Intracellular organelles in the saga of Ca<Superscript>2+</Superscript> homeostasis: different molecules for different purposes?

An increase in the concentration of cytosolic free Ca²⁺ is a key component regulating different cellular processes ranging from egg fertilization, active secretion and movement, to cell differentiation and death. The multitude of phenomena modulated by Ca²⁺, however, do not simply rely on increases/decreases in its concentration, but also on specific timing, shape and sub-cellular localization of its signals that, combined together, provide a huge versatility in Ca²⁺ signaling. Intracellular organelles and their Ca²⁺ handling machineries exert key roles in this complex and precise mechanism, and this review will try to depict a map of Ca²⁺ routes inside cells, highlighting the uniqueness of the different Ca²⁺ toolkit components and the complexity of the interactions between them.     

CD8<Superscript>+</Superscript> Tregs in autoimmunity: learning “self”-control from experience

Autoreactive CD8⁺ regulatory T cells (Tregs) play important roles as modulators of immune responses against self, and numerical and functional defects in CD8⁺ Tregs have been linked to autoimmunity. Several subsets of CD8⁺ Tregs have been described. However, the origin of these T cells and how they participate in the natural progression of autoimmunity remain poorly defined. We discuss several lines of evidence suggesting that the autoimmune process itself promotes the development of autoregulatory CD8⁺ T cells. We posit that chronic autoantigenic exposure fosters the differentiation of non-pathogenic autoreactive CD8⁺ T cells into antigen-experienced, memory-like autoregulatory T cells, to generate a “negative feedback” regulatory loop capable of countering pathogenic autoreactive effectors. This hypothesis predicts that approaches capable of boosting autoregulatory T cell memory will be able to blunt autoimmunity without compromising systemic immunity.     

RIPK4 activity in keratinocytes is controlled by the SCF<Superscript>β-TrCP</Superscript> ubiquitin ligase to maintain cortical actin organization

RIPK4 is a key player in epidermal differentiation and barrier formation. RIPK4 signaling pathways controlling keratinocyte proliferation and differentiation depend on its kinase activity leading to Dvl2, Pkp1 and IRF6 phosphorylation and NF-κB activation. However, the mechanism regulating RIPK4 activity levels remains elusive. We show that cultured keratinocytes display constitutive active phosphorylated RIPK4 while PKC signaling can trigger RIPK4 activation in various non-keratinocyte cell lines, in which RIPK4 is present in a non-phosphorylated state. Interestingly, we identified the SCF^β-TrCP ubiquitin E3 ligase complex responsible for regulating the active RIPK4 protein level. The SCF^β-TrCP complex binds to a conserved phosphodegron motif in the intermediate domain of RIPK4, subsequently leading to K48-linked ubiquitinylation and degradation. The recruitment of β-TrCP is dependent on RIPK4 activation and trans-autophosphorylation. β-TrCP knock-down resulted in RIPK4-dependent formation of actin stress fibers, cell scattering and increased cell motility, suggesting that tight control of RIPK4 activity levels is crucial to maintain cell shape and behavior in keratinocytes.     

Cl<Superscript>–</Superscript> affects the function of the GABA cotransporter rGAT1 but preserves the mutal relationship between transient and transport currents

The effects of reducing external Cl- on the electrophysiological properties of the Na+/Cl(-)-dependent GABA transporter rGAT1 expressed in Xenopus oocytes were investigated. In agreement with a recently proposed kinetic scheme, the effects of Cl- are complex but preserve the mutual relationship that links the transport-associated current, I(tr), measured in saturating GABA concentration, and the transient current, I(pre), recorded in the absence of GABA following a voltage step from the holding potential Vh to V. In particular, I(tr) (V) - I(tr) (Vh) = r integral I(pre) (V) dt, where r is the relaxation rate of I(pre) at the same membrane potential and Cl- concentration. The model also predicts a relationship between charge relaxation rate and apparent affinity for GABA, which is also verified in the presence of lowered Na+ or Cl- concentrations. In these conditions, the binding rate of GABA to the transporter is increased. All these effects are consistent with the hypothesis that interaction of the organic substrate with rGAT1 induces a conversion from a capacitive to a conductive mode of operation without strongly altering either the amount or the rate of charge movement.     

