A multimechanistic antibody targeting receptor-binding sites potently cross-protects against influenza B viruses

流感病毒HA是研制流感药物和流感疫苗的重要靶标，但HA具有高度变异性，如何在高变异HA中找到不变之处，即高度保守表位，是研制流感特效药物和广谱疫苗的关键。近年来国外报道的流感HA广谱中和单抗的识别位点均在较为保守的HA茎部区，而针对流感病毒与细胞受体结合部位的HA头部区尤其是RBS区，一直未能发现广谱中和抗体。夏宁邵教授团队通过探索多种免疫策略和筛选策略，成功筛选出一株广谱中和单抗12G6，识别一个位于HA头部RBS上的全新保守性表位。体外实验显示12G6人源化改造的C12G6抗体能高效中和1940-2016年间世界各地历年流行的代表三个遗传变异亚系的18个乙型流感病毒代表株对细胞的感染，并能保护小鼠致死性感染，治疗效果显著优于已报道的代表性抗体以及抗流感药物；C12G6与“达菲”联合用药具有明显的协同效果。此外，雪貂感染模型的预防和治疗效果进一步证实了C12G6作为抗体药物的治疗潜能。研究还显示该表位是病毒感染复制的关键表位，该位点的突变会造成病毒毒力显著下降。最后，研究揭示了C12G6通过五种不同的抗病毒作用机制发挥作用，提示其高效的抗病毒活性得益于多机制协同效应，这也是目前国内外第一次发现一个流感抗体能通过如此全面的抗病毒机制发挥作用。 该发现为研制能抵抗各种变异株的乙型流感特效治疗药物和通用疫苗带来新希望。 该研究工作依托分子疫苗学和分子诊断学国家重点实验室（厦门大学）、国家传染病诊断试剂与疫苗工程技术研究中心、厦门大学养生堂生物药物联合实验室完成。陈毅歆副教授、夏宁邵教授为该研究论文的共同通讯作者。在读博士研究生沈晨光、陈俊煜、李睿、王国松和硕士研究生张梦娅等为共同第一作者。【Abstract】Influenza B virus causes considerable disease burden worldwide annually, highlighting the limitations of current influenza vaccines and antiviral drugs. In recent years, broadly neutralizing antibodies (bnAbs) against hemagglutinin (HA) have emerged as a new approach for combating influenza. We describe the generation and characterization of a chimeric monoclonal antibody, C12G6, that cross-neutralizes representative viruses spanning the 76 years of influenza B antigenic evolution since 1940, including viruses belonging to the Yamagata, Victoria, and earlier lineages. Notably, C12G6 exhibits broad cross-lineage hemagglutination inhibition activity against influenza B viruses and has higher potency and breadth of neutralization when compared to four previously reported influenza B bnAbs. In vivo, C12G6 confers stronger cross-protection against Yamagata and Victoria lineages of influenza B viruses in mice and ferrets than other bnAbs or the anti-influenza drug oseltamivir and has an additive antiviral effect when administered in combination with oseltamivir. Epitope mapping indicated that C12G6 targets a conserved epitope that overlaps with the receptor binding site in the HA region of influenza B virus, indicating why it neutralizes virus so potently. Mechanistic analyses revealed that C12G6 inhibits influenza B viruses via multiple mechanisms, including preventing viral entry, egress, and HA-mediated membrane fusion and triggering antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity responses. C12G6 is therefore a promising candidate for the development of prophylactics or therapeutics against influenza B infection and may inform the design of a truly universal influenza vaccine.This research was supported by grants from the National Natural Science Foundation of China (31670934 and 81371817), the Ministry of Science and Technology of the People’s Republic of China (2011ZX09102-009-12 and 2012DFH30020), the Research Grants Council of the Hong Kong Special Administrative Region (7629/13M, 17103214, and 17154516), and a sponsored research agreement from Sanofi Pasteur. 研究工作得到了香港大学新发传染病国家重点实验室和赛诺菲巴斯德公司的技术支持和帮助，获得国家自然科学基金、新药创制国家科技重大专项、科技部对港科技合作项目等课题资助

What has rural life to offer?

