Chaperone-mediated autophagy: machinery,regulation and biological consequences

Degradation of dysfunctional intracellular components in the lysosome system can occur through three different pathways, i.e., macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). In this review, we focus on CMA, a type of autophagy distinct from the other two autophagic pathways owing to its selectivity, saturability and competitivity by which a subset of long-lived cytosolic soluble proteins are directly delivered into the lysosomal lumen via specific receptors. CMA participates in quality control to maintain normal cell functions by clearing “old” proteins and provides energy to cells under nutritional stress. Deregulation of CMA has recently been shown to underlie some diseases, especially neurodegenerative disorders for which the decline with age in the activity of CMA may become a major aggravating factor. Therefore, targeting aberrant alteration in CMA under pathological conditions could serve as a potential therapeutic strategy for treating related diseases.     

The Absolute and Its Measurement: William Thomson on Temperature

In this paper we give a full account of the work of William Thomson (Lord Kelvin) on absolute temperature, which to this day provides the theoretical underpinnings for the most rigorous measurements of temperature. When Thomson fashioned his concepts of ‘absolute’ temperature, his main concern was to make the definition of temperature independent of the properties of particular thermometric substances (rather than to count temperature from an absolute zero). He tried out a succession of definitions based on the thermodynamics of ideal heat engines; most notably, in 1854 he gave the ratio of two temperatures as the ratio of quantities of heat taken in and given out at those temperatures in a Carnot cycle. But there were difficulties with using such definitions for experimental work, since it was not possible even to approximate an ideal Carnot engine in reality. More generally, it is not trivial to connect an abstract concept with concrete operations in order to make physical measurements possible. In the end, Thomson argued that an ideal gas thermometer would indicate his absolute temperature, and that the deviation of actual gas thermometers from the ideal could be estimated by means of the Joule‐Thomson effect. However, the measurement of the Joule‐Thomson effect itself required measurements of temperature, so there was a problem of circularity.     

RNA editing in plant organelles: machinery, physiological function and evolution

In plants, RNA editing is a process for converting a specific nucleotide of RNA from C to U and less frequently from U to C in mitochondria and plastids. To specify the site of editing, the cis-element adjacent to the editing site functions as a binding site for the trans-acting factor. Genetic approaches using Arabidopsis thaliana have clarified that a member of the protein family with pentatricopeptide repeat (PPR) motifs is essential for RNA editing to generate a translational initiation codon of the chloroplast ndhD gene. The PPR motif is a highly degenerate unit of 35 amino acids and appears as tandem repeats in proteins that are involved in RNA maturation steps in mitochondria and plastids. The Arabidopsis genome encodes approximately 450 members of the PPR family, some of which possibly function as trans-acting factors binding the cis-elements of the RNA editing sites to facilitate access of an unidentified RNA editing enzyme. Based on this breakthrough in the research on plant RNA editing, I would like to discuss the possible steps of co-evolution of RNA editing events and PPR proteins. Received 30 September 2005; received after revision 5 November 2005; accepted 28 November 2005     

Molecular machinery mediating vesicle budding,docking and fusion

A general machinery buds and fuses transport vesicles which connect intracellular compartments with each other and allow communication with the extracellular environment. Cytoplasmic coat proteins deform membranes to bud vesicles and interact directly or indirectly with cargo molecules. Compartment-specific SNAREs (SNAP receptors) on vesicles and target membranes dock vesicles and provide a scaffolding for the general fusion machinery to initiate lipid bilayer fusion.     

能源、环境和纳米技术

本文讨论了有关能源供应的短途径和无环境污染的能源技术的未来发展,提出了利用太阳能和氢燃料所驱动的“氢经济”模式,论述了纳米科学与技术的历史背景和现状,指出了发展纳米技术是历史和未来赋予我们的机遇和挑战,讨论了能源和环境领域的纳米技术,并提出了培养“纳人才”的概念和的迫切性。     

Reconsidering the dynamics of reason: Response to Ferrari,Mormann, Nordmann,and Uebel

I address the points raised by the four commentators by indicating how I have been thinking about extending and expanding my perspective since Dynamics of Reason (2001). This involves reinterpreting the Kantian distinction between understanding and sensibility, and thereby rethinking the relativized a priori. I connect these ideas with experimental contexts and technology, as well as with the wider culture context. I suggest implications for the relationships among science, democracy, and religion—and eventually reconceptualizing Kant’s original Enlightenment project.     

