bluuebunny/crossref_metadata_2025 huggingface dataset:
Accurate prediction of transmembraneβ-barrel proteins from sequences
Authors: Hayat Sikander , Sander Chris , Elofsson Arne , Marks Debora S.
Published: June 2014

Transmembraneβ-barrels are known to play major roles in substrate transport and protein biogenesis in gram-negative bacteria, chloroplasts and mitochondria. However, the exact number of transmembraneβ-barrel families is unknown and experimental structure determination is challenging. In theory, if one knows the number of strands in theβ-barrel, then the 3D structure of the barrel could be trivial, but current topology predictions do not predict accurate structures and are unable to give information beyond theβ-strands in the barrel. Recent work has shown successful prediction of globular and alpha-helical membrane proteins from sequence alignments, by using high ranked evolutionary couplings between residues as distance constraints to fold extended polypeptides. However, these methods, have not addressed the calculation of preciseβ-sheet hydrogen bonding that defines transmembraneβ-barrels, and would be required to fold these proteins successfully. Hence we developed a method (EVFold_BB) that can successfully model transmembraneβ-barrels by combining evolutionary couplings together with topology predictions. EVFold_BB is validated by the accurate all-atom 3D modeling of 18 proteins, representing all known membraneβ-barrel families that have sufficient sequences available. To demonstrate the potential of our approach we predict the unknown 3D structure of the LptD protein, the plausibility of its accuracy is supported by the blindly predicted benchmarks, and is consistent with experimental observations. Our approach can naturally be extended to all unknownβ-barrel proteins with sufficient sequence information.

Significance

EVFold_BB predicts fast, accurate 3D models of large membraneβ-barrels that are notoriously hard to solve experimentally. The major advance is the use of evolutionary couplings from sequence alignments together with theβ-strand prediction to ascertain accurate hydrogen bond between theβ-strands that gives rise to the canonical barrel shapes. The method will enable biological research into outer-membrane proteins.
Converging structural and functional connectivity of orbitofrontal, dorsolateral prefrontal, and posterior parietal cortex in the human striatum
Authors: Jarbo Kevin , Verstynen Timothy D.
Published: June 2014

Modification of spatial attention via reinforcement learning (Lee & Shomstein, 2013) requires the integration of reward, attention, and executive processes. Corticostriatal pathways are an ideal neural substrate for this integration because these projections exhibit a globally parallel (Alexander, De Long, and Strick, 1985), but locally overlapping (Haber, 2003), topographical organization. Here, we explored whether there are unique striatal regions that exhibit convergent anatomical connections from orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex. Deterministic fiber tractography on diffusion spectrum imaging data from neurologically healthy adults (N=60) was used to map fronto-and parieto-striatal projections. In general, projections from cortex were organized in a rostral-caudal gradient along the striatal nuclei; however, we also identified two bilateral convergence zones—one in the caudate nucleus and another in the putamen—that consisted of voxels with projections from OFC, DLPFC, and parietal regions. The distributed cortical connectivity of these striatal convergence zones was confirmed with follow-up functional connectivity analysis from resting state fMRI data from 55 of the participants, in which a high percentage (62-80%) of structurally connected voxels also showed significant functional connectivity. These results delineate a neurologically plausible network of converging corticostriatal projections that may support the integration of reward, executive control, and spatial attention that occurs during spatial reinforcement learning.
Microbiota modulate transcription in the intestinal epithelium without remodeling the accessible chromatin landscape
Authors: Camp J. Gray , Frank Christopher L. , Lickwar Colin R. , Guturu Harendra , Rube Tomas , Wenger Aaron M. , Chen Jenny , Bejerano Gill , Crawford Gregory E. , Rawls John F.
Published: June 2014

Microbiota regulate intestinal physiology by modifying host gene expression along the length of the intestine, but the underlying regulatory mechanisms remain unresolved. Transcriptional specificity occurs through interactions between transcription factors (TFs) and cis-regulatory regions (CRRs) characterized by nucleosome-depleted accessible chromatin. We profiled transcriptome and accessible chromatin landscapes in intestinal epithelial cells (IECs) from mice reared in the presence or absence of microbiota. We show that regional differences in gene transcription along the intestinal tract were accompanied by major alterations in chromatin accessibility. Surprisingly, we discovered that microbiota modify host gene transcription in IECs without significantly impacting the accessible chromatin landscape. Instead, microbiota regulation of host gene transcription might be achieved by differential expression of specific TFs and enrichment of their binding sites in nucleosome-depleted CRRs near target genes. Our results suggest that the chromatin landscape in IECs is preprogrammed by the host in a region-specific manner to permit responses to microbiota through binding of open CRRs by specific TFs.
MultiBLUP: improved SNP-based prediction for complex traits
Authors: Speed Doug , Balding David J.
Published: June 2014

