Structural, magnetic, and electronic properties of VxCr2−xS3(0

A new family of vanadium-substituted chromium sulfides (VxCr2-xS3, 0 < x < 2) has been prepared and characterized by powder X-ray and neutron diffraction, SQUID magnetometry, electrical resistivity, and Seebeck coefficient measurements. Vanadium substitution leads to a single-phase region with a rhombohedral Cr2S3 structure over the composition range 0.0 < x e 0.75, while at higher vanadium contents (1.6 e x < 2.0) a second single-phase region, in which materials adopt a cation-deficient Cr3S4 structure, is observed. Materials with the Cr2S3 structure all exhibit semiconducting behavior. However, both transport and magnetic properties indicate an increasing degree of electron delocalization with increasing vanadium content in this compositional region. Materials that adopt a Cr3S4-type structure exhibit metallic behavior. Magnetic susceptibility data reveal that all materials undergo a magnetic ordering transition at temperatures in the range 90–118 K. Low-temperature magnetization data suggest that this involves a transition to a ferrimagnetic state.

Endocannabinoids in neuroendopsychology: multiphasic control of mitochondrial function

The endocannabinoid system (ECS) is a construct based on the discovery of receptors that are modulated by the plant compound tetrahydrocannabinol and the subsequent identification of a family of nascent ligands, the 'endocannabinoids'. The function of the ECS is thus defined by modulation of these receptors-in particular, by two of the best-described ligands (2-arachidonyl glycerol and anandamide), and by their metabolic pathways. Endocannabinoids are released by cell stress, and promote both cell survival and death according to concentration. The ECS appears to shift the immune system towards a type 2 response, while maintaining a positive energy balance and reducing anxiety. It may therefore be important in resolution of injury and inflammation. Data suggest that the ECS could potentially modulate mitochondrial function by several different pathways; this may help explain its actions in the central nervous system. Dose-related control of mitochondrial function could therefore provide an insight into its role in health and disease, and why it might have its own pathology, and possibly, new therapeutic directions.

Detection of Oxidation Products of 5-Methyl-2′-Deoxycytidine in Arabidopsis DNA

Epigenetic regulations play important roles in plant development and adaptation to environmental stress. Recent studies from mammalian systems have demonstrated the involvement of ten-eleven translocation (Tet) family of dioxygenases in the generation of a series of oxidized derivatives of 5-methylcytosine (5-mC) in mammalian DNA. In addition, these oxidized 5-mC nucleobases have important roles in epigenetic remodeling and aberrant levels of 5-hydroxymethyl-29-deoxycytidine (5-HmdC) were found to be associated with different types of human cancers. However, there is a lack of evidence supporting the presence of these modified bases in plant DNA. Here we reported the use of a reversed-phase HPLC coupled with tandem mass spectrometry method and stable isotope-labeled standards for assessing the levels of the oxidized 5-mC nucleosides along with two other oxidatively induced DNA modifications in genomic DNA of Arabidopsis. These included 5- HmdC, 5-formyl-29-deoxycytidine (5-FodC), 5-carboxyl-29-deoxycytidine (5-CadC), 5-hydroxymethyl-29-deoxyuridine (5- HmdU), and the (59S) diastereomer of 8,59-cyclo-29-deoxyguanosine (S-cdG). We found that, in Arabidopsis DNA, the levels of 5-HmdC, 5-FodC, and 5-CadC are approximately 0.8 modifications per 106 nucleosides, with the frequency of 5-HmdC (per 5-mdC) being comparable to that of 5-HmdU (per thymidine). The relatively low levels of the 5-mdC oxidation products suggest that they arise likely from reactive oxygen species present in cells, which is in line with the lack of homologous Tetfamily dioxygenase enzymes in Arabidopsis.

How the double spherules of infectious bronchitis virus impact our understanding of RNA virus replicative organelles

Powered by advances in electron tomography, recent studies have extended our understanding of how viruses construct "replication factories" inside infected cells. Their function, however, remains an area of speculation with important implications for human health. It is clear from these studies that whatever their purpose, organelle structure is dynamic (M. Ulasli, M. H. Verheije, C. A. de Haan, and F. Reggiori, Cell. Microbiol. 12:844-861, 2010) and intricate (K. Knoops, M. Kikkert, S. H. Worm, J. C. Zevenhoven-Dobbe, Y. van der Meer, et al., PLOS Biol. 6:e226, 2008). But by concentrating on medically important viruses, these studies have failed to take advantage of the genetic variation inherent in a family of viruses that is as diverse as the archaea, bacteria, and eukaryotes combined (C. Lauber, J. J. Goeman, M. del Carmen Parquet, P. T. Nga, E. J. Snijder, et al., PLOS Pathog. 9:e1003500, 2013). In this climate, Maier et al. (H. J. Maier, P. C. Hawes, E. M. Cottam, J. Mantell, P. Verkade, et al., mBio 4:e00801-13, 2013) explored the replicative structures formed by an avian coronavirus that appears to have diverged at an early point in coronavirus evolution and shed light on controversial aspects of viral biology.

