“黄河口演变的多时空尺度混合模拟技术”是国家重点研发计划“水资源高效开发利用”专项项目“黄河口演变与流路稳定综合治理”的关键技术之一。项目立项以来，主要围绕水库~河道~河口整体数学模型、三维波流耦合数学模型和实体模型开展工作。在分析下游河道和河口冲淤特点的基础上，完善了黄河下游水库~河道~河口整体数学模型，模型验证结果良好，并计算了6亿t和3亿t两个情景方案黄河下游水沙演进过程，得到进入河口的水沙过程，为远黄河口演变及流路稳定预测提供了边界条件。系统总结了黄河口三维波流及泥沙数学模型，确定了SWAN模型计算波浪、以FVCOM和FVCOM-SED模型为基础进行黄河口三维潮流泥沙模型的完善与开发，提出了黄河口水沙模拟的波流耦合机制，初步形成适合黄河口水沙运用特点的三维波流耦合模型，并进行了黄河口三维水动力数值验证计算，潮位、潮流验证结果较好，含沙量及冲淤地形验证尚需进一步优化。调研国内外大型河口实体模型试验的基础上，完成黄河口实体模型模拟设计、模型沙选择、测控系统设计和模型验证方案设计，完成模型基建及生控潮系统安装。为下一步实体模型试验及混合模拟技术研发打下了扎实的基础。提出以实体模型自动测控为基础，以信息传输为纽带，以水利仿真计算系统云平台为载体的系统集成及与数学模型信息互馈技术解决方案，初步形成了混合模拟技术。

The activation of relatively inert non-polar chemical bonds is key to numerous catalytic functionalization processes generating high value-added chemical products.In the region of 75%of all chemicals currently require catalysts at some stage in their manufacture,and typical catalysts feature heavier late Transition Metals,reflecting their amenability to bond modifying redox processes.Issues relating to the sustainable availability/cost of such elements and the incorporation of heavy metals into products,mean that the search for alternative catalytic platforms is at the cutting edge scientifically and economically.Main Group metals,by contrast,are inexpensive,abundant,and in the cases of the lighter elements(such as the germanium compounds ultimately targeted here)less of an issue with regard to toxicity. In recent years,research into Main Group element compounds has highlighted the accessibility of low-valent derivatives with vacant coordination sites,and frontier orbitals with relatively small energy gaps able to facilitate bond activation by oxidative addition.Thus,a fundamental mode of reactivity typical of late Transition Metals has been opened up,and small molecule activation under mild conditions can be envisaged.Complementary strategies utilising redox inert metals(e.g.Ca2+)in constant oxidation state catalysis(e.g.via sigma-bond metathesis)have also emerged.Thus,the opportunity to exploit Main Group elements,once perceived as catalytically inert,as novel catalysts is not only at the cutting edge scientifically,but also offers huge potential for growth.With regard to redox-based processes,Main Group systems capable of effecting oxidative activation of E-H bonds are now known(e.g.for E=H,C,N,O,Si).Reagents capable of such insertion chemistry,however,are often highly reactive sub-valent species,and E-H bond activation processes typically generate products in thermodynamically very stable oxidation states.Catalytic turnover via reductive regeneration of the active species similar to late d-block catalysis is thus difficult to effect.However,our recent work and related research into Group 15 systems gives encouragement that catalytic cycles based on n/n+2 oxidation states for Main Group elements are indeed viable. The step change in homogenous catalysis which this proposal seeks to bring about is to open up catalytic bond modification processes based on redox chemistry(oxidative addition/reductive elimination)to Main Group metals.Our approach will be built on exciting preliminary results for tin systems,while ultimately targeting catalysts based around germanium,which is more environmentally benign,but a more challenging redox prospect.Our goals for the lifetime of this project are not necessarily to produce immediate replacements for existing Transition Metal systems in societally important catalytic transformations,but rather to establish the fundamental ground rules for catalyst design in what is an entirely new area of endeavour. Planned Impact:The aim of this proposal is to establish the ground rules for a step-change in homogenous catalysis.We aim to establish the fundamental science underpinning redox-based bond modifying catalysis using Main Group elements(rather than Transition Metals)as the active site.While these are adventurous goals(albeit de-risked to a significant degree by extensive preliminary results),we believe that the potential impact especially in the medium to long term is very high.Catalysis in general is acknowledged to be critical to the delivery of future growth in the manufacturing sector:ca.75%of all chemicals currently require catalysts at some stage in their manufacture,with catalytic processes generating £700 billion in products worldwide.In the US,for example,catalysis and catalytic processes account for ca.20%of GDP,with 30 of the 50 largest volume chemicals currently produced via catalytic routes.The development and fundamental understanding of innovative new catalyst systems therefore has clear,direct and long-term benefits to the chemical manufacturing sector and to the broader knowledge-based economy.Moreover,reflecting its national importance,the catalysis research area has been identified as a'growth area'in the EPSRC portfolio,and a priority area in its own right,as exemplified by the recent launch of the £13 million Harwell-based'Catalysis Hub'. The selectivity and mild reaction conditions implicit in homogenous catalysts,allied to their amenability to both mechanistic investigation and systematic tuning mean that such systems are widely employed in key industrial processes.A significant proportion of currently employed industrial catalysts use expensive late Transition Metals(e.g.Rh,Ir,Pd,Pt).Increasing scarcity,exacerbated by global industrialization,has led to a sharp increase in the cost of such commodities,and leads to critical questions concerning,for example,their long term sustainability.Current prices of Rh(US$65,000/kg)and Pt(US$55,000/kg),for example,mean that precious metal recovery has become a major growth sector.By contrast,catalysts utilizing inexpensive and abundant s and p-block elements have recently begun to emerge.Drawing on this theme,the current proposal is centred around elements costing a small fraction(ca.2-3%)of widely used precious metals,and seeks to develop viable processes based on single-site Main Group catalysts.Thus,the opportunity to exploit Main Group elements,once perceived as catalytically inert,as novel catalysts is not only at the cutting edge scientifically,but also offers huge potential for growth. While our initial approach will be built on exciting preliminary results for tin compounds,we ultimately target catalysts based around more environmentally benign germanium systems.Our goals for the lifetime of this project are therefore to establish the fundamental ground rules for catalyst design in what is an entirely new area of endeavour.As such,we feel that the proposed work fits within the remit of'Structural and kinetic studies to understand the molecular mechanisms involved in catalytic reactions,preparation of novel or improved catalysts and the development of new catalytic processes'as defined by the EPSRC's explicit interpretation of catalysis in its research portfolio.In the wider scheme,the delivery of a new library of catalytic systems has longer term relevance in the manufacture of commodity and fine chemicals,as well as being a significant enabling discipline to EPSRC priority areas such as innovative and sustainable future energy systems,solar technologies,synthetic biology,water and environment,sustainable chemistry,manufacturing and healthcare and grand challenges of urgent societal need such as sustainable energy and new functional materials by design.

