bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary X-ray crystallographic studies on acetate kinase (AckA) fromSalmonella typhimuriumin two crystal forms
Authors: Chittori Sagar , Savithri H. S. , Murthy M. R. N. 
Published: December 2011

Acetate kinase (AckA) catalyzes the reversible transfer of a phosphate group from acetyl phosphate to ADP, generating acetate and ATP, and plays a central role in carbon metabolism. In the present work, the gene corresponding to AckA fromSalmonella typhimurium(StAckA) was cloned in the IPTG-inducible pRSET C vector, resulting in the attachment of a hexahistidine tag to the N-terminus of the expressed enzyme. The recombinant protein was overexpressed, purified and crystallized in two different crystal forms using the microbatch-under-oil method. Form I crystals diffracted to 2.70 Å resolution when examined using X-rays from a rotating-anode X-ray generator and belonged to the monoclinic space groupC2, with unit-cell parametersa = 283.16,b= 62.17,c= 91.69 Å, β = 93.57°. Form II crystals, which diffracted to a higher resolution of 2.35 Å on the rotating-anode X-ray generator and to 1.90 Å on beamline BM14 of the ESRF, Grenoble, also belonged to space groupC2 but with smaller unit-cell parameters (a= 151.01,b= 78.50,c = 97.48 Å, β = 116.37°). Calculation of Matthews coefficients for the two crystal forms suggested the presence of four and two protomers ofStAckA in the asymmetric units of forms I and II, respectively. Initial phases for the form I diffraction data were obtained by molecular replacement using the coordinates ofThermotoga maritimaAckA (TmAckA) as the search model. The form II structure was phased using a monomer of form I as the phasing model. Inspection of the initial electron-density maps suggests dramatic conformational differences between residues 230 and 300 of the two crystal forms and warrants further investigation.
A randomized controlled trial of a brief intervention for illicit drugs linked to the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in clients recruited from primary health‐care settings in four countries
Authors: Humeniuk Rachel , Ali Robert , Babor Thomas , Souza‐Formigoni Maria Lucia O. , de Lacerda Roseli Boerngen , Ling Walter , McRee Bonnie , Newcombe David , Pal Hemraj , Poznyak Vladimir , Simon Sara , Vendetti Janice 
Published: December 2011