Presence and bronchomotor activity of protease-activated receptor-2 in guinea pig airways

The protease activated receptor-2 (PAR-2) belongs to a family of G-protein-coupled receptors that are activated by proteolysis. Trypsin cleaves PAR-2, exposing an N-terminal tethered ligand (SLIGRL) that activates the receptor. Messenger RNA (mRNA) for PAR-2 was found in guinea pig airway tissue by reverse transcription-polymerase chain reaction, and PAR-2 was found by immunohistochemistry in airway epithelial and smooth-muscle cells. In anesthetized guinea pigs, trypsin and SLIGRL-NH(2) (given intratracheally or intravenously) caused a bronchoconstriction that was inhibited by the combination of tachykinin-NK(1) and -NK(2) receptor antagonists and was potentiated by inhibition of nitric oxide synthase (NOS). Trypsin and SLIGRL-NH(2) relaxed isolated trachea and main bronchi, and contracted intrapulmonary bronchi. Relaxation of main bronchi was abolished or reversed to contraction by removal of epithelium, administration of indomethacin, and NOS inhibition. PAR-1, PAR-3, and PAR-4 were not involved in the bronchomotor action of either trypsin or SLIGRL-NH(2), because ligands of these receptors were inactive either in vitro or in vivo, and because thrombin (a PAR-1 and PAR-3 agonist) did not show cross-desensitization with PAR-2 agonists in vivo. Thus, we have localized PAR-2 to the guinea-pig airways, and have shown that activation of PAR-2 causes multiple motor effects in these airways, including in vivo bronchoconstriction, which is in part mediated by a neural mechanism.

Propeptide-mediated inhibition of myostatin increases muscle mass through inhibiting proteolytic pathways in aged mice

Mammalian aging is accompanied by a progressive loss of skeletal muscle, a process called sarcopenia. Myostatin, a secreted member of the transforming growth factor-β family of signaling molecules, has been shown to be a potent inhibitor of muscle growth. Here, we examined whether muscle growth could be promoted in aged animals by antagonizing the activity of myostatin through the neutralizing activity of the myostatin propeptide. We show that a single injection of an AAV8 virus expressing the myostatin propeptide induced an increase in whole body weights and all muscles examined within 7 weeks of treatment. Our cellular studies demonstrate that muscle enlargement was due to selective fiber type hypertrophy, which was accompanied by a shift toward a glycolytic phenotype. Our molecular investigations elucidate the mechanism underpinning muscle hypertrophy by showing a decrease in the expression of key genes that control ubiquitin-mediated protein breakdown. Most importantly, we show that the hypertrophic muscle that develops as a consequence of myostatin propeptide in aged mice has normal contractile properties. We suggest that attenuating myostatin signaling could be a very attractive strategy to halt and possibly reverse age-related muscle loss.

Application of complex extreme learning machine to multiclass classification problems with high dimensionality: a THz spectra classification problem

We extend extreme learning machine (ELM) classifiers to complex Reproducing Kernel Hilbert Spaces (RKHS) where the input/output variables as well as the optimization variables are complex-valued. A new family of classifiers, called complex-valued ELM (CELM) suitable for complex-valued multiple-input–multiple-output processing is introduced. In the proposed method, the associated Lagrangian is computed using induced RKHS kernels, adopting a Wirtinger calculus approach formulated as a constrained optimization problem similarly to the conventional ELM classifier formulation. When training the CELM, the Karush–Khun–Tuker (KKT) theorem is used to solve the dual optimization problem that consists of satisfying simultaneously smallest training error as well as smallest norm of output weights criteria. The proposed formulation also addresses aspects of quaternary classification within a Clifford algebra context. For 2D complex-valued inputs, user-defined complex-coupled hyper-planes divide the classifier input space into four partitions. For 3D complex-valued inputs, the formulation generates three pairs of complex-coupled hyper-planes through orthogonal projections. The six hyper-planes then divide the 3D space into eight partitions. It is shown that the CELM problem formulation is equivalent to solving six real-valued ELM tasks, which are induced by projecting the chosen complex kernel across the different user-defined coordinate planes. A classification example of powdered samples on the basis of their terahertz spectral signatures is used to demonstrate the advantages of the CELM classifiers compared to their SVM counterparts. The proposed classifiers retain the advantages of their ELM counterparts, in that they can perform multiclass classification with lower computational complexity than SVM classifiers. Furthermore, because of their ability to perform classification tasks fast, the proposed formulations are of interest to real-time applications.