BLUP (best linear unbiased prediction) is widely used to predict complex traits in plant and animal breeding, and increasingly in human genetics. The BLUP mathematical model, which consists of a single random effect term, was adequate when kinships were measured from pedigrees. However, when genome-wide SNPs are used to measure kinships, the BLUP model implicitly assumes that all SNPs have the same effect-size distribution, which is a severe and unnecessary limitation. We propose MultiBLUP, which extends the BLUP model to include multiple random effects, allowing greatly improved prediction when the random effects correspond to classes of SNPs with distinct effect-size variances. The SNP classes can be specified in advance, for example, based on SNP functional annotations, and we also provide an adaptive procedure for determining a suitable partition of SNPs. We apply MultiBLUP to genome-wide association data from the Wellcome Trust Case Control Consortium (seven diseases), and from much larger studies of celiac disease and inflammatory bowel disease, finding that it consistently provides better prediction than alternative methods. Moreover, MultiBLUP is computationally very efficient; for the largest data set, which includes 12,678 individuals and 1.5 M SNPs, the total analysis can be run on a single desktop PC in less than a day and can be parallelized to run even faster. Tools to perform MultiBLUP are freely available in our software LDAK.
Genetic Evidence That Chain Length and Branch Point Distributions Are Linked Determinants of Starch Granule Formation in Arabidopsis
Authors: Pfister Barbara , Lu Kuan-Jen , Eicke Simona , Feil Regina , Lunn John E. , Streb Sebastian , Zeeman Samuel C.
Published: June 2014

The major component of starch is the branched glucan amylopectin. Structural features of amylopectin, such as the branching pattern and the chain length distribution, are thought to be key factors that enable it to form semicrystalline starch granules. We varied both structural parameters by creating Arabidopsis (Arabidopsis thaliana) mutants lacking combinations of starch synthases (SSs) SS1, SS2, and SS3 (to vary chain lengths) and the debranching enzyme ISOAMYLASE1-ISOAMYLASE2 (ISA; to alter branching pattern). The isa mutant accumulates primarily phytoglycogen in leaf mesophyll cells, with only small amounts of starch in other cell types (epidermis and bundle sheath cells). This balance can be significantly shifted by mutating different SSs. Mutation of SS1 promoted starch synthesis, restoring granules in mesophyll cell plastids. Mutation of SS2 decreased starch synthesis, abolishing granules in epidermal and bundle sheath cells. Thus, the types of SSs present affect the crystallinity and thus the solubility of the glucans made, compensating for or compounding the effects of an aberrant branching pattern. Interestingly, ss2 mutant plants contained small amounts of phytoglycogen in addition to aberrant starch. Likewise, ss2ss3 plants contained phytoglycogen, but were almost devoid of glucan despite retaining other SS isoforms. Surprisingly, glucan production was restored in the ss2ss3isa triple mutants, indicating that SS activity in ss2ss3 per se is not limiting but that the isoamylase suppresses glucan accumulation. We conclude that loss of only SSs can cause phytoglycogen production. This is readily degraded by isoamylase and other enzymes so it does not accumulate and was previously unnoticed.
Crystal structures ofN-(pyridin-2-ylmethyl)pyrazine-2-carboxamide (monoclinic polymorph) andN-(pyridin-4-ylmethyl)pyrazine-2-carboxamide
Authors: Cati Dilovan S. , Stoeckli-Evans Helen
Published: June 2014

The title compounds, C11H10N4O (HL1) and C11H10N4O (HL2), are pyridine 2-ylmethyl and 4-ylmethyl derivatives, respectively, of pyrazine-2-carboxamide. HL1 was measured at 153 K and crystallized in the monoclinic space groupP21/cwithZ= 4. There has been a report of the same structure measured at room temperature but assumed to crystallize in the triclinic space groupP-1 withZ= 4 [Sasanet al.(2008).Monatsh. Chem.139, 773–780]. In HL1, the pyridine ring is inclined to the pyrazine ring by 61.34 (6)°, while in HL2 this dihedral angle is 84.33 (12)°. In both molecules, there is a short N—H...N interaction involving the pyrazine carboxamide unit. In the crystal of HL1, molecules are linked by N—H...N hydrogen bonds, forming inversion dimers with anR22(10) ring motif. The dimers are linkedviabifurcated-acceptor C—H...O hydrogen bonds, forming sheets lying parallel to (102). The sheets are linkedviaC—H...N hydrogen bonds, forming a three-dimensional structure. In the crystal of HL2, molecules are linked by N—H...N and C—H...N hydrogen bonds to form chains propagating along [010]. The chains are linkedviaC—H...O hydrogen bonds, forming sheets lying parallel to (100). Within the sheets there are π–π interactions involving neighbouring pyrazine rings [inter-centroid distance = 3.711 (15) Å]. Adjacent sheets are linkedviaparallel slipped π–π interactions involving inversion-related pyridine rings [inter-centroid distance = 3.6395 (17) Å], forming a three-dimensional structure.
Crystal structure of Pb3(IO4(OH)2)2
Authors: Weil Matthias
Published: June 2014

The structure of the title compound, trilead(II) bis[dihydroxidotetraoxidoiodate(VII)], was determined from a crystal twinned by non-merohedry with two twin domains present [twin fraction 0.73 (1):0.27 (1)]. It contains three Pb2+cations and two IO4(OH)23−anions in the asymmetric unit. Each of the Pb2+cations is surrounded by eight O atoms (cut-off value = 3.1 Å) in the form of a distorted polyhedron. The octahedral IO4(OH)23−anions are arranged in rows extending parallel to [021], forming a distorted hexagonal rod packing. The cations and anions are linked into a framework structure. Although H-atom positions could not be located, O...O distances suggest medium-strength hydrogen-bonding interactions between the IO4(OH)2octahedra, further consolidating the crystal packing.
Plant functional diversity drives niche‐size‐structure of dominant microbial consumers along a poor to extremely rich fen gradient
Authors: Jassey Vincent E. J. , Lamentowicz Łukasz , Robroek Bjorn J. M. , Gąbka Maciej , Rusińska Anna , Lamentowicz Mariusz
Published: June 2014

Plant community composition is recognized more and more for playing an important role in ecosystem processes, such as C cycling. In particular, plant functional type (PFT) composition seems to have a key regulatory role, yet the underlying mechanisms in the interaction between PFTs and ecosystem processes are still to be identified.