Beta-carotene affects gene expression in lungs of male and female <Emphasis Type="Italic">Bcmo1</Emphasis><Superscript>−/−</Superscript> mice in opposite directions

Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1 ^−/−) mice, which are—like humans—able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1 ^−/− mice by BC. The steroid biosynthetic pathway was overrepresented in BC-supplemented male Bcmo1 ^−/− mice. Testosterone levels were higher after BC supplementation only in Bcmo1 ^−/− mice, which had, unlike wild-type (Bcmo1 ^+/+) mice, large variations. We hypothesize that BC possibly affects hormone synthesis or metabolism. Since sex hormones influence lung cancer risk, these data might contribute to an explanation for the previously found increased lung cancer risk after BC supplementation (ATBC and CARET studies). Moreover, effects of BC may depend on the presence of frequent human BCMO1 polymorphisms, since these effects were not found in wild-type mice.     

<Emphasis Type="Italic">Ginkgo biloba</Emphasis> extract EGb<Superscript>®</Superscript> 761 increases endothelial nitric oxide production <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis>

Beneficial effects of Ginkgo biloba on peripheral arterial occlusive disease have been repeatedly shown in clinical trials, especially after use of EGb 761, a standardized special extract. Since the underlying mechanisms are widely unknown, we aimed to elucidate the molecular basis on which EGb 761 protects against endothelial dysfunction in vitro and in vivo. Application of therapeutically feasible doses of EGb 761 for 48 h caused endothelial nitric oxide (NO) production by increasing endothelial nitric oxide synthase (eNOS) promoter activity and eNOS expression in vitro. Phosphorylation of eNOS at a site typical for Akt (Ser 1177) was acutely enhanced by treatment with EGb 761, as was Akt phosphorylation at Ser 478. Furthermore, the extract caused acute relaxation of isolated aortic rings and NO-dependent reduction of blood pressure in vivo in rats. These influences on eNOS represent a putative molecular basis for the protective cardiovascular properties of EGb 761.     

Impaired apoptosis in lymphoblasts from Alzheimer’s disease patients: Cross-talk of Ca<Superscript>2+</Superscript>/calmodulin and ERK1/2 signaling pathways

We have analyzed the intracellular signals that allow lymphoblasts from Alzheimer’s disease (AD) patients to escape from serum deprivation-induced apoptosis. The following observations suggested that modulation of ERK1/2 activity by Ca²⁺/calmodulin (CaM) is involved in preventing apoptosis: (i) ERK1/2 activity seems to support lethality in control cells, as PD98059, the inhibitor of the activating MEK prevented cell death; (ii) control cells show a persistent and higher stimulation of ERK1/2 than that of AD cells in the absence of serum; (iii) CaM antagonists have no effects on control cells, but sensitize AD cells to death induced by serum withdrawal and increased ERK1/2 phosphorylation, and (iv) no apoptotic effects of CaM antagonists were observed in AD cells treated with PD98059. These results suggest the existence of an activation threshold of the ERK1/2 pathway setting by Ca²⁺/CaM-dependent mechanisms, which appears to be the critical factor controlling cell survival or death decision under trophic factor withdrawal. F. Bartolomé, N. de las Cuevas: These authors contributed equally to this work. Received 14 February 2007; received after revision 16 April 2007; accepted 23 April 2007     

<Emphasis Type="Italic">Cis</Emphasis>–<Emphasis Type="Italic">trans</Emphasis> interactions of cell surface receptors: biological roles and structural basis

Cell surface receptors bind ligands expressed on other cells (in trans) in order to communicate with neighboring cells. However, an increasing number of cell surface receptors are found to also interact with ligands expressed on the same cell (in cis). These observations raise questions regarding the biological role of such cis interactions. Specifically, it is important to know whether cis and trans binding have distinct functional effects and, if so, how a single cell discriminates between interactions in cis versus trans. Further, what are the structural features that allow certain cell surface receptors to engage ligand both on the same as well as on an apposed cell membrane? Here, we summarize known examples of receptors that display cis–trans binding and discuss the emerging diversity of biological roles played by these unconventional two-way interactions, along with their structural basis.     