Synthesis and thermoelectric properties of the new skutterudites Yb x Fe2Ni2Sb12 (0 ≤ x ≤ 0.4)

The family of materials Yb x Fe2 Ni 2Sb12 (0 ≤ x ≤ 0.4) has been prepared by solid-state synthesis from the pure elements and characterized by powder X-ray diffraction. These materials crystallize in the skutterudite structure, with the framework voids partially filled with Yb atoms. Electrical resistivity, Seebeck coefficient and thermal conductivity measurements have been performed on hot-pressed samples, and indicate that the thermoelectric performance is significantly improved by increasing the Yb content. The decomposition of the compounds under oxidizing atmosphere at elevated temperatures has also been studied by thermogravimetric analysis. The physical properties and thermal stability of the new compounds are further discussed in comparison with those of the reported isostructural and isoelectronic Yb x Co4Sb12 (0 ≤ x ≤ 0.19).

Uniqueness of signature for simple curves

We propose a topological approach to the problem of determining a curve from its iterated integrals. In particular, we prove that a family of terms in the signature series of a two dimensional closed curve with finite p-variation, 1≤p<2, are in fact moments of its winding number. This relation allows us to prove that the signature series of a class of simple non-smooth curves uniquely determine the curves. This implies that outside a Chordal SLEκ null set, where 0<κ≤4, the signature series of curves uniquely determine the curves. Our calculations also enable us to express the Fourier transform of the n-point functions of SLE curves in terms of the expected signature of SLE curves. Although the techniques used in this article are deterministic, the results provide a platform for studying SLE curves through the signatures of their sample paths.

Electronic structure of porphyrin-based metal-organic frameworks and their suitability for solar fuel production photocatalysis

Metal-organic frameworks (MOFs) can be exceptionally good catalytic materials thanks to the presence of active metal centres and a porous structure that is advantageous for molecular adsorption and confinement. We present here a first-principles investigation of the electronic structure of a family of MOFs based on porphyrins connected through phenyl-carboxyl ligands and AlOH species, in order to assess their suitability for the photocatalysis of fuel production reactions using sunlight. We consider structures with protonated porphyrins and those with the protons exchanged with late 3d metal cations (Fe2+, Co2+, Ni2+, Cu2+, Zn2+), a process that we find to be thermodynamically favorable from aqueous solution for all these metals. Our band structure calculations, based on an accurate screened hybrid functional, reveal that the bandgaps are in a favorable range (2.0 to 2.6 eV) for efficient adsorption of solar light. Furthermore, by approximating the vacuum level to the pore center potential, we provide the alignment of the MOFs’ band edges with the redox potentials for water splitting and carbon dioxide reduction, and show that the structures studied here have band edges positions suitable for these reactions at neutral pH.

Regulation of actin assembly by SCAR/WAVE proteins.

Actin reorganization is a tightly regulated process that co-ordinates complex cellular events, such as cell migration, chemotaxis, phagocytosis and adhesion, but the molecular mechanisms that underlie these processes are not well understood. SCAR (suppressor of cAMP receptor)/WAVE [WASP (Wiskott-Aldrich syndrome protein)-family verprolin homology protein] proteins are members of the conserved WASP family of cytoskeletal regulators, which play a critical role in actin dynamics by triggering Arp2/3 (actin-related protein 2/3)-dependent actin nucleation. SCAR/WAVEs are thought to be regulated by a pentameric complex which also contains Abi (Abl-interactor), Nap (Nck-associated protein), PIR121 (p53-inducible mRNA 121) and HSPC300 (haematopoietic stem progenitor cell 300), but the structural organization of the complex and the contribution of its individual components to the regulation of SCAR/WAVE function remain unclear. Additional features of SCAR/WAVE regulation are highlighted by the discovery of other interactors and distinct complexes. It is likely that the combinatorial assembly of different components of SCAR/WAVE complexes will prove to be vital for their roles at the centre of dynamic actin reorganization.

Accumulation of complex eigenvalues of an indefinite Sturm--Liouville operator with a shifted Coulomb potential

For a particular family of long-range potentials V, we prove that the eigenvalues of the indefinite Sturm–Liouville operator A = sign(x)(−Δ+V(x)) accumulate to zero asymptotically along specific curves in the complex plane. Additionally, we relate the asymptotics of complex eigenvalues to the two-term asymptotics of the eigenvalues of associated self-adjoint operators.

Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Jun N-terminal kinases are required for efficient up-regulation of c-Jun protein.

