Dynamic and static baroreflex control of muscle sympathetic nerve activity (SNA) parallels that of renal and cardiac SNA during physiological change in pressure

Despite accumulated knowledge on human baroreflex control of muscle sympathetic nerve activity (SNA), whether baroreflex control of muscle SNA parallels that of other SNAs, in particular renal and cardiac SNAs, remains unclear. Using urethane and alpha-chloralose-anesthetized, vagotomized and aortic-denervated rabbits (n = 10), we recorded muscle SNA from tibial nerve by microneurography, simultaneously with renal and cardiac SNAs by wire electrode. To produce a baroreflex open-loop condition, we isolated the carotid sinuses from systemic circulation and altered the intracarotid sinus pressure (CSP) according to a binary white noise sequence of operating pressure +/- 20 mmHg (for investigating dynamic characteristics of baroreflex) or in stepwise 20-mmHg increments from 40 to 160 mmHg (for investigating static characteristics of baroreflex). Dynamic high-pass characteristics of baroreflex control of muscle SNA, assessed by the increasing slope of transfer gain, showed that more rapid change of arterial pressure resulted in greater response of muscle SNA to pressure change and that these characteristics were similar to cardiac SNA but greater than renal SNA. However, numerical simulation based on the transfer function shows that the differences in dynamic baroreflex control at various organs result in detectable differences among SNAs only when CSP changes at unphysiologically high rates (i.e., 5 mmHg/s). On the other hand, static reverse-sigmoid characteristics of baroreflex control of muscle SNA agreed well with those of renal or cardiac SNAs. In conclusion, dynamic-linear and static-nonlinear baroreflex control of muscle SNA is similar to that of renal and cardiac SNAs under physiological pressure change.     

Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 use different receptor complexes to enter T cells

Studies using adherent cell lines have shown that glucose transporter-1 (GLUT-1) can function as a receptor for human T-cell leukemia virus type 1 (HTLV). In primary CD4(+) T cells, heparan sulfate proteoglycans (HSPGs) are required for efficient entry of HTLV-1. Here, the roles of HSPGs and GLUT-1 in HTLV-1 and HTLV-2 Env-mediated binding and entry into primary T cells were studied. Examination of the cell surface of activated primary T cells revealed that CD4(+) T cells, the primary target of HTLV-1, expressed significantly higher levels of HSPGs than CD8(+) T cells. Conversely, CD8(+) T cells, the primary target of HTLV-2, expressed GLUT-1 at dramatically higher levels than CD4(+) T cells. Under these conditions, the HTLV-2 surface glycoprotein (SU) binding and viral entry were markedly higher on CD8(+) T cells while HTLV-1 SU binding and viral entry were higher on CD4(+) T cells. Binding studies with HTLV-1/HTLV-2 SU recombinants showed that preferential binding to CD4(+) T cells expressing high levels of HSPGs mapped to the C-terminal portion of SU. Transfection studies revealed that overexpression of GLUT-1 in CD4(+) T cells increased HTLV-2 entry, while expression of HSPGs on CD8(+) T cells increased entry of HTLV-1. These studies demonstrate that HTLV-1 and HTLV-2 differ in their T-cell entry requirements and suggest that the differences in the in vitro cellular tropism for transformation and in vivo pathobiology of these viruses reflect different interactions between their Env proteins and molecules on CD4(+) and CD8(+) T cells involved in entry.     

A mitochondrial thioredoxin-sensitive mechanism regulates TGF-β-mediated gene expression associated with epithelial–mesenchymal transition

Transforming growth factor (TGF)-β is a pro-oncogenic cytokine that induces the epithelial–mesenchymal transition (EMT), a crucial event in tumor progression. During TGF-β-mediated EMT in NMuMG mouse mammary epithelial cells, we observed sustained increases in reactive oxygen species (ROS) levels in the cytoplasm and mitochondria with a concomitant decrease in mitochondrial membrane potential and intracellular glutathione levels. In pseudo ρ0 cells, whose respiratory chain function was impaired, the increase in intracellular ROS levels was abrogated, suggesting an important role of mitochondrial activity as a trigger for TGF-β-stimulated ROS generation. In line with this, TGF-β-mediated expression of the EMT marker fibronectin was inhibited not only by chemicals that interfere with ROS signaling but also by exogenously expressed mitochondrial thioredoxin (TXN2) independent of Smad signaling. Of note, TGF-β-mediated induction of HMGA2, a central mediator of EMT and metastatic progression, was similarly impaired by TXN2 expression, revealing a novel mechanism involving a thiol oxidation reaction in mitochondria, which regulates TGF-β-mediated gene expression associated with EMT.     

