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The patient was a "73" -year-old woman who visited our hospital with the chief complaint of weight loss. Upper gastrointestinal endoscopy revealed an enlarged ampulla of Vater, and a biopsy led to a diagnosis of Group "4" gastric carcinoma; suspicious of adenocarcinoma. There were no findings suggesting invasion into the muscle layer of duodenum, despite tumor mass formation being observed in the sphincter of Oddi. We performed endoscopic papillectomy for both diagnostic and therapeutic purposes. Pathologically, a well-differentiated adenocarcinoma existed in the superficial layer of the mucous membrane of the papilla of Vater, and gangliocytic paraganglioma was present in the deep portion. The resected margins of both lesions were negative.

Annobón is an extinct volcano about 17.5 km2 in area, and it is the furthest out and one of the smallest islands of the Gulf of Guinea, which also include Bioko, Príncipe, and São Tomé. A series of Prosopocoilus Westwood, 1845 collected from Annobón was found in the collection of the Natural History Museum, London (BMNH), where it was misidentified as Prosopocoilus natalensis (Parry, 1864).

Previous studies conducted on children with autism spectrum disorder (ASD) and their abilities to recognize the psychological states of others have primarily focused on visual aspects such as facial expression and perception. The aims of this study were to clarify the characteristics of auditory information processing mechanisms in individuals with ASD in order to expand our understanding of those with ASD and to contribute to improvements in their social adaptability. The behavioral characteristics of voice cognition in ASD were investigated in 12 individuals with ASD (mean age = 11.83 years) and 12 matched typical development (TD) controls (mean age = 11.58 years). Participants were asked to judge the emotional valence of vocal stimuli with happy, angry, or neutral expressions (emotion task) and select illustrations that best correspond to the semantics of the vocal stimuli (semantic task). The ASD group had significantly (p = 0.013) longer reaction times in the emotion task, suggesting that they have difficulty distinguishing emotional valence. In the semantic task, the ASD group had lower understanding of the meaning of sentences when voices were presented with angry expressions. These results suggest the importance of the emotions conveyed in verbal speech during conversations with individuals with ASD.

We herein report a case of local recurrence of T1a rectal cancer following radical endoscopic mucosal resection (EMR). A 63-year-old man underwent EMR for a 0-IIa lesion of the Ra portion of the rectum. The findings on pathological examination were tub1, T1a (SM1, 420 µm), ly0 and v0, and the EMR had been considered a transitional procedure. Colonoscopy performed 26 months after EMR revealed a submucosal tumor (SMT) near the EMR scar in the left wall of the Ra portion of the rectum. An abdominal enhanced computed tomography scan revealed infiltration of the thickness of the wall with limited extramural extension, and a lymph node 10 mm in diameter. Endoscopic ultrasound-guided fine-needle aspiration also indicated a SMT on the left side of the Ra portion of the rectum that extended from the submucosal layer to beyond the serosal layer, and a lymph node sized 17×11 mm to the left of the Ra portion near the oral side 2 cm from the SMT. The pathological findings confirmed the SMT to be an adenocarcinoma with a metastatic lymph node. Local and lymph node recurrence of rectal cancer following radical EMR was diagnosed, and laparoscopic ultra-low anterior resection, D3 lymph node dissection and a diverting ileostomy were performed. The pathological findings of the excised specimen were T3 (A/SS), ly0, v3, PN1b, pPM0, pDM0, pRM0 (100 µm) and pN0 (0/15). XELOX therapy was administered for 6 months postoperatively as adjuvant chemotherapy, and there has been no recurrence during the first 12 months of follow-up.

