Protease-activated-receptor-2 affects protease-activated-receptor-1-driven breast cancer

Mammalian protease-activated-receptor-1 and -2 (PAR₁ and PAR₂) are activated by proteases found in the flexible microenvironment of a tumor and play a central role in breast cancer. We propose in the present study that PAR₁ and PAR₂ act together as a functional unit during malignant and physiological invasion processes. This notion is supported by assessing pro-tumor functions in the presence of short hairpin; shRNA knocked-down hPar2 or by the use of a truncated PAR₂ devoid of the entire cytoplasmic tail. Silencing of hPar2 by shRNA-attenuated thrombin induced PAR₁ signaling as recapitulated by inhibiting the assembly of Etk/Bmx or Akt onto PAR₁-C-tail, by thrombin-instigated colony formation and invasion. Strikingly, shRNA-hPar2 also inhibited the TFLLRN selective PAR₁ pro-tumor functions. In addition, while evaluating the physiological invasion process of placenta extravillous trophoblast (EVT) organ culture, we observed inhibition of both thrombin or the selective PAR₁ ligand; TFLLRNPNDK induced EVT invasion by shRNA-hPar2 but not by scrambled shRNA-hPar2. In parallel, when a truncated PAR₂ was utilized in a xenograft mouse model, it inhibited PAR₁–PAR₂-driven tumor growth in vivo. Similarly, it also attenuated the interaction of Etk/Bmx with the PAR₁-C-tail in vitro and decreased markedly selective PAR₁-induced Matrigel invasion. Confocal images demonstrated co-localization of PAR₁ and PAR₂ in HEK293T cells over-expressing YFP-hPar2 and HA-hPar1. Co-immuno-precipitation analyses revealed PAR₁-PAR₂ complex formation but no PAR₁-CXCR4 complex was formed. Taken together, our observations show that PAR₁ and PAR₂ act as a functional unit in tumor development and placenta-uterus interactions. This conclusion may have significant consequences on future breast cancer therapeutic modalities and improved late pregnancy outcome.     

被遗弃的皮拉米登

<正>皮拉米登在传说中是一夜间被苏联遗弃的;现实中,小镇的消失用了几个月的时间。小镇给人的感觉就像是几百人突然同时停止手头工作后一起迅速离开。空无一人的小镇上,枯萎的植物还摆在窗边,干净的碗碟堆放在架子上,新换的被子整齐地叠放着。采矿的设备还在,就好像离开的工人还会突然回来按下按钮,然后一切照旧。但这只是错觉,没有人再回来,现在小镇仍是最后一个人离开时的样子。皮拉米登位于挪威和北极之间的斯瓦尔巴群岛,具有独特的风貌。每年5月中旬到10月初可以乘船到达,在寒冷的冬季,     

PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans

The ability to maintain adequate nutrient intake is critical for survival. Complex interrelated neuronal circuits have developed in the mammalian brain to regulate many aspects of feeding behaviour, from food-seeking to meal termination. The hypothalamus and brainstem are thought to be the principal homeostatic brain areas responsible for regulating body weight. However, in the current 'obesogenic' human environment food intake is largely determined by non-homeostatic factors including cognition, emotion and reward, which are primarily processed in corticolimbic and higher cortical brain regions. Although the pleasure of eating is modulated by satiety and food deprivation increases the reward value of food, there is currently no adequate neurobiological account of this interaction between homeostatic and higher centres in the regulation of food intake in humans. Here we show, using functional magnetic resonance imaging, that peptide YY3-36 (PYY), a physiological gut-derived satiety signal, modulates neural activity within both corticolimbic and higher-cortical areas as well as homeostatic brain regions. Under conditions of high plasma PYY concentrations, mimicking the fed state, changes in neural activity within the caudolateral orbital frontal cortex predict feeding behaviour independently of meal-related sensory experiences. In contrast, in conditions of low levels of PYY, hypothalamic activation predicts food intake. Thus, the presence of a postprandial satiety factor switches food intake regulation from a homeostatic to a hedonic, corticolimbic area. Our studies give insights into the neural networks in humans that respond to a specific satiety signal to regulate food intake. An increased understanding of how such homeostatic and higher brain functions are integrated may pave the way for the development of new treatment strategies for obesity.     

A second generation human haplotype map of over 3.1 million SNPs

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.     

Geochemical evidence for widespread euxinia in the later Cambrian ocean

Widespread anoxia in the ocean is frequently invoked as a primary driver of mass extinction as well as a long-term inhibitor of evolutionary radiation on early Earth. In recent biogeochemical studies it has been hypothesized that oxygen deficiency was widespread in subsurface water masses of later Cambrian oceans, possibly influencing evolutionary events during this time. Physical evidence of widespread anoxia in Cambrian oceans has remained elusive and thus its potential relationship to the palaeontological record remains largely unexplored. Here we present sulphur isotope records from six globally distributed stratigraphic sections of later Cambrian marine rocks (about 499 million years old). We find a positive sulphur isotope excursion in phase with the Steptoean Positive Carbon Isotope Excursion (SPICE), a large and rapid excursion in the marine carbon isotope record, which is thought to be indicative of a global carbon cycle perturbation. Numerical box modelling of the paired carbon sulphur isotope data indicates that these isotope shifts reflect transient increases in the burial of organic carbon and pyrite sulphur in sediments deposited under large-scale anoxic and sulphidic (euxinic) conditions. Independently, molybdenum abundances in a coeval black shale point convincingly to the transient spread of anoxia. These results identify the SPICE interval as the best characterized ocean anoxic event in the pre-Mesozoic ocean and an extreme example of oxygen deficiency in the later Cambrian ocean. Thus, a redox structure similar to those in Proterozoic oceans may have persisted or returned in the oceans of the early Phanerozoic eon. Indeed, the environmental challenges presented by widespread anoxia may have been a prevalent if not dominant influence on animal evolution in Cambrian oceans.     

An integrated semiconductor device enabling non-optical genome sequencing

The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.     

Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor

Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor. We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.     

Common variants near MC4R are associated with fat mass, weight and risk of obesity

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.     

A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration

Epithelial organs, including the lung, are known to possess regenerative abilities through activation of endogenous stem cell populations, but the molecular pathways regulating stem cell expansion and regeneration are not well understood. Here we show that Gata6 regulates the temporal appearance and number of bronchioalveolar stem cells (BASCs) in the lung, its absence in Gata6-null lung epithelium leading to the precocious appearance of BASCs and concurrent loss in epithelial differentiation. This expansion of BASCs was the result of a pronounced increase in canonical Wnt signaling in lung epithelium upon loss of Gata6. Expression of the noncanonical Wnt receptor Fzd2 was downregulated in Gata6 mutants and increased Fzd2 or decreased beta-catenin expression rescued, in part, the lung epithelial defects in Gata6 mutants. During lung epithelial regeneration, canonical Wnt signaling was activated in the niche containing BASCs and forced activation of Wnt signaling led to a large increase in BASC numbers. Moreover, Gata6 was required for proper lung epithelial regeneration, and postnatal loss of Gata6 led to increased BASC expansion and decreased differentiation. Together, these data demonstrate that Gata6-regulated Wnt signaling controls the balance between progenitor expansion and epithelial differentiation required for both lung development and regeneration.