Branching patterns of trunk lateral line nerves in Pleuronectiformes: uniformity and diversity

Branching patterns of the trunk lateral line nerves were studied in 46 pleuronectiform species, representing nine families in two suborders. The dorsal fin longitudinal ramus (DFLR), derived from the main nerve (horizontal septum lateral line nerve), passed closely along the course of the middle trunk lateral line in all specimens examined, the dorsal longitudinal collector nerve (DLCN) partly coalescing with the DFLR along the arched part of the lateral line in Psettodes erumei (Psettodoidei), compared with the entire length of the latter in all other species (Pleuronectoidei). Citharidae, Paralichthyidae, and Pleuronectidae were characterized by having a simple, elongated dorsal ramule; Bothidae was unique in having more than one dorsal ramule, forming a ladder-like network and peripherally giving off numerous minute branches; Poecilopsettidae and Samaridae possessed a few, short dorsal ramules; Soleidae and Cynoglossidae were characteristic in having a dendritic dorsal ramule. Secondary modifications of the course of the middle trunk lateral line were detected by nerve information, the arched part of the lateral line having been secondarily highly elevated in some genera of Pleuronectidae, but secondarily straightened in Samaridae.     

Design, total synthesis, and biological evaluation of neodysiherbaine A derivative as potential probes

To enable studies to elucidate the detailed biological function of dysiherbaine and neodysiherbaine A, potent and subunit-selective agonists for ionotropic glutamate receptors, the derivative with a hydroxymethyl substituent at the C10 position has been developed. Preliminary biological evaluation of the analogue showed that a C10 hydroxymethyl substituent produced significant alterations in binding affinities for the ionotropic glutamate receptor subtypes.     

Synthesis and biological evaluation of benzamides and benzamidines as selective inhibitors of VEGFR tyrosine kinases

A series of benzamidines and benzamides was synthesized as selective inhibitors of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, and tested for inhibitory activity toward autophosphorylation by the enzyme assay. Selective inhibition of VEGFR-2 tyrosine kinase was observed in the salicylic amide 4e and the anthranilic amidine 5a, and their percent inhibitions of VEGFR-2 tyrosine kinase were 44-60% at a 10 microM concentration of compounds. The salicylic amide 4a showed inhibition of both VEGFR-1 and VEGFR-2 tyrosine kinases at a 10 microM concentration.     

Antimalarial effect of bis-pyridinium salts, N,N'-hexamethylenebis(4-carbamoyl-1-alkylpyridinium bromide)

The in vitro antimalarial activity of bis-pyridinium salts, N,N'-hexamethylenebis(4-carbamoyl-1-decylpyridinium bromide) and their derivatives, against the Plasmodium falciparum FCR-3 strain (ATCC 30932, chloroquine-sensitive) was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 3.5microM to 10nM. The chain length of the N1-alkyl moiety was found to be very beneficial in terms of antimalarial activity, and in this series of compounds, the most appropriate N1-alkyl chain length was found to be eight.     

Myosin-Va facilitates the accumulation of mRNA/protein complex in dendritic spines

mRNA localization has an essential role in localizing cytoplasmic determinants, controlling the direction of protein secretion, and allowing the local control of protein synthesis in neurons. In neuronal dendrites, the localization and translocation of mRNA is considered as one of the molecular bases of synaptic plasticity. Recent imaging and functional studies revealed that several RNA-binding proteins form a large messenger ribonucleoprotein (mRNP) complex that is involved in transport and translation of mRNA in dendrites. However, the mechanism of mRNA translocation into dendritic spines is unknown. Here, we show that an actin-based motor, myosin-Va, plays a significant role in mRNP transport in neuronal dendrites and spines. Myosin-Va was Ca2+-dependently associated with TLS, an RNA-binding protein, and its target RNA Nd1-L, an actin stabilizer. A dominant-negative mutant or RNAi of myosin-Va in neurons suppressed TLS accumulation in spines and further impaired TLS dynamics upon activation of mGluRs. The TLS translocation into spines was impeded also in neurons prepared from myosin-Va-null dilute-lethal (dl) mice, which exhibit neurological defects. Our results demonstrate that myosin-Va facilitates the transport of TLS-containing mRNP complexes in spines and may function in synaptic plasticity through Ca2+ signaling.     

