Lineage-Specific Duplication and Loss of Pepsinogen Genes in Hominoid Evolution

Fourteen different pepsinogen-A cDNAs and one pepsinogen-C cDNA have been cloned from gastric mucosa of the orangutan, Pongo pygmaeus. Encoded pepsinogens A were classified into two groups, i.e., types A1 and A2, which are different in acidic character. The occurrence of 9 and 5 alleles of A1 and A2 genes (at least 5 and 3 loci), respectively was anticipated. Respective orthologous genes are present in the chimpanzee genome although their copy numbers are much smaller than those of the orangutan genes. Only A1 genes are present in the human probably due to the loss of the A2 gene. Molecular phylogenetic analyses showed that A1 and A2 genes diverged before the speciation of great hominoids. Further reduplications of respective genes occurred several times in the orangutan lineage, with much higher frequencies than those occurred in the chimpanzee and human lineages. The rates of non-synonymous substitutions were higher than those of synonymous ones in the lineage of A2 genes, implying the contribution of the positive selection on the encoded enzymes. Several sites of pepsin moieties were indeed found to be under positive selection, and most of them locate on the surface of the molecule, being involved in the conformational flexibility. Deduced from the known genomic structures of pepsinogen-A genes of primates and other mammals, the duplication/loss were frequent during their evolution. The extreme multiplication in the orangutan might be advantageous for digestion of herbaceous foods due to the increase in the level of enzymes in stomach and the diversification of enzyme specificit

Carrier-mediated active transport of the glucuronide and sulfate of 6- hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) into rat liver: quantitative comparison of permeability in isolated hepatocytes, perfused liver and liver i

ABSTRACT The hepatic uptake of glucuronic acid and sulfate conjugates of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040), a dual inhibitor of 5-lipoxygenase and thromboxane A 2 synthetase, was investigated in rats. The biliary excretion clearance values for the glucuronide and the sulfate, obtained after i.v. administration of E3040, were similar and corresponded to approximately 30% of the hepatic blood flow rate. The influx clearance values of E3040 conjugates in the presence of 3% bovine serum albumin, measured by a multiple indicator dilution method in the perfused liver, were 1.20 ml/min/g liver for the glucuronide and 0.74 ml/min/g liver for the sulfate, which were twice and equal to the normal hepatic plasma flow rate, respectively, which suggests the presence of an efficient transport system(s). The uptake of E3040 conjugates into the isolated hepatocytes is mediated by Na ϩ -independent active transport system(s), which is inhibited by dibromosulfophthalein and bile acids. The uptake for the sulfate had high-affinity and high-capacity transport activity (K m ϭ 25 M; V max ϭ 7.8 nmol/min/10 6 cells) compared with that for the glucuronide (K m ϭ 59 M; V max ϭ 2.2 nmol/min/10 6 cells). The uptakes of E3040 conjugates (glucuronide, sulfate) exhibited a mutual competitive inhibition. It is suggested that both conjugates share a multispecific organic anion transporter located on the sinusoidal membrane. Conjugative metabolism, such as glucuronidation and sulfation, is an important pathway for the inactivation or detoxification of xenobiotics. On the other hand, conjugative metabolites of certain drugs with pharmacologically active (such as the 6-glucuronide of morphine; In previous studies, we reported the disposition of glucuronide and sulfate of E3040, a novel dual inhibitor of 5-lipoxygenase and thromboxane A 2 synthetase, after administration Received for publication May 24, 1996. ABBREVIATIONS: E3040, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole; [ C]E3040, [2- 14 C]6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole dihydrochloride; SD rats, Sprague-Dawley rats; DBSP, dibromosulfophthalein; HEPES, N-2-hydroxyethylpiperazine-NЈ-2-ethanesulfonic acid; MID method, multiple indicator dilution method; HPLC, high-performance liquid chromatography; BSA, bovine serum albumin; TLC, thin-layer chromatography; AUC ϱ , the area under the plasma concentration-time profiles from zero to infinity; CL bile , the biliary excretion clearance; CL renal , the urinary excretion clearance; CL u,renal , the unbound urinary excretion clearance; X bile , the amount excreted into the bile; X urine , the amount excreted into the urine; CL tot , the total body clearance; PS inf , the influx clearance; PS u,inf , the unbound influx clearance; K inf , the influx rate constant; K eff , the efflux rate constant; K seq , the sequestration rate constant; K m , Michaelis constant; V max , maximal uptake rate; P dif , the nonspecific uptake clearance; LUR, the first-pass liver uptake ratio; UWL, the unstirred water layer; PCMBS, p-chloromercuriphenylsulfonic acid; DIDS, 4,4Ј-diisothiocyanatostilbene-2,2Ј-disulfonic acid; FCCP, carbonyl cyanide-p-(trifluoromethoxy)-phenylhydrazone; C/M, cell-to-medium concentration