ABSTRACTAims  This study evaluated the effectiveness of a brief intervention (BI) for illicit drugs (cannabis, cocaine, amphetamine‐type stimulants and opioids) linked to the World Health Organization (WHO) Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). The ASSIST screens for problem or risky use of 10 psychoactive substances, producing a score for each substance that falls into either a low‐, moderate‐ or high‐risk category.Design  Prospective, randomized controlled trial in which participants were either assigned to a 3‐month waiting‐list control condition or received brief motivational counselling lasting an average of 13.8 minutes for the drug receiving the highest ASSIST score.Setting  Primary health‐care settings in four countries: Australia, Brazil, India and the United States.Participants  A total of 731 males and females scoring within the moderate‐risk range of the ASSIST for cannabis, cocaine, amphetamine‐type stimulants or opioids.Measurements  ASSIST‐specific substance involvement scores for cannabis, stimulants or opioids and ASSIST total illicit substance involvement score at baseline and 3 months post‐randomization.Findings  Omnibus analyses indicated that those receiving the BI had significantly reduced scores for all measures, compared with control participants. Country‐specific analyses showed that, with the exception of the site in the United States, BI participants had significantly lower ASSIST total illicit substance involvement scores at follow‐up compared with the control participants. The sites in India and Brazil demonstrated a very strong brief intervention effect for cannabis scores (P < 0.005 for both sites), as did the sites in Australia (P < 0.005) and Brazil (P < 0.01) for stimulant scores and the Indian site for opioid scores (P < 0.01).Conclusions  The Alcohol, Smoking and Substance Involvement Screening Test‐linked brief intervention aimed at reducing illicit substance use and related risks is effective, at least in the short term, and the effect generalizes across countries.
A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABAA receptor modulator – an in vitro and in vivo comparison
Authors: Zhou Diansong , Sunzel Maria , Ribadeneira Maria D. , Smith Mark A. , Desai Dhaval , Lin Jianrong , Grimm Scott W. 
Published: November 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• AZD7325 is an orally administered, potent, selective gamma‐amino‐butyric acid (GABAA) α2,3 receptor modulator intended for the treatment of anxiety.• The induction effects of AZD7325 on CYP1A2 and CYP3A4 have not been systematically studied.WHAT THIS STUDY ADDS• The in vitro studies showed that AZD7325 was a moderate CYP1A2 inducer and potent CYP3A4 inducer.• The follow‐up clinical studies in healthy volunteers demonstrated that the expected efficacious daily dose of AZD7325 only weakly induced the pharmacokinetics of the CYP3A4 sensitive substrate, midazolam, and had no effect on the pharmacokinetics of the CYP1A2 substrate, caffeine. There was no apparent change in AZD7325 exposure following co‐administration of midazolam or caffeine compared with AZD7325 alone.• The study demonstrated that clinical exposure of the inducer plays a critical role in the determination of cytochrome P450 induction risk of a drug candidate.AIM(S) To investigate the potential of AZD7325 to induce CYP1A2 and CYP3A4 enzyme activities.METHODS Induction of CYP1A2 and CYP3A4 by AZD7325 was first evaluated using cultured human hepatocytes. The effect of multiple doses of 10 mg AZD7325 on the pharmacokinetics of midazolam and caffeine was then examined in healthy subjects.RESULTS The highest CYP1A2 and CYP3A4 induction responses were observed in human hepatocytes treated with 1 or 10 µm of AZD7325, in the range of 17.9%–54.9% and 76.9%–85.7% of the positive control responses, respectively. The results triggered the further clinical evaluation of AZD7325 induction potential. AZD7325 reached a plasma Cmax of 0.2 µm after 10 mg daily dosing to steady‐state. AZD7325 decreased midazolam geometric mean AUC by 19% (0.81‐fold, 90% CI 0.77, 0.87), but had no effect on midazolam Cmax (90% CI 0.82, 0.97). The mean CL/F of midazolam increased from 62 l h−1 (midazolam alone) to 76 l h−1 when co‐administered with AZD7325. The AUC and Cmax of caffeine were not changed after co‐administration of AZD7325, with geometric mean ratios (90% CI) of 1.17 (1.12, 1.23) and 0.99 (0.95, 1.03), respectively.CONCLUSIONS While AZD7325 appeared to be a potent CYP3A4 inducer and a moderate CYP1A2 inducer from in vitro studies, the expected efficacious dose of AZD7325 had no effect on CYP1A2 activity and only a weak inducing effect on CYP3A4 activity. This comparison of in vitro and in vivo results demonstrates the critical role that clinical exposure plays in evaluating the CYP induction risk of a drug candidate.
Impact of geographical isolation on genetic differentiation in insular and mainland populations of Weigela coraeensis (Caprifoliaceae) on Honshu and the Izu Islands
Authors: Yamada Takayuki , Maki Masayuki 
Published: November 2011

AbstractAim  To provide insights into genetic differentiation between insular endemic Weigela coraeensis var. fragrans and its progenitor variety W. coraeensis var. coraeensis, the population genetic structure of both varieties was examined, and factors promoting genetic differentiation between the two taxa were explored.Location  The natural range of W. coraeensis (sensu lato) throughout mainland Japan (Honshu) and the Izu Islands.Methods  The analysis included 349 and 504 individuals across the mainland (Honshu) and the Izu Islands, respectively, using 10 allozyme and 10 microsatellite loci. The population genetic structure of W. coraeensis was assessed by analysing genetic diversity indices for each population, genetic differentiation among populations, model‐based Bayesian clustering or distance‐based clustering, and bottleneck tests.Results  The level of genetic diversity in each of the populations on the Izu Islands was negatively correlated with geographical distance between each island and the mainland. The populations on the mainland and on the Izu Islands were genetically differentiated to a certain extent; however, the microsatellite analyses suggested that gene flow also occurred between the mainland and the islands, and among individual islands. These microsatellite analyses also suggested recent bottlenecks in several populations in both areas.Main conclusions  The decrease in genetic diversity throughout the Izu Islands, which correlated with distance to the mainland, Honshu, may be the result of a repeated founder effect occurring at a series of inter‐island colonizations from north to south. The stepping stone‐like configuration of the islands may have played a role in the dispersal of the species. Geographical isolation by sea would effectively result in genetic differentiation of W. coraeensis between mainland Honshu and the Izu Islands, although some gene flow may still occur between Honshu and the northern Izu Islands. The differentiation process of the endemic plants on the Izu Islands is anagenetic but not completed, and the study of these plants will provide insightful knowledge concerning the evolution of insular endemics.
The evolution of cardenolide‐resistant forms of Na+,K+‐ATPase in Danainae butterflies
Authors: AARDEMA MATTHEW L. , ZHEN YING , ANDOLFATTO PETER 
Published: December 2011

