Model of bidirectional modulated parasystole as a mechanism for cyclic bursts of ventricular premature contractions

Cyclic bursts of ventricular premature contractions (VPC) coming at minute-order intervals have been discerned by analyzing ambulatory ECG recordings, and their mechanism has not been clarified. The present study simulates this phenomenon by constructing a bidirectional modulated parasystole model. With Ts and Te as the intrinsic periods of the sinus and ectopic pacemakers, there are distinct and initial condition-dependent solutions in the model with Ts/Te values close to 1, 1/2, 1/4, etc. Typically, two distinct stable solutions are found existing together around Ts/Te = 1/2. We have verified theoretically the coexistence of different solutions and their dependence on the model parameters. The solution presented switches between those by a premature stimulus and those by fluctuations in the model parameters such as Ts. Patterns of RR intervals were generated by simulation with randomly fluctuating Ts. They included cyclic bursts of bigeminy of the flat type and the dome type reported by Takayanagi et al. (1999) and other transient types with Wenckebach or reverse Wenckebach rhythm of coupling intervals. This model provides a mathematical representation of the atrioventricular feedback mechanism and enables the modulated parasystole hypothesis to be applied to wider classes of VPCs.     

Alterations in the Function of Cerebral Dopaminergic and Serotonergic Systems Following Electroacupuncture and Moxibustion Applications: Possible Correlates with Their Antistress and Psychosomatic Actions

Alterations in cerebral monoamines following application of electroacupuncture were investigated using conscious rats with and without application of restraining stress. The dopamine and serotonin levels were significantly decreased in the nucleus accumbens, caudate putamen, and lateral hypothalamus and increased in the dorsal raphe nucleus by restraining stress. On the other hand, application of electroacupuncture on the lumbar and hindlimb segments eliminated the above changes in dopamine, while the changes in serotonin were attenuated by lumbar and hindlimb electroacupuncture. However, the effects of hindlimb electroacupuncture were greater than those of lumbar electroacupuncture. These results clearly indicate that lumbar and hindlimb electroacupuncture stimulations have differential effects on brain monoaminergic neurons in rats exposed to restraining stress. Moxa burning stimulation was applied to the lumbar and hindlimb segments of rats without restraining stress. The dopamine level was significantly increased in the midbrain substantia nigra-ventrotegmental area by hindlimb moxibusion. On the other hand, the serotonin levels were significantly increased in the nucleus amygdala by lumber moxibusion and decreased in the nucleus accumbens by hindlimb moxibusion. The present results indicate that electroacupuncture applied to the lumbar and hindlimb segments has an antistress effect, while the application of moxibustion to the lumbar and hindlimb segments was likely to stimulate the functions of mesocortical and mesolimbic dopaminergic and serotonergic neurons. We suggest that functional alterations in cerebral dopaminergic and serotonergic neurons are involved in the clinical efficacy of electroacupuncture and moxibustion, especially because of their antistress and psychosomatic actions.     

X-ray structures of NADPH-dependent carbonyl reductase from Sporobolomyces salmonicolor provide insights into stereoselective reductions of carbonyl compounds

The X-ray structures of red yeast Sporobolomyces salmonicolor carbonyl reductase (SSCR) and its complex with a coenzyme, NADPH, have been determined at a resolution of 1.8A and 1.6A, respectively. SSCR was crystallized in an orthorhombic system with the space group P2(1)2(1)2(1) and cell dimensions of a=54.86 A, b=83.49 A, and c=148.72 A. On its cocrystallization with NADPH, isomorphous crystals of the SSCR/NADPH complex were obtained. The structure of SSCR was solved by a single wavelength anomalous diffraction measurement using a selenomethionine-substituted enzyme, and that of the SSCR/NADPH complex was solved by a molecular replacement method using the solved structure of SSCR. The structures of SSCR and the SSCR/NADPH complex were refined to an R-factor of 0.193 (R(free)=0.233) and 0.211 (R(free)=0.238), respectively. SSCR has two domains, an NADPH-binding domain and a substrate-binding domain, and belongs to the short-chain dehydrogenases/reductases family. The structure of the NADPH-binding domain and the interaction between the enzyme and NADPH are very similar to those found in other structure-solved enzymes belonging to the short-chain dehydrogenases/reductases family, while the structure of the substrate-binding domain is unique. SSCR has stereoselectivity in its catalytic reaction, giving rise to excessive production of (S)-alcohols from ethyl 4-chloro-3-oxobutanoate. The X-ray structure of the SSCR/NADPH complex and preliminary modeling show that the formation of the hydrophobic channel induced by the binding of NADPH is closely related to the stereoselective reduction by SSCR.     

Tubulin and CRMP-2 complex is transported via Kinesin-1

The transport of tubulin and microtubules in a growing axon is essential for axonal growth and maintenance. However, the molecular mechanism underlying the linkage of tubulin and microtubules to motor proteins is not yet clear. Collapsin response mediator protein-2 (CRMP-2) is enriched at the distal part of growing axons in primary hippocampal neurons and plays a critical role in axon differentiation through its interaction with tubulin dimer and Numb. In this study, we show that CRMP-2 regulates tubulin transport by linking tubulin and Kinesin-1. The C-terminal region of CRMP-2 directly binds to the tetratricopeptide repeat domain of kinesin light chain 1 (KLC1). Soluble tubulin binds to the middle of CRMP-2 and forms a trimeric complex with CRMP-2/KLC1. Furthermore, the movement of GFP-tubulin in the photobleached area is weakened by knockdown of KLCs or CRMP-2. These results indicate that the CRMP-2/Kinesin-1 complex regulates soluble tubulin transport to the distal part of the growing axon.     