Recent decades have witnessed a growing tide of migration of rural people to large urban centres. The flight from country to town has been both because of the lure of city life - employment, social amenities, and escape from traditional social restrictions - and because of the absence in rural areas of basic facilities such as roads, water and electricity, schools and health services. The fact that most migrants have failed to realize their dreams for a brighter future has not slowed the flow. People appear to prefer urban poverty to rural poverty, perhaps maintaining a fading hope that some day their chance will come. The fact that millions of people have come to believe that life in the villages offers no hope whatever is the clearest indication of the failure of rural development in recent years. Yet the opportunities exist for providing an alternative to emigration but they require a change in priorities. Policy makers are confronted with a choice of either encouraging the development of economic activity and supporting services in rural areas or of accepting the status quo and its inevitable consequence; a depopulated, ageing and predominantly female rural sector, agricultural production lagging ever further behind national needs, and ever swelling numbers of desperate urban poor. Towns and cities grow out of the countryside. The greatest cities of the world were once mere collections of a few dwellings. What enabled them to develop into larger communities was either commerce (trade) or industry, and originally industry and trade were based on the needs and production of agriculture. In the past change was slow because population growth was slow, and population movement was in response to urban demand for labour. Famine and military activities forced short term major population shifts to secure cities but the ample opportunity to achieve a degree of self-sufficiency in the rural areas usually drew people back to grow their own food and to benefit from living as extended families in small communities. For much of history there has been a symbiotic relationship between town and country, the former providing the centre of administration and defence in times of trouble, and acting as centres for learning, craftsmanship and trade while the rural hinterland has provided the food and raw materials for processing and trade. But, while history demonstrates that a balanced development of commerce and industry in rural centres can stimulate national development and prosperity, recent policies have diverted many countries from this path with disastrous social and economic consequences. Colonization by foreign powers required that administration, commerce and, more rarely industry, were centralized for easier control. Since the rural hinterland was invariably looked on as only a source of raw materials and labour it was left without investment or development. As examples, the copper mines of Zambia, the coal fields of Zimbabwe and the gold and diamond deposits of South Africa demanded for the most part very large work-forces. Since supervisors and management were colonists there was no perceived requirement to develop education in the rural areas from which this labour was drawn. Similarly, plantations drew labour from as far afield as, for example, to Côte d'lvoire, from Mali and Burkina Faso. And, since the administration adopted a laissez faire attitude to life in the villages, little was done initially to try and change traditional techniques of agriculture or to improve facilities. Belatedly some colonial powers instituted basic education and health in rural districts. However, the pattern of roads suited to central government, absence of rural electricity and other amenities, and lack of any alternative sources of employment other than subsistence agriculture or migrant labour, was inherited and perpetuated by national governments after Independence. Western Nigeria provides a typical example of how changes in attitude and priorities damaged and distorted development. Traditionally in Nigeria, as in many other countries, the market place was a focal point of economic life and around it developed a hierarchy of settlements ranging from small hamlets to large cities. However, the values implicit in these traditional settlement and market patterns in Nigeria seem to have been overlooked or ignored in post-independence developments such as the building of transport routes. Trunk and even feeder roads have often by-passed centres of production and trade with the result that produce has frequently failed to reach the more distant and larger market centres. Changing perceptions and priorities The International Food Policy Research Institute (IFPRI), which is based in Washington, organized a meeting of leading African anglophone and francophone policy-makers and researchers in Saly Portugal, Senegal in December 1994 as part of its 2020 Vision for Food, Agriculture and the Environment initiative. A synthesis of the views included the observation that, 'Most governments want to reduce poverty but many are doubtful that it can be done on a sustainable basis. This illustrates the importance of understanding both the sources of poverty in Africa and the links between economic growth and poverty alleviation. Since 90% of Africa's poor live in rural areas, key poverty reduction strategies should aim at raising rural incomes. This necessarily involves measures to increase agricultural productivity which will directly increase rural incomes. Incomes will also increase indirectly through the creation of effective purchasing power in rural areas for services and local manufactured items, thus increasing off-farm employment.' Until recently, the role of small towns and the need for off-farm employment as foci for rural change and transformation in Africa have generally been neglected by national governments and by the aid community and development organizations. Instead, integrated rural development programmes were adopted by many administrations and development agencies to the exclusion of the development of small urban centres, which were neglected and often dismissed as 'problem areas'. There has now been a gradual shift in the ways of thinking and as the IFPRI seminar revealed, there is growing acknowledgement of the interdependence and complementary roles of rural and urban sectors. The symbiotic relationship between country and town is being recognized and it can be seen that neither can survive let alone thrive without the other. Despite the lack of recognition given to them, traditional market centres can provide off-farm employment and a link between the production and consumption centres of the economies within which they are located. They also act as the centres of information for the surrounding areas and have various facilities such as health, credit and postal services. Suitable industries for off-farm employment Ideally industries for development in rural areas should utilize the raw materials available in the locality. Agroprocessing is an obvious choice since it not only utilizes farm produce but adds value. It also reduces the need for transport to more distant and centralized sites and therefore reduces costs; only the less bulky processed goods have need of transport out of the area while the by-products, such as cotton seed and palm kernel and grain polishings, remain in the rural areas where they are easily accessible for farmers wishing to purchase them for feeding to livestock. In large urban centres such materials are, more often than not, an inconvenient and potentially polluting biomass. Food processing lends itself to decentralization and small-scale development. On a small scale, it requires very little equipment and capital investment, and suitable technologies exist for small scale drying of fruits, nuts and vegetables oil extraction, baked goods and snack food production. Conversely there are technologies which are inappropriate for small-scale adoption; these include operations that require substantial capital outlay for equipment, for example the canning of fruit, making juices and bottling or dried milk production. If there