AbstractCardenolides are a class of plant secondary compounds that inhibit the proper functioning of the Na+, K+‐ATPase enzyme in susceptible animals. Nonetheless, many insect species are able to sequester cardenolides for their own defence. These include butterflies in the subfamily Danainae (Family: Nymphalidae) such as the monarch (Danaus plexippus). Previous studies demonstrated that monarchs harbour an asparagine (N) to histidine (H) substitution (N122H) in the α subunit of Na+, K+‐ATPase (ATPα) that reduces this enzyme’s sensitivity to cardenolides. More recently, it has been suggested that at ATPα position 111, monarchs may also harbour a leucine (L)/glutamine (Q) polymorphism. This later amino acid could also contribute to cardenolide insensitivity. However, here we find that incorrect annotation of the initially reported DNA sequence for ATPα has led to several erroneous conclusions. Using a population genetic and phylogenetic analysis of monarchs and their close relatives, we show that an ancient Q111L substitution occurred prior to the radiation of all Danainae, followed by a second substitution at the same site to valine (V), which arose before the diversification of the Danaus genus. In contrast, N122H appears to be a recent substitution specific to monarchs. Surprisingly, examination of a broader insect phylogeny reveals that the same progression of amino acid substitutions (Q111L → L111V + N122H) has also occurred in Chyrsochus beetles (Family: Chrysomelidae, Subfamily: Eumolpinae) that feed on cardenolide‐containing host plants. The parallel pattern of amino acid substitution in these two distantly related lineages is consistent with an adaptive role for these substitutions in reducing cardenolide sensitivity and suggests that their temporal order may be limited by epistatic interactions.
Multi locus analysis of Pristionchus pacificus on La Réunion Island reveals an evolutionary history shaped by multiple introductions, constrained dispersal events and rare out‐crossing
Authors: MORGAN KATY , McGAUGHRAN ANGELA , VILLATE LAURE , HERRMANN MATTHIAS , WITTE HANH , BARTELMES GABI , ROCHAT JACQUES , SOMMER RALF J. 
Published: December 2011

AbstractPristionchus pacificus, recently established as a model organism in evolutionary biology, is a cosmopolitan nematode that has a necromenic association with scarab beetles. The diverse array of host beetle species and habitat types occupied by P. pacificus make it a good model for investigating local adaptation to novel environments. Presence of P. pacificus on La Réunion Island, a young volcanic island with a dynamic geological history and a wide variety of ecozones, facilitates such investigation in an island biogeographic setting. Microsatellite data from 20 markers and 223 strains and mitochondrial sequence data from 272 strains reveal rich genetic diversity among La Réunion P. pacificus isolates, shaped by differentially timed introductions from diverse sources and in association with different beetle species. Distinctions between volcanic zones and between arid western and wet eastern climatic zones have likely limited westward dispersal of recently colonized lineages and maintained a genetic distinction between eastern and western clades. The highly selfing lifestyle of P. pacificus contributes to the strong fine‐scale population structure detected, with each beetle host harbouring strongly differentiated assemblages of strains. Periodic out‐crossing generates admixture between genetically diverse lineages, creating a diverse array of allelic combinations likely to increase the evolutionary potential of the species and facilitate adaptation to local environments and beetle hosts.
Mast cells trigger epithelial barrier dysfunction, bacterial translocation and postoperative ileus in a mouse model
Authors: Snoek S. A. , Dhawan S. , van Bree S. H. , Cailotto C. , van Diest S. A. , Duarte J. M. , Stanisor O. I. , Hilbers F. W. , Nijhuis L. , Koeman A. , van den Wijngaard R. M. , Zuurbier C. J. , Boeckxstaens G. E. , de Jonge W. J. 
Published: November 2011