Here, we assess the link between PFTs and dominant microbial consumers along a calcareous poor to extremely rich fen gradient in western Poland. We particularly focussed on dominant microbial consumers (testate amoebae), which can exert large effects on the functioning of peatlands. Using moving‐window analyses and path‐relation networks subjected to structural equation modelling (SEM), we investigated linkages among abiotic factors, PFTs and testate amoebae.

We show that along the poor to extremely rich fen gradient, the dependence of testate amoebae to PFTs is higher than their dependence to abiotic factors. We also found that the link between testate amoebae and PFTs differs between size assemblages of testate amoebae. While large testate amoeba species (i.e. high trophic level) were highly linked to Sphagnum mosses cover, small species (i.e. low trophic level) were linked to brown mosses. Distinction between shallow‐rooted and deep‐rooted vascular plants also showed that shallow‐rooted plants play a role on testate amoeba community structure at the ‘poor’ side of the gradient.

Our results further show a dominant role for calcium content and the structure of the bryophyte community on testate amoeba size assemblages at the poor to extremely rich fen scale, both for diversity and abundance of testate amoebae.

Synthesis. Variations in plant functional type composition drive niche‐size‐structure of testate amoebae along the (calcareous) poor to extremely rich fen gradient. Furthermore, strong relationships between moss types and testate amoeba size‐structure suggest that mosses specifically influence testate amoeba development through autogenic effects. Therefore, moss cover composition is key to microbial consumers and may be the driving factor determining microbial network structure and associated ecosystem processes, such as carbon cycling.
Functional attributes of savanna soils: contrasting effects of tree canopies and herbivores on bulk density, nutrients and moisture dynamics
Authors: Holdo Ricardo M. , Mack Michelle C.
Published: June 2014

Savannas are highly heterogeneous tree‐grass mixtures, and the structural variation imposed by a discontinuous canopy cover results in spatial variation in soil properties such as plant‐available nutrients, temperature and soil moisture. Many savannas are also dominated by large vertebrate herbivores, which impose a different suite of effects on soil properties related to consumption, excretion and physical disturbance.

In nutrient‐poor, water‐limited systems, variation in soil resource availability may play a fundamental role in structuring plant communities, but the relative and interactive effects of key drivers of heterogeneity have received little attention in savanna ecosystems.

We investigated the independent and interactive effects of herbivores and tree canopy cover on multiple soil properties up to a depth of 10 cm, including bulk density, soil C pools, total and plant‐available nutrients, moisture dynamics and temperature at two contrasting sites in Kruger National Park, South Africa. We analysed samples from locations under and between adult tree canopies and inside and outside long‐term herbivore exclosures using a nested design.

We found strong positive effects of tree canopies on total and labile pools of soil C and N and negative effects on plant‐available P and soil temperature. Tree canopy effects on soil moisture availability were small but clearly detectable. During precipitation events, trees increased moisture inputs on granite soils but decreased moisture inputs on basalt soils compared to open sites.

Conversely, we found mixed evidence for herbivore effects on soil chemistry and temperature, but a clearer effect on soil moisture, with areas outside exclosures experiencing higher soil moisture retention, particularly immediately following precipitation events. Soil bulk density, a driver of both nutrient and soil moisture dynamics, was lower under trees and when herbivores were excluded.

Synthesis. Our results suggest that variation in tree cover is the dominant biotic driver of C, N and P dynamics in these savanna systems in the top 10 cm of soil, that herbivores primarily affect soil moisture content, and that canopy and herbivore effects tend to be additive rather than synergistic.
Bbmsn2 acts as a pH‐dependent negative regulator of secondary metabolite production in the entomopathogenic fungus Beauveria bassiana
Authors: Luo Zhibing , Li Yujie , Mousa Jarrod , Bruner Steven , Zhang Yongjun , Pei Yan , Keyhani Nemat O.
Published: June 2014

Fungal secondary metabolites are chemical compounds important for development, environmental adaptation and for potential biotechnological and pharmaceutical applications. Oosporein, a red‐pigmented benzoquinone, produced by many fungal insect pathogenic Beauveria spp., shows remarkable functional diversity, displaying antimicrobial, antiviral and even anti‐proliferative activities. A homologue of the msn2/seb1 transcription factor was identified in a Beauveria bassiana random T‐DNA insertion library. Targeted gene‐knockout of Bbmsn2 resulted in reduced growth and increased sensitivity to Calcofluor White, H2O2 and Congo Red. However, when normalized to growth at 26°C, the ΔBbmsn2 mutant was more tolerant to high temperature (32°C) than the wild type parent. The ΔBbmsn2 mutant also displayed a pH‐dependent growth phenotype, with little growth seen at pH < 5.0 but, better growth at alkaline conditions (pH > 8.0). Unexpectedly, a pH‐dependent deregulation of a red pigment, identified as oosporein, was seen in the ΔBbmsn2 mutant. The ΔBbmsn2 strain was impaired in virulence in both topical and intrahaemocoel injection bioassays against Galleria mellonella. ΔBbmsn2 proliferation in the host haemolymph and conidiation on the host cadaver was reduced. These data indicate that Bbmsn2 acts as a negative regulator of oosporein production and contributes to virulence and growth in response to external pH in B. bassiana.
External Validity of the ARISTOTLE Trial in Real‐Life Atrial Fibrillation Patients
Authors: Hägg Lovisa , Johansson Cecilia , Jansson Jan‐Håkan , Johansson Lars
Published: June 2014

Objective

Our primary objective was to determine the proportion of patients with atrial fibrillation (AF) eligible for enrollment in a randomized controlled trial for a novel oral anticoagulant, the ARISTOTLE trial. A secondary objective was to describe the reasons for trial ineligibility.

