A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation

Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIβ and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate-limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIβ and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver disease.     

Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms

Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca2+ channels but stimulates sarcoplasmic reticulum (SR) Ca2+ release, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit beta-adrenergic-induced inotropy. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro, suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both NOS1-/- and NOS3-/- mice develop age-related hypertrophy, although only NOS3-/- mice are hypertensive. NOS1/3-/- double knockout mice have suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function.     

The Ontological Constitution of Bounding-Judging in the Phenomenological Epistemology of von Bertalanffy's General System Theory

An analysis of the current presentation of boundary judgments in the Critical Systems literature highlights a general result: that the activity of bounding has been, implicitly or explicitly, considered as an epistemological issue. By arguing that knowledge is not produced singularly by bounding, the paper informs this general result. This, in turn, informs other results, which have emerged in current understanding. In particular, the paper argues (a) the reason why knowledge indeed never attains the status of "objective or right" knowledge, (b) how critique is dependent on some positing of knowledge, and (c) the exact place where critique is actioned. von Bertalanffy's attempted systems epistemology is considered at length because it explains and informs the epistemological conclusions seen to have been drawn in the current Critical Systems literature. von Bertalanffy's attempt requires the support of Husserlian phenomenology, especially Sartre's understanding of it. This requires an in-depth discussion of the phenomenological understanding of consciousness. Since the conclusions stem from von Bertalanffy, the paper reconsiders the status of General System Theory in Critical Systems Thinking.     

The Ontological Status of Critique

Two previous papers by the author are summarized in order to provide the context for the arguments and results of the present paper. The author's previous research has identified the exact place where critique is epistemologically actioned and this enables the present paper to argue for the attribution of ontological status to critique. Since it is commonly acknowledged that a lack of critique results in dogmatism or bounded rationality, these latter two are investigated—in greater depth than previously considered in the literature—and, though they are shown to be inescapable, they provide a route toward a fundamental principle which systemically brings together ontological, epistemological, ethical, and emancipatory concerns. The principle can be stated as follows: One is more or less emancipated depending upon the extent to which one is aware of critique-bounded emancipation as an ontological necessity and thus to the degree to which one ceases to attempt escaping from practical critique into the realms of dogmatic emancipation and rationally bounded emancipation. The paper provides accurate definitions of critique and emancipation, showing that one cannot be considered without the other, thus framing the manner in which further discussion of these two intimately related issues can be continued. In keeping with the author's previous published research, the relevance of von Bertalanffy's deliberations to Critical Systems Thinking, as well as Sartre's philosophy to systems thinking in general, is upheld.     

三轴超形变核态的实验证据

利用轴对称超形变和三轴超形变模型研究了１６５Ｌｕπ［６６０１／２］带两种模型计算的γ跃迁能量都能较好地符合实验值,然而,能量的ｓｉｇｎａｔｕｒｅ颤动指数、三轴因子、两类动力学电四极矩之比却存在明显的差别,这些差别可以用来识别三轴超形变核态     

Optimization of the Chemical Composition of Cast Iron Used for Casting Ball Bearing Grinding Disks

The chemical composition of cast iron used for casting ball bearing machining disks was varied to optimize the properties such as castability, hardenability, and durability in ball machining. The cast iron characteristics were most strongly dependent on the Ni content and the carbon saturation degree, So. This paper describes the types of test specimens, the working conditions, and the experimental results. The increase of the degree of carbon saturation reduces the tendency to form shrinkholes in the castings. The decrease in the Ni content negatively affects the final hardening treatment. A way to control solidification defects in cast iron, by reducing the Ni content, has been verified on cast disks.     

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.     

钛锰二元合金的吸放氢性能

系统地研究了钛锰二元合金的吸、放氢量,压力组成等温线以及吸氢过程热力学函数(ΔHΔS)的变化。实验证实,对于不加均匀化退火和活化处理的二元钛锰合金,其综合吸放氢性能最佳的组成为TiMn_(1.15)-TiMn_(1.25)。     

伪东方罂粟愈伤组织细胞核型研究

本文研究了伪东方罂粟（Ｐａｒａｖｅｒｐｓｅｕｄｏｏｒｉｅｎｔａｌｅ）愈伤组织细胞核型的变化特点，结果证明培养初期的愈伤组织细胞经常发生染色体的大量丢失．继代培养两个月的愈伤组织细胞染色体数目变化较大，培养３个月、４个月、５个月以后染色体数目减少到２１条时趋于稳定，经对各个时期细胞的２１条染色体测量分析，证明这些细胞不是真正的单倍性细胞．随着培养时间的延长，染色体的结构变化也越大．在每一个具有２１条染色体的细胞中发现都有一条较长的具中部着丝粒的染色体．     

Reconstitution of a microtubule plus-end tracking system in vitro

The microtubule cytoskeleton is essential to cell morphogenesis. Growing microtubule plus ends have emerged as dynamic regulatory sites in which specialized proteins, called plus-end-binding proteins (+TIPs), bind and regulate the proper functioning of microtubules. However, the molecular mechanism of plus-end association by +TIPs and their ability to track the growing end are not well understood. Here we report the in vitro reconstitution of a minimal plus-end tracking system consisting of the three fission yeast proteins Mal3, Tip1 and the kinesin Tea2. Using time-lapse total internal reflection fluorescence microscopy, we show that the EB1 homologue Mal3 has an enhanced affinity for growing microtubule end structures as opposed to the microtubule lattice. This allows it to track growing microtubule ends autonomously by an end recognition mechanism. In addition, Mal3 acts as a factor that mediates loading of the processive motor Tea2 and its cargo, the Clip170 homologue Tip1, onto the microtubule lattice. The interaction of all three proteins is required for the selective tracking of growing microtubule plus ends by both Tea2 and Tip1. Our results dissect the collective interactions of the constituents of this plus-end tracking system and show how these interactions lead to the emergence of its dynamic behaviour. We expect that such in vitro reconstitutions will also be essential for the mechanistic dissection of other plus-end tracking systems.