is a local demand from consumers for a particular product, turnover is rapid and initial investments can be recouped quickly. Food processing adds value to raw products and prevents wastage by converting produce into less perishable forms. Because the consumption of food is a basic requirement of all people, rural and urban, and because families are increasingly seeking timesaving ways of preparing foods, food processing can be a very successful small enterprise. In contrast, the introduction of large-scale food processing factories can be detrimental to rural people. Because such factories are often highly automated, they employ few people and many of these are skilled technicians and supervisors trained in electronics and nutrition sciences. Many less educated yet enterprising and hard working people, particularly women heads of households, who are reliant on traditional food processing practices such as hand operated milling, grinding and oil extraction, are forced out of the market through competition. Yet if all the costs of establishing, running and maintaining modern factories were shown, including the social and environmental costs, the small-scale enterprises would often have a clear advantage. Large-scale food processing may also result in products that are nutritionally inferior to traditional products. For example, polished rice, white bread made from refined flour, and white sugar are all less nutritious than their traditional counterparts, hand-pounded rice, ground maize-meal and gun Some manufactured products may even be injurious to health: in Nigeria, for example, the manufacture of gari from cassava is now frequently mechanized. Because it contains cyanide, some varieties of fresh cassava traditionally undergo a laborious process to effect detoxification and render it safe for consumption. In terms of cyanide removal, the longer this process takes, the better is the end product. Mechanization has meant , that the traditional 4-6 , day processes have been reduced to one : day with variable effects on product quality and nutritional value. One of the arguments used to support the development of large-scale food processing plants is that they will provide a guaranteed market for rural production that would otherwise go to waste. In practice these plants are often sited in cities which are either inaccessible because of lack of feeder roads, or incur an unacceptably high transport cost for rural people. Plant managers may also impose strict limitations on the quality and minimum quantity of raw material that will be accepted. These obstacles force many small producers out of the market and discourage potential newcomers. Ironically, the self-same inhibiting factors can lead to the demise of the large processing plants since they fail to operate at full capacity and therefore are unable to deliver the low cost of production that processing in large quantity should provide. In Zimbabwe decentralized production of edible oil from sunflower seed proved to be a successful initiative (See box). Since independence in 1980, the government of Zimbabwe has embarked on a national programme to restructure the economy. One of the major thrusts has been to develop the communal lands through the development of rural settlement infrastructure in district and rural service centres. The government believed that centres could provide a growth point. In the hierarchy of settlements, growth points lie between existing town and district service centres in terms of the facilities which are available. Some of the characteristics of a growth point include: · the existence of a proven economy, which through utilizing local raw materials is capable of sustainable growth; · a high potential for the development of substantial forward and backward linkages with the surrounding hinterlands through vertical and horizontal integration; · the ability to facilitate industrial decentralization by providing alternative but viable opportunities. These growth points are basically urban but some are in the hinterland. Some 20 growth points were identified but of these only four or five have demonstrated potential. The majority of the centres were selected because they were administrative centres but many proved to be little more than small towns that had grown up around administrative offices, police, army, courts and supermarkets with no real opportunities for small businesses. Similar development and planning policies have been implemented in Malawi and Tanzania. Jonathan Barker of the Scandinavian Institute of African Studies, Uppsala, Sweden, reported on the results of a SlDA-commissioned study of these towns in northern Tanzania which 'show that the most economically successful and secure households in surrounding villages are those which combine crop production and sales with a variety of non-farm and off-farm income-generating activities. 'Nor-farm' production refers to work which is carried out on the farm but which is not related to crop production; for example, making furniture and bricks for sale in both small town and village markets. 'Off-farm' refers to activities carried out elsewhere. These include employment in town and ownership of urban assets such as shops or rooms for renting.' People and policy Government policy can encourage or inhibit individuals to greater or lesser endeavour and entrepreneurship. If there is to be growth of small businesses in rural areas crucial needs are ready access to finance and to an all-weather transport system. Both needs can be greatly assisted by central and regional governments. A good road network will itself encourage the development of small transport businesses but whether entrepreneurs turn to trucking, agroprocessing or the many associated activities that are needed by a prospering community (ranging from engineering repair shops, agricultural supplies merchants and fuel suppliers to tailors, clothes outfitters, food shops and restaurants) most will require finance to get started. Few rural people have the collateral necessary to secure standard bank borrowing and government guaranteeing of 'seed money' loans can result in substantial pay-back for relatively small initial investment. Once businesses are established and have accumulated financial resources, both as working capital and purchased plant, they can use these as security for any further loans from the official banking sector in order to expand further. Provided that potential borrowers have made clear to them the basis of 'start-up' loans and terms of repayment, and are guided to draw up an outline business plan to establish how the borrowing is to be serviced, funds will be repaid and the money will be available for further lending ' to others. Experience in Africa and Asia , has shown that provision of credit can , stimulate dramatic changes in the prosperity of people previously consider unbankable and destined for perpetual poverty. All this will require a major change in outlook at the most senior levels of government. Finding resources to fund development in rural areas at this time of financial constraint will be difficult but, as the participants of IFPRI's 2020 Vision for Food, Agriculture and the Environment in sub-Saharan African concluded on this issue: 'Although this need comes at a time of public retrenchment, it is a question of priorities. In most countries, the rate of national public investment in agriculture must be raised significantly. Given the size of the agricultural sector, its present and potential contributions to the economy, and its share in export earnings and fiscal revenues, as much as 30-40% of national budget outlays should be invested in agriculture. This is a figure that far exceeds the historical average of 7% of budgetary expenditure going to this sector.' Some may say that governments have a choice but others might observe that in reality they have no choice.Recent decades have witnessed a growing tide of migration of rural people to large urban centres. The flight from country to town has been both because of the lure of city life - employment, social amenities, and escape from traditional social..

