On the role of the Agulhas system in ocean circulation and climate

The Atlantic Ocean receives warm, saline water from the Indo-Pacific Ocean through Agulhas leakage around the southern tip of Africa. Recent findings suggest that Agulhas leakage is a crucial component of the climate system and that ongoing increases in leakage under anthropogenic warming could strengthen the Atlantic overturning circulation at a time when warming and accelerated meltwater input in the North Atlantic is predicted to weaken it. Yet in comparison with processes in the North Atlantic, the overall Agulhas system is largely overlooked as a potential climate trigger or feedback mechanism. Detailed modelling experiments--backed by palaeoceanographic and sustained modern observations--are required to establish firmly the role of the Agulhas system in a warming climate.     

Calcineurin sets the bandwidth for discrimination of signals during thymocyte development

At critical times in development, cells are able to convert graded signals into discrete developmental outcomes; however, the mechanisms involved are poorly understood. During thymocyte development, cell fate is determined by signals originating from the alphabeta T-cell receptor. Low-affinity/avidity interactions between the T-cell receptor and peptide-MHC complexes direct differentiation to the single-positive stage (positive selection), whereas high-affinity/avidity interactions induce death by apoptosis (negative selection). Here we show that mice deficient in both calcineurin and nuclear factor of activated T cells (NFAT)c2/c3 lack a population of preselection thymocytes with enhanced ability to activate the mitogen-activated protein kinase (Raf-MEK-ERK) pathway, and fail to undergo positive selection. This defect can be partially rescued with constitutively active Raf, indicating that calcineurin controls MAPK signalling. Analysis of mice deficient in both Bim (which is required for negative selection) and calcineurin revealed that calcineurin-induced ERK (extracellular signal-regulated kinase) sensitization is required for differentiation in response to 'weak' positive selecting signals but not in response to 'strong' negative selecting signals (which normally induce apoptosis). These results indicate that early calcineurin/NFAT signalling produces a developmental period of ERK hypersensitivity, allowing very weak signals to induce positive selection. This mechanism might be generally useful in the discrimination of graded signals that induce different cell fates.     

Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.     

No supernovae associated with two long-duration gamma-ray bursts

It is now accepted that long-duration gamma-ray bursts (GRBs) are produced during the collapse of a massive star. The standard 'collapsar' model predicts that a broad-lined and luminous type Ic core-collapse supernova accompanies every long-duration GRB. This association has been confirmed in observations of several nearby GRBs. Here we report that GRB 060505 (ref. 10) and GRB 060614 (ref. 11) were not accompanied by supernova emission down to limits hundreds of times fainter than the archetypal supernova SN 1998bw that accompanied GRB 980425, and fainter than any type Ic supernova ever observed. Multi-band observations of the early afterglows, as well as spectroscopy of the host galaxies, exclude the possibility of significant dust obscuration and show that the bursts originated in actively star-forming regions. The absence of a supernova to such deep limits is qualitatively different from all previous nearby long-duration GRBs and suggests a new phenomenological type of massive stellar death.     

RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases

RNASEL (encoding ribonuclease L) has recently been proposed as a candidate for the hereditary prostate cancer (HPC1) gene. We determined that the RNASEL variant Arg462Gln has three times less enzymatic activity than the wildtype and is significantly associated with prostate cancer risk (P = 0.007). At least one copy of the mutated allele that causes this substitution is carried by nearly 60% of the men in our study. Men that are heterozygous with respect to the mutated allele have 50% greater risk of prostate cancer than non-carriers, and homozygotes have more than double the risk.     

Ⅱ,Ⅲ期乳腺癌综合疗法对比分析（附69例报告）

对Ⅱ、Ⅲ期乳腺癌６９例综合方法疗效对比分析。全组５年生存率５３６％，Ⅱ期７８％，Ⅲ期４７２％，Ⅱ期各组（Ｓ，Ｓ＋Ｃ，Ｓ＋Ｒ，Ｓ＋Ｒ＋Ｃ）无显著差别；Ⅲ期各组Ｓ１４２％，Ｓ＋Ｃ３３％，Ｓ＋Ｒ４７３％，Ｓ＋Ｒ＋Ｃ６０％（Ｐ＜００５）说明综合治疗方法对生存率有影响，增加放疗对Ⅲ期尤为显著；加放组淋巴区胸壁３年复发率与未加放组比为１∶２（９／５０：７／１９），其复发平均时间为３１８∶１３５（月），说明加放对局部控制效果的肯定。增加化疗（ＣＭＦ／ＣＡＦ／ＣＥＦ）与未加化疗比生存率有改变，前者为５９５％（２２／３７），后者为３３３％（３／９），而除Ｓ组外，增加化疗使Ｓ＋Ｒ＋Ｃ达６０％，Ｓ＋Ｒ４７３％组无显著性差别（０２５＞Ｐ＞０１０）。Ｓ＋（Ｓ＋Ｃ）与（Ｓ＋Ｒ）＋（Ｓ＋Ｒ＋Ｃ）组５年生存率，前者为３６８％（７／１９），后者为６０％（３０／５０）。     

A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers

Cyclin D1 is a component of the core cell cycle machinery. Abnormally high levels of cyclin D1 are detected in many human cancer types. To elucidate the molecular functions of cyclin D1 in human cancers, we performed a proteomic screen for cyclin D1 protein partners in several types of human tumours. Analyses of cyclin D1 interactors revealed a network of DNA repair proteins, including RAD51, a recombinase that drives the homologous recombination process. We found that cyclin D1 directly binds RAD51, and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein, which do not require D-cyclins for proliferation. These findings reveal an unexpected function of a core cell cycle protein in DNA repair and suggest that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers which are currently thought to be unaffected by cyclin D1 inhibition.     

Germline transmission of genetically modified primordial germ cells

Primordial germ cells (PGCs) are the precursors of sperm and eggs. In most animals, segregation of the germ line from the somatic lineages is one of the earliest events in development; in avian embryos, PGCs are first identified in an extra-embryonic region, the germinal crescent, after approximately 18 h of incubation. After 50-55 h of development, PGCs migrate to the gonad and subsequently produce functional sperm and oocytes. So far, cultures of PGCs that remain restricted to the germ line have not been reported in any species. Here we show that chicken PGCs can be isolated, cultured and genetically modified while maintaining their commitment to the germ line. Furthermore, we show that chicken PGCs can be induced in vitro to differentiate into embryonic germ cells that contribute to somatic tissues. Retention of the commitment of PGCs to the germ line after extended periods in culture and after genetic modification combined with their capacity to acquire somatic competence in vitro provides a new model for developmental biology. The utility of the model is enhanced by the accessibility of the avian embryo, which facilitates access to the earliest stages of development and supplies a facile route for the reintroduction of PGCs into the embryonic vasculature. In addition, these attributes create new opportunities to manipulate the genome of chickens for agricultural and pharmaceutical applications.     

景观与建筑:一个集成的网络——布鲁克林中心区人性化的景观(英文)

This project investigates the relationship between landscape and architecture and the importance of an integrated approach towards city design.Too often,landscape design and architectural design are addressed separately.The belief behind this project is that through a holistic integration of landscape and architectural design we can create a truly sustainable urban structure.Through adopting an actual urban context this project questions a sanctioned approach towards development and creates an integrated ne...