bluuebunny/crossref_metadata_2025 huggingface dataset:
Population Pharmacokinetic Modeling and Dosing Simulations of Nitrogen‐Scavenging Compounds: Disposition of Glycerol Phenylbutyrate and Sodium Phenylbutyrate in Adult and Pediatric Patients with Urea Cycle Disorders
Authors: Monteleone Jon P. R. , Mokhtarani M. , Diaz G. A. , Rhead W. , Lichter‐Konecki U. , Berry S. A. , LeMons C. , Dickinson K. , Coakley D. , Lee B. , Scharschmidt B. F.
Published: June 2013

Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data from four Phase II/III trials that collectively enrolled patients ages 2 months to 72 years. Dose simulations were performed with particular attention to phenylacetic acid (PAA), which has been associated with adverse events in non‐UCD populations. The final model described metabolite levels in plasma and urine for both drugs and was characterized by (a) partial presystemic metabolism of phenylbutyric acid (PBA) to PAA and/or PAGN, (b) slower PBA absorption and greater presystemic conversion with glycerol phenylbutyrate, (c) similar systemic disposition with saturable conversion of PAA to PAGN for both drugs, and (d) body surface area (BSA) as a significant covariate accounting for age‐related PK differences. Dose simulations demonstrated similar PAA exposure following mole‐equivalent PBA dosing of both drugs and greater PAA exposure in younger patients based on BSA.
The role of oxygen as a regulator of stem cell fate during fracture repair in TSP2‐null mice
Authors: Burke Darren , Dishowitz Michael , Sweetwyne Mariya , Miedel Emily , Hankenson Kurt D. , Kelly Daniel J.
Published: June 2013

It is often difficult to decouple the relative importance of different factors in regulating MSC differentiation. Genetically modified mice provide model systems whereby some variables can be manipulated while others are kept constant. Fracture repair in thrombospondin‐2 (TSP2)‐null mice is characterized by reduced endochondral ossification and enhanced intramembranous bone formation. The proposed mechanism for this shift in MSC fate is that increased vascular density and hence oxygen availability in TSP2‐null mice regulates differentiation. However, TSP2 is multifunctional and regulates other aspects of the regenerative cascade, such as MSC proliferation. The objective of this study is to use a previously developed computational model of tissue differentiation, in which substrate stiffness and oxygen tension regulate stem cell differentiation, to simulate potential mechanisms which may drive alterations in MSC fate in TSP2‐null mice. Four models (increased cell proliferation, increased numbers of MSCs in the marrow decreased cellular oxygen consumption, and an initially stiffer callus) were not predictive of experimental observations in TSP2‐null mice. In contrast, increasing the rate of angiogenic progression led to a prediction of greater intramembranous ossification, diminished endochondral ossification, and a reduced region of hypoxia in the fracture callus similar to that quantified experimentally by the immunohistochemical detection of pimonidazole adducts that develop with hypoxia. This study therefore provides further support for the hypothesis that oxygen availability during early fracture healing is a key regulator of MSC bipotential differentiation, and furthermore, it highlights the advantages of integrating computational models with genetically modified mouse studies for further elucidating mechanisms regulating stem cell fate. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1585–1596, 2013.
The Use of Goats Grazing to Restore Pastures Invaded by Shrubs and Avoid Desertification: A Preliminary Case Study in the Spanish Cantabrian Mountains
Authors: Álvarez‐Martínez Javier , Gómez‐Villar Amelia , Lasanta Teodoro
Published: June 2013

Spanish mountains have been affected by the expansion of shrubs and forests since the mid‐20th century. This secondary succession in vegetation has some positive effects, but also drawbacks, such as an increase in fire risk, loss of diversity in land use, a reduction in landscape and cultural value, less water available in river channels and reservoirs, constraints on livestock farming, a reduced number of local species and loss of biodiversity. This paper analyses the potential for grazing domestic goats to help control the spread of several species of shrubs such as the common broom (Cytisus scoparius), red raspberry (Rubus idaeus) and roses (Rosasp.) that are commonly found in degraded pastures in the Cantabrian Mountains of northern Spain. Using experimental plots, the effects of two levels of stocking density (4·5 and 9 goats ha−1y−1) are compared with other land management systems used in the region: burning, mechanical clearing and trimming. The combined use of goats with support from burning, clearing and trimming controls the spread of shrubs. The most efficient treatment was found with nine goats ha−1y−1. Goat grazing also changes the distribution of shrubs, transforming a dense and continuous coverage into separate clumps and thereby enabling livestock to graze more easily. Maintaining a mixed structure of shrubs and pastures is the best treatment due to the low population density of the Cantabrian Mountains, as this enhances the biodiversity, controls fire risk and enriches the landscape; it also allows extensive livestock grazing as a main economic resource. Copyright © 2013 John Wiley & Sons, Ltd.
Improved Waiting-List Outcomes in Argentina After the Adoption of a Model for End-Stage Liver Disease–Based Liver Allocation Policy
Authors: Cejas Nora Gabriela , Villamil Federico G. , Lendoire Javier C. , Tagliafichi Viviana , Lopez Arturo , Krogh Daniela Hansen , Soratti Carlos A. , Bisigniano Liliana
Published: June 2013

