Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells

Several proteins implicated in the pathogenesis of polycystic kidney disease (PKD) localize to cilia. Furthermore, cilia are malformed in mice with PKD with mutations in TgN737Rpw (encoding polaris). It is not known, however, whether ciliary dysfunction occurs or is relevant to cyst formation in PKD. Here, we show that polycystin-1 (PC1) and polycystin-2 (PC2), proteins respectively encoded by Pkd1 and Pkd2, mouse orthologs of genes mutated in human autosomal dominant PKD, co-distribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca(2+) influx in response to physiological fluid flow. Blocking antibodies directed against PC2 similarly abolished the flow response in wild-type cells as did inhibitors of the ryanodine receptor, whereas inhibitors of G-proteins, phospholipase C and InsP(3) receptors had no effect. These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis.     

The mammalian sodium channel BNC1 is required for normal touch sensation

Of the vertebrate senses, touch is the least understood at the molecular level The ion channels that form the core of the mechanosensory complex and confer touch sensitivity remain unknown. However, the similarity of the brain sodium channel 1 (BNC1) to nematode proteins involved in mechanotransduction indicated that it might be a part of such a mechanosensor. Here we show that disrupting the mouse BNC1 gene markedly reduces the sensitivity of a specific component of mechanosensation: low-threshold rapidly adapting mechanoreceptors. In rodent hairy skin these mechanoreceptors are excited by hair movement. Consistent with this function, we found BNC1 in the lanceolate nerve endings that lie adjacent to and surround the hair follicle. Although BNC1 has been proposed to have a role in pH sensing, the acid-evoked current in cultured sensory neurons and the response of acid-stimulated nociceptors were normal in BNC1 null mice. These data identify the BNC1 channel as essential for the normal detection of light touch and indicate that BNC1 may be a central component of a mechanosensory complex.     

A multiple intelligent agent system for credit risk prediction via an optimization of localized generalization error with diversity

Company bankruptcies cost billions of dollars in losses to banks each year. Thus credit risk prediction is a critical part of a bank＇s loan approval decision process. Traditional financial models for credit risk prediction are no longer adequate for describing today＇s complex relationship between the financial health and potential bankruptcy of a company. In this work, a multiple classifier system （embedded in a multiple intelligent agent system） is proposed to predict the financial health of a company. In our model, each individual agent （classifier） makes a prediction on the likelihood of credit risk based on only partial information of the company. Each of the agents is an expert, but has limited knowledge （represented by features） about the company. The decisions of all agents are combined together to form a final credit risk prediction. Experiments show that our model out-performs other existing methods using the benchmarking Compustat American Corporations dataset.     

Spatial differences in rock uplift rates inferred from channel steepness indices along the northern flank of the Qilian Mountain, northeast Tibetan Plateau

The rate and distribution of deformation along the Qilian Mountain, on the northeastern Tibetan Plateau, is needed to understand the evolution of high topography associated with the plateau. Recently, a number of empirical studies have provided support for the contention, common to most models of fluvial incision, that rock uplift rate exerts a first-order control on the gradient of longitudinal river profiles. Along the northern Qilian Mountain, this method is used to extract information about the spatial patterns of differential rock uplift. Analysis of the longitudinal profiles of bedrock channels reveals systematic differences in the channel steepness index along the trend of the frontal ranges. Local comparisons of channel steepness reveal that lithology and precipitation have limited influence on channel steepness. Similarly, there is little evidence suggesting that channel steepness is influenced by differences in the sediment loads. We argue that the distribution of channel steepness in the Qilian Mountain is mostly the result of differential rates of rock uplift. Thus, channel steepness indices reveal a lower rock uplift rate in the eastern portion of the Qilian Mountain and a higher rate in the middle and west. The highest rates appear to occur in the middle-west portions of the range, just to the west of the Yumu Shan.     

Newtonian Emanation, Spinozism, Measurement and the Baconian Origins of the Laws of Nature

The first two sections of this paper investigate what Newton could have meant in a now famous passage from “De Graviatione” (hereafter “DeGrav”) that “space is as it were an emanative effect of God.” First it offers a careful examination of the four key passages within DeGrav that bear on this. The paper shows that the internal logic of Newton’s argument permits several interpretations. In doing so, the paper calls attention to a Spinozistic strain in Newton’s thought. Second it sketches four interpretive options: (i) one approach is generic neo-Platonic; (ii) another approach is associated with the Cambridge Platonist, Henry More; a variant on this (ii*) emphasizes that Newton mixes Platonist and Epicurean themes; (iii) a necessitarian approach; (iv) an approach connected with Bacon’s efforts to reformulate a useful notion of form and laws of nature. Hitherto only the second and third options have received scholarly attention in scholarship on DeGrav. The paper offers new arguments to treat Newtonian emanation as a species of Baconian formal causation as articulated, especially, in the first few aphorisms of part two of Bacon’s New Organon. If we treat Newtonian emanation as a species of formal causation then the necessitarian reading can be combined with most of the Platonist elements that others have discerned in DeGrav, especially Newton’s commitment to doctrines of different degrees of reality as well as the manner in which the first existing being ‘transfers’ its qualities to space (as a kind of causa-sui). This can clarify the conceptual relationship between space and its formal cause in Newton as well as Newton’s commitment to the spatial extended-ness of all existing beings. While the first two sections of this paper engage with existing scholarly controversies, in the final section the paper argues that the recent focus on emanation has obscured the importance of Newton’s very interesting claims about existence and measurement in “DeGrav”. The paper argues that according to Newton God and other entities have the same kind of quantities of existence; Newton is concerned with how measurement clarifies the way of being of entities. Newton is not claiming that measurement reveals all aspects of an entity. But if we measure something then it exists as a magnitude in space and as a magnitude in time. This is why in DeGrav Newton’s conception of existence really helps to “lay truer foundations of the mechanical sciences.”     

Purity and Danger of an Information Infrastructure

We critically assess deep-seated assumptions and images of an information infrastructure, namely, that it needs to be uniform, tidy, and nonfragmented. This is necessary because our perception of order is socially constructed and, more importantly, because it has implications. Based on an historical reconstruction of the establishment of a Lotus Notes-based infrastructure in an internationally oriented oil company with 17,000 employees, we describe and analyze the productive role that appeals to an orderly infrastructure play. We trace its sources and describe how it operates. We also identify the implications in terms of choice of technological solution, delegation of organizational roles, and making organizational actors (in)visible.