The allocation of attention on a perpendicular visual display during reaching movements in depth

We investigated how visual attentional resources are allocated during reaching movements. Particularly, this study examined whether or not the direction of the reaching movement affected visual attention resource allocation. Participants held a stylus pen to reach their hand toward a target stimulus on a graphics tablet as quickly and accurately as possible. The direction of the hand movement was either from near to far space or the reverse. They observed visual stimuli and a cursor, which represented the hand position, on a perpendicularly positioned display, instead of directly seeing their hand movements. Regardless of the movement direction, the participants tended with quickly responding to the target stimuli located far from the start position as compared with those located near to the start position. These results led us to conclude that attentional resources were preferentially allocated in the areas far from the start position of reaching movements. These findings may provide important information for basic research on attention, but also contribute to a decrease of human errors in manipulation tasks performed with visual feedback on visual display terminals.     

A deletion in a cis element of Foxe3 causes cataracts and microphthalmia in rct mice

The Rinshoken cataract (rct) mutation, which causes congenital cataracts, is a recessive mutation found in SJL/J mice. All mutants present with opacity in the lens by 2?months of age. The rct locus was mapped to a 1.6-Mb region in Chr 4 that contains the Foxe3 gene. This gene is responsible for cataracts in humans and mice, and it plays a crucial role in the development of the lens. Furthermore, mutation of Foxe3 causes various ocular defects. We sequenced the genomic region of Foxe3, including the coding exons and UTRs; however, no mutations were discovered in these regions. Because there were no differences in Foxe3 sequences between the rct/rct and wild-type mice, we inferred that a mutation was located in the regulatory regions of the Foxe3 gene. To test this possibility, we sequenced a 5' noncoding region that is highly conserved among vertebrates and is predicted to be the major enhancer of Foxe3. This analysis revealed a deletion of 22-bp located approximately 3.2-kb upstream of the start codon of Foxe3 in rct mice. Moreover, we demonstrated by RT-PCR and in situ hybridization that the rct mutant has reduced expression of Foxe3 in the lens during development. We therefore suggest that cataracts in rct mice are caused by reduced Foxe3 expression in the lens and that this decreased expression is a result of a deletion in a cis-acting regulatory element.     

Wobble modification deficiency in mutant tRNAs in patients with mitochondrial diseases

Point mutations in mitochondrial (mt) tRNA genes are associated with a variety of human mitochondrial diseases. We have shown previously that mt tRNA(Leu(UUR)) with a MELAS A3243G mutation and mt tRNA(Lys) with a MERRF A8344G mutation derived from HeLa background cybrid cells are deficient in normal taurine-containing modifications [taum(5)(s(2))U; 5-taurinomethyl-(2-thio)uridine] at the anticodon wobble position in both cases. The wobble modification deficiency results in defective translation. We report here wobble modification deficiencies of mutant mt tRNAs from cybrid cells with different nuclear backgrounds, as well as from patient tissues. These findings demonstrate the generality of the wobble modification deficiency in mutant tRNAs in MELAS and MERRF.     

PMA activation of macrophages alters macrophage metabolism of aggregated LDL

Aggregation of LDL may contribute to its retention in atherosclerotic lesions. Previously, we showed that aggregated LDL induces and enters surface-connected compartments (SCCs) in human monocyte-derived macrophages by a process we have named patocytosis. Aggregated LDL was disaggregated and released from SCCs of macrophages when exposed to human lipoprotein-deficient serum. The serum factor that mediated aggregated LDL release and disaggregation was plasmin generated from plasminogen by macrophage urokinase plasminogen activator. We now show that activation of macrophages with PMA inhibits plasmin-mediated release of aggregated LDL from macrophages. With macrophage activation, plasminogen released about 60% less cholesterol and 63% less TCA-insoluble (125)I-aggregated LDL than when macrophages were not activated. Electron microscopy showed that PMA did not cause SCCs to close, which could have trapped aggregated LDL within the SCCs and limited protease access to aggregated LDL. Rather, PMA decreased macrophage generation of plasmin by 61%, and stimulated lysosomal degradation of aggregated LDL by more than 2-fold. Degradation was mediated by protein kinase C, shown by the finding that degradation was inhibited by the protein kinase C inhibitor G?6976. PMA-stimulated degradation of aggregated LDL was associated with a 3-fold increase in cholesterol esterification, consistent with hydrolysis and re-esterification of aggregated LDL-derived cholesteryl ester. In conclusion, macrophage activation with PMA causes more of the aggregated LDL that enters macrophage SCCs to be metabolized by lysosomes. This results in more cholesterol to be stored in macrophages and less aggregated LDL to be available for plasmin-mediated release from macrophage SCCs.     