Methods

We performed a cross‐sectional study of an unselected population including 2274 patients in Skellefteå, Sweden with at least one verified episode of AF on or before December 31, 2010. Patients were classified as suitable or unsuitable for anticoagulant treatment according to current guidelines. The enrollment criteria from the ARISTOTLE trial were extracted from the original publication and applied to the population.

Results

Among all patients with AF, 1579 were classified as suitable for anticoagulant treatment. Of these, only 658 patients (42%) were eligible for participation in the ARISTOTLE trial. Among the 921 patients ineligible for participation, 498 did not meet the ECG criteria, 272 had psychosocial problems, and in addition, 78 patients were excluded due to both of these criteria.

Conclusion

Our study shows that a majority of the patients in an unselected population with AF suitable for anticoagulant treatment were ineligible for participation in the ARISTOTLE trial. The applicability of the ARISTOTLE trial is therefore unknown for a considerable proportion of patients with AF in real life.
Treatment of lupus nephritis: practical issues in Asian countries
Authors: Yap Desmond Y. H. , Chan Tak Mao
Published: June 2014

Lupus nephritis (LN) is a common and severe manifestation of systemic lupus erythematosus in Asian patients, and is an important cause of renal failure in Asian countries. Immunosuppressive treatments of LN have evolved over the past few decades and resulted in improvements in patient outcomes. Treatment guidelines have been recently published by rheumatology and nephrology communities in the USA and Europe, but the emphasis was more on patients of African or Hispanic descent and Caucasians. There is increasing evidence that racial and ethnic variations are associated with differences in disease manifestations, pharmacogenomics/kinetics, response to therapy and complications of disease or treatment. There is substantial data confirming the efficacy of combined corticosteroids and either cyclophosphamide or mycophenolate mofetil (MMF) as initial treatments for active Class III/IV LN in Asian patients. Azathioprine, MMF or a calcineurin inhibitor, or possibly mizoribine which requires further investigation in non‐Japanese patients, in combination with low‐dose corticosteroids, can be considered as maintenance immunosuppression to prevent disease flares, and the optimal choice needs to take into account tolerability and prior induction therapy. Treatment costs and accessibility to specialist healthcare facilities, compliance which in turn is related to socio‐economic and education status, as well as regional variations in risk of infections, including subacute infection such as tuberculosis or chronic infections such as hepatitis B or C, are issues that are distinctly pertinent in Asia.
Economic burden of inadequate management of allergic diseases in the European Union: a GA2LEN review
Authors: Zuberbier T. , Lötvall J. , Simoens S. , Subramanian S. V. , Church M. K.
Published: June 2014

Background

In the European Union (EU), between 44 and 76 million individuals of the 217 million EU employees suffer from allergic disease of the airways or the skin. Up to 90% of these persons are untreated or insufficiently treated. This has major socio‐economic consequences such as absence from work (absenteeism), particularly reduced productivity at work (presenteeism).

Methods

We used published literature and online statistical information from Eurostat and Eurofound to assess the costs of allergic disease to society.

Results

Allergies have an impact on direct, indirect, intangible and opportunity costs. Most importantly, for the EU, avoidable indirect costs per patient insufficiently treated for allergy range between €55 and €151 billion per annum due to absenteeism and presenteeism, that is, €2405 per untreated patient per year. On the other hand, appropriate therapy for allergic diseases is available at comparatively low costs at an average of €125 per patient annually, equalling only 5% of the costs of untreated disease, allowing potential savings of up to €142 billion.

Conclusions

A better care for allergies based on guideline‐based treatment would allow Europe's economy substantial savings. In addition, allergies have an impact on learning and performance at school and university, leading to opportunity costs for society. This cannot be calculated moneywise but will have an impact in a modern knowledge‐based society. Still allergies are trivialized in society, noting that the costs of therapy are paid by patients and healthcare services, whereas economic savings are made by employers and society. A change of this mindset is urgently needed.
Comparison of macular GCIPL and peripapillary RNFL deviation maps for detection of glaucomatous eye with localized RNFL defect
Authors: Kim Mi Jeung , Park Ki Ho , Yoo Beong Wook , Jeoung Jin Wook , Kim Hee Chan , Kim Dong Myung
Published: June 2014

Purpose

To evaluate the ability of the deviation map of macular ganglion cell–inner plexiform layer (GCIPL) thickness compared with that of peripapillary retinal nerve fibre layer (pRNFL) thickness for detection of localized RNFL defects shown on red‐free RNFL photography.

Methods

This prospective cross‐sectional study included 69 eyes of 69 subjects with preperimetric or perimetric glaucoma (mean deviation (MD) >−12dB) and localized RNFL defects along with 79 eyes of 79 normal control subjects. The number of abnormal superpixels on the both macular GCIPL and pRNFL deviation maps by Cirrus OCT corresponding to localized RNFL defects was calculated using a customized Matlab program and presented as severity indices according to each of the probability levels. The areas under the receiver operating characteristic curves (AUROCs) of the severity indices were compared between the two deviation maps.

