Molecular mechanisms and clinical applications of angiogenesis

Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.     

Chemical space and biology

Chemical space--which encompasses all possible small organic molecules, including those present in biological systems--is vast. So vast, in fact, that so far only a tiny fraction of it has been explored. Nevertheless, these explorations have greatly enhanced our understanding of biology, and have led to the development of many of today's drugs. The discovery of new bioactive molecules, facilitated by a deeper understanding of the nature of the regions of chemical space that are relevant to biology, will advance our knowledge of biological processes and lead to new strategies to treat disease.     

Glial and neuronal control of brain blood flow

Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches.     

Frontal and stealth attack strategies in microbial pathogenesis

Interactions between microbes and human hosts can range from a benign, even symbiotic collaboration to a competition that may turn fatal--resulting in death of the host, the microbe or both. Despite advances that have been made over the past decades in understanding microbial pathogens, more people worldwide still die every year from infectious disease than from any other cause. This highlights the relevance of continuing to probe the mechanisms used by microorganisms to cause disease, and emphasizes the need for new model systems to advance our understanding of host-pathogen interactions.     

Predicting disease using genomics

Information from the human genome sequence will eventually alter many aspects of clinical practice. It will increase through our understanding of disease mechanisms, and guide the development of new drugs and therapeutic procedures. In the short term, however, knowledge of the genome will have a profound clinical impact on the diagnostic capability of clinical genetics laboratories. Molecular phenotyping using genetic and genomic information will allow early and more accurate prediction and diagnosis of disease and of disease progression. Medicine will become oriented towards disease prevention rather than efforts to cure people at late stages of illness.     

Supernova explosions in the Universe

During the lifetime of our Milky Way galaxy, there have been something like 100 million supernova explosions, which have enriched the Galaxy with the oxygen we breathe, the iron in our cars, the calcium in our bones and the silicon in the rocks beneath our feet. These exploding stars also influence the birth of new stars and are the source of the energetic cosmic rays that irradiate us on the Earth. The prodigious amount of energy (approximately 10(51), or approximately 2.5 x 10(28) megatonnes of TNT equivalent) and momentum associated with each supernova may even have helped to shape galaxies as they formed in the early Universe. Supernovae are now being used to measure the geometry of the Universe, and have recently been implicated in the decades-old mystery of the origin of the gamma-ray bursts. Together with major conceptual advances in our theoretical understanding of supernovae, these developments have made supernovae the centre of attention in astrophysics.     

Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha

Macrophages are important in the induction of new blood vessel growth during wound repair, inflammation and tumour growth. We show here that tumour necrosis factor-alpha (TNF-alpha), a secretory product of activated macrophages that is believed to mediate tumour cytotoxicity, is a potent inducer of new blood vessel growth (angiogenesis). In vivo, TNF-alpha induces capillary blood vessel formation in the rat cornea and the developing chick chorioallantoic membrane at very low doses. In vitro, TNF-alpha stimulates chemotaxis of bovine adrenal capillary endothelial cells and induces cultures of these cells grown on type-1 collagen gels to form capillary-tube-like structures. The angiogenic activity produced by activated murine peritoneal macrophages is completely neutralized by a polyclonal antibody to TNF-alpha, suggesting immunological features are common to TNF-alpha and the protein responsible for macrophage-derived angiogenic activity. In inflammation and wound repair, TNF-alpha could augment repair by stimulating new blood vessel growth; in tumours, TNF-alpha might both stimulate tumour development by promoting vessel growth and participate in tumour destruction by direct cytotoxicity.     

Role of cholesterol and lipid organization in disease

Membrane lipids are essential for biological functions ranging from membrane trafficking to signal transduction. The composition of lipid membranes influences their organization and properties, so it is not surprising that disorders in lipid metabolism and transport have a role in human disease. Significant recent progress has enhanced our understanding of the molecular and cellular basis of lipid-associated disorders such as Tangier disease, Niemann-Pick disease type C and atherosclerosis. These insights have also led to improved understanding of normal physiology.     

国际视野下的创新评价指数研究

随着人们对于创新的理解不断深化以及新的创新分类的出现,创新评价愈益引起学界的关注。通过对国际上出现的"国家创新能力指数"、"全球综合创新指数"和"世界知识竞争力指数"等创新评价指数及其相关内容进行些许分析,通过对这些评价指数的了解而更为准确地认识我国在创建创新型国家进程中所面临的有利条件和不利因素。     

基于饥饿源于菌群的新发现将引发慢病防控突破性进展

 当前持续高发的慢病严重影响社会发展,迫切需要找到有效的解决方案。虽然近年来生命科学和传统医学及当代医学取得了长足进步,但是当前的慢病高发现状反过来提示人们,必须采用全新的、甚至是颠覆性思维模式重新思考慢病的病因学问题,方有可能从根本上解决慢病防控难题。在长期从事生命科学和生物医学研究的基础上,结合自身的测试与体验,陆续形成了饥饿源于菌群及慢病源于菌群的系列新发现,并在此基础上形成了菌心说学说（简称菌心学说）及其相应技术。本文系统阐述菌心学说的观点,以及基于该观点形成的慢病起源的新认识,同时提出有效的慢病防控方案。以往中医主张"天人合一",西医主张"人类基因异常导致慢病",在菌心学说框架下所形成的肠道菌群异常（通过导致人类基因异常）而导致慢病的新医学体系,恰好对应了医学发展过程中的不同阶段和不同版本（中医对应于"医学1.0"版本,西医对应于"医学2.0"版本,新医学对应于"医学3.0"版本）。     

新生儿溶血病血清学检查分析

通过对我院临床确诊的34例新生儿溶血病血清学检查回顾,对血清学诊断方法进行分析评价。确诊为高胆红质血症,新生儿溶血病患儿进行血型鉴定、直接抗球蛋白试验(DAT)、血清游离抗体测定试验、新生儿红细胞抗体释放试验检测。结果显示34例ABOHDN患儿中新生儿红细胞直抗试验阳性率85.29%,血清游离抗体试验76.47%,新生儿红细胞抗体释放试验100%。说明新生儿红细胞抗体释放试验是鉴定新生儿溶血病最敏感的一项试验。     

Molecular identification of a renal urate anion exchanger that regulates blood urate levels

Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.     

