Cancer therapy

In recent years a growing recognition that molecularly-targeted therapies face formidable obstacles has revived interest in more generic tumor cell phenotypes that could be exploited for therapy. Two recent reports demonstrate that cancer cell survival is critically dependent on the activity of MTH1, a nucleotide pyrophosphatase that converts the oxidized nucleotides 8-oxo-dGTP and 2-OH-dATP to the corresponding monophosphates, thus preventing their incorporation into genomic DNA. Tumor cells frequently overexpress MTH1, probably because malignant transformation creates oxidative stress that renders the nucleotide pool highly vulnerable to oxidation. As a result, MTH1 inhibition in cancer cells results in accumulation and incorporation of 8-oxo-dGTP and 2-OH-dATP into DNA, leading to DNA damage and cell death. This toxic effect is highly cancer cell-specific, as MTH1 is generally dispensable for the survival of normal, untransformed cells. Importantly, MTH1 proves to be a “druggable” enzyme that can be inhibited both by an existing protein kinase inhibitor drug, crizotinib, and by novel compounds identified through screening. Inhibition of MTH1 leading to toxic accumulation of oxidized nucleotides specifically in tumor cells therefore represents an example of a “non-personalised” approach to cancer therapy.     

Indirect parental effects on offspring viability by egg-derived fluids in an external fertilizer

The capacity for parents to influence offspring phenotypes via nongenetic inheritance is currently a major area of focus in evolutionary biology. Intriguing recent evidence suggests that sexual interactions among males and females, both before and during mating, are important mediators of such effects. Sexual interactions typically extend beyond gamete release, involving both sperm and eggs, and their associated fluids. However, the potential for gamete-level interactions to induce nongenetic parental effects remains under-investigated. Here, we test for such effects using an emerging model system for studying gamete interactions, the external fertilizer Mytilus galloprovincialis. We employed a split-ejaculate design to test whether exposing sperm to egg-derived chemicals (ECs) from a female would affect fertilization rate and offspring viability when those sperm were used to fertilize a different female''s eggs. We found separate, significant effects of ECs from non-fertilizing females on both fertilization rate and offspring viability. The offspring viability effect indicates that EC-driven interactions can have nongenetic implications for offspring fitness independent of the genotypes inherited by those offspring. These findings provide a rare test of indirect parental effects driven exclusively by gamete-level interactions, and to our knowledge the first evidence that such effects occur via the gametic fluids of females.     

Echinococcus: biology and strain variation

Biology and strain variation in the causative agent of hydatid disease is reviewed with emphasis on developmental and genetic aspects. In vitro cultivation experiments have made a significant contribution to current knowledge of the developmental plasticity of Echinococcus. However, the mechanisms which regulate and determine developmental strategies in the parasite, as well as the characteristics, source and cytodifferentiation of germinal cells, are not understood. The nature, significance and origin of strain variation in Echinococcus are examined. Before we can fully appreciate the phenotypic consequences of genetic differentiation between populations, we need to know something about the genetic and environmental components of variation in traits such as development rate, host preference, host specificity, virulence and drug resistance. There is an urgent need for research on the developmental pathways by which genetic differences within and between strains of E. granulosus are translated to phenotypic differences in these traits.     

尊重斯德哥尔摩的历史中心—骑士岛的激活改造

瑞典国家财产委员会拥有骑士岛的所有权与管理权，并计划对该岛上所有的公共空间进行更新和开发，以提高其可达性与吸引力。该项目的核心是找到一种更新和修复岛屿的方法，从而在尊重历史价值的同时满足现代功能需求。对骑士岛南部的改造是岛上公共空间更新的第一部分。设计的关键条件是沿滨水区域创造可以供人步行与停坐的大面积空间，并在保持开放海港氛围的同时，对旧的道路铺装进行管理。设计者设计了一套灵活使用公共空间的综合解决方案，将开放空间与之前的码头一样，沿着水滨的形态进行布局。