AbstractBackground  Abdominal surgery involving bowel manipulation commonly results in inflammation of the bowel wall, which leads to impaired intestinal motility and postoperative ileus (POI). Mast cells have shown to play a key role in the pathogenesis of POI in mouse models and human studies. We studied whether mast cells contribute to the pathogenesis of POI by eliciting intestinal barrier dysfunction.Methods  C57BL/6 mice, and two mast cell‐deficient mutant mice KitW/W‐v, and KitW‐sh/W‐sh underwent laparotomy (L) or manipulation of the small bowel (IM). Postoperative inflammatory infiltrates and cytokine production were assessed. Epithelial barrier function was determined in Ussing chambers, by measuring transport of luminal particles to the vena mesenterica, and by assessing bacterial translocation.Key Results  In WT mice, IM resulted in pro‐inflammatory cytokine and chemokine production, and neutrophil extravasation to the manipulated bowel wall. This response to IM was reduced in mast cell‐deficient mice. IM caused epithelial barrier dysfunction in WT mice, but not in the two mast cell‐deficient strains. IM resulted in a decrease in mean arterial pressure in both WT and mast cell‐deficient mice, indicating that impaired barrier function was not explained by tissue hypoperfusion, but involved mast cell mediators.Conclusions & Inferences  Mast cell activation during abdominal surgery causes epithelial barrier dysfunction and inflammation of the muscularis externa of the bowel. The impairment of the epithelial barrier likely contributes to the pathogenesis of POI. Our data further underscore that mast cells are bona fide cellular targets to ameliorate POI.
Sedimentological and ichnological signatures of changes in wave, river and tidal influence along a Neogene tropical deltaic shoreline
Authors: BUATOIS LUIS A. , SANTIAGO NUBIA , HERRERA MEYLIN , PLINK‐BJÖRKLUND PIRET , STEEL RON , ESPIN MARÍA , PARRA KAOLU 
Published: December 2011

AbstractAnalysis of Neogene cores from the Eastern Venezuela Basin along 65 km of a west–east trending shoreline allows characterization of the sedimentological and ichnological signatures of wave, river and tidal processes. The area displays deltas prograding northward from the Guyana Shield. Twenty‐three facies are defined and grouped into four categories (wave‐influenced, river‐influenced, tide‐influenced and basinal). Wave‐dominated deltaic deposits occur mostly in the Tácata Field. The delta plain was characterized by tide‐influenced distributary channels separated by interdistributary bays. Fluvial discharge in the delta front and prodelta was repeatedly interrupted by storm‐wave reworking and suspended sediment fallout. Delta‐front and prodelta deposits contain some ichnotaxa that typically do not occur in brackish water (for example, Chondrites and Phycosiphon). Amalgamated storm deposits are unburrowed or contain vertical Ophiomorpha. Lateral (especially on the updrift side) to the river mouths, waves caused nearly continuous accretion of the associated strandplains. These deposits are the most intensely bioturbated, and are dominated by the estenohaline echinoid‐generated ichnogenus Scolicia. River‐dominated deltaic deposits are present in the Santa Bárbara, Mulata, Carito and El Furrial Fields. Low‐sinuosity rivers characterized the alluvial plain, whereas the subaerial delta plain was occupied by higher‐sinuosity rivers. The subaqueous delta plain includes distributary channels and tide‐influenced interdistributary bays. Further seaward, successions are characterized by terminal distributary‐channel and distributary mouth‐bar deposits, as well as by delta‐front and prodelta deposits showing evidence of sediment gravity‐flow and fluid‐mud emplacement. Delta‐front and prodelta deposits are unbioturbated to sparsely bioturbated, suggesting extreme stress, mostly as a result of high fluvial discharge and generation of sediment gravity flows. Tidal influence is restricted to interdistributary bays, lagoons and some distributary channels. From an ichnological perspective, and in order of decreasing stress levels, four main depositional settings are identified: river‐dominated deltas, tide‐influenced delta plains, wave‐dominated deltas and wave‐dominated strandplain–offshore complexes.
Decrease in interleukin‐21 in children suffering with severe atopic dermatitis
Authors: Lin Sheng‐Chieh , Chuang Ya‐Hui , Yang Yao‐Hsu , Chiang Bor‐Luen 
Published: November 2011