Brillouin light scattering measurements were performed in the backscattering geometry on a Bi-substituted rare earth iron garnet. We observed two different peaks, one attributed to a surface spin wave in the dipole-exchange regime. The other is referred to as a backscattering magnon mode, because the incident light in this case is scattered backward by exchange-dominated spin wave inside the material. We propose a method to estimate the exchange stiffness constant from the frequency of the backscattering magnon mode. The obtained value is comparable with the previously reported values for Y$ _3 $Fe$ _5 $O$ _{12} $., 11 pages, 6figures

When male animals engage in intrasexual contests then any alternative tactics they use can be associated with dimorphisms in the expression of weapons. Some species have recently been found to exhibit trimorphism in their weaponry, suggesting that the processes leading to their evolution and maintenance of these polymorphisms can be more complex than previously thought. Here, we describe the extraordinary diversity of polymorphism within the genus Odontolabis: there are dimorphic species (O. siva and O. platynota), trimorphic species (O. cuvera, as previously described, and O. sommeri s.stricto) and, uniquely, tetramorphic species, with males of O. sommeri lowei and O. brookeana showing four clearly differentiated male morphs: small “Gammas”, “Alphas” which express large, long mandibles, “Betas” which have long mandibles with different morphology and “Boltcutters”, with short, wide mandibles. Such polymorphisms are usually thought of as being maintained as a status-dependent conditional strategy, but we found only one size threshold: in most cases males develop into Gamma males below a certain size but there is no relationship between morph and body size amongst the larger, ‘weaponised’ morphs. We suggest that the complex polymorphisms in these animals are probably maintained by a combination of a conditional strategy and a genetic polymorphism.

Recent studies suggest that the severity and drug response of depression and anxiety are correlated with childhood abuse. However, whether a history of child abuse can predict the severity and/or drug response of attention-deficit/hyperactivity disorder (ADHD) is unclear. Therefore, we conducted a retrospective study to assess the efficacy of atomoxetine in children with a history of child abuse.We reviewed 41 cases of children treated with atomoxetine. Specifically, we compared dissociation associating symptoms (DAS) and other symptoms (OS) measured via the ADHD Rating Scale (ADHD-RS) in abused and nonabused children at baseline and at 8 weeks after atomoxetine administration.At baseline, abused children had higher total scores (38.7±9.3 vs. 30.5±9.4, p=0.011), and greater levels of hyperactivity/impulsivity (17.3±5.8 vs. 11.3±6.0, p=0.004) on the ADHD-RS than did nonabused children, whereas the inattention scores were similar between the two groups (21.4±4.8 vs. 19.2±4.6). Additionally, the total score and the two subscores decreased at week 8 for both groups. In the nonabused group, DAS (5.5±2.3 vs. 3.9±1.7, p0.001) and OS (25.0±8.1 vs. 17.4±6.7, p0.001) significantly decreased after atomoxetine treatment. However, DAS in the abused group did not change after atomoxetine treatment (5.9±2.3 vs. 5.1±1.8), whereas OS significantly decreased (32.8±7.6 vs. 25.7±7.2, p=0.002).If DAS were caused by traumatic experiences in abused children, trauma treatment tools other than pharmacotherapy might be useful to treat DAS. These tools may include eye movement desensitization and reprocessing and trauma-focused cognitive behavioral therapy.

It is very important to evaluate the soundness of the injection site by simulating the behavior of carbon dioxide injected into the reservoir. Monte Carlo approach is often used for the statistical evaluation of reservoir because its models include much uncertainty. This approach requires a large number of simulations and it is very time consuming. Therefore we accelerated the simulation with GPU (Graphics Processing Unit) computing technology. We used the simulator called TOUGH2/ECO2N. As a result, we achieved acceleration rate more than 8 times with the simulation for the three -dimensional reservoir model of the Nagaoka project site having 110,000 grids.

