他汀类药物是临床疗效确切的HMG-GoA还原酶抑制剂，其转运、代谢和效应靶点的基因多态性明显影响调脂效应，而联用丹参制剂后他汀类药物调脂效果却显著增强。我们前期研究发现丹参素是OATP1B1底物，可抑制他汀类药物转运，造成作用靶点药物浓度下降，是否因此减低疗效不得而知。有资料显示丹参素能抑制CYP2C9酶活性，此作用是否降低他汀类药物代谢因而提高疗效尚不清楚。至于丹参素在OATP1B1、CYP2C9、ApoE及HMG-GoA还原酶基因突变时对他汀类药物转运、代谢的影响与疗效有何关联更值得关注。因此本课题拟①通过构建不同基因质粒，研究基因突变下丹参素对他汀类药物转运、代谢的影响及分子机制;②运用联合用药群体PK-PD链式模型，构建基因多态"网络",阐明多态"网络"下丹参素对他汀类药物转运、代谢与疗效的影响及其内在关联性；为拓展联合用药在基因多态"网络"下多通道、多靶点的关联研究增添新思路。

准确检测和定量评估碳纤维复合材料构件缺陷和损伤，确保其完整、可靠、安全是许多重要领域急需解决的具有基础性、关键性和先导性的极具挑战的前沿问题。围绕病态反问题的先验统计模型及非线性优化、优质快速成像、图像分析与缺陷智能识别及定量化评估关键科学问题，主要研究内容是:①建立由碳纤维复合材料构件缺陷脉冲涡流成像与图像分析先验统计模型导引的新的非线性优化算法，为实现检测信息的优质快速处理提供理论基础;②开发TMR 阵列探头，研究优质快速的碳纤维复合材料构件缺陷脉冲涡流成像方法，以提供高质量的图像信息;③研究碳纤维复合材料构件缺陷脉冲涡流图像分析与缺陷智能识别及定量化评估方法，实现缺陷的精确定量评估;④构建原理样机，完成新理论和方法的原理性验证和工程适用性评估。最终形成完整的碳纤维复合材料构件缺陷脉冲涡流成像与图像分析的基础理论和关键技术，推动涡流检测理论和技术发展，促进碳纤维复合材料的研发及应用。

DESCRIPTION (provided by applicant): Targeting mechanisms that are especially important in the DNA damage response of pre-malignant and cancer cells may lead to development of novel chemosensitizing agents. Cancer cells are deficient in the primary G1/S cell cycle checkpoint, often through p53 functional loss. Therefore, their survival after DNA damage is more dependent on later cell cycle checkpoints such as the replication checkpoint that ensures DNA is copied fully before mitosis begins. Caffeine is the most commonly used inhibitor of this checkpoint and our prior studies have shown promise for caffeine as an inhibitor of ultraviolet-induced skin cancer by suppressing the ATR/Chk1 pathway required for replication checkpoint function. Beyond the unique case of UV-induced skin malignancies, caffeine cannot be used to sensitize cancers due to non-specific toxicity at the required doses. Through an unbiased screen for DNA damage response inhibitors, we discovered four novel compounds that are non-toxic to cells when given alone, but sensitize p53-deficient cells to diverse classes of chemotherapeutic agents. All four compounds disrupted the normal cellular response to DNA stresses, inhibited Chk1 phosphorylation via mechanism(s) that are distinct from that of caffeine, and were >250 times more potent than caffeine. The broad long-term goals of this proposal are: to gain insight into therapeutically targetable components of the DNA damage response; to explore the feasibility of using these targets to make cancers more sensitive to existing chemotherapeutics; and to further examine the unique potential of using checkpoint inhibition to reduce UV-induced skin cancer. In Aim 1 we will determine the general mechanistic class to which the novel compounds belong as inhibitors of Chk1 phosphorylation and hypothesize that studying these inhibitors isolated through an unbiased chemical genetic screen will provide new mechanistic insights on the DNA damage response. In Aim 2 we will test the hypothesis that the identified compounds will act as chemosensitizers in vitro and in vivo when combined with DNA-damaging agents. In Aim 3 we will test the hypothesis that checkpoint inhibition will be therapeutically useful to eliminate UV-damaged cells and prevent UV-induced skin cancers. We thus propose to extend our work from the prior funding period to further develop the rational biological basis and practical means to selectively target malignant cells to established therapies.