Improving bonding strength by non-thermal atmospheric pressure plasma-assisted technology for A5052/PEEK direct joining

The direct bonding of A5052 aluminum (Al) alloy to the engineering polymer poly(ether ether ketone) (PEEK) using an atmospheric pressure plasma-assisted process was demonstrated. The effect of plasma irradiation on the bonding surface of metal resin on the bonding strength following thermal press fitting method was investigated. Specimens bonded by plasma irradiation on the PEEK surface only showed a high tensile shear stress of 15.5 MPa. With increasing plasma irradiation time, the bond strength of the samples bonded to the PEEK surface by plasma irradiation increased. The increase in the bond strength between metals and polymers following direct bonding is caused by the addition of oxygen functional groups on the polymer. In contrast, specimens in which only the Al was exposed to the plasma showed a decrease in bond strength compared with unirradiated samples. This reduction in bond strength is attributed to the forming magnesium oxide, which forms in the early stages of participation due to plasma irradiation.The version of record of this article, first published in International Journal of Advanced Manufacturing Technology, is available online at Publisher’s website: https://doi.org/10.1007/s00170-023-12747-

Influence of pre-treatment with non-thermal atmospheric pressure plasma on bond strength of TP340 titanium-PEEK direct bonding

The version of record of this article, first published in International Journal of Advanced Manufacturing Technology, is available online at Publisher’s website: https://doi.org/10.1007/s00170-024-14160-z.Direct bonding of a TP340 titanium to PEEK by hot pressing via pre-treatment of non-thermal atmospheric pressure plasma jet has been demonstrated. The plasma irradiation effect on the bonding surface on the bond strength after hot pressing was investigated. The tensile shear strength of TP340-PEEK joined by hot pressing after plasma pre-treatment was measured by comparing specimens bonded using conventional hot pressing and those bonded using adhesives. The plasma treatment to the TP340 side resulted in the formation of TiO2, which is chemically fed to oxide formation due to the irradiation of oxygen radicals generated by the plasma, resulting in a bond strength of less than 1 MPa, similar to the bond strength of the untreated specimens. The plasma irradiation effect on the PEEK side on the bond strength of TP340-PEEK bonded samples was also investigated. The bonding strength was increased by plasma irradiation to PEEK. As the plasma irradiation time was increased, the bonding strength gradually increased to 9.2 MPa, which is about 19 times higher than the bonding strength without plasma irradiation. These results suggest that oxygen radicals in the atmospheric pressure RF plasma jet produced oxygen-containing surface functional groups on the PEEK surface, which increased the strength of the TP340-PEEK direct joining

Influence of pre-treatment using non-thermal atmospheric pressure plasma jet on aluminum alloy A1050 to PEEK direct joining with hot-pressing process

The version of record of this article, first published in International Journal of Advanced Manufacturing Technology, is available online at Publisher’s website: https://doi.org/10.1007/s00170-023-12827-7.Aluminum alloy A1050 to polyetheretherketone (PEEK) direct joining with hot-pressing process via pre-treatment using non-thermal atmospheric pressure plasma jet has been performed. The effect of plasma irradiation on the tensile shear strength of A1050-PEEK direct bonded specimens joined by a combination of hot-pressing process and pre-plasma treatment using non-thermal atmospheric pressure plasma jet was investigated. A1050-PEEK bonded samples with plasma-treated PEEK only showed high tensile shear stress of 13.4 MPa. This increase in tensile shear strength is attributed to the addition of oxygen functional groups on the surface of the PEEK by reactive oxygen species produced by the plasma jet

