Cartilage link protein interacts with neurocan, which shows hyaluronan binding characteristics different from CD44 and TSG-6

The interaction of neurocan with hyaluronan was qualitatively characterized with alkaline phosphatase fusion proteins secreted by mammalian cells. The wild type neurocan hyaluronan binding domain fused to alkaline phosphatase bound to immobilized hyaluronan under physiological as well as moderately hypertonic conditions, whereas its ability to bind to immobilized chondroitin sulfate dropped rapidly with increasing salt concentration. Strong hyaluronan binding ability was still evident when in both link modules within the hyaluronan binding domain a basic amino acid was mutated, which is well conserved among link modules of hyaluronan binding proteins. A strong enhancement of the binding of neurocan to immobilized hyaluronan was observed after preincubation of the immobilized hyaluronan with cartilage link protein. Moreover, this preincubation mediated also the binding of a fusion protein representing only the immunoglobulin module of neurocan linked to alkaline phosphatase, which showed no binding to immobilized hyaluronan alone. The interaction of the neurocan immunoglobulin module with link protein could also be shown by overlay blot analysis. These observations suggest that the hyaluronan binding characteristics of paired link modules are different from those of single link modules, and that the reported temporal co-expression of cartilage link protein and of neurocan in developing brain implicates the possibility of a cooperative function of these molecules.     

Possible requirement of intercellular adhesion molecule-1 for invasion of gingival epithelial cells by Treponema medium

Oral treponemes are members of the spirochete family of bacteria associated with periodontal diseases. In the present study, we demonstrate that intercellular adhesion molecule-1 (ICAM-1) on human gingival epithelial cells (HGEC) contributed to the invasion of Treponema medium, a medium-sized oral Treponema, into those cells. The quantity of T. medium in HGEC was found to peak at 2 h after inoculation and then decreased gradually. Immunofluorescence microscopy findings showed that the bacteria were colocalized with ICAM-1 on HGEC. Furthermore, knockdown of ICAM-1 in HGEC resulted in inhibition of T. medium invasion by RNA interference, whereas that of Toll-like receptor 2 did not. These results suggest that ICAM-1 may be required for the invasion of T. medium into HGEC, and they indicate that the molecule plays a principal role in the primary stages of the development and progression of chronic periodontitis.     

Somatic hypermutation and selection of B cells in thymic germinal centers responding to acetylcholine receptor in myasthenia gravis

The muscle weakness in myasthenia gravis (MG) is mediated by autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. Production of these pathogenic autoantibodies is believed to be associated with germinal centers (GC) and anti-AChR-secreting plasma cells in the hyperplastic thymus of patients with early onset MG (EOMG). Here, we describe the repertoire of rearranged heavy chain V genes and their clonal origins in GC from a typical EOMG patient. Three hundred fifteen rearranged Ig V(H) genes were amplified, cloned, and sequenced from sections of four thymic GC containing AChR-specific B cells. We found that thymic GC contain a remarkably heterogeneous population of B cells. Both naive and circulating memory B cells undergo Ag-driven clonal proliferation, somatic hypermutation, and selection. Numerous B cell clones were present, with no individual clone dominating the response. Comparisons of B cell clonal sequences from different GC and known anti-AChR Abs from other patients showed convergent mutations in the complementarity determining regions. These results are consistent with AChR driving an ongoing GC response in the thymus of EOMG patients. This is the first detailed analysis of B cell clones in human GC responding to a defined protein Ag, and the response we observed may reflect the effects of chronic stimulation by autoantigen.     

Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment

In humans, phencyclidine (PCP), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, the glutamatergic neuronal dysfunction hypothesis is one of the main explanatory hypotheses and PCP-treated animals have been utilized as an animal model of schizophrenia. The adult rodents treated with PCP repeatedly exhibit hyperlocomotion as an index of positive symptoms, a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show a sensorimotor gating deficits and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes endure after withdrawal from repeated PCP treatment. Furthermore, repeated PCP treatment induces some neurochemical and neuroanatomical changes. On the other hand, the exposure to viral or environmental insult in the second trimester of pregnancy increases the probability of subsequently developing schizophrenia as an adult. NMDA receptor has been implicated in controlling the structure and plasticity of developing brain circuitry. Based on neurodevelopment hypothesis of schizophrenia, schizophrenia model rats treated with PCP at the perinatal stage is developed. Perinatal PCP treatment impairs neuronal development and induces long-lasting schizophrenia-like behaviors in adult period. Many findings suggest that these PCP animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.     

Environmental filters shaping angiosperm tree assembly along climatic and geographic gradients

Question

Global‐scale forest censuses provide an opportunity to understand diversification processes in woody plant communities. Based on the climatic or geographic filtering hypotheses associated with tropical niche conservatism and dispersal limitation, we analysed phylogenetic community structures across a wide range of biomes and evaluated to what extent region‐specific processes have influenced large‐scale diversity patterns of tree species communities across latitude or continent.

Location

Global.

Methods

We generated a data set of species abundances for 21,379 angiosperm woody plants in 843 plots worldwide. We calculated net relatedness index (NRI) for each plot, based on a single global species pool and regional species pools, and phylogenetic β‐diversity (PBD) between plots. Then, we explored the correlations of NRI with climatic and geographic variables, and clarified phylogenetic dissimilarity along geographic and climatic differences. We also compared these patterns for South America, Africa, the Indo‐Pacific, Australia, the Nearctic, Western Palearctic and Eastern Palearctic.