Results

According to three criteria and corresponding probability levels, the AUROCs of the GCIPL and pRNFL deviation maps ranged from 0.910 to 0.931 and 0.934 to 0.950, respectively. However, the differences were not statistically significant (all p > 0.05). Significant correlations were observed between the severity indices of the GCIPL deviation map and those of the pRNFL deviation map, regardless of the criteria (all p < 0.0001).

Conclusions

In the detection of glaucomatous eyes with localized RNFL defects, the macular GCIPL thickness deviation map showed a level of diagnostic performance comparable to that of the pRNFL thickness deviation map.
Genetic parameters of postnatal mortality and birth weight in Japanese Black calves
Authors: Ibi Takayuki , Kahi Alexander K. , Hirooka Hiroyuki
Published: June 2014

Postnatal mortality (PM) of calves is an economically important trait, because a high mortality rate of calves decreases farm income and significantly increases production costs. In spite of the economic importance of PM, genetic studies on PM have been scarce for Japanese Black cattle. The objectives of this study were to estimate the direct and maternal heritability for PM using a Bayesian threshold model with Gibbs sampling in Japanese Black cattle. The original data consisted of 43 723 records of animals born from January 2005 to June 2006. Four binary traits of mortality were considered: D1‐14, D15‐60, D61‐180 and D1‐180 with numbers indicating the period of risk in days after birth. Direct heritabilities for PM ranged from 0.12 to 0.31 and maternal heritabilities for PM were lower than the direct heritabilities and ranged from 0.02 to 0.16. Direct genetic correlations between D1‐14 and D15‐60, between D15‐60 and D61‐180, and between D1‐14 and D61‐180 were 0.501, 0.689 and 0.062, respectively. Direct genetic correlations of birth weight with D1‐14, D15‐60, D61‐180 and D1‐180 were 0.089, 0.482, 0.434 and 0.394, respectively. These results indicated that different genes were responsible for early and late PM and early PM (D1‐14) can be genetically reduced without influencing birth weight.
Milk as a diagnostic sample for a commercially available ELISA to identify bovine viral diarrhoea (BVD) antibodies in dairy herds
Authors: Lanyon SR , McCoy R , Bergman E , Reichel MP
Published: June 2014

Objective

The aims of this study were to evaluate a commercially available ELISA for the detection of bovine viral diarrhoea virus (BVDV)‐specific antibodies in individual milk compared with individual serum samples, and in bulk milk samples compared with within‐herd antibody prevalence and bulk milk quantitative reverse transcription polymerase chain reaction (qRT‐PCR) results.

Methods

Paired individual serum and individual milk samples were collected from 125 lactating cows and tested by ELISA; 96 bulk milk samples were also tested. Within‐herd antibody prevalence was calculated based on milk ELISA results for 25 individual cows in each herd. Additionally, 167 bulk milk samples were tested for BVDV‐specific antibodies by ELISA and for the presence of BVDV by qRT‐PCR to establish the correlation between antibody result and virus presence.

Results

Good agreement was observed between individual milk and serum results (Kappa = 0.865). The ELISA was observed to detect BVDV‐specific antibodies in individual milk samples with a relative sensitivity of 96.6% and specificity of 89.2%. The bulk milk samples revealed a strong (r2 = 0.95) relationship between the ELISA result and the within‐herd antibody prevalence. The proportion of herds that tested positive by bulk milk qRT‐PCR increased as the bulk milk antibody S/P ratio increased.

Conclusion

Commercially available ELISA testing of individual and bulk milk samples is an appropriate alternative to serum testing with good test performance in these samples. Determining a threshold for the detection of herds containing active BVD infection by testing bulk milk is a novel use for an antibody ELISA kit and provides more practical, relevant test results.
Acquired urethral obstruction in New World camelids: 34 cases (1995–2008)
Authors: Duesterdieck‐Zellmer KF , Van Metre DC , Cardenas A , Cebra CK
Published: June 2014

Objective

Document the clinical features, short‐ and long‐term outcomes and prognostic factors in New World camelids with acquired urethral obstruction.

Design

Retrospective case study.

Methods

Case data from medical records of 34 New World camelids presenting with acquired urethral obstruction were collected and follow‐up information on discharged patients was obtained. Associations with short‐ and long‐term survival were evaluated using Wilcoxon rank‐sum tests, exact‐logistic regressions and Kaplan‐Meier survival curves.

Results

Of the 34 New World camelids 23 were intact males and 11 were castrated; 4 animals were euthanased upon presentation, 7 were treated medically and 23 surgically, including urethrotomy, bladder marsupialisation, tube cystostomy alone or combined with urethrotomy, urethrostomy or penile reefing. Necrosis of the distal penis was found in 4 animals and all were short‐term non‐survivors. Short‐term survival for surgical cases was 65%, and 57% for medical cases. Incomplete urethral obstruction at admission and surgical treatment were associated with increased odds of short‐term survival. Of 14 records available for long‐term follow‐up, 6 animals were alive and 8 were dead (median follow‐up 4.5 years, median survival time 2.5 years). Recurrence of urethral obstruction was associated with long‐term non‐survival.

