Developing anti-neoplastic biotherapeutics against eIF4F

Biotherapeutics have revolutionized modern medicine by providing medicines that would not have been possible with small molecules. With respect to cancer therapies, this represents the current sector of the pharmaceutical industry having the largest therapeutic impact, as exemplified by the development of recombinant antibodies and cell-based therapies. In cancer, one of the most common regulatory alterations is the perturbation of translational control. Among these, changes in eukaryotic initiation factor 4F (eIF4F) are associated with tumor initiation, progression, and drug resistance in a number of settings. This, coupled with the fact that systemic suppression of eIF4F appears well tolerated, indicates that therapeutic agents targeting eIF4F hold much therapeutic potential. Here, we discuss opportunities offered by biologicals for this purpose.     

A new method of scenario analysis for strategic planning

We first present scenario analysis as a qualitative forecasting technique useful for strategic planning. Then we develop an overview of the two classes of methods for scenario analysis described in the literature. Based on both classes, a new method is developed which especially fits the needs of strategic planning. The method can be divided into three stages: 1. Determination of compatible scenarios, 2. Determination of scenario probabilities, and 3. Determination of main scenarios. An example is given to illustrate the method.     

“Exploratory experimentation” as a probe into the relation between historiography and philosophy of science

This essay utilizes the concept “exploratory experimentation” as a probe into the relation between historiography and philosophy of science. The essay traces the emergence of the historiographical concept “exploratory experimentation” in the late 1990s. The reconstruction of the early discussions about exploratory experimentation shows that the introduction of the concept had unintended consequences: Initially designed to debunk philosophical ideas about theory testing, the concept “exploratory experimentation” quickly exposed the poverty of our conceptual tools for the analysis of experimental practice. Looking back at a number of detailed analyses of experimental research, we can now appreciate that the concept of exploratory experimentation is too vague and too elusive to fill the desideratum whose existence it revealed.     

An integrated view of the chemistry and mineralogy of martian soils

The mineralogical and elemental compositions of the martian soil are indicators of chemical and physical weathering processes. Using data from the Mars Exploration Rovers, we show that bright dust deposits on opposite sides of the planet are part of a global unit and not dominated by the composition of local rocks. Dark soil deposits at both sites have similar basaltic mineralogies, and could reflect either a global component or the general similarity in the compositions of the rocks from which they were derived. Increased levels of bromine are consistent with mobilization of soluble salts by thin films of liquid water, but the presence of olivine in analysed soil samples indicates that the extent of aqueous alteration of soils has been limited. Nickel abundances are enhanced at the immediate surface and indicate that the upper few millimetres of soil could contain up to one per cent meteoritic material.     

Water alteration of rocks and soils on Mars at the Spirit rover site in Gusev crater

Gusev crater was selected as the landing site for the Spirit rover because of the possibility that it once held a lake. Thus one of the rover's tasks was to search for evidence of lake sediments. However, the plains at the landing site were found to be covered by a regolith composed of olivine-rich basaltic rock and windblown 'global' dust. The analyses of three rock interiors exposed by the rock abrasion tool showed that they are similar to one another, consistent with having originated from a common lava flow. Here we report the investigation of soils, rock coatings and rock interiors by the Spirit rover from sol (martian day) 1 to sol 156, from its landing site to the base of the Columbia hills. The physical and chemical characteristics of the materials analysed provide evidence for limited but unequivocal interaction between water and the volcanic rocks of the Gusev plains. This evidence includes the softness of rock interiors that contain anomalously high concentrations of sulphur, chlorine and bromine relative to terrestrial basalts and martian meteorites; sulphur, chlorine and ferric iron enrichments in multilayer coatings on the light-toned rock Mazatzal; high bromine concentration in filled vugs and veins within the plains basalts; positive correlations between magnesium, sulphur and other salt components in trench soils; and decoupling of sulphur, chlorine and bromine concentrations in trench soils compared to Gusev surface soils, indicating chemical mobility and separation.     

Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Loci associated with FEVR map to 11q13-q23 (EVR1; OMIM 133780, ref. 1), Xp11.4 (EVR2; OMIM 305390, ref. 2) and 11p13-12 (EVR3; OMIM 605750, ref. 3). Here we have confirmed linkage to the 11q13-23 locus for autosomal dominant FEVR in one large multigenerational family and refined the disease locus to a genomic region spanning 1.55 Mb. Mutations in FZD4, encoding the putative Wnt receptor frizzled-4, segregated completely with affected individuals in the family and were detected in affected individuals from an additional unrelated family, but not in normal controls. FZD genes encode Wnt receptors, which are implicated in development and carcinogenesis. Injection of wildtype and mutated FZD4 into Xenopus laevis embryos revealed that wildtype, but not mutant, frizzled-4 activated calcium/calmodulin-dependent protein kinase II (CAMKII) and protein kinase C (PKC), components of the Wnt/Ca(2+) signaling pathway. In one of the mutants, altered subcellular trafficking led to defective signaling. These findings support a function for frizzled-4 in retinal angiogenesis and establish the first association between a Wnt receptor and human disease.     

包容性学习：开放教育资源和云服务

许多年来，技术性教育都承诺存在着能够适应每一个学习者学习经验的潜力.如果一个加入信息技术的学习环境能够了解到每一个学习者的学习偏好，那么学习环境就可能为他们提供一个独特的优化学习经验.云服务的聚合功能，以及由此发展而来的智能系统，都恰如其分地增强和替代了原有的资源，随之而来的可共享的、合理设计的以及可标记的资源又使之变为可能.为了达到这一目标，我们需要一个新的方式来看待、生产和传送教育学习资源.     

'Through thousands of errors we reach the truth' - but how? On the epistemic roles of error in scientific practice

This essay is concerned with the epistemic roles of error in scientific practice. Usually, error is regarded as something negative, as an impediment or obstacle for the advancement of science. However, we also frequently say that we are learning from error. This common expression suggests that the role of error is not - at least not always - negative but that errors can make a fruitful contribution to the scientific enterprise. My paper explores the latter possibility. Can errors play an epistemically productive role in scientific research? The paper begins with a review of several twentieth-century approaches to error and the various agendas behind them. It is shown that only very few scholars have considered whether errors can be productive. The main part of the paper examines a concrete debate in early nineteenth-century on this material, the article offers some terminological clarifications of the common notion 'learning from error'. The conclusion argues that error can indeed play epistemically productive roles in scientific practice.