A mathematical model for apoptosome assembly: the optimal cytochrome c/Apaf-1 ratio

Apoptosis, a highly conserved form of cell suicide, is regulated by apoptotic signals and their transduction with caspases, a family of cystein proteases. Caspases are constantly expressed in the normal cells as inactive pro-enzymes. The activity of caspase is regulated by the proteolysis. Sequential proteolytic reactions of caspases are needed to execute apoptosis. Mitochondrial pathway is one of these apoptotic signal pathways, in which caspases are oligomerized into characteristic heptamer structure, called apoptosome, with caspase-9 that activate the effector caspases for apoptosis. To investigate the dynamics of signal transduction pathway regulated by oligomerization, we construct a mathematical model for Apaf-1 heptamer assembly process. The model first reveals that intermediate products can remain unconverted even after all assemble reactions are completed. The second result of the model is that the conversion efficiency of Apaf-1 heptamer assembly is maximized when the initial concentration of cytochrome c is equal to that of Apaf-1. When the concentration of cytochrome c is sufficiently larger or smaller than that of Apaf-1, the final Apaf-1 heptamer production is decreased, because intermediate Apaf-1 oligomers (tetramers and bigger oligomers), which themselves are unable to form active heptamer, accumulate too fast in the cells, choking a smooth production of Apaf-1 heptamer. Slow activation of Apaf-1 monomers and small oligomers increase the conversion efficiency. We also study the optimal number of subunits comprising an active oligomer that maximize the conversion efficiency in assembly process, and found that the tetramer is the optimum.     

Differences in muscle function during walking and running at the same speed

Individual muscle contributions to body segment mechanical energetics and the functional tasks of body support and forward propulsion in walking and running at the same speed were quantified using forward dynamical simulations to elucidate differences in muscle function between the two different gait modes. Simulations that emulated experimentally measured kinesiological data of young adults walking and running at the preferred walk-to-run transition speed revealed that muscles use similar biomechanical mechanisms to provide support and forward propulsion during the two tasks. The primary exception was a decreased contribution of the soleus to forward propulsion in running, which was previously found to be significant in walking. In addition, the soleus distributed its mechanical power differently to individual body segments between the two gait modes from mid- to late stance. In walking, the soleus transferred mechanical energy from the leg to the trunk to provide support, but in running it delivered energy to both the leg and trunk. In running, earlier soleus excitation resulted in it working in synergy with the hip and knee extensors near mid-stance to provide the vertical acceleration for the subsequent flight phase in running. In addition, greater power output was produced by the soleus and hip and knee extensors in running. All other muscle groups distributed mechanical power among the body segments and provided support and forward propulsion in a qualitatively similar manner in both walking and running.     

Unloaded shortening velocity of voluntarily and electrically activated human dorsiflexor muscles in vivo

We have previously shown that unloaded shortening velocity (V ₀) of human plantar flexors can be determined in vivo, by applying the “slack test” to submaximal voluntary contractions (J Physiol 567:1047–1056, 2005). In the present study, to investigate the effect of motor unit recruitment pattern on V ₀ of human muscle, we modified the slack test and applied this method to both voluntary and electrically elicited contractions of dorsiflexors. A series of quick releases (i.e., rapid ankle joint rotation driven by an electrical dynamometer) was applied to voluntarily activated dorsiflexor muscles at three different contraction intensities (15, 50, and 85% of maximal voluntary contraction; MVC). The quick-release trials were also performed on electrically activated dorsiflexor muscles, in which three stimulus conditions were used: submaximal (equal to 15%MVC) 50-Hz stimulation, supramaximal 50-Hz stimulation, and supramaximal 20-Hz stimulation. Modification of the slack test in vivo resulted in good reproducibility of V ₀, with an intraclass correlation coefficient of 0.87 (95% confidence interval: 0.68–0.95). Regression analysis showed that V ₀ of voluntarily activated dorsiflexor muscles significantly increased with increasing contraction intensity (R ² = 0.52, P<0.001). By contrast, V ₀ of electrically activated dorsiflexor muscles remained unchanged (R ²<0.001, P = 0.98) among three different stimulus conditions showing a large variation of tetanic torque. These results suggest that the recruitment pattern of motor units, which is quite different between voluntary and electrically elicited contractions, plays an important role in determining shortening velocity of human skeletal muscle in vivo.     

Ionotropic glutamate receptor AMPA 1 is associated with ovulation rate

Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system by opening ion channels upon the binding of glutamate. Despite the essential roles of glutamate in the control of reproduction and anterior pituitary hormone secretion, there is a limited understanding of how glutamate receptors control ovulation. Here we reveal the function of the ionotropic glutamate receptor AMPA-1 (GRIA1) in ovulation. Based on a genome-wide association study in Bos taurus, we found that ovulation rate is influenced by a variation in the N-terminal leucine/isoleucine/valine-binding protein (LIVBP) domain of GRIA1, in which serine is replaced by asparagine. GRIA1(Asn) has a weaker affinity to glutamate than GRIA1(Ser), both in Xenopus oocytes and in the membrane fraction of bovine brain. This single amino acid substitution leads to the decreased release of gonadotropin-releasing hormone (GnRH) in immortalized hypothalamic GT1-7 cells. Cows with GRIA1(Asn) have a slower luteinizing hormone (LH) surge than cows with GRIA1(Ser). In addition, cows with GRIA1(Asn) possess fewer immature ovarian follicles before superovulation and have a lower response to hormone treatment than cows with GRIA1(Ser). Our work identified that GRIA1 is a critical mediator of ovulation and that GRIA1 might be a useful target for reproductive therapy.