CADM1 isoforms differentially regulate human mast cell survival and homotypic adhesion

Cell adhesion molecule 1 (CADM1), expressed by human lung mast cells (HLMCs), mediates their adhesion to airway smooth muscle (ASM), and contributes to ASM-dependent HLMC proliferation and survival. CADM1 is expressed in alternatively spliced isoforms, but those present in HLMCs and their function are not known. We cloned three functional and one cryptic non-functional isoform with alternative splicing between exons 7/11 and 1/2, respectively, from HLMCs and human MC lines (HMC-1 and LAD2). Differentiated HLMCs and LAD2 cells expressed the functional isoform SP4 containing exons 7/8/11 (~80% of clones), as well as SP1 (exons 7/8/9/11) and a novel SP6 (exons 7/8/9/10/11). In contrast, immature HMC-1 cells expressed only functional SP4. SP4 overexpression in HMC-1 cells and HLMCs augmented homotypic adhesion to a greater extent than SP1 in various conditions. In contrast, CADM1 downregulation abolished homotypic adhesion, indicating that CADM1 is the sole receptor mediating mast cell aggregation. CADM1-mediated adhesion was enhanced by the presence of cell survival factors. SP1 overexpression in HMC-1 cells compromised survival compared to SP4 overexpression or control. CADM1 downregulation resulted in reduced viability and decreased expression of the pro-survival protein Mcl-1(L), but not Blc-2 or Bcl-X(L), and increased caspase-3/7 activity in both HMC-1 cells and HLMCs. This coincided with decreased basal Kit levels in HLMCs. In summary, human MCs express multiple CADM1 isoforms which exhibit differential regulation of survival and homotypic adhesion. The most highly expressed SP4 isoform is likely to contribute to MC aggregation and longevity in mastocytosis, and augment the pathophysiology of allergic diseases.     

Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation

Chromatin insulators demarcate expression domains by blocking the cis effects of enhancers or silencers in a position-dependent manner. We show that the chromatin insulator protein CTCF carries a post-translational modification: poly(ADP-ribosyl)ation. Chromatin immunoprecipitation analysis showed that a poly(ADP-ribosyl)ation mark, which exclusively segregates with the maternal allele of the insulator domain in the H19 imprinting control region, requires the bases that are essential for interaction with CTCF. Chromatin immunoprecipitation-on-chip analysis documented that the link between CTCF and poly(ADP-ribosyl)ation extended to more than 140 mouse CTCF target sites. An insulator trap assay showed that the insulator function of most of these CTCF target sites is sensitive to 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase activity. We suggest that poly(ADP-ribosyl)ation imparts chromatin insulator properties to CTCF at both imprinted and nonimprinted loci, which has implications for the regulation of expression domains and their demise in pathological lesions.     

Structure of the Escherichia coli ribosomal termination complex with release factor 2

Termination of protein synthesis occurs when the messenger RNA presents a stop codon in the ribosomal aminoacyl (A) site. Class I release factor proteins (RF1 or RF2) are believed to recognize stop codons via tripeptide motifs, leading to release of the completed polypeptide chain from its covalent attachment to transfer RNA in the ribosomal peptidyl (P) site. Class I RFs possess a conserved GGQ amino-acid motif that is thought to be involved directly in protein-transfer-RNA bond hydrolysis. Crystal structures of bacterial and eukaryotic class I RFs have been determined, but the mechanism of stop codon recognition and peptidyl-tRNA hydrolysis remains unclear. Here we present the structure of the Escherichia coli ribosome in a post-termination complex with RF2, obtained by single-particle cryo-electron microscopy (cryo-EM). Fitting the known 70S and RF2 structures into the electron density map reveals that RF2 adopts a different conformation on the ribosome when compared with the crystal structure of the isolated protein. The amino-terminal helical domain of RF2 contacts the factor-binding site of the ribosome, the 'SPF' loop of the protein is situated close to the mRNA, and the GGQ-containing domain of RF2 interacts with the peptidyl-transferase centre (PTC). By connecting the ribosomal decoding centre with the PTC, RF2 functionally mimics a tRNA molecule in the A site. Translational termination in eukaryotes is likely to be based on a similar mechanism.     

Studies on lipid peroxidation using whole liver cells: Influence of damaged cells on the prooxidant effect of ADP-Fe3+ and CCl4

Summary An increase in the number of damaged cells produces an enhancement of lipid peroxidation induced by ADP-Fe³⁺ or CCl₄ in vitro on hepatocytes in single cell suspension.This work has been supported by the Consiglio Nazionale delle Ricerche, Roma, Italy, and the National Foundation for Cancer Research, Bethesda, Maryland, USA.     

Symmetry, Quantum Mechanics, and Beyond

The relevance of symmetry to today's physics is a widely acknowledged fact. A significant part of recent physical inquiry – especially the physics concerned with investigating the fundamentalbuilding blocks of nature – is grounded on symmetry principles andtheir many and far-reaching consequences. But where these symmetries come from and what their real meaning is are open questions, at the center of a developing debate among physicists and philosophers of science. To tackle the problems arising in considering the symmetry issue is the main purpose of this paper. Starting with briefly recalling the bases for the discussion – how symmetry enters and operates in physics, its special effectiveness in the quantum domain and the many relevant functions it performs (Sections 1–3), the paper then focus on the general interpretative questions that arise and the sorts of answers that have been given (Section 4).     

Zr~(4+)/F~– co-doped TiO_2(anatase) as high performance anode material for lithium-ion battery

Zr~(4+) and F~– co-doped TiO_2 with the formula of Ti_(0.97)Zr_(0.03)O_(1.98)F_(0.02) was facilely synthesized by a sol-gel template route.The crystal structure,morphology,composition,surface area,and conductivity were characterized by Raman spectroscopy,energy-dispersive X-ray analysis,scanning electron microscopy,Brunauer-Emmett-Teller measurements,X-ray photoelectron spectroscopy,and electrochemical impedance spectroscopy.The results demonstrate that Zr~(4+)and F~–homogeneously incorporated into TiO_2,forming solid solution with an anatase structure.Ti_(0.97)Zr_(0.03)O_(1.98)F_(0.02)shows outstanding electrochemical properties as Li-ion battery anode in comparison with Ti_(0.97)Zr_(0.03)O_2.In particular,upon 35-fold cycling at 1C-rate Zr~(4+)/F~–co-doped TiO_2delivers a reversible capacity of 163 mAh g~(–1),whereas Zr~(4+)-doped TiO_2gives only 34 mA h g~(–1).Additionally,Zr~(4+)/F~–co-doped TiO_2retains a capacity of 138 mA h g~(–1)during cycling even at 10 C.The enhance performance originates from improved conductivity of Zr~(4+)/F~–co-doped TiO_2material through generation of Ti~(3+)(serving as electron donors)into the crystal lattice and,possibly,due to F-doping blocked the anode surface from attack of HF formed as electrolyte decomposition product.