In order to clarify the role of the 1-substituent of quinazoline derivatives in their inhibitory activity against poly(ADP-ribose) polymerase (PARP), two novel inhibitors, 1 [8-hydroxy-1-(3-morpholinopropyl)-quinazoline-2,4(1H,3H)-dione] and 2 [8-hydroxy-1-(3-phenoxypropyl)-quinazoline-2,4(1H,3H)-dione], were synthesized and subjected to X-ray crystal analysis in complex with the PARP C-terminal catalytic domain (PARP-CD), which requires NAD+ coenzyme for biological function. The nicotinamide-mimicking part of the quinazoline skeleton of 1 and 2 were both located at the nicotinamide subsite of the NAD+-binding pocket in the same manner as previously reported inhibitors: three hydrogen bonds [(Gly-863)NH-O12, (Gly-863)O-HN3 and (Ser-904)O(gamma)-O12] and stacking interaction between the Tyr-907 phenol and the quinazoline ring. On the other hand, the N-morpholinoprop-3-yl moiety introduced at the 1-position of the quinazoline ring in 1 bridged the large gap between the donor site and the acceptor site through a (Met-890)NH-O20(morpholine) hydrogen bond, where the donor and the acceptor sites are classified as the binding sites of NAD+ and the ADP moiety of the poly(ADP-ribose) chain, respectively. In contrast, the N-phenoxyprop-3-yl moiety in 2 formed hydrophobic interactions close to the adenosine-binding site of NAD+, unlike the hydrogen bond such as in 1. As the inhibitory activities of 1 and 2 for PARP were much more potent than those of the unsubstituted nicotinamide analogues, these results suggest that the occupation of the proximal region of the ADP phosphate-and adenosine-binding subsite of the donor site or that of the gap between the donor and the acceptor site by the 1-substituent of quinazoline may increase the inhibitory activity considerably. The nearly equal inhibitory activities of 1 and 2, despite of their different binding modes at the active site, indicate that this 1-substituent is promising in improving the bioavailability of the inhibitor without compromising its inhibitory activity.

A novel sulfenylation method induced by aromatization of quinone mono-O,S-acetals is described. These sulfenylation reagents readily react with silyl enolethers or electron rich aromatic compounds to give sulfenylation products under mild conditions. In particular, O,S-acetal 2j, which possesses a pentafluorophenylthio function, is the most effective reagent from the standpoint of the adaptability for various substrates.

The Ile-Pro sequence of CA074, potent covalent-type inhibitor, is necessary to exhibit the specificity for cathepsin B, but not for papain. In order to elucidate how its sequence binds to papain and why such binding does not exhibit the specificity for papain at the atomic level, two CA074-related compounds, 1 (N-(L-3-carboxyloxirane-2-carbonyl)-L-isoleucyl-L-proline) and 2 (N-(L-3-carboxyloxirane-2-carbonyl)-L-isoleucyl-diethylamide), were designed and their structure--inhibitory activity relationship was investigated by the X-ray crystal analyses of the complexes with papain. The Ile-Pro moiety of 1 was located at the S2 and S3 subsites consisting of Val-133, Val-157, and Asp-158 and of Tyr-61, Gly-66, and Tyr-67 residues of papain, respectively, which is in contrast with the binding of CA074 to S'n (n = 1 approximately 2) subsites in the complex with cathepsin B. Although 2 in the complex with papain showed the similar binding pattern to 1, its inhibitory activity was about two-fold higher than of 1, suggesting the importance of tight S3-P3 hydrophobic interaction for the activity. The difference of the substrate specificity between papain and cathepsin B has also been discussed based on the X-ray results of the present and cathepsin B-inhibitor complexes.

A new platelet aggregation inhibitor, bassiatin, was isolated from the cultured broth of Beauveria bassiana which had been isolated from a soil sample collected in Yunnan province, China. The structure of bassiatin was determined to be (3S, 6R)-4-methyl-6-(1-methylethyl)-3-phenylmethyl-1, 4-perhydrooxazine-2,5-dione by NMR analysis, X-ray crystallographic analysis and chemical synthesis. Bassiatin inhibited ADP-induced aggregation of rabbit platelets with the IC50 being 1.9 x 10(-4) M.

In order to investigate the stereo specificity of papain Sn subsites (n = 1-4) at the atomic level, two kinds of covalent-type inhibitors were designed based on the previous results on papain-E-64 and papain-E-64-c interactions, and their complex crystals with papain were analyzed by X-ray diffraction. The results show that the hydrophobic regions consisting of Val-133, Val-157 and Asp-158 and of Tyr-61, Gly-66 and Tyr-67 residues interact with the hydrophobic P2 and P3 side chains of inhibitors, thus indicating the function of the former and latter binding pockets as S2 and S3 subsites, respectively. Furthermore, the X-ray analysis suggests that the papain has no definite Sn subsite of nor = 4, and the S3-P3 hydrophobic interaction is significantly affected by the Pn side chain (nor = 4) of both the substrate and the inhibitor.

