The Possible Mechanism of Idiosyncratic Lapatinib-Induced Liver Injury in Patients Carrying Human Leukocyte Antigen-DRB1*07:01

Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove. These results indicate that lapatinib affects the ligand binding to HLA-DRB1*07:01 and idiosyncratic lapatinib-induced liver injury might be triggered by this mechanism. This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.     

Self-thinning lines of organs and aboveground parts based on allometric relationships in overcrowded Pinus densiflora stands

The allometric relationships of mean tree height [`(H)]( μ [`(w)]_x^q ) \bar{H}( \propto \bar{w}_{\rm {x}}^{\theta } ) and of organ mass density [`(d)]<sub>x</sub> ( μ [`(w)]_x^d ) \bar{d}_{\rm {x}} ( \propto \bar{w}_{\rm {x}}^{\delta } ) to mean organ mass [`(w)]_x \bar{w}_{\rm {x}} were studied in self-thinning Pinus densiflora Sieb. et Zucc. stands. Tree height increased significantly with increasing mean mass of organs and aboveground parts on log–log coordinates. The value of the allometric constant θ ranged from 0.2878 to 0.3349. On the other hand, the constant value δ was not significantly different from zero, except for leaves. The value of the allometric constant δ ranged from −0.2926 to 0.0120. According to Weller’s allometric model, the slope of the self-thinning line was calculated from the allometric constants θ and δ. The thinning slope was estimated to be −1.51 in stem, −1.39 in branches, −1.00 in leaf and −1.41 in aboveground parts, respectively. Mass density was high in stem, medium in branches and low in leaves. Mean leaf mass density decreased significantly with decreasing stand density on log–log coordinates, which could be interpreted as indicating the importance of the constant final leaf biomass in overcrowded P. densiflora stands. The self-thinning exponents of branch, stem and aboveground parts were not significantly different from 3/2, which indicated that the 3/2 power law of self-thinning holds for stem mass, branch mass and aboveground mass in overcrowded P. densiflora stands.     

Genetic population structure and morphological characters of Japanese psychrolutids of genus <Emphasis Type="Italic">Malacocottus</Emphasis> (Scorpaeniformes: Psychrolutidae)

The genetic population structure and the diagnostic characters of Malacocottus gibber from the Japan Sea and Malacocottus zonurus from the Okhotsk Sea and the northwestern Pacific were compared. Analysis of the nucleotide sequences of the mitochondrial control region revealed no genetic differences between the populations of M. gibber and M. zonurus, even though most individuals of both the species were found to be morphologically distinct. Most of the Malacocottus gibber specimens had the typical morphological characters of this species, namely the absence of an accessory spine on the preopercle of both sides and the absence of modified body scales above the lateral line. All the specimens of M. zonurus had accessory spines on both sides, and most of them had modified body scales. The results of this study suggest that M. gibber should be treated as a subspecies or a synonym of M. zonurus. The nested clade analysis and the analysis of molecular variance (AMOVA) showed that the Japanese Malacocottus fishes are genetically homogenous over their geographical range. The mismatch distribution of the Japanese Malacocottus fishes indicated that a sudden population expansion had occurred recently. The contrast in phylogeographic structures between the Malacocottus fish and the zoarcid Bothrocara hollandi—the most dominant deep-sea demersal fish in the Japan Sea—might be attributed to the differences in the depths of the habitats and larval ecology between these two fishes.     

Leaf biomass changes with stand development in hinoki cypress (<Emphasis Type="Italic">Chamaecyparis obtusa</Emphasis> [Sieb. et Zucc.] Endl.)

We monitored a permanent plot of 3-year-old Chamaecyparis obtusa seedlings for 11 years after planting. As the stem cross-sectional area at the crown base can be regarded as a good predictor of leaf mass according to the pipe model theory, we measured this parameter to determine temporal trends in leaf biomass. The mean values showed asymptotic growth, maintaining a near-constant level after a stand age of 9 years. Peak values were found at 9 years, followed by a slight decrease because of a continuous reduction in stand density. This temporal trend suggests that the leaf biomass per unit land area attains a peak at an age of 9 years. As the stand density changes with stand age, the relationship between stand stem cross-sectional area at the crown base and stand density showed an optimum curve in which the optimum density was around 9200 ha⁻¹. We propose hypothetical trends in primary productivity and biomass density with stand age, based on the results of measurements of stem cross-sectional area at the crown base and stand density under the assumption of the 3/2 power law of self-thinning.     

The proteoglycan lectin domain binds sulfated cell surface glycolipids and promotes cell adhesion

The lecticans are a group of chondroitin sulfate proteoglycans characterized by the presence of C-type lectin domains. Despite the suggestion that their lectin domains interact with carbohydrate ligands, the identity of such ligands has not been elucidated. We previously showed that brevican, a nervous system-specific lectican, binds the surface of B28 glial cells (Yamada, H., Fredette, B., Shitara, K., Hagihara, K., Miura, R., Ranscht, B., Stallcup, W. B., and Yamaguchi, Y. (1997) J. Neurosci. 17, 7784-7795). In this paper, we demonstrate that two classes of sulfated glycolipids, sulfatides and HNK-1-reactive sulfoglucuronylglycolipids (SGGLs), act as cell surface receptors for brevican. The lectin domain of brevican binds sulfatides and SGGLs in a calcium-dependent manner as expected of a C-type lectin domain. Intact, full-length brevican also binds both sulfatides and SGGLs. The lectin domain immobilized as a substrate supports adhesion of cells expressing SGGLs or sulfatides, which was inhibited by monoclonal antibodies against these glycolipids or by treatment of the substrate with SGGLs or sulfatides. Our findings demonstrate that the interaction between the lectin domains of lecticans and sulfated glycolipids comprises a novel cell substrate recognition system, and suggest that lecticans in extracellular matrices serve as substrate for adhesion and migration of cells expressing these glycolipids in vivo.     

Identification and characterization of the SSB1 locus involved in symptom development by Spring beauty latent virus infection in Arabidopsis thaliana

The natural variation of Arabidopsis thaliana in response to a bromovirus, Spring beauty latent virus (SBLV), was examined. Of 63 Arabidopsis accessions tested, all were susceptible when inoculated with SBLV, although there was a large degree of variation in symptom development. Most accessions, including Columbia (Col-0), were symptomless or developed only mild symptoms, but four accessions, including S96, showed severe symptoms of SBLV infection. Genetic analysis suggested that the difference in the responses of Col-0 and S96 to SBLV was controlled by a single semidominant locus. We have designated this locus SSB1 (symptom development by SBLV infection). By using genetic markers, SSB1 was mapped to chromosome IV. The patterns of distribution and accumulation of SBLV in sensitive accessions were similar to those in the insensitive accessions. In addition, symptom development in S96 by SBLV infection was critically interrupted by the presence of the NahG gene, which encodes salicylic acid (SA) hydroxylase. These data suggest that symptom development in A. thaliana controlled by SSB1 is independent of the efficiency of SBLV multiplication and is dependent on SA signaling.