Trial designs for targeted therapies

This is a discussion of the paper 'Making efficient use of patients in designing phase III trials investigating simultaneously a set of targeted therapies with different targets' by Werner Vach and Rene dePont Christensen.     

植物对盐渍逆境的适应

主要讨论植物是如何对盐渍环境适应的,盐渍环境对植物产生两种胁迫因子－－渗透胁迫和离子胁迫,前者有水困难,后者对植物代谢生理功能产生毒害。植物要适应盐渍环境必须具备克服这两胁迫的能力。陆生植物对盐渍环境的适应方式在克服盐离子每害方面主要有3种：衡盐、泌盐和拒盐;在克服渗透胁迫方面主要是渗透调节。海洋植物的适应方式则较为复杂,既要适应盐渍环境,又要适应水环境。     

生物多样性保护适应气候变化的管理策略

应对气候变化和保护生物多样性是2大全球性热点环境问题。气候变化导致物种多样性丧失、生态系统服务降低和区域生态安全屏障功能受损,威胁到中国国土生态安全格局和生态脆弱区域的可持续发展,给生物多样性保护带来新的挑战。做好生物多样性保护适应气候变化的风险管理工作,既是生物多样性应对气候变化风险的必要措施,也是减缓气候变化的重要途径。结合爱知目标10的实现情况,分析了欧盟、澳大利亚、美国等发达国家发布的生物多样性适应气候变化技术政策制定情况、中国生物多样性应对气候变化进展情况,剖析了中国生物多样性保护适应气候变化存在的问题,包括生物多样性应对气候变化的科学认知亟待提高、生物多样性保护适应气候变化的能力建设不足、自然保护地之间缺乏适应气候变化的生态廊道网络、生物多样性保护适应气候变化的技术标准缺乏。研究提出了中国生物多样性应对气候变化的适应性管理策略,包括制定《中国生物多样性保护协同应对气候变化的国家方案》、加强生物多样性保护适应气候变化的能力建设、开展自然保护区适应气候变化的风险管理试点、强化生物多样性应对气候变化的科技支撑,以期为推进纳入气候变化风险管理的生物多样性保护工作提供决策依据。     

How proteins adapt to a membrane-water interface

Membrane proteins present a hydrophobic surface to the surrounding lipid, whereas portions protruding into the aqueous milieu expose a polar surface. But how have proteins evolved to deal with the complex environment at the membrane-water interface? Some insights have been provided by high-resolution structures of membrane proteins, and recent studies of the role of individual amino acids in mediating protein-lipid contacts have shed further light on this issue. It now appears clear that the polar-aromatic residues Trp and Tyr have a specific affinity for a region near the lipid carbonyls, whereas positively charged residues extend into the lipid phosphate region.     

Osteoclasts adapt to physioxia perturbation through DNA demethylation

Oxygen plays an important role in diverse biological processes. However, since quantitation of the partial pressure of cellular oxygen in vivo is challenging, the extent of oxygen perturbation in situ and its cellular response remains underexplored. Using two‐photon phosphorescence lifetime imaging microscopy, we determine the physiological range of oxygen tension in osteoclasts of live mice. We find that oxygen tension ranges from 17.4 to 36.4 mmHg, under hypoxic and normoxic conditions, respectively. Physiological normoxia thus corresponds to 5% and hypoxia to 2% oxygen in osteoclasts. Hypoxia in this range severely limits osteoclastogenesis, independent of energy metabolism and hypoxia‐inducible factor activity. We observe that hypoxia decreases ten‐eleven translocation (TET) activity. Tet2/3 cooperatively induces Prdm1 expression via oxygen‐dependent DNA demethylation, which in turn activates NFATc1 required for osteoclastogenesis. Taken together, our results reveal that TET enzymes, acting as functional oxygen sensors, regulate osteoclastogenesis within the physiological range of oxygen tension, thus opening new avenues for research on in vivo response to oxygen perturbation.     