Is Newton a ‘radical empiricist’ about method?

Recently, some Newton scholars have argued that Newton is an empiricist about metaphysics—that ideally, he wants to let advances in physical theory resolve either some or all metaphysical issues. But while proponents of this interpretation are using ‘metaphysics’ in a very broad sense, to include the ‘principles that enable our knowledge of natural phenomena’, attention has thus far been focused on Newton’s approach to ontological, not epistemological or methodological, issues. In this essay, I therefore consider whether Newton wants to let physical theory bear on the very ‘principles that enable our knowledge’. By examining two kinds of argument in the Principia, I contend that Newton can be considered a methodological empiricist in a substantial respect. I also argue, however, that he cannot be a ‘radical empiricist’—that he does not and cannot convert all methodological issues into empirical issues.     

What leads from <Emphasis Type="Italic">dead-end?</Emphasis>

The 129 mouse strain develops congenital testicular germ cell tumors (TGCTs) at a low frequency. TGCTs in mice resemble the testicular tumors (teratomas) that occur in human infants. The genes that cause these tumors in 129 have not been identified. The defect at the Ter locus increases TGCT incidence such that 94% of 129-Ter/Ter males develop TGCTs. The primary effect of the Ter mutation is progressive loss of primordial germ cells (PGCs) during embryonic development. This results in sterility in adult Ter/Ter mice on all mouse strain backgrounds. However, on the 129 background, Ter causes tumor development in addition to sterility. Therefore, Ter acts as a modifier of 129-derived TGCT susceptibility genes. Ter was identified to be a mutation that inactivates the Dead-end1 (Dnd1) gene. In this perspective, I discuss the possible areas of future investigations to elucidate the mechanism of TGCT development due to Dnd1 inactivation. Received 29 September 2006; received after revision 29 January 2007; accepted 19 February 2007     

Does Information Help Intra‐Day Volatility Forecasts?

While much research related to forecasting return volatility does so in a univariate setting, this paper includes proxies for information flows to forecast intra‐day volatility for the IBEX 35 futures market. The belief is that volume or the number of transactions conveys important information about the market that may be useful in forecasting. Our results suggest that augmenting a variety of GARCH‐type models with these proxies lead to improved forecasts across a range of intra‐day frequencies. Furthermore, our results present an interesting picture whereby the PARCH model generally performs well at the highest frequencies and shorter forecasting horizons, whereas the component model performs well at lower frequencies and longer forecast horizons. Both models attempt to capture long memory; the PARCH model allows for exponential decay in the autocorrelation function, while the component model captures trend volatility, which dominates over a longer horizon. These characteristics are likely to explain the success of each model. Copyright © 2013 John Wiley & Sons, Ltd.     

"Add-on" domains of<Emphasis Type="Italic"> Drosophila</Emphasis> β1,4-<Emphasis Type="Italic">N</Emphasis>-acetylgalactosaminyltransferase B in the stem region and its pilot protein