Relationship between Item Responses of Negative Affect Items and the Distribution of the Sum of the Item Scores in the General Population

BackgroundSeveral studies have shown that total depressive symptom scores in the general population approximate an exponential pattern, except for the lower end of the distribution. The Center for Epidemiologic Studies Depression Scale (CES-D) consists of 20 items, each of which may take on four scores: “rarely,” “some,” “occasionally,” and “most of the time.” Recently, we reported that the item responses for 16 negative affect items commonly exhibit exponential patterns, except for the level of “rarely,” leading us to hypothesize that the item responses at the level of “rarely” may be related to the non-exponential pattern typical of the lower end of the distribution. To verify this hypothesis, we investigated how the item responses contribute to the distribution of the sum of the item scores.MethodsData collected from 21,040 subjects who had completed the CES-D questionnaire as part of a Japanese national survey were analyzed. To assess the item responses of negative affect items, we used a parameter r, which denotes the ratio of “rarely” to “some” in each item response. The distributions of the sum of negative affect items in various combinations were analyzed using log-normal scales and curve fitting.ResultsThe sum of the item scores approximated an exponential pattern regardless of the combination of items, whereas, at the lower end of the distributions, there was a clear divergence between the actual data and the predicted exponential pattern. At the lower end of the distributions, the sum of the item scores with high values of r exhibited higher scores compared to those predicted from the exponential pattern, whereas the sum of the item scores with low values of r exhibited lower scores compared to those predicted.ConclusionsThe distributional pattern of the sum of the item scores could be predicted from the item responses of such items.     

Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors

A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.     

Treatment of Mid‐Pregnant Mice with KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase,Induces Abnormal Retinal Vascular Patterning in Their Newborn Pups

We previously reported that treatment of mid‐pregnant mice with KRN633, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, caused fetal growth restriction resulting from diminished vascularization in the placenta and fetal organs. In this study, we examined how the treatment of mid‐pregnant mice with KRN633 affects the development and morphology of vascular components (endothelial cells, pericytes, and basement membrane) in the retinas of their newborn pups. Pregnant mice were treated with KRN633 (5 mg/kg) once daily from embryonic day 13.5 until the day of delivery. Vascular components were examined using immunohistochemistry with specific markers for each component. Radial vascular growth in the retina was slightly delayed until postnatal day 4 (P4) in the newborn pups of KRN633‐treated mothers. On P8, compared with the pups of control mothers, the pups of KRN633‐treated mothers exhibited decreased numbers of central arteries and veins and abnormal branching of the central arteries. No apparent differences in pericytes or basement membrane were observed between the pups of control and KRN633‐treated mothers. These results suggest that a critical period for determining retinal vascular patterning is present at the earliest stages of retinal vascular development, and that the impaired vascular endothelial growth factor signaling during this period induces abnormal architecture in the retinal vascular network     

Procalpain I in cytoplasm is translocated onto plasma and granule membranes during platelet stimulation with thrombin and then activated on the membranes.

Thrombin stimulation of platelets resulted in changes in the subcellular localization of calpain I, with a concomitant alteration of its molecular weight as measured by immunoblotting. Calpain I in resting platelets was distributed as procalpain I, an 80 kDa form which does not exhibit the enzyme activity, and 83% of the total antigen was localized in the cytosol fraction. When platelets were stimulated with thrombin, the total content of calpain I antigen was not significantly changed as compared with that of the resting platelets, though a decrease in the cytosolic distribution of 80 kDa form (from 83% to 47% of the total antigen) was observed with concomitant appearance of the active 76 kDa and intermediate 78 kDa forms of calpain I and increase in the 80 kDa form in the granule and membrane fractions. These results indicated that calpain I was translocated from the cytosol to both the plasma and granule membranes as procalpain I and then activated on the membranes during platelet stimulation with thrombin.