Progerin-expressing endothelial cells are unable to adapt to shear stress

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease caused by a single-point mutation in the lamin A gene, resulting in a truncated and farnesylated form of lamin A. This mutant lamin A protein, known as progerin, accumulates at the periphery of the nuclear lamina, resulting in both an abnormal nuclear morphology and nuclear stiffening. Patients with HGPS experience rapid onset of atherosclerosis, with death from heart attack or stroke as teenagers. Progerin expression has been shown to cause dysfunction in both vascular smooth muscle cells and endothelial cells (ECs). In this study, we examined how progerin-expressing endothelial cells adapt to fluid shear stress, the principal mechanical force from blood flow. We compared the response to shear stress for progerin-expressing, wild-type lamin A overexpressing, and control endothelial cells to physiological levels of fluid shear stress. Additionally, we also knocked down ZMPSTE24 in endothelial cells, which results in increased farnesylation of lamin A and similar phenotypes to HGPS. Our results showed that endothelial cells either overexpressing progerin or with ZMPSTE24 knockdown were unable to adapt to shear stress, experiencing significant cell loss at a longer duration of exposure to shear stress (3 days). Endothelial cells overexpressing wild-type lamin A also exhibited similar impairments in adaptation to shear stress, including similar levels of cell loss. Quantification of nuclear morphology showed that progerin-expressing endothelial cells had similar nuclear abnormalities in both static and shear conditions. Treatment of progerin-expressing cells and ZMPSTE24 KD cells with lonafarnib and methystat, drugs previously shown to improve HGPS nuclear morphology, resulted in improvements in adaptation to shear stress. Additionally, the prealignment of cells to shear stress before progerin-expression prevented cell loss. Our results demonstrate that changes in nuclear lamins can affect the ability of endothelial cells to properly adapt to shear stress.     

Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology

Vaccination is one of the most effective interventions in global health. The worldwide vaccination programs significantly reduced the number of deaths caused by infectious agents. A successful example was the eradication of smallpox in 1979 after two centuries of vaccination campaigns. Since the first variolation administrations until today, the knowledge on immunology has increased substantially. This knowledge combined with the introduction of cell culture and DNA recombinant technologies revolutionized vaccine design. This review will focus on vaccines against human viral pathogens, recent developments on vaccine design and cell substrates used for their manufacture. While the production of attenuated and inactivated vaccines requires the use of the respective permissible cell substrates, the production of recombinant antigens, virus‐like particles, vectored vaccines and chimeric vaccines requires the use – and often the development – of specific cell lines. Indeed, the development of novel modern viral vaccine designs combined with, the stringent safety requirements for manufacture, and the better understanding on animal cell metabolism and physiology are increasing the awareness on the importance of cell line development and engineering areas. A new era of modern vaccinology is arriving, offering an extensive toolbox to materialize novel and creative ideas in vaccine design and its manufacture.     

Modelling the work to be done by Escherichia coli to adapt to sudden temperature upshifts

AIMS: This paper studies and models the effect of the amplitude of a sudden temperature upshift DeltaT on the adaptation period of Escherichia coli, in terms of the work to be done by the cells during the subsequent lag phase (i.e., the product of growth rate mumax and lag phase duration lambda). METHODS AND RESULTS: Experimental data are obtained from bioreactor experiments with E. coli K12 MG1655. At a predetermined time instant during the exponential growth phase, a sudden temperature upshift is applied (no other environmental changes take place). The length of the (possibly) induced lag phase and the specific growth rate after the shift are quantified with the growth model of Baranyi and Roberts (Int J Food Microbiol 23, 1994, 277). Different models to describe the evolution of the product lambda x mumax as a function of the amplitude of the temperature shift are statistically compared. CONCLUSIONS: The evolution of lambda x mumax is influenced by the amplitude of the temperature shift DeltaT and by the normal physiological temperature range. As some cut-off is observed, the linear model with translation is preferred to describe this evolution. SIGNIFICANCE AND IMPACT OF THE STUDY: This work contributes to the characterization of microbial lag phenomena, in this case for E. coli K12 MG1655, in view of accurate predictive model building.     

Many roads to resistance: how invertebrates adapt to Bt toxins

The Cry family of Bacillus thuringiensis insecticidal and nematicidal proteins constitutes a valuable source of environmentally benign compounds for the control of insect pests and disease agents. An understanding of Cry toxin resistance at a molecular level will be critical to the long-term utility of this technology; it may also shed light on basic mechanisms used by other bacterial toxins that target specific organisms or cell types. Selection and cross-resistance studies have confirmed that genetic adaptation can elicit varying patterns of Cry toxin resistance, which has been associated with deficient protoxin activation by host proteases, and defective Cry toxin-binding cell surface molecules, such as cadherins, aminopeptidases and glycolipids. Recent work also suggests Cry toxin resistance may be induced in invertebrates as an active immune response. The use of model invertebrates, such as Caenorhabditis elegans and Drosophila melanogaster, as well as advances in insect genomics, are likely to accelerate efforts to clone Cry toxin resistance genes and come to a detailed and broad understanding of Cry toxin resistance.