Faculty of Biological Sciences University of Leeds Leeds LS2 9JT United Kingdom

Methods developed to isolate intact cells from both unripe and ripe tomato fruit pericarp parenchyma have allowed the cell biological analysis of polysaccharide epitopes at the surface of separated cells. The LM7 pectic homogalacturonan epitope is a marker of the j.nctions of adhesion planes and intercellular spaces in parenchyma systems. The LM7 epitope persistently marked the former edge of adhesion planes at the surface of cells separated from unripe and ripened tomato fruit and also from fruits with the Cnr mutation. The LM 11 xylan epitope was associated, in sections, with cell walls lining intercellular space but the epitope was not detected at the surface of isolated cells, being lost during cell isolation. The LM15 xyloglucan epitope was present at the surface of cells isolated from unripe fruit in a pattern reflecting the former edge of cell adhesion planes/intercellular space but with gaps and apparent breaks. An equivalent pattern of LM15 epitope occurrence was revealed at the surface of cells isolated by pectate lyase action but was not present in cells isolated from ripe fruit or from Cnr fruit. In contrast to wild-type cells, the LM5 galactan and LM21 mannan epitopes occurred predominantly in positions reflecting intercellular space in Cnr, suggesting a concerted alteration in cell wall microstructure in response to this mutation. Galactanase and mannanase, along with pectic homogalacturonan-degrading enzymes, were capable of releasing cells from unripe fruit parenchyma. These observations indicate that hemicellulose polymers are present in architectural contexts reflecting cell adhesion and that several cell wall polysaccharide classes are likely to contribute to cell adhesion/cell separation in tomato fruit pericarp parenchyma.

关键词： Cell walls fruit development tomato cell adhesion cell separation polysaccharide.

Flow hydrodynamics in embankment breach

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j.urnal of Hydrodynamics 2015年第6期27卷 835-844页

作者： ZHAO Gensheng VISSER paul j. REN Yankai UIj.TEWAAL Wim S.j. Department of Hydraulic Engineering Delft University of Technology Flanders Hydraulics Research Flemish Government Department of Mobility and Public Works

Breaching flow occurs during the breach development of the embankment, dike, earthen dam, landslide barrier, etc. and plays an import role in the breaching erosion as the driving force. According to the previous research, the breaching process can be classified into initiation phase, breach widening phase and breach deepening phase. Based on the breaching development classifications, the breaching flow can be seen as a special compound weir flow when the breach channel is in the relatively equilibrium condition. There were five physical flow models were designed in the hypothesis of rectangular shape and trapezoidal shape for the breach channel cross sections to study the breaching flow characteristics. The distributions of water level and velocity were measured and analysed in the breaching flows in overtopping condition and emerged condition. There were two helicoidal flows above the breach channel slopes and triangular hydraulic j.mp in the downstream of the breach channel in the overtopping condition and emerged condition. The hydraulic energy loss was calculated according to the breaching velocity and water level distribution in the upstream and downstream of the model. It is found that the test results of the breach flow physical model can be valuable to bring insight of the breaching process of embankment and make contributions to the validations and verifications of breach numerical models.

关键词： embankment breach physical model breaching flow helicoidal flow hydraulic j.mp

Sexual/aggressive behavior of wild yak(Bos mutus Prej.valsky1883) during the rut: influence of female choice

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Chinese Science Bulletin 2014年第22期59卷 2756-2763页

作者： paul j. Buzzard Donghua Xu Huan Li China Exploration & Research Society

Wild yaks(Bos mutus)ranged across the Tibetan Plateau in large herds before being forced to remote areas of the ***,little has been published about their behavioral *** present the first extensive study on wild yak behavior during the *** gathered data on activity budgets,aggressive/sexual behaviors,and the behavior of bulls inside and outside mixed groups during 11 days in 2010 and 9 days in *** ate less and were more social during the rut than during *** ate less than females and socialized more during the *** observed yaks for 234.25 h and recorded 2,078 aggressive/sexual *** bulls inspected and tended cows showing off their profiles during lateral displays,the most common type of indirect *** bulls inside mixed sex groups rested less and socialized more than bulls *** initiated intense intra-sexual competition and led at least 25 bulls on *** then incited fight frenzies of numerous bulls from inside and outside the groups before copulations,and fights could be *** discuss female choice selecting for large size and fighting ability in males,the similarity of yak and bison(genus Bison)behavior,and conservation implications.