Keramaphidin B (1), a novel cytotoxic alkaloid possessing a 1,4-etheno-2,7-decahydronaphthylidine core with two macrocyclic rings has been isolated from an Okinawan marine sponge Amphimedon sp., and the structure was elucidated by extensive 2D NMR investigation as well as a single crystal X-ray analysis. Keramaphidin B (1) might be a plausible biogenetic precursor of manzamine alkaloids and a very important key compound to clarify the biogenetic path.

Human immunodeficiency virus (HIV) sentinel surveillance program for injecting drug users has been conducted in Metro Cebu, the Philippines. A low prevalence (0–0.52%) of anti-HIV-positivity had been detected in this population from 2002 to 2007. However, a 10-fold increase in HIV prevalence was detected in the 2009 national HIV sentinel surveillance program. It prompted an additional outreach program to be conducted in Metro Cebu in January 2010, which recorded the highest HIV prevalence rate ever documented in the Philippines (75%, 44/59). HIV genes from fourteen 2009 to 2010 Metro Cebu strains were clustered closely in the phylogenetic tree, but no other strain collected outside Metro Cebu and none stored in the International Nucleotide Sequence Database was allocated to the same phylogenetic cluster. All these HIV infections have emerged in the anti-hepatitis C virus (HCV)-positive population (100%, 62/62) in Metro Cebu from 2009 to 2010. The five HCV strains from the individuals harboring the closely related HIV strains were categorized into different subtypes. These results strongly suggest that HIV infections occurred recently and spread rapidly among injecting drug users, while HCV had been circulating previously among them. Considering the fact that injecting drug use was the first mode of HIV transmission in Asia, extensive monitoring of injecting drug users and associated bridging populations is necessary. Therefore, HCV-guided characterization of the spread of HIV to populations that are vulnerable to blood-borne infections could play an important role in alerting health authorities to the early phase of an HIV epidemic. J. Med. Virol. 83:941–947, 2011. © 2011 Wiley-Liss, Inc.

Hantzsch cyclization of cyanoethyl 3-aminocrotonate and (E,Z)-4-dialkoxymethyl-2-benzylidene-acetoacetates (5a,b) afforded 3,4-trans-2-hydr

Enantiomeric (+)- and (–)-methy3-nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl) pyridine-3,5-dicarboxylate 1 were synthesized by esterification of the optically active monocarboxylic acids (+)-6 and (–)-6, which are available from racemate (±)-6 by optical resolution using cinchonidine and cinchonine. The absolute configuration of the key intermediates (S)-(+)-6 and (R)-(–)-6, was also unambiguously determined by the comparison with optical active (+)- and (–)-1 derived from (R)-(–)- and (S)-(+)-7 and (+)- and (–)-6, and X-ray crystallographic analysis of bromoethyl ester (R)-(–)-8 prepared from the acid (S)-(+)-7.

Hantzsch cyclization of cyanoethyl 3-aminocrotonate and (E,Z)-4,4-dialkoxy-2-benzylideneacetoacetates 12a–h afforded the corresponding 3,4-trans-2-hydroxy-1,2,3,4-tetrahydropyridines 14a–h with high stereoselectivity. 1H NMR and X-ray analyses of compound 14a established the configuration of 3-H and 4-H as trans and that of 3-H and 2-OH as trans also.

A new platelet aggregation inhibitor, bassiatin, was isolated from the cultured broth of Beauveria bassiana which had been isolated from a soil sample collected in Yunnan province, China. The structure of bassiatin was determined to be (3S, 6R)-4-methyl-6-(1-methylethyl)-3-phenylmethyl-1, 4-perhydrooxazine-2,5-dione by NMR analysis, X-ray crystallographic analysis and chemical synthesis. Bassiatin inhibited ADP-induced aggregation of rabbit platelets with the IC50 being 1.9 x 10(-4) M.