This project will establish an open source set of software control algorithms that will allow an open source robotic prosthetic leg to facilitate rhythmic and non-rhythmic interactions between the human user and the environment.This project builds upon the Open-Source Leg,which is a robust,inexpensive,robotic leg platform that can be easily manufactured,assembled,and programmed.The project's overarching goal is to enable customizable behaviors that are continuously cued by the movement of the user?s body.The project promotes the progress of science by creating open source control hardware and software for compliant actuators that extend the capabilities of the Open-Source Leg.The advantages of compliant torque control,combined with intuitive,expressive control from the user,represents a significant improvement over currently-available prosthetic legs.The project will advance the national health by developing and testing high-level control software that will allow users of the Open Source Leg to seamlessly navigate around obstacles and perform dynamic activities.The improved mobility provided by these technologies will improve the quality of life and functional capabilities of many people living with mobility impairment.Open source hardware and software lower barriers to access for robotic technologies,which makes these robots great candidates not only as assistive co-robots in healthcare and other applications but also as educational tools for undergraduate and graduate students.Emerging powered prostheses such as the NSF-funded Open-Source Leg have motors that can restore normative biomechanics to above-knee amputees,but these devices are limited by their control strategies to a small set of pre-defined,steady-state activities.Each activity is typically divided into a discrete progression of gait periods called phases,resulting in a large set of distinct controllers that struggle to continuously coordinate prosthetic limb motion with the user.Discrete control paradigms have not been able to facilitate transient behaviors like transitions between activities or non-rhythmic motions like stepping backwards or stepping over obstacles.Recently,a new control paradigm has emerged that continuously synchronizes or coordinates prosthetic limb motion to the user based on inertial measurements from the user?s body(e.g.,the residual limb).However,prior implementations have been limited to lab-specific prosthetic leg designs with stiff actuators that rigidly enforce the kinematic mappings from user motion to prosthetic joint position rather than complying to varying environmental interactions.The recently developed Open-Source Leg presents a unique opportunity to integrate this state-of-the-art control paradigm in a universally accessible testbed with series elastic actuators that soften interactions between the user,prosthesis,and environment.The overall goals of this project are to 1)understand how to achieve closed-loop torque and impedance control in the series elastic actuator of the open-source leg despite unmodeled dynamics from its low-cost design,and 2)understand how to integrate high-fidelity joint impedance control with two novel continuous controllers that promise to allow users to flexibly and seamlessly navigate obstacles and perform dynamic activities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Проект направлен на решение крупной фундаментальной проблемы-выяснение механизмов адаптации растений к факторам антропогенного происхождения,из которых наиболее токсичными являются тяжелые металлы(ТМ).В рамках данной проблемы будут исследованы физиологические и молекулярные механизмы хелатирования,секвестеризации и гомеостатирования тяжелых металлов(прежде всего Cu,а также Zn и Ni)у растений и возможная регуляторная роль в этих процессах транскрипционного фактора MYB4.Эта проблема крайне актуальна,поскольку техногенное загрязнение касается огромных территорий,включающих зоны промышленного производства,территории мегаполисов и сельскохозяйственных угодий.Несмотря на это,механизмы устойчивости растений к ТМ остаются слабо изученными,а экспериментальные данные о регуляции процесса детоксикации ТМ,в основе которой лежат системы их хелатирования и гомеостатирования,носят фрагментарный характер.Для изучения механизмов детоксикации ТМ в данном проекте будет исследована Cu-зависимая транскрипция 2-х групп генов：(1)непосредственно вовлеченных в хелатирование и гомеостатирование ТМ-мембранных транспортеров ТМ семейств COPT,P1b-ATPase,ZIP,Nramp,YSP;хелаторов(PCS,MT1,MT2);металлошаперонов Cu(CCS,ATX1),и(2)генов антиоксидантной защиты от окислительного стресса,инициированного ТМ(SOD,POX,CAT),а также ферментов синтеза веществ с антиоксидантными свойствами(флавоноиды,антоцианы и др.).Особое внимание будет уделено выяснению характера взаимодействия Cu с повышенными концентрациями Ni и Zn с целью изучения участия трансфактора SPL7 в гомеостатировании Cu в связи с его вероятной регуляторной и сенсорной функциями.Сравнительный анализ профилей экспрессии Cu-регулируемых генов у растений рапса с.Вестар и рапса с геном трансфактора OsMyb4 риса позволит ответить на вопрос,вовлекается ли трансфактор OsMyb4 в процессы детоксикации ТМ.Наконец,предполагается исследовать вклад общих систем устойчивости в детоксикацию ТМ,используя для этого эксперименты по кросс-адаптации растений конститутивного галофита Thellungiella salsuginea к ТМ и солевому стрессу.Корреляционный анализ между уровнями экспрессии различных групп генов,регулируемых ТМ,ответными реакциями растения на уровне физиологических процессов и внутриклеточной аккумуляцией ТМ позволит получить принципиально новые знания,имеющие общебиологическое значение.Успешное выполнение проекта с помощью современных методов физико-химической биологии будет способствовать выяснению базовых принципов формирования устойчивости растений к загрязнению среды факторами техногенного происхождения и решению важных эколого-биотехнологических задач.