Stat3 in resident macrophages as a repressor protein of inflammatory response

Inflammation is counterbalanced by anti-inflammatory cytokines such as IL-10, in which Stat3 mediates the signaling pathway. In this study, we demonstrate that resident macrophages, but not other cell types, are important targets of IL-10 in a murine model of acute peritonitis. Injection of thioglycollate i.p. induced a considerable number of neutrophils and macrophages in the peritoneum, which was significantly augmented in mice with a cell-type specific disruption of the Stat3 gene in macrophages and neutrophils (LysMcre/Stat3flox/- mice). The augmented leukocyte infiltration was accompanied by increased peritoneal levels of TNF-alpha, MIP-2, KC chemokine (KC), and MCP-1/CCL2. Stat3 was tyrosine phosphorylated in peritoneal resident macrophages as well as infiltrating leukocytes in the littermate controls, suggesting that Stat3 in either or both of these cells might play a regulatory role in inflammation. The peritoneal levels of TNF-alpha, MIP-2, KC, and MCP-1 were similarly elevated in LysMcre/Stat3flox/- mice rendered leukopenic by cyclophosphamide treatment as compared with the controls. Adoptive transfer of resident macrophages from LysMcre/Stat3flox/- mice into the control littermates resulted in increases in the peritoneal level of TNF-alpha, MIP-2, KC, and MCP-1 after i.p. injection of thioglycollate. Under these conditions, control littermates harboring LysMcre/Stat3flox/- macrophages exhibited an augmented leukocyte infiltration relative to those received control macrophages. Taken together, these data provide evidence that resident macrophages, but not other cell types, play a regulatory role in inflammation through a Stat3 signaling pathway. Stat3 in resident macrophages appears to function as a repressor protein in this model of acute inflammation.     

New series of potent delta-opioid antagonists containing the H-Dmt-Tic-NH-hexyl-NH-R motif

Heterodimeric compounds H-Dmt-Tic-NH-hexyl-NH-R (R = Dmt, Tic, and Phe) exhibited high affinity to δ- (K_iδ = 0.13–0.89 nM) and μ-opioid receptors (K_iμ = 0.38–2.81 nM) with extraordinary potent δ antagonism (pA₂ = 10.2–10.4). These compounds represent the prototype for a new class of structural homologues lacking μ-opioid receptor-associated agonism (IC₅₀ = 1.6–5.8 μM) based on the framework of bis-[H-Dmt-NH]-alkyl (Okada, Y.; Tsuda, Y.; Fujita, Y.; Yokoi, T.; Sasaki, Y.; Ambo, A.; Konishi, R.; Nagata, M.; Salvadori, S.; Jinsmaa, Y.; Bryant, S. D.; Lazarus, L. H. J. Med. Chem. 2003, 46, 3201), which exhibited both high μ affinity and bioactivity.     

Osteoblastic differentiation of monkey embryonic stem cells in vitro

Monkey embryonic stem (ES) cell is a useful tool for preclinical studies of regenerative medicine. In this paper, we investigated whether monkey ES cells can be differentiated into osteoblasts in vitro using factors known to promote osteogenesis. We prepared embryoid bodies (EB) in the presence of retinoic acid (RA) and subsequently differentiated in the medium containing either dexamethasone (DEX) or bone morphogenetic protein (BMP)-2 in addition to osteogenic supplements (OS), specifically ascorbic acid and beta-glycerophosphate. RA treatment during EB formation induced osteoblastic marker genes, such as collagen type 1, osteopontin, and Cbfa1. For the expression of osteocalcin, however, cultivation with medium containing either DEX or BMP-2 in addition to OS was required. These results showed that osteoblasts could be derived from monkey ES cells in vitro and BMP-2 + OS was effective to induce calcification.     

Color pattern formation on the wing of a butterfly Pieris rapae. 2. Color determination and scale development

It has been shown that microcautery on the prospective apical black region of the early pupal forewing of a butterfly, Pieris rapae , causes alteration of the scale color on the adult wing and a delay in histogenesis of the pupal wing. From these results, it has been assumed that the developmental delay of scale cells in the pupal wing alters their developmental fate and the hypothesis that different color fates of scales are determined by differences in the developmental timetables between scale cells is proposed. In this study, we attempted to find the developmental timetables of individual scales expressing specific color to test this hypothesis. It was found that the holes on the upper surface of a scale become larger as they develop and the hole sizes of scales in the white region are always larger than in the black region on the same wings either during pupal period or after eclosion. This suggests that the scale hole size is a good index that reflects developmental rate of the scale and a difference in the hole size between adult scales is attributed to a difference in the developmental timetables when their ancestral scale precursor cells were in the pupal period. A comparison of the hole sizes between adult scales in different color regions suggested that normal white scales were in a more advanced state than were the black ones but white scales induced by microcautery were in a less advanced state than black ones on the same wing. This supports our hypothesis.     

Evidence that blue light induces betalain pigmentation in Portulaca callus

The wavelength range that activates betalain pigmentation has been studied following selection of light induelble betalain producing callus lines originating from Portulaca sp. Jewel seedlings. Light sources with different wave-lengths were used to irradiate the callus, resulting in blue light being effective in inducing betalain pigmentation. In addition, when UV light was combined with blue light, some calluses from this cell line showed high production of the pigment. This is a first report that betalain pigmentation in callus was induced by blue and blue/UV lights.Abbreviations UV ultra violet