Cardiac hypertrophy, an important adaptational response, is associated with up-regulation of the immediate early gene, c- jun, which encodes the c-Jun transcription factor. c-Jun may feed back to up-regulate its own transcription and, since the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs) phosphorylate c-Jun(Ser-63/73) to increase its transactivating activity, JNKs are thought to be the principal factors involved in c- jun up-regulation. Hypertrophy in primary cultures of cardiac myocytes is induced by endothelin-1, phenylephrine or PMA, probably through activation of one or more of the MAPK family. These three agonists increased c- jun mRNA with the rank order of potency of PMA approximately endothelin-1>phenylephrine. Up-regulation of c- jun mRNA by endothelin-1 was attenuated by inhibitors of protein kinase C (GF109203X) and the extracellular signal-regulated kinase (ERK) cascade (PD98059 or U0126), but not by inhibitors of the JNK (SP600125) or p38-MAPK (SB203580) cascades. Hyperosmotic shock (0.5 M sorbitol) powerfully activates JNKs, but did not increase c- jun mRNA. These data suggest that ERKs, rather than JNKs, are required for c- jun up-regulation. However, endothelin-1 and phenylephrine induced greater up-regulation of c-Jun protein than PMA and phosphorylation of c-Jun(Ser-63/73) correlated with the level of c-Jun protein. Up-regulation of c-Jun protein by endothelin-1 was attenuated by inhibitors of protein kinase C and the ERK cascade, probably correlating with a primary input of ERKs into transcription. In addition, SP600125 inhibited the phosphorylation of c-Jun(Ser-63/73), attenuated the increase in c-Jun protein induced by endothelin-1 and increased the rate of c-Jun degradation. Thus whereas ERKs are the principal MAPKs required for c- jun transcription, JNKs are necessary to stabilize c-Jun for efficient up-regulation of the protein.

Regulation of cardiac myocyte cell death.

Cardiac myocyte death, whether through necrotic or apoptotic mechanisms, is a contributing factor to many cardiac pathologies. Although necrosis and apoptosis are the widely accepted forms of cell death, they may utilize the same cell death machinery. The environment within the cell probably dictates the final outcome, producing a spectrum of response between the two extremes. This review examines the probable mechanisms involved in myocyte death. Caspases, the generally accepted executioners of apoptosis, are significant in executing cardiac myocyte death, but other proteases (e.g., calpains, cathepsins) also promote cell death, and these are discussed. The two principal cell death pathways (death receptor- and mitochondrial-mediated) are described in relation to the emerging structural information for the principal proteins, and they are discussed relative to current understanding of myocyte cell death mechanisms. Whereas the mitochondrial pathway is probably a significant factor in myocyte death in both acute and chronic phases of myocardial diseases, the death receptor pathway may prove significant in the longer term. The Bcl-2 family of proteins are key regulators of the mitochondrial death pathway. These proteins are described and their possible functions are discussed. The commitment to cell death is also influenced by protein kinase cascades that are activated in the cell. Whereas certain pathways are cytoprotective (e.g., phosphatidylinositol 3'-kinase), the roles of other kinases are less clear. Since myocyte death is implicated in a number of cardiac pathologies, attenuation of the death pathways may prove important in ameliorating such disease states, and possible therapeutic strategies are explored.

A new three-locus model for rootstock-induced dwarfing in apple revealed by genetic mapping of root bark percentage

Rootstock-induced dwarfing of apple scions revolutionized global apple production during the twentieth century, leading to the development of modern intensive orchards. A high root bark percentage (the percentage of the whole root area constituted by root cortex) has previously been associated with rootstock induced dwarfing in apple. In this study, the root bark percentage was measured in a full-sib family of ungrafted apple rootstocks and found to be under the control of three loci. Two QTL for root bark percentage were found to co-localise to the same genomic regions on chromosome 5 and chromosome 11 previously identified as controlling dwarfing, Dw1 and Dw2, respectively. A third QTL was identified on chromosome 13 in a region that has not been previously associated with dwarfing. The development of closely linked 3 Sequence-tagged site STS markers improved the resolution of allelic classes thereby allowing the detection of dominance and epistatic interactions between loci, with high root bark percentage only occurring in specific allelic combinations. In addition, we report a significant negative correlation between root bark percentage and stem diameter (an indicator of tree vigour), measured on a clonally propagated grafted subset of the mapping population. The demonstrated link between root bark percentage and rootstock-induced dwarfing of the scion leads us to propose a three-locus model that is able to explain levels of dwarfing from the dwarf ‘M.27’ to the semi-invigorating rootstock ‘M.116’. Moreover, we suggest that the QTL on chromosome 13 (Rb3) might be analogous to a third dwarfing QTL, Dw3 that has not previously been identified.