关键词：攻击行为野牦牛发情期女性战斗能力青藏高原行为生态学社会化

Stress, hippocampal neurogenesis and cognition： functional correlations

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Frontiers in Biology 2016年第3期11卷 182-192页

作者： paul j. Lucassen Charlotte A. Oomen Centre for Neuroscienee Swammerdam Institute for Life Sciences University of Amsterdam Science Park 904 1098 XH Amsterdam The Netherlands Department of Molecular and Cellular Neurobiology Center for Neurogenomics and Cognitive ResearchNeuroscience Campus Amsterdam VU University Amsterdam De Boelelaan 1085 1081 HV Amsterdam The Netherlands

The brain of many species including humans, harbors stem cells that continue to generate new neurons up into adulthood. This form of structural plasticity occurs in a limited number of brain regions, i.e. the subventricular zone and the hippocampal dentate gyrus and is regulated by environmental and hormonal factors. In this minireview, we provide an overview of the effects of stress and glucocorticoid hormones on adult hippocampal neurogenesis and discuss how these effects may be relevant for cognitive function and possibly, brain disease. While its exact functional role remains elusive, adult neurogenesis has been implicated in learning and memory, fear and mood regulation and recently, adult-born neurons were found to be involved in specific cognitive functions such as pattern separation （i.e. the ability to form unique memory representations） and cognitive flexibility. The process of adult neurogenesis is influenced by several factors; whereas e.g. exercise stimulates, exposure to stress and stress hormones generally inhibit neurogenesis. Effects of acute, mild stress are generally short-lasting and recover quickly, but chronic or severe forms of stress can induce lasting reductions in adult neurogenesis. Some of the inhibitory effects of stress can be rescued by exercise, by allowing a period of recovery from stress, by drugs that target the stress system, or by some, but not all, antidepressants. Stress may, partly through its effects on adult neurogenesis, alter structure and plasticity of the hippocampal circuit. This can lead to subsequent changes in stress responsivity and aspects of memory processing, which may be particularly relevant for stress related psychopathology or brain diseases that involve perturbed memory processing.

关键词： adult neurogenesis stem cells hippocampus stress memory pattern separation cognition

How Do Sugars Regulate Plant Growth and Development？ New Insight into the Role of Treha Iose-6-Phosphate

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Molecular Plant 2013年第2期6卷 261-274页

作者： Liam E. O'Hara Matthew j. paul Astrid Wingler Genetics Evolution and Environment University College London Gower Street London WCl E 6BT UK Plant Science Rothamsted Research Harpenden Hertfordshire AL5 2JQ UK

Plant growth and development are tightly controlled in response to environmental conditions that influence the availability of photosynthetic carbon in the form of sucrose. Trehalose-6-phosphate （T6P）, the precursor of trehalose in the biosynthetic pathway, is an important signaling metabolite that is involved in the regulation of plant growth and development in response to carbon availability. In addition to the plant＇s own pathway for trehalose synthesis, formation of T6P or trehalose by pathogens can result in the reprogramming of plant metabolism and development. Developmental processes that are regulated by T6P range from embryo development to leaf senescence. Some of these processes are regulated in interaction with phytohormones, such as auxin. A key interacting factor of T6P signaling in response to the environment is the protein kinase sucrose non-fermenting related kinase-1 （SnRK1）, whose catalytic activity is inhibited by T6R SnRK1 is most likely involved in the adj.stment of metabolism and growth in response to starvation. The transcription factor bZlP11 has recently been identified as a new player in the T6P/SnRK1 regulatory pathway. By inhibiting SnRK1, T6P promotes biosynthetic reactions. This regulation has important consequences for crop production, for example, in the developing wheat grain and during the growth of potato tubers.

关键词： bZlP11 carbon availability plant development starvation sucrose non-fermenting related kinase-1 (SnRK1) trehalose trehalose-6-phosphate.

Vibration induced flow in hoppers:DEM 2D polygon model

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Particuology 2008年第6期6卷 455-466页

作者： Feras Y. Fraige paul A. Langston Andrew j. Matchett j.hn Dodds Faculty of Mining and Environmental Engineering Al-Hussein Bin Talal University Jordan Chemical and Environmental Engineering Nottingham University University Park Chemical Engineering University of Teesside Centre RAPSODEE Ecole Des Mines

A two-dimensional discrete element model （DEM） simulation of cohesive polygonal particles has been developed to assess the benefit of point source vibration to induce flow in wedge-shaped hoppers. The particle-particle interaction model used is based on a multi-contact principle. The first part of the study investigated particle discharge under gravity without vibration to determine the critical orifice size （Bc） to j.st sustain flow as a function of particle shape. It is shown that polygonal-shaped particles need a larger orifice than circular particles. It is also shown that Bc decreases as the number of particle vertices increases. Addition of circular particles promotes flow of polygons in a linear manner. The second part of the study showed that vibration could enhance flow, effectively reducing Bc. The model demonstrated the importance of vibrator location （height）, consistent with previous continuum model results, and vibration amplitude in enhancing flow.

关键词： Bulk solids Vibration DEM Hoppers Materials handling Polygon