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Avian influenza H5N1 has shown high mortality rate in human. Non-structural protein 1 (NS1) is a virulence factor of H5N1. Mutation at the 42nd residue within the RNA-binding domain (RBD) of NS1 dramatically changes the degree of pathogenicity of H5N1 in mice. We here studied the impact of this mutation on the function of RBD, and found that RBD with serine at the 42th residue binds double-stranded RNA (dsRNA), whereas that with proline at the 42th residue does not. Analysis of structural models of the RBD proteins with S42 and P42 suggested remarkable difference in the structure of the dsRNA-binding interface, whereas structural analysis by analytical gel filtration and CD measurements did not indicate difference between those RBD proteins. Our results suggest that the single amino acid replacement induces a minor, but global structural change leading to the loss of function of NS1 thereby the change in the degree of pathogenicity.

The hydrogenation and dehydrogenation of C 4hydrocarbon molecules (1,3-butadiene, 1-butene, trans-2-butene, cis-2-butene, and n-butane) on the hydrogen-precovered Pd(110) surface have been investigated by high-resolution electron energy loss spectroscopy (HREELS) and temperature-programmed desorption (TPD). 1,3-Butadiene was found to be adsorbed molecularly on the surface below 350 K. Further heating of the surface resulted in decomposition, forming hydrocarbons at 350 K and finally the graphite layer at 550 K. The butene isomers and n-butane adsorbed on the surface were, however, relatively unstable compared with 1,3-butadiene when heated. Some of the adsorbed butenes were desorbed, and the species that remained on the surface were dehydrogenated to 1,3-butadiene between 150 and 250 K. n-Butane on the surface showed similar reaction behavior except for the lower dehydrogenation and desorption temperature. Our findings indicate that the dehydrogenations of π-bonded C 4hydrocarbons on the Pd surface show significantly different pathways compared with those of the σ-bonded C 4hydrocarbon on Pt and Ru surfaces. Here, we discuss the selective partial hydrogenation of 1,3-butadiene on hydrogen-precovered Pd(110) in terms of the reactivity of the butenes and butanes.

The reaction pathways for water dissociation at a model liquid−solid interface have been investigated by a combination of experimental and theoretical approaches. By scanning tunneling microscopy (STM) and high-resolution electron energy-loss spectroscopy (HREELS), we revealed that the fragments of condensed water molecules, i.e., OH and H, efficiently terminate the isolated dangling bonds on a precovered Si(001) surface, in comparison with those of the isolated water molecules on the same surface. The most favorable reaction mechanism was predicted by first-principles calculations. At the first stage, the condensed water molecules create a new surface OH group at one of the isolated dangling bond sites. Simultaneously, counter fragment H and surrounding water molecules form a flexible hydronium complex along hydrogen bonds, because the fragment H takes a certain positive charge. Then, another dangling bond is terminated by a H fragment under the proton relay mechanism via the hydronium complex, in which a very low activation energy is expected because the hydronium complex near the surface is not sufficiently stabilized as in the case of aqueous liquid but is hindered in shallow potential energy surfaces. Since the spatial hindrance near solid surfaces is a common property, the characteristic proton pathway should appear at various aqueous liquid−solid interfaces and enhance the surface reactions involving proton transfer.

To elucidate the thermal chemical processes of 1,4-cyclohexadiene (C6H8) on Si(001), the adsorption states were characterized by temperature-programmed desorption (TPD), low-energy electron diffraction (LEED), and high-resolution electron energy-loss spectroscopy (HREELS), in comparison with those for benzene (C6H6) and cyclohexene (C6H10). Consequently, three types of adsorption states, i.e., -complex, single di- bonding, and double di- bonding species, were identified. At 85 K, all 1,4-cyclohexadiene molecules are adsorbed as -complex species in the first layer. With increasing substrate temperature, above 150 K, these -complex species chemically convert to single di- bonding species by 2 2 cycloaddition with a Si dimer. Upon further heating above 300 K, most single di- bonding species are dehydrogenated into benzene and then the benzene molecules desorb from the surface. In contrast, double di- bonding species are formed preferentially in low exposure at 300 K, and are dehydrogenated into benzene above 600 K.

