SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors

The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity.     

Late survival of Neanderthals at the southernmost extreme of Europe

The late survival of archaic hominin populations and their long contemporaneity with modern humans is now clear for southeast Asia. In Europe the extinction of the Neanderthals, firmly associated with Mousterian technology, has received much attention, and evidence of their survival after 35 kyr bp has recently been put in doubt. Here we present data, based on a high-resolution record of human occupation from Gorham's Cave, Gibraltar, that establish the survival of a population of Neanderthals to 28 kyr bp. These Neanderthals survived in the southernmost point of Europe, within a particular physiographic context, and are the last currently recorded anywhere. Our results show that the Neanderthals survived in isolated refuges well after the arrival of modern humans in Europe.     

Charon's size and an upper limit on its atmosphere from a stellar occultation

Pluto and its satellite, Charon (discovered in 1978; ref. 1), appear to form a double planet, rather than a hierarchical planet/satellite couple. Charon is about half Pluto's size and about one-eighth its mass. The precise radii of Pluto and Charon have remained uncertain, leading to large uncertainties on their densities. Although stellar occultations by Charon are in principle a powerful way of measuring its size, they are rare, as the satellite subtends less than 0.3 microradians (0.06 arcsec) on the sky. One occultation (in 1980) yielded a lower limit of 600 km for the satellite's radius, which was later refined to 601.5 km (ref. 4). Here we report observations from a multi-station stellar occultation by Charon, which we use to derive a radius, R(C) = 603.6 +/- 1.4 km (1sigma), and a density of rho = 1.71 +/- 0.08 g cm(-3). This occultation also provides upper limits of 110 and 15 (3sigma) nanobar for an atmosphere around Charon, assuming respectively a pure nitrogen or pure methane atmosphere.     

Interneuronal barrages and ripple superposed on inhibitory postsynaptic potentials

Résumé L'activité électrique des neurones du noyau thalamique ventro-latéral est étudiée ici chez des chats anesthésiés au nembutal et immobilisés avec du flaxedil au moyen d'un enregistrement intracellulaire. Nous avons observé que l'enregistrement de certains neurones montre que le potentiel nommé inhibiteur postsynaptique (IPSP) est accompagné de la décharge en barrage d'un autre neurone probablement semblable à la cellule deRenshaw.

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We thank Mr.G. Bilanow for invaluable technical help.     

Selective inhibition of the multiplication of phage T1 inE. coli K12

Riassunto Un nuovo antibiotico, la Distamicina, inibisce selettivamente lo sviluppo del batteriofago T1 inE. coli K12 pur non esercitando alcuna azione sullo sviluppo del microorganismo ospite. L'antibiotico può inibire sia la penetrazione del batteriofago nelle cellule batteriche sia la sua liberazione.     

Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion

Peripheral infection is the natural route of transmission in most prion diseases. Peripheral prion infection is followed by rapid prion replication in lymphoid organs, neuroinvasion and progressive neurological disease. Both immune cells and nerves are involved in pathogenesis, but the mechanisms of prion transfer from the immune to the nervous system are unknown. Here we show that ablation of the chemokine receptor CXCR5 juxtaposes follicular dendritic cells (FDCs) to major splenic nerves, and accelerates the transfer of intraperitoneally administered prions into the spinal cord. Neuroinvasion velocity correlated exclusively with the relative locations of FDCs and nerves: transfer of CXCR5-/- bone marrow to wild-type mice induced perineural FDCs and enhanced neuroinvasion, whereas reciprocal transfer to CXCR5-/- mice abolished them and restored normal efficiency of neuroinvasion. Suppression of lymphotoxin signalling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in CXCR5-/- mice. This suggests that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection.     

意大利歌剧院的体形、体量及材料对声场的影响

针对意大利歌剧院进行研究，着重研究建筑设计对厅堂音质的影响．对两个剧院的常规音质参量进行了测量．这两座剧院是由同一建筑师Antonio Galli Bibiena设计的，分别是波仑亚的市立剧院和曼图亚的科学剧院．二者具有相当近似的形式，但尺寸不同，所用的材料也各畀，前者是用砖石建成，后者是用木料建成，因此在整修前采用了许多预应力钢筋混凝土结构．文中提供了不少数据并给出了对这些数据加以比较和分析的结果，特别是关于某些特征尺寸与扫频信号各可闻频率产生的空间听觉感受之间相关性的分析，以及若干有关材料和体型对IACC和EDT等音质参量的影响的思考．     

在脉冲响应频率分析比较中对客观声学参数EDT的新认识

对于客观参量EDT，或者更确切地说，对于稳态声场衰变曲线的初始斜率与包括所有简正模式在内的平均阻尼常数之间关系的研究工作，已有一些研究者做过，如H．库特鲁夫就曾指出此参量与所测试环境的几何细节有密切关系．因此，文中选择它作为分析工具，以一种较为深入的方式，通过对一个歌剧院的研究，来检验这种关系．通过对脉冲响应在频域上进行分析，这在前人的工作中也采用过．文中对EDT从倍频程以及1／3倍频程加以研究，并利用在Matlab环境下开发的一些工具来探讨乐池的简正模式与从频带中心频率导出的最大的时间值之间的相关关系．研完表明，在所考察的环境中简正模式与衰变曲线的初始斜率之间有良好的相关关系，与自相关系数（ACF）也有良好的相关关系；研究还证实，用于分析的参量本身既是时间的函数，也是脉冲响应频率变化的函数。