Conclusions

Surgically treated New World camelids with incomplete urethral obstruction have the best odds of short‐term survival and those with recurrence of urethral obstruction have a poor prognosis for long‐term survival.
Inhibition of UVB‐Induced Skin Damage by Exopolymers from Aureobasidium pullulans SM‐2001 in Hairless Mice
Authors: Kim Kyung Hu , Park Soo Jin , Lee Young Joon , Lee Ji Eun , Song Chang Hyun , Choi Seong Hun , Ku Sae Kwang , Kang Su Jin
Published: June 2014

Because antioxidants from natural sources may be an effective approach to the treatment and prevention of UV radiation‐induced skin damage, the effects of purified exopolymers from Aureobasidium pullulans SM‐2001 (‘E‐AP‐SM2001’) were evaluated in UVB‐induced hairless mice. E‐AP‐SM2001 consists of 1.7% β‐1,3/1,6‐glucan, fibrous polysaccharides and other organic materials, such as amino acids, and mono‐ and di‐unsaturated fatty acids (linoleic and linolenic acids) and shows anti‐osteoporotic and immunomodulatory effects, through antioxidant and anti‐inflammatory mechanisms. Hairless mice were treated topically with vehicle, E‐AP‐SM2001 stock and two and four times diluted solutions once per day for 15 weeks against UVB irradiation (three times per week at 0.18 J/cm2). The following parameters were evaluated in skin samples: myeloperoxidase (MPO) activity, cytokine levels [interleukin (IL)‐1β and IL‐10], endogenous antioxidant content (glutathione, GSH), malondialdehyde (MDA) levels, superoxide anion production; matrix metalloproteases (MMP‐1, ‐9 and ‐13), GSH reductase and Nox2 (gp91phox) mRNA levels, and immunoreactivity for nitrotyrosine (NT), 4‐hydroxynonenal (HNE), caspase‐3, and cleaved poly(ADP‐ribose) polymerase (PARP). Photoageing was induced by UVB irradiation through ROS‐mediated inflammation, which was related to the depletion of endogenous antioxidants, activation of MMPs and keratinocyte apoptosis. Topical treatment with all three doses of E‐AP‐SM2001 and 5 nm myricetin attenuated the UV‐induced depletion of GSH, activation of MMPs, production of IL‐1β, the decrease in IL‐10 and keratinocyte apoptosis. In this study, E‐AP‐SM2001 showed potent inhibitory effects against UVB‐induced skin photoageing. Thus, E‐AP‐SM2001 may be useful as a functional ingredient in cosmetics, especially as a protective agent against UVB‐induced skin photoageing.
Oseltamivir Blocks Human Neuronal Nicotinic Acetylcholine Receptor‐Mediated Currents
Authors: Muraki Katsuhiko , Hatano Noriyuki , Suzuki Hiroka , Muraki Yukiko , Iwajima Yui , Maeda Yasuhiro , Ono Hideki
Published: June 2014

The effects of oseltamivir, a neuraminidase inhibitor, were tested on the function of neuronal nicotinic acetylcholine receptors (nAChRs) in a neuroblastoma cell line IMR32 derived from human peripheral neurons and on recombinant human α3β4 nAChRs expressed in HEK cells. IMR32 cells predominately express α3β4 nAChRs. Nicotine (nic, 30 μm)‐evoked currents recorded at −90 mV in IMR32 cells using the whole‐cell patch clamp technique were reversibly blocked by oseltamivir in a concentration‐dependent manner. In contrast, an active metabolite of oseltamivir, oseltamivir carboxylate (OC) at 30 μm had little effect on the nic‐evoked currents. Oseltamivir also blocked nic‐evoked currents derived from HEK cells with recombinant α3β4 nAChRs. This blockade was voltage‐dependent with 10, 30 and 100 μm oseltamivir inhibiting ~50% at −100, −60 and −40 mV, respectively. Non‐inactivating currents in IMR32 cells and in HEK cells with α3β4 nAChRs, which were evoked by an endogenous nicotinic agonist, ACh (5 μm), were reversibly blocked by oseltamivir. These data demonstrate that oseltamivir blocks nAChRs, presumably via binding to a site in the channel pore.
Decision making in compromise situations: guidelines based onJ.S.Mill's doctrine of political half‐measures
Authors: Cejudo Rafael
Published: June 2014

The purpose of this article is to offer guidelines to deal with hard choices, specifically in situations where some compromise among opposing values is inescapable. The guidelines are intended to help ethicists and practitioners to delineate different alternatives and to dismiss some of them as morally unacceptable. This article explores the view that compromises arise from negotiations but from ethical predicaments as well. For this reason,Idistinguish betweenstrategicandmoralcompromises. Both managers and employees are individual moral agents who have to confront the possibility ofunpalatableand even disgusting compromises, so that they are forced to put their integrity into risk in certaincompromise situations. However,Ishall argue for the possibility ofpalatablemoral compromises. The guidelines to cope with those situations and to identify the unpalatable compromises are based onJ.S.Mill's moral philosophy. Mill suggested thathalf‐measurespassed inParliament must have certain key elements to be morally acceptable.Imake use of this doctrine to put forward compromise guidelines in the form of a set of hallmarks, internal and external elements of palatable compromises. Two minicases are used to test the guidelines and to emphasize the importance of compromises for ethical decision making and commitment to company.
A tangled web: views of deception from the customer's perspective
Authors: Gillespie Erin Adamson , Hybnerova Katie , Esmark Carol , Noble Stephanie M.
Published: June 2014