Tomotherapy?and?Hematopoietic?Stem?Cells?for?Tolerance?to?Kidney?Transplants ABSTRACT The overarching goal of this project is to develop a tolerance induction protocol for MHC disparate kidney transplants?in?rhesus?macaques?and?to?elucidate?the?underlying?mechanisms?of?the?induction?and?maintenance of?mixed?chimerism?and?tolerance?in?this?model.?The?primary?hypothesis?is?that?tolerance?to?MHC?mismatched kidney?transplants?can?be?safely?and?effectively?achieved?by?establishing?a?mixed?chimeric?state?using?a?newly established post?transplant non?myeloablative, helical tomotherapy?based total lymphoid irradiation (TLI) based conditioning regimen followed by donor bone marrow?CD34+ hematopoietic cell (HSC) infusions. In addition, we will elucidate mechanisms of host immunoregulatory characteristics that are associated with successful?HSC?engraftment?and?maintenance?of?the?chimeric?state.?We?propose?to?test?our?hypotheses?by?means of 2 specific aims: 1.) Combined Bone Marrow Hematopoietic Cell/Kidney Transplants to?determine the proportion?of?rhesus?macaque?recipients?of?disparate?unrelated?donor?kidney?transplants?that?achieve?chimerism (without GVHD) and can be withdrawn from all immunosuppressive drugs for greater than 2 years while maintaining?normal?allograft?function?and?without?rejection.?We?will?measure?the?state?of?mixed?chimerism?in recipients?as?a?function?of?time?post?transplant?and?according?to?various?peripheral?blood?and?bone?marrow?cell types using DNA (STR) analysis, and with flow cytometry using rhesus antibodies specific for MHC class I Mamu?alleles?of?the?donor.??2)?Immune?Monitoring,?Immunopathology?and?Immunocompetence.??We?will:?a.) determine early recipient immunoregulatory changes of host myeloid cells induced by the TLI?based conditioning?regimen?that?correlate?with?the?success?of?bone?marrow?engraftment,?b.)?determine?if?the?mixed chimeric state induces changes of host dendritic cell acquisition of donor MHC class I antigen and PD?LI expression at serial time points during and after withdrawing immunosuppression, c.) characterize the development?of?renal?allograft?immune?and?non?immune?injury?by?analysis?of?serial?renal?allograft?biopsies,?and d.)?determine?the?degree?of?recipient?immune?competency?after?immunosuppressive?drug?withdrawal?by?testing the recall T cell responses to cytomegalovirus antigens and tetanus toxoid. Knowledge gained through this rhesus tolerance induction protocol, including the underlying immunological mechanisms, will have direct relevance to a variety of deceased donor transplants. Furthermore, it will set a new course of healthcare innovation?and?delivery?that?will?greatly?benefit?transplant?patients,?and?other?patient?populations.