Actin polymerization machinery: the finish line of signaling networks, the starting point of cellular movement

Dynamic assembly of actin filaments generates the forces supporting cell motility. Several recent biochemical and genetic studies have revealed a plethora of different actin binding proteins whose coordinated activity regulates the turnover of actin filaments, thus controlling a variety of actin-based processes, including cell migration. Additionally, emerging evidence is highlighting a scenario whereby the same basic set of actin regulatory proteins is also the convergent node of different signaling pathways emanating from extracellular stimuli, like those from receptor tyrosine kinases. Here, we will focus on the molecular mechanisms of how the machinery of actin polymerization functions and is regulated, in a signaling-dependent mode, to generate site-directed actin assembly leading to cell motility.These authors contributed equally to this work.Received 26 October 2004; received after revision 27 December 2004; accepted 6 January 2005 Available online 09 March 2005     

The experimenters' regress reconsidered: Replication,tacit knowledge,and the dynamics of knowledge generation

This paper revisits the debate between Harry Collins and Allan Franklin, concerning the experimenters' regress. Focusing my attention on a case study from recent psychology (regarding experimental evidence for the existence of a Mozart Effect), I argue that Franklin is right to highlight the role of epistemological strategies in scientific practice, but that his account does not sufficiently appreciate Collins's point about the importance of tacit knowledge in experimental practice. In turn, Collins rightly highlights the epistemic uncertainty (and skepticism) surrounding much experimental research. However, I will argue that his analysis of tacit knowledge fails to elucidate the reasons why scientists often are (and should be) skeptical of other researchers' experimental results. I will present an analysis of tacit knowledge in experimental research that not only answers to this desideratum, but also shows how such skepticism can in fact be a vital enabling factor for the dynamic processes of experimental knowledge generation.     

Crossing paths: interactions between the cell death machinery and growth factor survival signals

Cytokines and growth factors play a crucial role in the maintenance of haematopoietic homeostasis. They transduce signals that regulate the competing commitments of haematopoietic stem cells, quiescence or proliferation, retention of stem cell pluripotency or differentiation, and survival or demise. When the balance between these commitments and the requirements of the organisms is disturbed, particularly when it favours survival and proliferation, cancer may result. Cell death provoked by loss of growth factor signalling is regulated by the Bcl-2 family of apoptosis regulators, and thus survival messages transduced by growth factors must regulate the activity of these proteins. Many aspects of direct interactions between cytokine signalling and regulation of apoptosis remain elusive. In this review, we explore the mechanisms by which cytokines, in particular Interleukin-3 and granulocyte–macrophage colony-stimulating factor, promote cell survival and suppress apoptosis as models of how cytokine signalling and apoptotic pathways intersect.     

Nuclear envelope and nuclear matrix: interactions and dynamics

The peripheral nuclear lamina is located near the nuclear inner membrane and consists of lamin filaments and integral membrane proteins, including the lamin B receptor and various isoforms of lamina-associated polypeptides (LAP) 1 and 2. Several nuclear membrane proteins also interact with chromatin proteins BAF and Hp1. Lamins in the nuclear interior associate with at least one soluble (non-membrane-bound) LAP2 isoform named LAP2alpha. The internal lamins, together with Tpr-based filaments that connect to nuclear pore complexes, are proposed to be major structural elements of the internal nuclear matrix. We describe the structural links between the peripheral lamina and the internal nuclear matrix that are thought to be mediated by LAP2 family members, filament protein Tpr and nucleoporin Nup153. These findings are discussed in relation to human diseases that arise from mutations in nuclear lamina proteins.     