Fully gapped superconductivity with no sign change in the prototypical heavy-fermion CeCu2Si2

In exotic superconductors including high-$T_c$ copper-oxides, the interactions mediating electron Cooper-pairing are widely considered to have a magnetic rather than the conventional electron-phonon origin. Interest in such exotic pairing was initiated by the 1979 discovery of heavy-fermion superconductivity in CeCu$_2$Si$_2$, which exhibits strong antiferromagnetic fluctuations. A hallmark of unconventional pairing by anisotropic repulsive interactions is that the superconducting energy gap changes sign as a function of the electron momentum, often leading to nodes where the gap goes to zero. Here, we report low-temperature specific heat, thermal conductivity and magnetic penetration depth measurements in CeCu$_2$Si$_2$, demonstrating the absence of gap nodes at any point on the Fermi surface. Moreover, electron-irradiation experiments reveal that the superconductivity survives even when the electron mean free path becomes substantially shorter than the superconducting coherence length. This indicates that superconductivity is robust against impurities, implying that there is no sign change in the gap function. These results show that, contrary to long-standing belief, heavy electrons with extremely strong Coulomb repulsions can condense into a fully-gapped s-wave superconducting state, which has an on-site attractive pairing interaction.Comment: 8 pages, 5 figures + Supplement (3 pages, 5 figures

Genome analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki

Ionizing radiation is a risk factor for myeloid neoplasms including myelodysplastic syndromes (MDS), and atomic bomb survivors have been shown to have a significantly higher risk of MDS. Our previous analyses demonstrated that MDS among these survivors had a significantly higher frequency of complex karyotypes and structural alterations of chromosomes 3, 8, and 11. However, there was no difference in the median survival time between MDS among survivors compared with those of de novo origin. This suggested that a different pathophysiology may underlie the causative genetic aberrations for those among survivors. In this study, we performed genome analyses of MDS among survivors and found that proximally exposed patients had significantly fewer mutations in genes such as TET2 along the DNA methylation pathways, and they had a significantly higher rate of 11q deletions. Among the genes located in the deleted portion of chromosome 11, alterations of ATM were significantly more frequent in proximally exposed group with mutations identified on the remaining allele in 2 out of 5 cases. TP53, which is frequently mutated in therapy-related myeloid neoplasms, was equally affected between proximally and distally exposed patients. These results suggested that the genetic aberration profiles in MDS among atomic bomb survivors differed from those in therapy-related and de novo origin. Considering the role of ATM in DNA damage response after radiation exposure, further studies are warranted to elucidate how 11q deletion and aberrations of ATM contribute to the pathogenesis of MDS after radiation exposure

A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn\u27s disease.

BACKGROUND:Small bowel stricture is one of the most common complications in patients with Crohn\u27s disease (CD). Endoscopic balloon dilatation (EBD) is a minimally invasive treatment intended to avoid surgery; however, whether EBD prevents subsequent surgery remains unclear. We aimed to reveal the factors contributing to surgery in patients with small bowel stricture and the factors associated with subsequent surgery after initial EBD.METHODS:Data were retrospectively collected from surgically untreated CD patients who developed symptomatic small bowel stricture after 2008 when the use of balloon-assisted enteroscopy and maintenance therapy with anti-tumor necrosis factor (TNF) became available.RESULTS:A total of 305 cases from 32 tertiary referral centers were enrolled. Cumulative surgery-free survival was 74.0% at 1 year, 54.4% at 5 years, and 44.3% at 10 years. The factors associated with avoiding surgery were non-stricturing, non-penetrating disease at onset, mild severity of symptoms, successful EBD, stricture length < 2 cm, and immunomodulator or anti-TNF added after onset of obstructive symptoms. In 95 cases with successful initial EBD, longer EBD interval was associated with lower risk of surgery. Receiver operating characteristic analysis revealed that an EBD interval of ≤ 446 days predicted subsequent surgery, and the proportion of smokers was significantly high in patients who required frequent dilatation.CONCLUSIONS:In CD patients with symptomatic small bowel stricture, addition of immunomodulator or anti-TNF and smoking cessation may improve the outcome of symptomatic small bowel stricture, by avoiding frequent EBD and subsequent surgery after initial EBD