To cite this article: Lin S‐C, Chuang Y‐H, Yang Y‐H, Chiang B‐L. Decrease in interleukin‐21 in children suffering with severe atopic dermatitis. Pediatr Allergy Immunol 2011: 22: 869–875.AbstractBackground:  Atopic dermatitis (AD) is a kind of eczema with an inflammatory, relapsing, non‐contagious, and pruritic skin disorder. It is associated with the local infiltration of T helper type 2 (Th2) cells that secrete interleukin (IL)‐4 and IL‐5. IL‐21 is a member of IL‐2 family cytokine mainly expressed by activated CD4+ T lymphocytes. Until now, there is no clinical research in the expression of IL‐21 in patients with AD.Methods:  We analyzed serum levels of total immunoglobulin E (IgE), allergen‐specific IgE, and cytokines IL‐4, IL‐5, IFN‐γ, IL‐17, and IL‐21 in AD cases and controls. In addition, cytokine levels in the culture supernatants of peripheral blood mononuclear cells stimulated with anti‐CD3 and anti‐CD28 Abs, phytohemagglutin (PHA), or pokeweed mitogen (PWM) were measured. We also assessed clinical skin severity by Scoring of Atopic Dermatitis (SCORAD) index.Results:  Our results showed that serum total IgE in the case group was significantly higher than that of control group (365.449 ± 52.945 and 39.243 ± 7.605 IU/ml, respectively). Logistic regression analysis system reveals serum levels of IL‐21 and IFN‐γ are significantly correlated. However, IL‐21 and IL‐4, IL‐21 and IL‐5, as well as IL‐21 and IL‐17 showed no correlation.Conclusion:  A significantly decreased level of IL‐21 was observed in children suffering with severe AD compared with controls, suggesting that IL‐21 may play a role in AD.
Allospecific CD154 + T‐cytotoxic memory cells as potential surrogate for rejection risk in pediatric intestine transplantation
Authors: Sindhi Rakesh , Ashokkumar Chethan , Higgs Brandon W. , Gilbert P. B. , Sun Qing , Ranganathan Sarangarajan , Jaffe Ron , Snyder Sara , Ningappa Mylarappa , Soltys Kyle A. , Bond Geoffrey J. , Mazariegos George V. , Abu‐Elmagd Kareem , Zeevi Adriana 
Published: November 2011

Sindhi R, Ashokkumar C, Higgs BW, Gilbert PB, Sun Q, Ranganathan S, Jaffe R, Snyder S, Ningappa M, Soltys KA, Bond GJ, Mazariegos GV, Abu‐Elmagd K, Zeevi A. Allospecific CD154 + T‐cytotoxic memory cells as potential surrogate for rejection risk in pediatric intestine transplantation.  Pediatr Transplantation 2012: 16: 83–91. © 2011 John Wiley & Sons A/S.Abstract:  Clinical end‐points dictate large trial enrollments and exclude children with the rare intestine transplant procedure (ITx), who experience higher drug‐related morbidity. We evaluate the novel rejection‐risk parameter, allo‐(antigen)‐specific CD154 + TcMs (i) as surrogates for ACR using Prentice’s criteria, (ii) for association with immunosuppression targets to determine Fleming’s surrogate end‐point designation, and (iii) as time‐to‐event end‐point in a simulated comparison of alemtuzumab (NCT#01208337, n = 14) and rabbit anti‐human thymocyte globulin (rATG, n = 16) among 30 children with ITx. CD154 + TcM were measured in MLR before, and at 1–60 and 61–200 days after ITx (NCT#01163578). CD154 + TcM correlate significantly with rejection severity (Spearman r = 0.685, p = 2.03E−5) and associate with biopsy‐proven ITx rejection with sensitivity/specificity of 90%/84% independent of immunosuppressant. The rejection‐risk threshold of CD154 + TcM resolves rapidly in 200‐day follow‐up (46 ± 20 vs. 158 ± 59 days, p = 0.009, K–M) with alemtuzumab, which demonstrates lower 90‐day ACR incidence (50% vs. 69%, p=NS, Fisher’s exact), and is associated with accelerated prednisone minimization to ≤2.5 mg/day, compared with rATG (120 ± 28 vs. 180 ± 30 days, p = 0.027, K–M). As a surrogate end‐point, time‐to‐rejection‐risk resolution measured with CD154 + TcM portends 50% reduction in sample sizes in a simulated trial of alemtuzumab vs. rATG. Rejection‐risk assessment with CD154 + TcM may enable informed immunosuppression minimization, and preliminary efficacy comparisons in pediatric ITx.