While there has been extensive research on deception, extant literature has not examined how deception is processed solely from the customer's perspective. Extensive qualitative interviews were conducted and analyzed to inform the proposed framework. Cognitive dissonance theory and attribution theory are used to frame the process consumers go through when deception is perceived. When consumers perceive deceit, they will consider attribution before determining intentionality. Internal attributions relieve the company of wrongdoing to some extent, whereas external attributions lead consumers to examine several elements of deception including intent. Unintentional deceit will trigger assessments of magnitude, stability, and switching costs; while less is considered when deceit is intentional. The findings of this research are important for advancing theory in relation to deceit and for helping practitioners understand the importance of changing consumer cognitions before consumers decide to change their behavior by discontinuing the relationship.
Unimodal regression using Bernstein–Schoenberg splines and penalties
Authors: Köllmann Claudia , Bornkamp Björn , Ickstadt Katja
Published: June 2014

Research in the field of nonparametric shape constrained regression has been intensive. However, only few publications explicitly deal with unimodality although there is need for such methods in applications, for example, in dose–response analysis. In this article, we propose unimodal spline regression methods that make use of Bernstein–Schoenberg splines and their shape preservation property. To achieve unimodal and smooth solutions we use penalized splines, and extend the penalized spline approach toward penalizing against general parametric functions, instead of using just difference penalties. For tuning parameter selection under a unimodality constraint a restricted maximum likelihood and an alternative Bayesian approach for unimodal regression are developed. We compare the proposed methodologies to other common approaches in a simulation study and apply it to a dose–response data set. All results suggest that the unimodality constraint or the combination of unimodality and a penalty can substantially improve estimation of the functional relationship.
Histopathological features and their prognostic impact in nodular lymphocyte‐predominant Hodgkin lymphoma – a matched pair analysis from the German Hodgkin Study Group (GHSG)
Authors: Hartmann Sylvia , Eichenauer Dennis A. , Plütschow Annette , Mottok Anja , Bob Roshanak , Koch Karoline , Bernd Heinz‐Wolfram , Cogliatti Sergio , Hummel Michael , Feller Alfred C. , Ott German , Möller Peter , Rosenwald Andreas , Stein Harald , Hansmann Martin‐Leo , Engert Andreas , Klapper Wolfram
Published: June 2014

Nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity. We performed a matched‐pair analysis to evaluate the prognostic impact of several histopathological features in this distinct Hodgkin lymphoma subtype. Lymph node samples of NLPHL patients were tested for CD15, IgD, phosphorylated STAT6, ICOS and Epstein–Barr virus status of the malignant lymphocyte‐predominant cells as well as epithelioid cell clusters and activated T cells in the microenvironment. None of these features was associated with a particular clinical outcome. However, patients presenting with epithelioid cell clusters showed a non‐significant trend towards a lower relapse rate, justifying further evaluation of this marker.
Mind attributions about moral actors: Intentionality is greater given coherent cues
Authors: Hughes Jamie S. , Trafimow David
Published: June 2014

Attributions about intentionality and the capacity for agency were explored from coherence perspectives. Coherence perspectives suggest that social perceivers use information about an actor's motives, traits, and the outcomes of action to create meaningful explanations of action. According to the typecasting theory, intentionality and agency attributions should be related and predicted by one's role in a moral dyad. Across four studies, with different operational definitions of moral dyads and agency, we found evidence in favour of coherence perspectives. Social perceivers relied on mental states, character, and behavioural cues to make intentionality judgments. Further, intentionality attributions about behaviours were unrelated to inferences about agency. The discussion centres on the importance of coherent explanation in moral judgment.
Engagement of Toll-like receptor 2 enhances interleukin (IL)-17+ autoreactive T cell responses via p38 mitogen-activated protein kinase signalling in dendritic cells
Authors: Wei R , Dong L , Xiao Q , Sun D , Li X , Nian H
Published: June 2014

Functional analysis of single Toll-like receptors (TLRs) in vivo is necessary to understand how they shape the ocular inflammation involved in uveitis. In this study we explored the role and mechanisms of TLR-2 agonists on the autoreactive T helper type 17 (Th17) response in experimental autoimmune uveitis (EAU). Treatment by peptidoglycan (PGN), a specific TLR-2 agonist, remarkably increased mRNA levels of Th17-lineage genes interleukin (IL)-17A, IL-21 and RAR-related orphan receptor (ROR)γt and promoted antigen-specific Th17 response in EAU mice. A mixture of PGN and interphotoreceptor retinoid-binding protein peptide (IRBP161–180) could effectively induce EAU in the absence of complete Freund's adjuvant (CFA). PGN treatment also enhanced the pathogenic activities of activated antigen-specific Th17 cells in vivo. PGN significantly increased the production of IL-1β, IL-6 and IL-23 of dendritic cells (DCs) and enhanced their ability to promote IL-17+ uveitogenic T cells. Enhanced immunostimulatory activities of PGN-DCs depend upon p38 activation. Inhibition of p38 mitogen-activated protein kinase (MAPK) activity dramatically decreased IL-17 gene expression and antigen-specific Th17 responses stimulated by PGN-DCs. Our findings suggest that PGN treatment dramatically promotes the IL-17+ uveitogenic T cell responses via enhancing the immunostimulatory activities of DCs. This effect may be mediated, at least in part, by activation of the p38 signalling pathway in DCs.
MEFV gene polymorphisms and TNFRSF1A mutation in patients with inflammatory myopathy with abundant macrophages
Authors: Fujikawa K , Migita K , Shigemitsu Y , Umeda M , Nonaka F , Tamai M , Nakamura H , Mizokami A , Tsukada T , Origuchi T , Yonemitsu N , Yasunami M , Kawakami A , Eguchi K
Published: June 2014

Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinical condition. Although IMAM shares certain similarities with other inflammatory myopathies, the mechanisms responsible for this condition remain unknown. Patients with familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) also often develop myalgia. We therefore investigated the polymorphisms or mutations of MEFV and TNFRSF1A genes in patients with IMAM to identify their potential role in this condition. We analysed the clinical features of nine patients with IMAM and sequenced exons of the MEFV and TNFRSF1A genes. The patients with IMAM had clinical symptoms such as myalgia, muscle weakness, erythema, fever and arthralgia. Although none of the patients were diagnosed with FMF or TRAPS, seven demonstrated MEFV polymorphisms (G304R, R202R, E148Q, E148Q-L110P and P369S-R408Q), and one demonstrated a TNFRSF1A mutation (C43R). These results suggest that MEFV gene polymorphisms and TNFRSF1A mutation are susceptibility and modifier genes in IMAM.
Fingolimod ameliorates axonal damage in experimental autoimmune encephalomyelitis
Authors: Jin Shijie , Takeuchi Hideyuki , Horiuchi Hiroshi , Wang Yue , Kawanokuchi Jun , Mizuno Tetsuya , Suzumura Akio
Published: June 2014

Objectives

Fingolimod (FTY) is a new oral drug for multiple sclerosis. It acts as a functional antagonist for sphingosine 1‐phosphate receptor (S1PR). After phosphorylateion by sphingosine kinase in vivo, FTY binds to S1PR on lymphocytes to downregulate S1PR, thereby preventing lymphocyte egress from lymphoid tissues to reduce infiltration of autoreactive lymphocytes into the central nervous system. FTY easily passes through the blood–brain barrier and directly affects cells in the central nervous system. Recently, we have shown that FTY exerts neuroprotective effects by suppressing pro‐inflammatory functions of glial cells and by upregulating neuroprotective functions of neuronal and glial cells in vitro. In the present study, we examined whether FTY exerts neuroprotective effects in vivo in the chronic phase of experimental autoimmune encephalomyelitis (EAE).

Methods

Myelin oligodendrocyte glycoprotein‐induced EAE mice were orally treated with FTY (1 mg/kg/day) or vehicle (water) once a day starting at the disease peak (15 days after immunization). To evaluate gliosis and axonal damage, the lumbar spinal cords were examined immunohistochemically at 28 days after immunization.

Results

FTY treatment starting at disease peak improved the severity of symptoms, and reduced gliosis and axonal damage in the spinal cord, as assessed by glial staining and formation of neuritic bead/spheroid.

Conclusions

FTY exerts protective effects on axonal impairments during the chronic phase of EAE. The neuroprotective effect of FTY could synergistically suppress pathology of multiple sclerosis with its immunosuppressive effect.
Variational Tree Synthesis
Authors: Wang Rui , Yang Yinhui , Zhang Hongxin , Bao Hujun
Published: June 2014

Modelling trees according to desired shapes is important for many applications. Despite numerous methods having been proposed in tree modelling, it is still a non‐trivial task and challenging. In this paper, we present a new variational computing approach for generating realistic trees in specific shapes. Instead of directly modelling trees from symbolic rules, we formulate the tree modelling as an optimization process, in which a variational cost function is iteratively minimized. This cost function measures the difference between the guidance shape and the target tree crown. In addition, to faithfully capture the branch structure of trees, several botanical factors, including the minimum total branches volume and spatial branches patterns, are considered in the optimization to guide the tree modelling process. We demonstrate that our approach is applicable to generate trees with different shapes, from interactive design and complex polygonal meshes.
In silico analysis and experimental validation of azelastine hydrochloride (N4) targeting sodium taurocholate co‐transporting polypeptide (NTCP) in HBV therapy
Authors: Fu L.‐L. , Liu J. , Chen Y , Wang F.‐T. , Wen X. , Liu H.‐Q. , Wang M.‐Y. , Ouyang L. , Huang J. , Bao J.‐K. , Wei Y.‐Q.
Published: June 2014

Objectives

The aim of this study was to explore sodium taurocholate co‐transporting polypeptide (NTCP) exerting its function with hepatitis B virus (HBV) and its targeted candidate compounds, in HBV therapy.

Materials and methods

Identification of NTCP as a novel HBV target for screening candidate small molecules, was used by phylogenetic analysis, network construction, molecular modelling, molecular docking and molecular dynamics (MD) simulation. In vitro virological examination, q‐PCR, western blotting and cytotoxicity studies were used for validating efficacy of the candidate compound.

Results

We used the phylogenetic analysis of NTCP and constructed its protein–protein network. Also, we screened compounds from Drugbank and ZINC, among which five were validated for their authentication in HepG 2.2.15 cells. Then, we selected compound N4 (azelastine hydrochloride) as the most potent of them. This showed good inhibitory activity against HBsAg (IC50 = 7.5 μm) and HBeAg (IC50 = 3.7 μm), as well as high SI value (SI = 4.68). Further MD simulation results supported good interaction between compound N4 and NTCP.

Conclusions

In silico analysis and experimental validation together demonstrated that compound N4 can target NTCP in HepG2.2.15 cells, which may shed light on exploring it as a potential anti‐HBV drug.