The glycolipid specific Drosophila melanogaster β1,4-N-acetylgalactosaminyltransferase B (β4GalNAcTB) depends on a zinc finger DHHC protein family member named GalNAcTB pilot (GABPI) for activity and translocation to the Golgi. The six-membrane spanning protein actually lacks the cysteine in the cytoplasmic DHHC motif, displaying DHHS instead. Here we show that the whole conserved region around the DHHS sequence, which is essential for palmitoylation in DHHC proteins, is not required for GABPI to interact with β4GalNAcTB. In contrast, the two luminal loops between transmembrane domain 3–4 and 5–6 contain conserved amino acids, which are crucial for activity. Besides the dependence on GABPI, β4GalNAcTB requires its exceptional short stem region for activity. A few hydrophobic amino acids positioned close to the transmembrane domain are essential for the interaction with GABPI. Along with its catalytic domain, β4GalNAcTB, thus, requires an area in its own stem region and two small luminal loops of GABPI as "add-on" domains. Moreover, some inactive GABPI mutants could be rescued by fusion with β4GalNAcTB, indicating their importance in direct GABPI-β4GalNAcTB interaction.     

回复“对‘辐射热力学的新进展——辐射有效能 光量子等效温度光量子熵常数’一文的讨论”

本文关于“对‘辐射热力学的新进展——辐射有效能 光量子等效温度 光量子熵常数’一文的讨论”中所举例证进行了分析, 指明其例证中对相关概念的理解和使用有误. 同时进一步阐述了光量子等效温度、光谱辐射有效能和光子熵常数与宏观态温度、热能有效能和宏观态熵的异同点, 指出辐射能具有微观态的量子作用特性和宏观态的平均热能作用特性的双重性.     

Elemental sulphur (S<Subscript>8</Subscript>) in higher plants — biogenic or anthropogenic origin

In the course of investigating lipophilic air pollutants in the epicuticular wax ofPinus sylvestris L. needles, elemental sulphur, S₈, was found in all samples. An investigation was conducted to determined the origin of this substance. No correlation between the level of S₈ in the needles and human activities in the sampling area could be found, contrary to what would have been expected of an anthropogenic compound. The internal lipids ofP. sylvestris as well as the epicuticular wax of historical herbarium material and seedlings grown in clean, filtered air, and the epicuticular wax of several other species, both gymnosperms and angiosperms, also contained S₈. Quantitation of S₈ inP. sylvestris gave levels of 7.2±2.9 μg/g wax, 3.8±1.9 μg/g internal lipid and 0.43±0.17 μg/g total needle dry weight. Almost 0.1% of the total sulphur in pine needles is S₈, and approximately half of the total S₈ is found in the wax. The results suggest that S₈ is endogenous in many higher plants. A function for S₈ as part of an antifungal defence system is possible.     

国家自然科学基金重大研究计划“重大工程的动力灾变”研究进展

重大研究计划“重大工程的动力灾变”瞄准强地震动场和强/台风场及其动力作用下重大工程的损伤演化破坏过程的国际研究前沿, 重点解决两大关键科学问题, 即: (1) 强地震动场和强/台风场的特性与规律; (2) 重大工程动力灾变的过程与机理. 为此重点开展4个方面的研究工作, 包括: (1) 强地震动场和强/台风场的建模与预测; (2) 重大工程动力灾变的关键效应; (3) 重大工程动力灾变的全过程分析; (4) 重大工程动力灾变模拟系统的集成与验证.     

Proposition II (Book I) of Newton’s <Emphasis Type="Italic">Principia</Emphasis>

After preparing the way with comments on evanescent quantities and then Newton’s interpretation of his second law, this study of Proposition II (Book I)— Proposition II Every body that moves in some curved line described in a plane and, by a radius drawn to a point, either unmoving or moving uniformly forward with a rectilinear motion, describes areas around that point proportional to the times, is urged by a centripetal force tending toward that same point. —asks and answers the following questions: When does a version of Proposition II first appear in Newton’s work? What revisions bring that initial version to the final form in the 1726 Principia? What, exactly, does this proposition assert? In particular, what does Newton mean by the motion of a body “urged by a centripetal force”? Does it assert a true mathematical claim? If not, what revision makes it true? Does the demonstration of Proposition II persuade? Is it as convincing, for example, as the most convincing arguments of the Principia? If not, what revisions would make the demonstration more persuasive? What is the importance of Proposition II, to the physics of Book III and the mathematics of Book I?