Reexamination of silicon effects on rice growth and production under field conditions using a low silicon mutant

Silicon (Si) is a beneficial element for healthy growth and high and sustainable production of rice, but the mode of action of the beneficial effects has not been well understood. We carried out field trials for four years at two different locations to re-examine the effects of Si on the growth and production of rice using a low silicon rice (lsi1) mutant. The mutant accumulated much lower Si at each growth stage compared with the wild-type rice (Oryza sativa L. cv Oochikara), but there was no difference in the accumulation of other nutrients including N, P, and K. Measurements at different growth stages showed that low Si in the mutant hardly affected the tiller number, chlorophyll content (SPAD value), and root growth. The plant height and shoot dry weight of the wild-type rice were slightly higher than those of the mutant at a later growth stage, but the difference was not significant between the two lines. However, grain yield was reduced by 79–98%, depending on year, due to a low Si accumulation in the mutant, which showed the largest effect of Si on rice production among all studies reported so far. Among the yield components, the percentage of filled spikelets was mostly affected, being only 13.9% of the wild-type rice in the mutant. The grain color of the mutant became brown because of excessive transpiration and infection of pathogens. These results indicate that Si increases rice yield mainly by enhancing the fertility of spikelets.     

Quantitative Trait Loci (QTL) Associated with Resistance to a Monogenean Parasite (Benedenia seriolae) in Yellowtail (Seriola quinqueradiata) through Genome Wide Analysis

Benedenia infections caused by the monogenean fluke ectoparasite Benedenia seriolae seriously impact marine finfish aquaculture. Genetic variation has been inferred to play a significant role in determining the susceptibility to this parasitic disease. To evaluate the genetic basis of Benedenia disease resistance in yellowtail (Seriola quinqueradiata), a genome-wide and chromosome-wide linkage analyses were initiated using F₁ yellowtail families (n = 90 per family) based on a high-density linkage map with 860 microsatellite and 142 single nucleotide polymorphism (SNP) markers. Two major quantitative trait loci (QTL) regions on linkage groups Squ2 (BDR-1) and Squ20 (BDR-2) were identified. These QTL regions explained 32.9–35.5% of the phenotypic variance. On the other hand, we investigated the relationship between QTL for susceptibility to B. seriolae and QTL for fish body size. The QTL related to growth was found on another linkage group (Squ7). As a result, this is the first genetic evidence that contributes to detailing phenotypic resistance to Benedenia disease, and the results will help resolve the mechanism of resistance to this important parasitic infection of yellowtail.     

Bezold-Jarisch reflex attenuates dynamic gain of baroreflex neural arc

Although acute myocardial ischemia or infarction may induce the Bezold-Jarisch (BJ) reflex through the activation of serotonin receptors on vagal afferent nerves, the mechanism by which the BJ reflex modulates the dynamic characteristics of arterial pressure (AP) regulation is unknown. The purpose of this study was to examine the effects of the BJ reflex induced by intravenous phenylbiguanide (PBG) on the dynamic characteristics of the arterial baroreflex. In seven anesthetized rabbits, we perturbed intracarotid sinus pressure (CSP) according to a white noise sequence while renal sympathetic nerve activity (RSNA), AP, and heart rate (HR) were recorded. We estimated the transfer function from CSP to RSNA (neural arc) and from RSNA to AP (peripheral arc) before and after 10 min of intravenous administration of PBG (100 microg. kg-1. min-1). The intravenous PBG decreased mean AP from 84.5 +/- 4.0 to 68.2 +/- 4.7 mmHg (P < 0.01), mean RSNA to 76.2 +/- 7.0% (P < 0.05), and mean HR from 301.6 +/- 7.7 to 288.4 +/- 9.0 beats/min (P < 0.01). The intravenous PBG significantly decreased neural arc dynamic gain at 0.01 Hz (1.06 +/- 0.08 vs. 0.59 +/- 0.17, P < 0.05), whereas it did not affect that of the peripheral arc (1.20 +/- 0.12 vs. 1.18 +/- 0.41). In six different rabbits without intravenous PBG, the neural arc transfer function did not change between two experimental runs with intervening interval of 10 min, excluding the possibility that the cumulative effects of anesthetics had altered the neural arc transfer function. In conclusion, excessive activation of the BJ reflex during acute myocardial ischemia may exert an adverse effect on AP regulation, not only by sympathetic suppression, but also by attenuating baroreflex dynamic gain.     