Results

NRI based on a global‐scale species pool was negatively associated with precipitation and positively associated with Quaternary temperature change. PBD was positively associated with geographic distance and precipitation difference between plots across tropical and extratropical biomes. Moreover, phylogenetic dissimilarity was smaller in extratropical regions than in regions including the tropics, although temperate forests of the Eastern Palearctic showed a greater dissimilarity within extratropical regions.

Conclusions

Our findings support predictions of the climatic and geographic filtering hypotheses. Climatic filtering (climatic harshness and paleoclimatic change) relative to tropical niche conservatism played a role in sorting species from the global species pool and shaped the large‐scale diversity patterns, such as the latitudinal gradient observed across continents. Geographic filtering associated with dispersal limitation substantially contributed to regional divergence of tropical/extratropical biomes among continents. Old, long‐standing geographic barriers and recent climatic events differently influenced evolutionary diversification of angiosperm tree communities in tropical and extratropical biomes.     

Acute and chronic effects of FR-149175, a beta 3-adrenergic receptor agonist, on energy expenditure in Zucker fatty rats

Clinical therapies for both obesity and obese non-insulin-dependent diabetes mellitus require maintenance of reduced body weight after the initial successful reduction resulting from calorie control, exercise, or medication. Although beta(3)-adrenergic receptor (beta(3)-AR) agonists have been shown to stimulate whole body energy expenditure and lipid mobilization, whether stimulatory effects on oxygen consumption and lipolysis are influenced by chronic exposure to agonists has not been fully characterized. We therefore examined the acute and chronic effects of FR-149175, a selective beta(3)-AR agonist, on whole body oxygen consumption in genetically obese Zucker fatty rats. Chronic treatment with FR-149175 caused a decrease in both body weight gain and white fat pad weight at doses that induced lipolysis in acute treatment (1 and 3.2 mg/kg p.o.). Single administration of FR-149175 (0.1, 1, and 3.2 mg/kg p.o.) dose dependently increased whole body oxygen consumption. Repetitive administration did not cause attenuation of the thermogenic response at lower doses (0.1 and 1 mg/kg 2 times daily), whereas the highest dose (3.2 mg/kg 2 times daily) induced a progressive increase in oxygen consumption. PCR analyses of retroperitoneal white adipose tissue indicated little or no change in beta(3)-AR mRNA levels. Uncoupling protein 1 gene expression increased at 1 mg/kg, and drastic upregulation was detected at 3.2 mg/kg. FR-149175 also increased HSL mRNA levels in a dose-related manner, whereas there was no effect on genes involved in beta-oxidation. These results support that the thermogenic effect of beta(3)-AR agonists is not attenuated by chronic exposure to agonists.     

Role for brain-derived neurotrophic factor in learning and memory

In addition to its actions on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) has a role in the regulation of synaptic strength. Long-term potentiation, a form of synaptic plasticity, is markedly impaired in BDNF mutant mice, but the changes were restored by the re-expression of BDNF. BDNF also influences the development of patterned connections and the growth and complexity of dendrites in the cerebral cortex. These results suggest a role for BDNF in learning and memory processes, since memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Memory acquisition is associated with an increase in BDNF mRNA and TrkB receptor activation in specific brain areas. Moreover, the pharmacologic and genetic deprivation of BDNF or its receptor TrkB results in severe impairment of learning and memory in mice, rats and chicks. The effect of BDNF on learning and memory may be linked to the modulation of NMDA and non-NMDA receptor functions as well as the expression of synaptic proteins required for exocytosis. Activation of the mitogen-associated protein kinase and/or phosphatidylinositol 3-kinase signaling pathways may be involved in BDNF-dependent learning and memory formation. It is concluded that BDNF/TrkB signaling plays an important role in learning and memory.     

Changes in unit structures and infanticide observed in Arsi geladas

In 1989 a new gelada baboon (Theropithecus gelada) population was found in Arsi, on the opposite side of the Rift Valley to that of the known gelada populations of Semien and Showa. Previous comparisons of units of the band at Gado Goro, Arsi, in the same season in consecutive years, indicated that unit structure is less stable among Arsi geladas as compared to the Semien population. Gelada units of the band at Gado-Goro were studied for 7 months in order to investigate the processes of social changes. Changes in unit structure were observed. Provisioning was carried out for 1.5 months at the beginning of the 7-month study period, in order to capture and obtain blood samples from the geladas. Following this, changes in male leadership of some units were observed, presumably as a consequence of the capture. However, natural changes also occurred. One change in unit structure occurred after a female gave birth, and changes in another unit occurred after the disappearance of the leader male. These changes involved female desertion of a unit, her subsequent transfer to a male unit, and culminated in the formation of a unit consisting of one female and one male. One successful and one attempted case of unification of units, and one case of change of a unit leader male are reported. These changes occurred among eight resident units in a period of 7 months (196 female months). Though the types of social changes were not much different from previous observations in Semien National Park, their frequencies seemed to be much higher. The characteristics of Arsi gelada social changes are proposed to be related to the small size of the units. We also describe a new confirmed case and one suspected case of infanticide, as well as one case of abortion at the time of male leader change.