При решении задач оптимального управления на базе принципа максимума необходимо сначала определить геометрию оптимальной траектории и после этого проверить выполнение необходимых условий экстремума.Для определения геометрии оптимальной траектории проводится дискретизация исходной постановки задачи.В результате получаем задачу линейного(нелинейного)программирования большой размерности.Для решения задачи линейного программирования применяется метод главных компонент в факторном анализе.Факторный анализ позволяет за счет параметризации функционала задачи и регуляризации линейной алгебраической системы решать несобственные задачи линейного программирования с противоречивыми ограничениями.При этом возникает проблема поиска собственных значений матрицы наблюдений.Для решения указанной проблемы применяется распределенные вычисления и GRID-технологии.С другой стороны,принцип максимума редуцирует исходную задачу к краевой задаче для системы дифференциальных уравнений.Возникает необходимость вычисления матрицы Якоби,которая требуется для решения краевой задачи обобщенным методом Ньютона или градиентных методов(непрерывные аналоги).Здесь также используются распределенные вычисления и GRID-технологии,обеспечивающие обмен данными между географически распределенными пакетами оптимизации для решения большого числа независимых промежуточных подзадач.

В рамках проекта планируется проведение исследований влияния примесей на сверхтекучесть 3Не.Объектом экспериментов будет сверхтекучий 3Не,заполняющий аэрогель высокой пористости,нити которого и играют роль примесей.Существенным обстоятельством является то,что будет использоваться новый аэрогель(на основе окиси алюминия),нити которого ориентированы практически параллельно друг к другу.Такая высокая степень анизотропии приводит к тому,что аэрогель не только ориентирует параметр порядка,но и существенно меняет его вид.Исследования сверхтекучего 3Не в таком"нематически упорядоченном"аэрогеле были нами начаты в рамках предыдущего проекта РФФИ.Было установлено,что в такой системе фазовая диаграмма сверхтекучих фаз сильно отличается от случая объемного 3Не или от случая 3Не в стандартном кремниевом аэрогеле.Доказано,что А-подобные фазы(а их обнаружено две)соответствуют А фазе объемного 3Не,но испытывают сильное полярное искажение,причем в области низких давлений возможно реализуется и чистая полярная фаза,которая ранее никогда не наблюдалась.В рамках данного проекта мы планируем проведение экспериментов по измерению параметров полярного искажения в зависимости от температуры и давления,что позволит определить область существования полярной фазы,если она действительно реализуется.При этом планируется более подробно исследовать В-подобную фазу,которая в предыдущих экспериментах была исследована мало,и ее природа пока точно не установлена.

Fibroblast-like synoviocytes from rheumatoid arthritis patients (RA-FLS) exhibit several tumor cell-like characteristics； however, the role of glucose and glutamine metabolism in the aberrant proliferation of these cells is unclear. We evaluated the role of these metabolic pathways in RA-FLS and in mouse model of RA. GLS1 expression was increased in RA-FLS. RA-FLS proliferation was reduced under glutamine-deprived, but not glucose-deprived, conditions. Cell growth of RA-FLS was inhibited by GLS1 siRNA or GLS1 inhibitor treatment. Treating RA-FLS with either IL-17 or PDGF resulted in increased GLS1 levels. GLS1 inhibitor ameliorated the arthritis and decreased the number of Ki-67-positive synovial cells in SKG mice. Our results suggested that glutamine metabolism is involved in the pathogenesis of RA and that GLS1 plays an important role in regulating RA-FLS proliferation, and may be a novel therapeutic target for RA.

Dysfunction of circadian clock along with aging is implicated with development of lifestyle-related diseases,such as diabetes,cancers,and cardiovascular diseases.However,there was no preventive strategy for lifestyle-related diseases by activation of circadian clock.In this study,we found that ATF4,a circadian clock-regulatory factor,regulates cellular oncogenic transformation and the sensitivity of tumor cells.In addition,control of the activity of ATF4 enabled to prevent oncogenesis.Since ATF4 was also involved in the regulation of amino acid synthesis and cellular senescence,control of the activity of ATF4 may lead to develop the preventive method for lifestyle-related diseases through activating the circadian clock.