日本九州西部赤崎组和中甑组始新世哺乳动物:初步结果及其与亚洲陆相哺乳动物分期的对比(英文)

日本已知时代最早的古近纪哺乳动物化石产自九州西部熊本县天草(Amakusa)地区始新世地层赤崎(Akasaki)组以及鹿儿岛县甑岛(Koshiki Islands)相当层位的中甑(Nakakoshiki)组。初步研究显示这两个组产出的哺乳动物分异度较高,包括9个目的至少18种动物。赤崎动物群有3种trogosine裂齿类、2种冠齿兽科全齿类、1种等脊貘科奇蹄类、2种dichobunoid偶蹄类、1种下齿兽科踝节类、1种西瓦兔猴科灵长类、1种未定食虫类以及2种可能的梳趾鼠类。中甑动物群包括1种冠齿兽科全齿类、2种小型雷兽科奇蹄类、1种高冠的下齿兽科踝节类、2种啮齿类和1种细齿兽科食肉类。这两个日本哺乳动物组合很接近早-中始新世界线。由于出现了trogosine裂齿类和雷兽,它们的时代要晚于伯姆巴动物群,极有可能与亚洲大陆阿山头期哺乳动物群相当。这两个动物群还包含了在亚洲大陆没有发现过的几个新种,并具有独特的哺乳动物组合。     

A Novel Antiviral Target Structure Involved in the RNA Binding,Dimerization, and Nuclear Export Functions of the Influenza A Virus Nucleoprotein

Developing antiviral therapies for influenza A virus (IAV) infection is an ongoing process because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. The ideal strategy is to develop drugs that target well-conserved, functionally restricted, and unique surface structures without affecting host cell function. We recently identified the antiviral compound, RK424, by screening a library of 50,000 compounds using cell-based infection assays. RK424 showed potent antiviral activity against many different subtypes of IAV in vitro and partially protected mice from a lethal dose of A/WSN/1933 (H1N1) virus in vivo. Here, we show that RK424 inhibits viral ribonucleoprotein complex (vRNP) activity, causing the viral nucleoprotein (NP) to accumulate in the cell nucleus. In silico docking analysis revealed that RK424 bound to a small pocket in the viral NP. This pocket was surrounded by three functionally important domains: the RNA binding groove, the NP dimer interface, and nuclear export signal (NES) 3, indicating that it may be involved in the RNA binding, oligomerization, and nuclear export functions of NP. The accuracy of this binding model was confirmed in a NP-RK424 binding assay incorporating photo-cross-linked RK424 affinity beads and in a plaque assay evaluating the structure-activity relationship of RK424. Surface plasmon resonance (SPR) and pull-down assays showed that RK424 inhibited both the NP-RNA and NP-NP interactions, whereas size exclusion chromatography showed that RK424 disrupted viral RNA-induced NP oligomerization. In addition, in vitro nuclear export assays confirmed that RK424 inhibited nuclear export of NP. The amino acid residues comprising the NP pocket play a crucial role in viral replication and are highly conserved in more than 7,000 NP sequences from avian, human, and swine influenza viruses. Furthermore, we found that the NP pocket has a surface structure different from that of the pocket in host molecules. Taken together, these results describe a promising new approach to developing influenza virus drugs that target a novel pocket structure within NP.