杭州西湖浮游藻类变化规律与水质的关系

于2006～2007年对杭州西湖浮游藻类的种类及个体丰度进行初步研究,并依据《水和废水监测分析方法》对其水质现状进行了生物学评价。综合生物和理化指标数据,对杭州西湖的水质作一总体评估,并对西湖水中的物种多样性保护及水质的可持续利用提出了建议。共鉴定浮游藻类179种,其中蓝藻25种,隐藻1种,金藻3种,甲藻3种,黄藻5种,裸藻23种,硅藻41种和绿藻78种。分析了杭州西湖浮游藻类的组成和分布的特点,揭示出西湖浮游藻类的种类组成与西湖水质变化之间的关系。结果表明：藻类的组成和分布与水质变化规律基本吻合,西湖水质较整治前有明显的改善,一些清水藻类的物种逐步增多

JUNO Sensitivity on Proton Decay p→νˉK+p\to \bar\nu K^+ Searches

The Jiangmen Underground Neutrino Observatory (JUNO) is a large liquid scintillator detector designed to explore many topics in fundamental physics. In this paper, the potential on searching for proton decay in $p\to \bar\nu K^+$ mode with JUNO is investigated.The kaon and its decay particles feature a clear three-fold coincidence signature that results in a high efficiency for identification. Moreover, the excellent energy resolution of JUNO permits to suppress the sizable background caused by other delayed signals. Based on these advantages, the detection efficiency for the proton decay via $p\to \bar\nu K^+$ is 36.9% with a background level of 0.2 events after 10 years of data taking. The estimated sensitivity based on 200 kton-years exposure is $9.6 \times 10^{33}$ years, competitive with the current best limits on the proton lifetime in this channel

JUNO sensitivity on proton decay p → ν K + searches*

The Jiangmen Underground Neutrino Observatory (JUNO) is a large liquid scintillator detector designed to explore many topics in fundamental physics. In this study, the potential of searching for proton decay in the $p\to \bar{\nu} K^+$ mode with JUNO is investigated. The kaon and its decay particles feature a clear three-fold coincidence signature that results in a high efficiency for identification. Moreover, the excellent energy resolution of JUNO permits suppression of the sizable background caused by other delayed signals. Based on these advantages, the detection efficiency for the proton decay via $p\to \bar{\nu} K^+$ is 36.9% ± 4.9% with a background level of $0.2\pm 0.05({\rm syst})\pm$$0.2({\rm stat})$ events after 10 years of data collection. The estimated sensitivity based on 200 kton-years of exposure is $9.6 \times 10^{33}$ years, which is competitive with the current best limits on the proton lifetime in this channel and complements the use of different detection technologies