Dominant missense mutations in ABCC9 cause Cantú syndrome

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.     

Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses

The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses. The cytoplasmic helicase proteins RIG-I (retinoic-acid-inducible protein I, also known as Ddx58) and MDA5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) have been implicated in viral dsRNA recognition. In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue. Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified, the functional role of MDA5 and the relationship between these dsRNA detectors in vivo are yet to be determined. Here we use mice deficient in MDA5 (MDA5-/-) to show that MDA5 and RIG-I recognize different types of dsRNAs: MDA5 recognizes poly(I:C), and RIG-I detects in vitro transcribed dsRNAs. RNA viruses are also differentially recognized by RIG-I and MDA5. We find that RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, RIG-I-/- and MDA5-/- mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Together, our data show that RIG-I and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.     

SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion

Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using cis-Apc(+/Delta716) Smad4(+/-) mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-beta family signaling is blocked, we show here that a new type of immature myeloid cell (iMC) is recruited from the bone marrow to the tumor invasion front. These CD34(+) iMCs express the matrix metalloproteinases MMP9 and MMP2 and the CC-chemokine receptor 1 (CCR1) and migrate toward the CCR1 ligand CCL9. In adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the cis-Apc/Smad4 mutant, we further show that lack of CCR1 prevents accumulation of CD34(+) iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of transforming growth factor-beta family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.     

Responses of pink shrimp Farfantepenaeus brasiliensis (Latreille, 1817) (Penaeoidea) to physico-chemical parameters in a marine protected area: changes in abundance and distribution after 20 years

ABSTRACT

This study analysed the influence of temperature, salinity and sediment texture on the distribution of pink shrimp juveniles (Farfantepenaeus brasiliensis) over a 20-year period. The shrimps were sampled monthly in Fortaleza Bay, north coast of São Paulo, Brazil, in November 1988–October 1989 (period 1) and then 20 years later in November 2008–October 2009 (period 2). In period 1 we captured 80 juveniles whereas in period 2 we captured 226. The abundance and distribution of F. brasiliensis seemed to be modulated by temperature and sediment texture, along with the fishing activity. The management strategies established between the samplings might have been responsible for the higher abundance of juveniles seen during period 2. The strategies included the limitation of fishing effort, regulation of fishing equipment and the establishment of environmental protection areas and temporary fishing ban.     

中庸主义、个人主义对中国现代知识分子人格的影响--以周作人及与鲁迅的比较为例

周作人在<谈龙集·上海气>中说"我终于是一个中庸主义的人."看来周作人对自己的了解是很深的.对于周作人的复杂人格,任何一种简单化的说明都是有害的,因此,以矛盾分析的办法以及与鲁迅进行人格对比的方法,论证鲁迅的人格是殉道的、苦行主义的,而周作人的人格则是中庸的、现世主义的,对于探讨周作人的人格的形成、发展以及内在矛盾,并以此关照中国现代社会条件之下知识分子的精神处境以及人格分裂问题,也许不无意义.     

Self-organizing optic-cup morphogenesis in three-dimensional culture

Balanced organogenesis requires the orchestration of multiple cellular interactions to create the collective cell behaviours that progressively shape developing tissues. It is currently unclear how individual, localized parts are able to coordinate with each other to develop a whole organ shape. Here we report the dynamic, autonomous formation of the optic cup (retinal primordium) structure from a three-dimensional culture of mouse embryonic stem cell aggregates. Embryonic-stem-cell-derived retinal epithelium spontaneously formed hemispherical epithelial vesicles that became patterned along their proximal-distal axis. Whereas the proximal portion differentiated into mechanically rigid pigment epithelium, the flexible distal portion progressively folded inward to form a shape reminiscent of the embryonic optic cup, exhibited interkinetic nuclear migration and generated stratified neural retinal tissue, as seen in vivo. We demonstrate that optic-cup morphogenesis in this simple cell culture depends on an intrinsic self-organizing program involving stepwise and domain-specific regulation of local epithelial properties.     

氦浴温度对超流氦噪声沸腾压力振动的影响

噪声沸腾是超流氦传热中的一个特殊现象，对这种现象的充分认识有助于超流氦在诸如超导磁体的冷却等方面的实际应用．氦浴温度是影响噪声沸腾的一个重要因素．本文运用脉冲电流加热一个大小为２．５ｃｍ×２．５ｃｍ的小试样，同时用一个压力传感器测量了在不同氦浴温度下噪声沸腾时的压力振动，并对不同氦浴温度下噪声沸腾的压力振动曲线进行了详细的分析．实验结果显示在过冷态超流氦的沸腾中，一个极薄的气膜在小试样上振动，几乎没有什么噪声；而在饱和态超流氦的沸腾中，一个小试样大小相当的气泡在其表面上反复振动，并伴随着巨大的噪声和强烈的机械振动．氦浴温度对噪声沸腾的影响主要体现在对噪声沸腾的特征频率和沸腾状态发生改变时的临界静压液柱等方面．     

Thyrotrophin in the pars tuberalis triggers photoperiodic response

Molecular mechanisms regulating animal seasonal breeding in response to changing photoperiod are not well understood. Rapid induction of gene expression of thyroid-hormone-activating enzyme (type 2 deiodinase, DIO2) in the mediobasal hypothalamus (MBH) of the Japanese quail (Coturnix japonica) is the earliest event yet recorded in the photoperiodic signal transduction pathway. Here we show cascades of gene expression in the quail MBH associated with the initiation of photoinduced secretion of luteinizing hormone. We identified two waves of gene expression. The first was initiated about 14 h after dawn of the first long day and included increased thyrotrophin (TSH) beta-subunit expression in the pars tuberalis; the second occurred approximately 4 h later and included increased expression of DIO2. Intracerebroventricular (ICV) administration of TSH to short-day quail stimulated gonadal growth and expression of DIO2 which was shown to be mediated through a TSH receptor-cyclic AMP (cAMP) signalling pathway. Increased TSH in the pars tuberalis therefore seems to trigger long-day photoinduced seasonal breeding.