A novel sulfenylation method induced by aromatization of quinone mono-O,S-acetals is described. These sulfenylation reagents readily react with silyl enolethers or electron rich aromatic compounds to give sulfenylation products under mild conditions. In particular, O,S-acetal 2j, which possesses a pentafluorophenylthio function, is the most effective reagent from the standpoint of the adaptability for various substrates.

A new neuritogenic compound NGA0187 was isolated from the fermentation broth of Acremonium sp. TF-0356. The structure of NGA0187 was determined by means of spectroscopic analysis and X-Ray diffraction. NGA0187 induced significant neurite outgrowth in PC12 cells. However, survival effect of NGA0187 on the primary culture of cerebral cortical neurons was not observed.

In order to investigate the binding mode of E64-c (a synthetic cysteine proteinase inhibitor) to papain at the atomic level, the crystal structure of the complex was analysed by X-ray diffraction at 1.9 A (1 A is expressed in SI units as 0.1 nm) resolution. The crystal has a space group P2(1)2(1)2(1) with a = 43.37, b = 102.34 and c = 49.95 A. A total of 21,135 observed reflections were collected from the same crystal, and 14811 unique reflections of up to 1.9 A resolution [Fo > 3 sigma(Fo)] were used for the structure solution and refinement. The papain structure was determined by means of the molecular replacement method, and then the inhibitor was observed on a (2 magnitude of Fo-magnitude of Fc) difference Fourier map. The complex structure was finally refined to R = 19.4% including 207 solvent molecules. Although this complex crystal (Form II) was polymorphous as compared with the previously analysed one (Form I), the binding modes of leucine and isoamylamide moieties of E64-c were significantly different from each other. By the calculation of accessible surface area for each complex atom, these two different binding modes were both shown to be tight enough to prevent the access of solvent molecules to the papain active site. With respect to the E64-c-papain binding mode, molecular-dynamics simulations proposed two kinds of stationary states which were derived from the crystal structures of Forms I and II. One of these, which corresponds to the binding mode simulated from Form I, was essentially the same as that observed in the crystal structure, and the other was somewhat different from the crystal structure of Form II, especially with respect to the binding of the isoamylamide moiety with the papain S subsites. The substrate specificity for the papain active site is discussed on the basis of the present results.

To quantitatively estimate the inhibitory effect of each substrate-binding subsite of cathepsin B (CB), a series of epoxysuccinyl derivatives with different functional groups bound to both carbon atoms of the epoxy ring were synthesized, and the relationship between their inhibitory activities and binding modes at CB subsites was evaluated by the X-ray crystal structure analyses of eight complexes. With the common reaction in which the epoxy ring of inhibitor was opened to form a covalent bond with the SgammaH group of the active center Cys29, the observed binding modes of the substituents of inhibitors at the binding subsites of CB enabled the quantitative assessment of the inhibitory effect of each subsite. Although the single blockage of S1' or S2' subsite exerts only the inhibitory effect of IC50 = approximately 24 microM (k2 = approximately 1250 M(-1) s(-1)) or approximately 15 microM (k2 = approximately 1800 M(-1) s(-1)), respectively, the synchronous block of both subsites leads to IC50 = approximately 23 nM (k2 = 153,000 - 185,000 M(-1) s(-1)), under the condition that (i) the inhibitor possesses a P1' hydrophobic residue such as Ile and a P2' hydrophobic residue such as Ala, Ile or Pro, and (ii) the C-terminal carboxyl group of a P2' residue is able to form paired hydrogen bonds with the imidazole NH of His110 and the imidazole N of His111 of CB. The inhibitor of a Pn' > or = 3' substituent was not potentiated by collision with the occluding loop. On the other hand, it was suggested that the inhibitory effects of Sn subsites are independent of those of Sn' subsites, and the simultaneous blockage of the funnel-like arrangement of S2 and S3 subsites leads to the inhibition of IC50 = approximately 40 nM (k2 = approximately 66,600 M(-1) s(-1)) regardless of the lack of Pn' substituents. Here we present a systematic X-ray structure-based evaluation of structure-inhibitory activity relationship of each binding subsite of CB, and the results provide the structural basis for designing a more potent CB-specific inhibitor.