The environmental estrogen bisphenol A, orally introduced into the body, passes through the liver and modulates the endocrine system to elicit irreversible changes in the functioning of reproduction. To elucidate the actual and dynamic metabolism of bisphenol A in the liver before its arrival at target organs, this study evaluated the metabolism and disposition of the compound within the passage through the liver in Sprague-Dawley rats. On perfusion of 7.5 micromol of bisphenol A into the liver via the portal vein, approximately 91% of the infused bisphenol A was absorbed by the liver tissue, and about 65% of the absorbed bisphenol A was glucuronidated within 60 min. Roughly 65% of the bisphenol A glucuronide that formed in the liver was excreted into the bile and about 35% into the hepatic vein. On perfusion of 0.01, 0.05, and 0.1 mM bisphenol A solution into the liver, free bisphenol A was excreted only into the vein at 5.6, 9.3, and 14.6%, respectively, of the total bisphenol A. These results suggest that most bisphenol A absorbed by the intestine is probably glucuronidated exclusively in the liver and the conjugate is excreted mainly into the bile.

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is an adhesion molecule that mediates recruitment of lymphocytes into the gut mucosa. Attenuation of excessive expression of MAdCAM-1 in the inflamed mucosa could be useful for treatment of inflammatory bowel diseases. The aim of this study was to investigate whether anti-MAdCAM-1 antibody has a prophylactic effect on experimental colitis induced by dextran sulfate sodium (DSS). Colitis was induced by orally feeding BALB/c mice 5% DSS (mol. wt. 5000). Mice were sacrificed at intervals up to 21 days after administration to evaluate the changes over time in intestinal damage. The infiltrating lymphocytes and their subpopulations, and the expression of cell adhesion molecules were determined by immunohistochemistry. In another set of experiments, the attenuating effect of i.p.-injected anti-MAdCAM-1 antibody on colonic lesions was evaluated on day 14. Significant histological damage with shortening of crypts was observed on day 14 in colonic mucosa of DSS-treated mice. Before mucosal inflammation had become significant, expression of MAdCAM-1 was already increased in the microvessels of lamina propria on day 7. Significant infiltration of beta7-integrin-positive T and B cells in the mucosa was then noted on day 14. Administration of anti-MAdCAM-1 antibody significantly reduced colonic injury as well as the infiltration of beta7-integrin-positive lymphocytes in the colonic mucosa. This antibody also was effective when given 7 days after the start of DSS treatment. In the present study, we demonstrated that anti-MAdCAM-1 antibody significantly ameliorates DSS-induced colitis, suggesting that MAdCAM-1 may be useful for control of inflammatory bowel diseases.

The mechanism underlying acid hypersecretion induced by gastric distention was investigated in rats, especially in relation to endogenous nitric oxide (NO). Under urethane anesthesia, rat stomach was distended by instillation of saline (1-10 ml) through the acute fistula that was provided through a pylorus. Gastric samples were collected every 1 h, and the acid secretion was measured by titration with 100 mM NaOH. Gastric acid secretion was increased by distention, and the degree of stimulation was dependent on the volume of saline instillation; a maximal response occurred with 6-ml instillation, which maintained the intraluminal pressure of about 20 cm H(2)O. The increased acid secretory response induced by distention was completely blocked by omeprazole and significantly mitigated by vagotomy, sensory deafferentation, atropine, or famotidine but markedly enhanced by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). On the other hand, the enhanced acid response in the presence of L-NAME occurred in an L-arginine-sensitive manner and was almost totally abolished by vagotomy and sensory deafferentation as well as by atropine. Gastric distention increased the release of NO metabolites and histamine into the gastric lumen. The NO metabolite release in the distended stomach was significantly decreased by vagotomy or L-NAME, whereas the histamine output was decreased by vagotomy but increased by L-NAME in an L-arginine-sensitive manner, respectively. These results suggest that 1) gastric distention increases acid secretion, initially through the perception by sensory neurons of the mechanical stimulation and mainly through the efferent vagocholinergic pathway, with the process being modified by endogenous NO, and 2) this molecule, released in a vagal-dependent manner, exerts a negative influence on acid secretion, at least in part by suppressing histamine release from the histamine-containing cells.