Reconsidering the Fresnel–Maxwell theory shift: how the realist can have her cake and EAT it too

This paper takes another look at a case study which has featured prominently in a variety of arguments for rival realist positions. After critically reviewing the previous commentaries of the theory shift that took place in the transition from Fresnel’s ether to Maxwell’s electromagnetic theory of optics, it will defend a slightly different reading of this historical case study. Central to this task is the notion of explanatory approximate truth, a concept which must be carefully analysed to begin with. With this notion properly understood, it will be finally argued, the popular Fresnel–Maxwell case study points towards a novel formulation of scientific realism.     

Adipocyte extracellular matrix composition, dynamics and role in obesity

The central role of the adipose tissue in lipid metabolism places specific demands on the cell structure of adipocytes. The protein composition and dynamics of the extracellular matrix (ECM) is of crucial importance for the functioning of those cells. Adipogenesis is a bi-phasic process in which the ECM develops from a fibrillar to a laminar structure as cells move from the commitment phase to the growth phase characterized by storage of vast amounts of triglycerides. Mature adipocytes appear to spend a lot of energy on the maintenance of the ECM. ECM remodeling is mediated by a balanced complement of constructive and destructive enzymes together with their enhancers and inhibitors. ECM remodeling is an energy costing process regulated by insulin, by the energy metabolism, and by mechanical forces. In the obese, overgrowth of adipocytes may lead to instability of the ECM, possibly mediated by hypoxia.     

Regulation of mitochondrial dynamics: convergences and divergences between yeast and vertebrates

In eukaryotic cells, the shape of mitochondria can be tuned to various physiological conditions by a balance of fusion and fission processes termed mitochondrial dynamics. Mitochondrial dynamics controls not only the morphology but also the function of mitochondria, and therefore is crucial in many aspects of a cell’s life. Consequently, dysfunction of mitochondrial dynamics has been implicated in a variety of human diseases including cancer. Several proteins important for mitochondrial fusion and fission have been discovered over the past decade. However, there is emerging evidence that there are as yet unidentified proteins important for these processes and that the fusion/fission machinery is not completely conserved between yeast and vertebrates. The recent characterization of several mammalian proteins important for the process that were not conserved in yeast, may indicate that the molecular mechanisms regulating and controlling the morphology and function of mitochondria are more elaborate and complex in vertebrates. This difference could possibly be a consequence of different needs in the different cell types of multicellular organisms. Here, we review recent advances in the field of mitochondrial dynamics. We highlight and discuss the mechanisms regulating recruitment of cytosolic Drp1 to the mitochondrial outer membrane by Fis1, Mff, and MIEF1 in mammals and the divergences in regulation of mitochondrial dynamics between yeast and vertebrates.     

The dynamics of reason and its elusive object in Kant, Fichte and Schelling

Kant used transcendental reflection to distinguish in judgment what belongs to its form and what to its material. Regarding the form of judgment, Buchdahl’s work highlights the analogies between the different levels of judgment in Kant’s transcendental ontology. He uses the explicit contingency of judgments of the system of nature to illuminate the contingency of judgments of objects in general. In the Critique of pure reason, Kant had left much of the work of judgment to the unconscious imagination. Fichte and Schelling attempted to make conscious and determinate the work of the unconscious imagination, but found themselves unable to avoid a reflexive regress in trying to objectify and provide a foundation for the activity of the self in judgment. Buchdahl also clarifies the role Kant gave to the object in judgment, as the indeterminate ‘thinghood’ remaining once all forms of cognition are abstracted. Fichte represented this objective side of consciousness as the not-I, as the limit of the activity of the I, as an unconscious, alien element within consciousness. Schelling struggled to illuminate this unconscious object in judgment, to provide a construction of nature, without dissolving its positive presence into abstract formulations. In pursuing relentlessly Kant’s critique of judgment, Fichte and Schelling exposed its opaque points and problematized the ambition to build a complete system of philosophy.