Progress in Research on the Role of Angiomotins in Cancer

Cancer is a major public health problem worldwide and its overall morbidity and mortality have been increasing every year. The growth, invasion and metastasis of cancer are vital traits of malignancy causing extreme difficulties in therapeutic management. These behavioral characteristics of cancer are closely related to tumor angiogenesis. The argument was put forward that tumorigenesis depended on the formation of new blood vessels, which gained insight into a promising treatment strategy for cancer based on the inhibition of tumor angiogenesis. To date, many new therapeutic strategies targeting tumor vessels are universally accepted and become a hotspot in oncology research. Angiomotin(Amot), encoded by Amot gene, is expressed predominantly in endothelial cells of capillaries as well as larger vessels of the placenta. During the formation of new blood vessels, Amot may play an inhibitory effect of angiostatin on tube formation and the migration of endothelial cells toward growth factors. In this review, we summarized the structure and function of Amot, and its mechanism and research progress in cancer.     

The search for new cardiovascular biomarkers

Despite considerable advances in the treatment of cardiovascular disease, it remains the leading cause of death in developed countries. Assessment of classic cardiovascular risk factors--including high blood pressure, diabetes and smoking--has a central role in disease prevention. However, many individuals with coronary heart disease (a narrowing of the blood vessels that supply the heart) have only one, or none, of the classic risk factors. Thus, new biomarkers are needed to augment the information obtained from traditional indicators and to illuminate disease mechanisms.     

当前慢病防控困境迫切呼唤新医学和菌心说

 进入21 世纪以来,国际社会所面临的慢病防控形势愈发严峻,不仅对于肥胖、糖尿病、高血压、肿瘤等慢病仍然缺乏良策,而且新药研发速度也并没有随着人类基因组计划的完成得到提高,进而导致欧美以及中国医疗改革举步维艰,反过来提示当代医疗模式可能存在一定问题。结合国际上的研究进展,针对这些问题进行系统分析以及基于大量志愿者进行科学研究的基础上,提出“慢病的菌源性学说”,倾向于认为人体慢病主要是由于多种因素所导致的人体共生微生物菌群紊乱造成的,同时证明可通过纠正胃肠道菌群紊乱显著改善包括便秘、肥胖、糖尿病等在内的慢病症状。在此基础上,还进一步提出“心理活动的菌源性学说”,认为人类的心理活动除了与大脑密切相关之外,还与人体共生菌群密切相关,甚至不排除人类心理活动有可能是微生物菌群通过人体大脑控制下的机体行为所展示出来的一种表现。进而提出新医学理论和菌心说学说,认为人菌平衡是健康的标志,而人菌失衡是慢病的根源,而且人菌失衡的关键在于人体和菌群之间的碳源竞争。菌心说学说认为相对于人体的躯体和大脑而言,由人体共生微生物菌群所构成的“心脑菌脑”有可能是人类心理活动的核心、中心和重心,而人体则有可能是被设计为菌群微生态系统提供生存与发展作用的场所和工具。基于这一观点,不仅可望实现慢病防控与健康管理领域的新突破,而且还有可能实现对人类心理活动以及精神意识活动的物质基础的认知与升华,对于重新认识人类以及人类社会将有可能带来前所未有的新突破。     

The complexities of skeletal biology

For a long time, the skeleton was seen as an amorphous tissue of little biological interest. But such a view ignored the large number of genetic and degenerative diseases affecting this organ. Over the past 15 years, molecular and genetic studies have modified our understanding of skeletal biology. By so doing this progress has affected our understanding of diseases and suggested in many instances new therapeutic opportunities.     

New gene functions in megakaryopoiesis and platelet formation

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.     

Stem-cell-based therapy and lessons from the heart

The potential usefulness of human embryonic stem cells for therapy derives from their ability to form any cell in the body. This potential has been used to justify intensive research despite some ethical concerns. In parallel, scientists have searched for adult stem cells that can be used as an alternative to embryonic cells, and, for the heart at least, these efforts have led to promising results. However, most adult cardiomyocytes are unable to divide and form new cardiomyocytes and would therefore be unable to replace those lost as a result of disease. Basic questions--for example, whether cardiomyocyte replacement or alternatives, such as providing the damaged heart with new blood vessels or growth factors to activate resident stem cells, are the best approach--remain to be fully addressed. Despite this, preclinical studies on cardiomyocyte transplantation in animals and the first clinical trials with adult stem cells have recently been published with mixed results.     

科技型新创企业社会资本、资源拼凑与成长绩效的关系研究

已有研究显示社会资本对企业成长既有正面的促进作用，又会产生锁定等负面作用。基于社会建构理论，资源拼凑将通过重新定义和组合现有资源，降低社会资本锁定的负面效应。通过215家新创企业的调查样本验证了研究假设。结果表明，外部社会资本和内部社会资本均与新创企业资源拼凑行为正向相关，企业资源拼凑行为能促进企业的成长绩效，而资源拼凑在外部、内部社会资本与成长绩效间关系中起着中介作用。上述研究成果为理解我国新创企业的成长提供了新的理论贡献和实践启示。