BACKGROUND: There is a difference in the location of colorectal mucosal lesions and invasive cancers. AIMS: To ascertain whether the location of colorectal neoplasms reflects the carcinogenesis pathway. METHODS: The subject material consisted of 4147 neoplastic lesions that had been resected endoscopically or surgically from 5025 patients. Mucosal lesions and submucosal cancers were classified into depressed and non-depressed types endoscopically or histologically. The relations between macroscopic type, size, histology, and location were investigated. RESULTS: (a) Non-depressed type. A total of 1774 of 3454 (51%) mucosal lesions were located in the right colon, 1212 (35%) in the left colon, and 468 (14%) in the rectum. The incidence of mucosal lesions larger than 10 mm was 10% (185/1774) in the right colon, 21% (254/1212) in the left colon, and 27% (127/468) in the rectum. The incidence of mucosal lesions with villous components was 2% (32/1774) in the right colon, 5% (63/1212) in the left colon, and 13% (62/468) in the rectum. The ratio of submucosal cancers to mucosal lesions was significantly higher in the rectum (0.064, 30/469) than in the left (0.034, 43/1279) or right (0.010, 18/1857) colon. (b) Depressed type. The incidences of depressed type mucosal lesions and submucosal cancers were 5% (83/1857) and 17% (3/18) in the right colon, 5% (67/1279) and 5% (2/43) in the left colon, and 0.2% (1/469) and 0% (0/30) in the rectum, respectively. CONCLUSION: There may be some mechanisms that promote the progression of mucosal lesions to invasive cancers in the left colon and rectum, whereas a de novo pathway from depressed type lesions may be implicated in some cancers of the right colon.

The mechanisms of gastric hyperemic response during vagally mediated acid secretion induced by YM-14673, an analog of thyrotropin-releasing hormone, were investigated in urethane-anesthetized rats. The stomach was mounted on an ex vivo chamber and perfused with saline, and gastric mucosal blood flow (GMBF) was measured using a laser Doppler flowmeter, simultaneously with acid secretion. The i.v. injection of YM-14673 (0.1 approximately 1 mg/kg) increased both GMBF and acid secretion in a dose-dependent manner, and these responses persisted during a 90-min test period. The increases in GMBF and acid secretion induced by YM-14673 (0.3 mg/kg) were totally abolished by either bilateral vagotomy or atropine. Sensory ablation by capsaicin also significantly attenuated GMBF response without affecting acid secretion. On the other hand, N(G)-nitro-L-arginine methyl ester (L-NAME), but not D-NAME, significantly attenuated the increase in GMBF in an L-arginine-sensitive manner, although acid secretion was slightly augmented; in particular, gastric hyperemic response during the first 30 min (early period) was almost totally abolished. In contrast, omeprazole significantly attenuated GMBF response only in the late period, although it completely inhibited acid secretion in response to YM-14673. Combined treatment of omeprazole and L-NAME totally abolished hyperemic responses induced by YM-14673 during the test period. YM-14673 significantly elevated the release of nitrite and nitrate into the gastric lumen, and this response was inhibited by either atropine or L-NAME. These results suggest that YM-14673 increases GMBF as well as acid secretion, mediated by vagal-cholinergic pathways, and that gastric hyperemia is further regulated by two distinct mechanisms. The response in the early period is independent of acid secretion and mediated mainly by nitric oxide, whereas that in the later period occurs in association with acid secretion and may be mediated by nitric oxide and sensory neurons.

