The objective of this study was to show a new function of Se in IgG absorption from colostrum by newborn calves. The same amount and quality of colostrum with or without Se addition was fed to paired calves (n = 60) 4 times at <2, 12, 24, and 36 h after birth, respectively. Four-time feeding of colostrum containing 1.0 ppm Se significantly increased IgG amount in the blood plasma of calves 24 h after birth; however, its effect was small (about 20% increase). Although the addition of 3.0 ppm Se once at the first colostrum feeding was more effective on IgG absorption, its significant effect was a 42% increase on average. The increased IgG concentration of blood plasma continued for about 2 wk. It is known that the absorption of colostrum IgG is mediated by intestinal pinocytosis, which continues for only 24 h after birth. The addition of Se to colostrum might directly activate this physiological pinocytosis of intestinal epithelial cells because of the rapidity of the reaction. This effect is not nutritional but rather pharmacological. Supplemented Se also resulted in its increased concentration in blood plasma. Selenium is an essential mineral for animals; however, newborn calves are always deficient in Se at birth. Application of this method in calves would also provide an immediate supply of Se and might contribute to the development of the immune system of calves. This study showed that Se supplementation to colostrum increased IgG amount and Se concentration in blood plasma in newborn calves.

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It has been reported that reduction of masticatory afferent stimulation might influence learning and memory function. In order to clarify the influences of reduced masticatory sensory input on spatial memory/learning ability and neuropathological changes, we conducted the Morris water maze experiment and investigated the number of hippocampal neurons in association with the differences in masticatory afferent stimuli from hard-and soft-diet feeding in mice. The water maze experiment showed no significant difference in learning ability between 180-day-old solid-and powderdiet groups. Meanwhile, the ability was significantly reduced in the 360-day-old powder-diet group as compared with the age-matched solid-diet group. The total number of pyramidal cells in the hippocampal CA1 and CA3 regions was significantly smaller in 360-day-old powder-diet group than in the remaining groups. These results demonstrate that reduction of masticatory afferent stimuli due to long-term soft-diet feeding may induce neuron loss in the hippocampus and reduced memory/learning ability.Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which was first reported by Alzheimer in 1907 (1, 18). It is, in general, divided into early and late-onset types, but both have similar clinical and pathological features. It has long been suggested that there is a certain relationship between loss of teeth and dementia. Kondo et al. (6) reported that tooth loss was one of the risk factors of AD. Shigetomi et al. (17) reported that the risk of AD onset increased significantly in a group with lessnumber teeth than in the age-matched control with more-number teeth. Animal experiments revealed that tooth loss or long-term soft-diet feeding caused a decrease of learning and memory ability. Yamamoto and Hirayama showed that the SAMR1 and SAMP8 mice fed on a solid diet were superior in an eight-arm radial maze to the powder-diet group (21). It was also reported that the aged SAMP8 mice, after the molar extraction, showed a decrease in both learning ability and neuron density in the hippocampal CA1 region compared with the controls (14). Furthermore, it is suggested that afferent sensory input is highly dependent on masticatory function or hardness of the diet (13). Ishizuka (5) demonstrated that the action potential of the masseter muscle in rats was significantly lower in the powder-diet group than in the solid-diet group.It is reasonably assumed from these findings that tooth loss and the relevant reduction of masticatory afferent stimuli may influence the structure and function of the central nervous system (CNS). However, little information is available for the relation-

SUMMARYThis report presents a technique based on the particle method to simulate the process of thrombogenesis while considering platelet aggregation under the influence of fluid dynamics. In the employed particle method, the blood region was discretized by particles that were assumed to have the characteristics of plasma and platelets. The moving particle semi-implicit (MPS) method developed for incompressible viscous flow was applied to the flow of plasma and platelets. Adhesion of platelets to the injured vessel wall was expressed by a spring force acting between them. The same modeling was applied for the aggregation of platelets. Three-dimensional computer simulation of thrombogenesis was performed in a rectangular flow channel under the condition of Re = 0.02. We demonstrated that the proposed method can simulate the formation and destruction of a thrombus with the inclusion of feedback reactions of thrombus development and flow. The results revealed that the growth rate of a thrombus, its height, and time required from the beginning of thrombus formation to its collapse vary according to the flow rate, indicating that flow dynamics plays an important role in regulating the development of a primary thrombus.

Dysregulation of histone H3 lysine 4 (H3K4) methylation has been implicated in the pathogenesis of several neurodevelopmental disorders. Targeting lysine-specific demethylase 1 (LSD1), an H3K4 demethylase, is therefore a promising approach to treat these disorders. However, LSD1 forms complexes with cofactors including growth factor independent 1B (GFI1B), a critical regulator of hematopoietic differentiation. Known tranylcypromine-based irreversible LSD1 inhibitors bind to coenzyme flavin adenine dinucleotide (FAD) and disrupt the LSD1-GFI1B complex, which is associated with hematotoxicity such as thrombocytopenia, representing a major hurdle in the development of LSD1 inhibitors as therapeutic agents. To discover LSD1 inhibitors with potent epigenetic modulation and lower risk of hematotoxicity, we screened small molecules that enhance H3K4 methylation by the inhibition of LSD1 enzyme activity in primary cultured rat neurons but have little impact on LSD1-GFI1B complex in human TF-1a erythroblasts. Here we report the discovery of a specific inhibitor of LSD1 enzyme activity, T-448 (3-((1S,2R)-2-(cyclobutylamino) cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide fumarate). T-448 has minimal impact on the LSD1-GFI1B complex and a superior hematological safety profile in mice via the generation of a compact formyl-FAD adduct. T-448 increased brain H3K4 methylation and partially restored learning function in mice with NMDA receptor hypofunction. T-448-type LSD1 inhibitors with improved safety profiles may provide unique therapeutic approaches for central nervous system disorders associated with epigenetic dysregulation.

It has been reported that vascular endothelial growth factor (VEGF), expressed by osteoblasts, can induce osteoclast recruitment and thus affects bone remodeling. The purpose of this study was to investigate the effects of cyclic tensile forces on the expression of VEGF and macrophage-colony-stimulating factor (M-CSF) in osteoblastic MC3T3-E1 cells. VEGF and M-CSF gene expression and protein concentration were determined by real-time PCR and enzyme-linked immunoassay. The expression of VEGF and M-CSF mRNA in the experimental group was higher than in the control group. The increase in the concentration of VEGF and M-CSF protein in the experimental group was time-dependent. Moreover, gadolinium (an S-A channel inhibitor), but not nifedipine (L-Type Ca2+ channel blocker), treatment reduced the concentration of VEGF and M-CSF mRNA and protein in the experimental groups. These findings suggest that cyclic tensile forces increase the expression of VEGF and M-CSF in osteoblastic MC3T3-E1 cells via a stretch-activated channel (S-A channel).

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