Maritime Delimitation and Fishery Cooperation in the Tonkin Gulf

In June 2004 China and Vietnam ratified both a maritime boundary agreement for the Tonkin Gulf (Beibu Gulf) and a fisheries cooperation agreement for the Gulf. These agreements end years of negotiation and debate regarding the rights of the respective states to the ocean areas and resources in the Gulf.     

Toward the structure of presenilin/γ-secretase and presenilin homologs

Presenilin is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of Alzheimer’s disease. Upon assembly with its three protein cofactors (nicastrin, Aph-1 and Pen-2), presenilin undergoes autoproteolysis into two subunits, each of which contributes one of the catalytic aspartates to the active site. A family of presenilin homologs, including signal peptide peptidase, possess proteolytic activity without the need for other protein factors, and these simpler intramembane aspartyl proteases have given insight into the action of presenilin within the γ-secretase complex. Cellular and molecular studies support a nine-transmembrane topology for presenilins and their homologs, and small-molecule inhibitors and cysteine scanning with crosslinking have suggested certain presenilin residues and regions that contribute to substrate recognition and handling. Identification of partial complexes has also offered clues to protein–protein interactions within the γ-secretase complex. Biophysical methods have allowed 3D views of the γ-secretase complex and presenilins. Most recently, the crystal structure of a microbial presenilin homolog has confirmed a nine-transmembrane topology and intramembranous location and proximity of the two conserved and essential aspartates. The crystal structure also provides a platform for the formulation of specific hypotheses regarding substrate interaction and catalysis as well as the pathogenic mechanism of Alzheimer-causing presenilin mutations. This article is part of a Special Issue entitled: Intramembrane Proteases.     

Advanced glycation end products suppress osteoblastic differentiation of stromal cells by activating endoplasmic reticulum stress

Advanced glycation end products (AGEs) are involved in bone quality deterioration in diabetes mellitus. We previously showed that AGE2 or AGE3 inhibited osteoblastic differentiation and mineralization of mouse stromal ST2 cells, and also induced apoptosis and decreased cell growth. Although quality management for synthesized proteins in endoplasmic reticulum (ER) is crucial for the maturation of osteoblasts, the effects of AGEs on ER stress in osteoblast lineage are unknown. We thus examined roles of ER stress in AGE2- or AGE3-induced suppression of osteoblastogenesis of ST2 cells. An ER stress inducer, thapsigargin (TG), induced osteoblastic differentiation of ST2 cells by increasing the levels of Osterix, type 1 collagen (Col1), alkaline phosphatase (ALP) and osteocalcin (OCN) mRNA. AGE2 or AGE3 suppressed the levels of ER stress sensors such as IRE1α, ATF6 and OASIS, while they increased the levels of PERK and its downstream molecules, ATF4. A reduction in PERK level by siRNA did not affect the AGEs-induced suppression of the levels of Osterix, Col1 and OCN mRNA. In conclusion, AGEs inhibited the osteoblastic differentiation of stromal cells by suppressing ER stress sensors and accumulating abnormal proteins in the cells. This process might accelerate AGEs-induced suppression of bone formation found in diabetes mellitus.     

Cationic antioxidants as a powerful tool against mitochondrial oxidative stress

This review describes evidence that mitochondrial reactive oxygen species (mROS) are of great importance under many physiological and pathological conditions. The most demonstrative indications favoring this conclusion originate from recent discoveries of the in vivo effects of mitochondria-targeted antioxidants (MitoQ and SkQs). The latter compounds look promising in treating several incurable pathologies as well as aging.     

Synchronous plasma membrane electrochemical potential oscillations during yeast colony development and aging

Microorganisms that survive in natural environments form organized multicellular communities, biofilms and colonies with specific properties. During stress and nutrient limitation, slow growing and senescent cells in such communities retain vital processes by maintaining plasma membrane integrity and retaining the ability to generate transmembrane electrochemical gradients. We report the use of a Saccharomyces cerevisiae colonial model to show that population growth in a multicellular community depends on nutrient diffusion and that resting cells start to accumulate from the beginning of the second acidic phase of colony development. Despite differentiation of colony members, synchronous transmembrane potential oscillation was detected in the organized colony. The electrochemical membrane potential periodically oscillated at frequencies between those for circadian to infradian rhythms during colony aging and transiently decreased at time points previously linked with rebuilding of yeast metabolism. Despite extensive decreases in the intracellular ATP concentration and in the amount and activity of the plasma membrane proton pump during nutrient limited growth and colony aging, the transmembrane electrochemical potential appeared to be maintained above a level critical for population survival.     

VdSho1 Regulates Growth,Oxidant Adaptation and Virulence in Verticillium dahliae

Verticillium dahliae infection leads to Verticillium wilt in cotton and other dicotyledon crops. To reduce the loss of economic crops, more attention has been focused on the key genes involved in pathogenicity of this soil‐borne plant fungal pathogen. Sho1 encodes a conserved tetraspan transmembrane protein which is a key element of the two upstream branches of the HOG‐MAPK pathway in fungi. Sho1 is required for full virulence in a wide variety of pathogenic fungi. In this study, sho1 mutant in V. dahliae (designated ΔVdsho1) was generated by Agrobacterium tumefaciens‐mediated transformation. ΔVdsho1 strain was highly sensitive to menadione (at concentration of 120 μm ) and hydrogen peroxide (at concentration of 250 μm ), displayed delayed spore germination and reduced spore production compared with the wild type and the complemented strains. During infection of host cotton plants, ΔVdsho1 exhibited impaired ability of root attachment and invasive growth. Results from the present work suggest that VdSho1 controls external sensing, virulence and multiple growth‐related traits in V. dahliae and might serve as a potential target for control of Verticillium wilt.     

Cellular functions of NSF: not just SNAPs and SNAREs

N-ethylmaleimide sensitive factor (NSF) is an ATPases associated with various cellular activities protein (AAA), broadly required for intracellular membrane fusion. NSF functions as a SNAP receptor (SNARE) chaperone which binds, through soluble NSF attachment proteins (SNAPs), to SNARE complexes and utilizes the energy of ATP hydrolysis to disassemble them thus facilitating SNARE recycling. While this is a major function of NSF, it does seem to interact with other proteins, such as the AMPA receptor subunit, GluR2, and beta2-AR and is thought to affect their trafficking patterns. New data suggest that NSF may be regulated by transient post-translational modifications such as phosphorylation and nitrosylation. These new aspects of NSF function as well as its role in SNARE complex dynamics will be discussed.     

P-glycoprotein models of the apo and ATP-bound states based on homology with Sav1866 and MalK

We exploit the biochemical and sequence similarity between Staphylococcus aureus Sav1866 and P-glycoprotein to develop a homology model of P-glycoprotein representing an ATP-bound state, which captures the major features of the low-resolution EM structure and is consistent with cysteine mutagenesis studies. Using insights from the MalK crystal structures and BtuCD simulations, we model two nucleotide-free conformations. Conformational changes are characterized by pincering rigid-body rotations of the nucleotide-binding domains, inducing transmembrane domain reorganizations which correspond to the two lowest frequency normal modes of the protein. These conformations (see supplementary material) may characterize some of the major steps in the nucleotide catalytic cycle.