nnotation：Complement is a central part of innate immunity,which,as you know,serves as the first line of defense against foreign cells and altered host cells.At the moment,complement is undergoing a renaissance in modern immunology.The role of complement is not only the detection,labeling and elimination of microbial invasions with almost instant reactivity,but also with sufficient specificity to avoid damage to the host cells.Both ineffective and excessive complement stimulation are associated with increased susceptibility to infectious or non-infectious diseases,including autoimmune disorders,chronic inflammation,thrombotic microangiopathy,transplant rejection and oncology.It is worth noting that,as a result of the recently proved noncanonical activation of complement by coagulation/fibrinolytic cascade enzymes,anaphylotoxins are the main product of enzymatic catalysis.Anaphylotoxins mediate chemotaxis,inflammation and the formation of cytotoxic oxygen radicals,also cause smooth muscle contraction,the release of histamine from mast cells and increased vascular permeability.The listed properties of these molecules thus have a pronounced pro-inflammatory effect and,therefore,are the target of many anti-inflammatory drugs.A number of complement regulators,such as factor H and properdine,interact with carbohydrate molecules,primarily glycosaminoglycans and sialic acid,on the membranes of the host and pathogen cells and direct the corresponding complement response by stimulating the binding of complement activators or inhibitors.Sulfated polysaccharides are one of the promising candidates for imitating the structure of glycosaminoglycans,and hence regulating complement. The proposed project,therefore,is aimed at solving the problem of modulating the immune system of the human body using natural sulfated polysaccharides from red algae.The main goal of the project is to reveal the glycoaminoglycan-mimicking properties of sulfated polysaccharides on the complement protein cascade system.To better understand the role of sulfated galactans in the complement system,the contribution of proteins from other protein cascades,for example,fibrinolytic,will also be taken into account in order to establish the mechanism of action and expand the potential spectrum of application of algae polysaccharides with respect to anaphylotoxins. The scientific novelty of the project is determined by the choice of substances and biochemical studies necessary to develop and evaluate the effectiveness of new tools for regulating and/or inhibiting both the activity of the canonical pathways of complement activation and a more in-depth action.The latter will be oriented to proteins of other non-complement cascades whose complement activating action was recognized only in 2010.The innovativeness of the proposed approaches and methods for the study of complement activity in the presence of sulfated polysaccharides of red algae consists in using not hemolysis models,but experiments conducted on the surface of microplates coated with specific activators that act selectively and with a high level of sensitivity.In addition,an experiment will be conducted for the first time on the involvement of proteases of an incomplete cascade(coagulation/fibrinolytic),as well as regulatory factors of the complement system.The knowledge gained as a result of the project will open up the prospect of a new use of biopolymers with a unique structure,due to the marine origin and habitat of algae,for the prevention and development of inflammatory reactions of the body,which are based on incorrect functioning of the complement system. Expected results：The complement system is an effective first line of defense against the invasion of pathogenic microorganisms,the violation of the delicate balance of which in its activating or controlling proteins is increasingly associated with the pathology of diseases.The results expected from the implementation of this project will show the possible prospects of using polysaccharides of natural origin for the correction of complement disorders by simulating the properties of glycosaminoglycans of cell membranes.Since the proteins of the complement system are synthesized in all human organs and tissues,the spectrum of the possible use of the studied substances includes ophthalmology,dermatology and the work of the gastrointestinal tract.For all three of the above areas,algae polysaccharides are allowed and used by humans,thereby revealing the potential use of these substances in medical practice. At the moment,the world literature contains only partial information about the ability of these substances to modulate complement and they are performed on non-modern hemolysis models,not to mention the complete lack of data on their effect on regulatory factors of complement.The depth and versatility of the proposed project(for example,canonical and non-canonical activation paths)will allow a comprehensive study of the ability of sulfated polysaccharides to modulate a variety of complement links(complement activation and,conversely,regulation,H/D factor).

In this study, solid-phase total synthesis of a peptide antibiotic WAP-8294A2 was achieved. Further functional evaluation revealed the antimicrobial activity of WAP-8294A2 is due to their membrane-disrupting effects depend on the presence of menaquinone. We also achieved solid-phase total synthesis of a channel-forming peptide polytheonamide B, which enabled the investigation of the mechanism of action. The addition of polytheonamide B to MCF-7 cells rapidly diminished a potential across the plasma membrane. Furthermore, polytheonamide B was found to be internalized into the cells, accumulating in lysosomes and neutralizing the lysosomal pH gradient. In addition, the cellular target of yaku’amide B was elucidated. Pull-down assays with biotinylated probes revealed FoF1-ATP synthase as the major target protein of yaku’amide B.

ppropriate installment of wireless base station plays an important role for supporting a recent growth of high speed mobile communications. In order to realize such communication system, one needs fast and accurate radio wave propagation estimation method. In this investigation, shooting and bouncing rays (SBR) algorithm has been proposed to analyze the radio wave propagation. For high frequency regime, waves can be regarded as rays and the multiple reflections and transmissions at the building walls have been treated effectively and the field strength can be visualized in a map, so that one can easily observe and analyze the field distribution.