A new neuritogenic compound NGA0187 was isolated from the fermentation broth of Acremonium sp. TF-0356. The structure of NGA0187 was determined by means of spectroscopic analysis and X-Ray diffraction. NGA0187 induced significant neurite outgrowth in PC12 cells. However, survival effect of NGA0187 on the primary culture of cerebral cortical neurons was not observed.

The novel 6-O-methyl tricyclic ketolides TE-802 and its analogs were synthesized by two successive cyclization reactions, 11,12-cyclic carbamate formation by intramolecular Michael addition and 9,11-diazaheptene ring construction by intramolecular dehydration reaction. These new tricyclic ketolides exhibited good in vitro antibacterial activity against not only erythromycin-susceptible strains but also erythromycin-resistant Staphylococcus aureus and Streptococcus pneumoniae, which are problematic pathogens of nosocomial and community-acquired respiratory tract infections, respectively.

This paper focuses on the inhibitory mechanism of E-64 and its derivatives (epoxysuccinyl-based inhibitors) with some cysteine proteases, based on the binding modes observed in the x-ray crystal structures of their enzyme-inhibitor complexes. E-64 is a potent irreversible inhibitor against general cysteine proteases, and its binding modes with papain, actinidin, cathepsin L, and cathepsin K have been reviewed at the atomic level. E-64 interacts with the Sn subsites of cysteine proteases. Although the Sn-Pn (n = 1-3) interactions of the inhibitor with the main chains of the active site residues are similar in respective complexes, the significant difference is observed in the side-chain interactions of S2-P2 and S3-P3 pairs because of different residues constituting the respective subsites. E-64-c and CA074 are representative derivatives developed from E-64 as a clinical usable and a cathepsin B-specific inhibitors, respectively. In contrast with similar binding/inhibitory modes of E-64-c and E-64 for cysteine proteases, the inhibitory mechanism of cathepsin B-specific CA074 results from the binding to the Sn' subsite.

The effect of pulverization on the dehydration behavior of 2-[(2-methylimidazol-1-yl)methyl]benzo[f]thiochromen-1-one monohydro-chloride hemihydrate (GK-128), a newly developed serotonin3 receptor antagonist, was studied using powder X-ray diffraction analysis, thermo-gravimetry (TG), and differential scanning calorimetry (DSC). The crystalline forms of GK-128 obtained by pulverizing with a jet mill and an agate mortar were each confirmed to be the same as that of intact GK-128, since the powder X-ray diffraction patterns of the two prepared samples were identical with that of intact GK-128. However, after pulverization by jet mill, the dehydration temperature of GK-128 was markedly lowered and the DSC endothermic peak due to dehydration disappeared. The activation energy for dehydration, calculated by the Ozawa method using TG data, decreased with decreasing particle size and/or crystallinity of GK-128 crystals, e.g., the activation energies for dehydration of intact and jet-milled GK-128 were 128.1 and 75.9 kJ/mol, respectively. The results of comparison of powder X-ray diffraction patterns of pulverized GK-128 and intact GK-128 and of determination of the crystal structure of GK-128 suggested that water molecules could be removed easily along the c-axis of GK-128 crystals.

2-Acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanonic acid (KE-298) is an antirheumatic agent. To elucidate the effects of optically active KE-298, we resolved the racemic acid and obtained the two optical isomers. (+)-KE-298 was converted to the 4-bromobenzyl ester derivative and the absolute structure was confirmed as (S) by X-ray crystallographic analysis. The pharmacological activities of the optical isomers and racemic KE-298 were compared by using the characteristic tests for KE-298. Though (+)-KE-298 showed a stronger suppressive effect on rat adjuvant arthritis than (-)-KE-298, no difference between the two isomers was detected in in vitro tests (enhancing effect on lymphocyte transformation, IL-1 antagonistic effect).

A novel chlorinated steroid, aragusterol C, was isolated from an Okinawan marine sponge of the genus Xestospongia. The compound strongly inhibited the proliferation of KB cells in vitro, and also showed potent in vivo antitumor activity against L1210 cells in mice. The complete structure of aragusterol C was determined by spectroscopic analysis and X-ray crystallographic analysis.