We examined the influence of diabetes on the healing of HCI-induced gastric lesions and the healing promoting effect of basic fibroblast growth factor (bFGF) on these lesions under diabetic conditions induced in rats by streptozotocin (70 mg/kg, i.p.). The experiments were performed using 2-wk streptozocin-diabetic rats with blood glucose levels of >300 mg/dl. After 18 hr fasting, these animals were given 1 ml of 0.6 N HCl by gavage, and 1 hr later they were fed normally before being killed on various days after HCI treatment. Recombinant human basic fibroblast growth factor (acid resistant recombinant human basic fibroblast growth factor mutein CS-23: 10 to 1000 ng/kg x 2, p.o.) or insulin (4 U/rat x 1, s.c.) was given 5 days after HCl treatment. Gastric lesions induced by HCI healed to quiescent state within 5 days both macro- and microscopically. Diabetic conditions did not affect the development of HCI-induced gastric lesions but significantly delayed the healing of these lesions. Daily administration of insulin returned high blood glucose levels to within normal ranges (120-140 mg/dl) and significantly antagonized the delayed healing of these lesions. The delayed healing in diabetic rats was also significantly promoted by recombinant human basic fibroblast growth factor (>300 ng/kg x 2) without any effect on blood glucose level. In normal rats, the mucosal levels of bFGF increased significantly in response to gastric injury at 3 days after HCI treatment. The mucosal bFGF levels in streptozotocin-diabetic rats were significantly lower under basal conditions before HCI treatment and did not increase after injury, yet such dysregulation of bFGF production was partially restored by insulin treatment. rhbFGF even at 1000 ng/kg had no effect on gastric acid secretion in either normal or streptozotocin-diabetic rats. These results suggest that diabetic conditions have deleterious influences on the healing of acute gastric lesions in both an insulin- and bFGF-sensitive manner, and that the administration of exogenous bFGF antagonizes the delayed healing of gastric lesions observed in diabetic animals.

Sean Escola, Saul Kato, and Pavan Ramkumar explain the importance of data science in their research. They have developed a simple non-parametric statistical method called the Rank-to-Group (RTG) score that identifies hierarchical confounder effects in raw data and machine learning-derived data embeddings. This approach should be generally useful in experiment-analysis cycles and to ensure confounder robustness in machine learning models., (© 2022 The Authors.)

In a randomized trial, higher all-cause and cardiovascular mortality was observed in treatment with febuxostat than with allopurinol in patients with coexisting gout and serious cardiovascular conditions. In this study, we focus on an intervention of febuxostat or allopurinol as an anti-inflammatory treatment to reduce the transcription of nuclear factor-kappa B (NF-κB) and production of relevant inflammatory factors. We evaluated the effect of febuxostat on vascular cell adhesion protein 1 (VCAM-1) induction in cultured human umbilical vein endothelial cells (HUVECs). Cells were exposed to tumor necrosis factor (TNF)-α (10 ng/mL) treatment for 24 h. Febuxostat or allopurinol (0.1-100 μM) was added to the bath medium 15 min before TNF-α treatment. VCAM-1 levels in HUVECs increased after 24-h TNF-α treatment (n = 4). Febuxostat and allopurinol significantly suppressed VCAM-1 induced by treatment with TNF-α in a dose-dependent manner (p < 0.05, n = 4). Furthermore, these drugs suppressed the NF-κB protein levels in the nucleus 4 h after TNF-α treatment (n = 3 or 4). Our results suggest that TNF-α induces VCAM-1 production via NF-κB, which can be blocked by febuxostat or allopurinol. The effect of febuxostat treatment on cardiovascular events may be associated with protection against the infiltration of lymphocytes or monocytes through VCAM-1 induction in inflamed endothelial cells such as arterial sclerosis., (© 2020 S. Karger AG, Basel.)