In July 2005, Argentina became the first country after the United States to introduce the Model for End-Stage Liver Disease (MELD) for organ allocation. In this study, we investigated waiting-list (WL) outcomes (n = 3272) and post–liver transplantation (LT) survival in 2 consecutive periods of 5 years before and after the implementation of a MELD-based allocation policy. Data were obtained from the database of the national institute for organ allocation in Argentina. After the adoption of the MELD system, there were significant reductions in WL mortality [28.5% versus 21.9%, P < 0.001, hazard ratio (HR) = 1.57, 95% confidence interval (CI) = 1.37-1.81] and total dropout rates (38.6% versus 29.1%, P < 0.001, HR = 1.31, 95% CI = 1.16-1.48) despite significantly less LT accessibility (57.4% versus 50.7%, P < 0.001, HR = 1.53, 95% CI = 1.39-1.68). The annual number of deaths per 1000 patient-years at risk decreased from 273 in 2005 to 173 in 2010, and the number of LT procedures per 1000 patient-years at risk decreased from 564 to 422. MELD and Model for End-Stage Liver Disease–Sodium scores were excellent predictors of 3-month WL mortality with c statistics of 0.828 and 0.857, respectively (P < 0.001). No difference was observed in 1-year posttransplant survival between the 2 periods (81.1% versus 81.3%). Although patients with a MELD score > 30 had lower posttransplant survival, the global accuracy of the score for predicting outcomes was poor, as indicated by a c statistic of only 0.523. Patients with granted MELD exceptions (158 for hepatocellular carcinoma and 52 for other reasons) had significantly higher access to LT (80.4%) in comparison with nonexception patients with equivalent listing priority (MELD score = 18-25; 54.6%, P < 0.001, HR = 0.49, 95% CI = 0.40-0.61). In conclusion, the adoption of the MELD model in Argentina has resulted in improved liver organ allocation without compromising posttransplant survival. Liver Transpl 19:711–720, 2013.. © 2013 AASLD.
Proteomic approaches to evaluate protein s‐nitrosylation in disease
Authors: López‐Sánchez Laura M. , López‐Pedrera Chary , Rodríguez‐Ariza Antonio
Published: June 2013

Many of nitric oxide (NO) actions are mediated through the coupling of a nitroso moiety to a reactive cysteine leading to the formation of a S‐nitrosothiol (SNO), a process known as S‐nitrosylation or S‐nitrosation. In many cases this reversible post‐translational modification is accompanied by altered protein function and aberrant S‐nitrosylation of proteins, caused by altered production of NO and/or impaired SNO homeostasis, has been repeatedly reported in a variety of pathophysiological settings. A growing number of studies are directed to the identification and characterization of those proteins that undergo S‐nitrosylation and the analysis of S‐nitrosoproteomes under pathological conditions is beginning to be reported. The study of these S‐nitrosoproteomes has been fueled by advances in proteomic technologies that are providing researchers with improved tools for exploring this post‐translational modification. Here we review novel refinements and improvements to these methods, and some recent studies of the S‐nitrosoproteome in disease. © 2013 Wiley Periodicals, Inc. Mass Spec Rev 33: 7–20, 2014.
Effectiveness, efficiency, duration, and costs of recruiting for an African American women's lifestyle physical activity program
Authors: Wilbur JoEllen , Buchholz Susan W. , Ingram Diana M. , Braun Lynne T. , Johnson Tricia J. , Fogg Louis , Miller Arlene M. , Volgman Annabelle S. , McDevitt Judith
Published: June 2013

In a 48‐week lifestyle physical activity controlled trial in African American women, we analyzed recruitment effectiveness, efficiency, duration, and costs. Social networking was the most effective approach for inviting women to the trial. Of the 609 who responded to invitations, 514 completed telephone screening; of these, 409 (80%) were found eligible. The health assessment screening was completed by 337 women; of these, 297 (88%) were found eligible. The mean number of days from completion of the telephone and health assessment screenings to beginning the intervention was 23.01, and the mean cost was $74.57 per person. Results suggest that provision of health assessment screening by study staff as part of recruitment is effective for minimizing attrition and also might be cost‐effective. © 2013 Wiley Periodicals, Inc. Res Nurs Health 36: 487–499, 2013.
Novel dominant β‐thalassemia: Hb Boston‐Kuwait [Codon 139/140(+T)]
Authors: Croteau Stacy E. , Luo Hong‐Yuan , Lehmann Leslie E. , Chui David H.K. , Neufeld Ellis J.
Published: June 2013

Dominant β‐thalassemias exhibit a hybrid phenotype of unstable hemoglobin and ineffective erythropoiesis. Most arise from heterozygous β‐globin gene mutations in exons 3 or 2 and present in adulthood as thalassemia intermedia. We report a novel, de novo β‐globin mutation presenting in a toddler with features of thalassemia major and chromaturia. Hemoglobin Boston–Kuwait is an elongated β‐chain variant (163 amino acids) that results from a frameshift mutation caused by a thymidine insertion in codons 139/140. Hematopoietic stem cell transplant provided a successful alternative therapy for this severe form of dominant β‐thalassemia. Pediatr Blood Cancer 2013;60:E131–E134. © 2013 Wiley Periodicals, Inc.
Crystal structures of ASK1‐inhibtor complexes provide a platform for structure‐based drug design
Authors: Singh Onkar , Shillings Anthony , Craggs Peter , Wall Ian , Rowland Paul , Skarzynski Tadeusz , Hobbs Clare I. , Hardwick Phil , Tanner Rob , Blunt Michelle , Witty David R. , Smith Kathrine J.
Published: June 2013

ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a ‘replacement‐soaking’ method that has enabled the high‐throughput X‐ray structure determination of ASK1/ligand complexes. Comparison of the X‐ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement‐soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.
The backreaction of anti-D3 branes on the Klebanov-Strassler geometry
Authors: Bena Iosif , Giecold Gregory , Graña Mariana , Halmagyi Nick , Massai Stefano
Published: June 2013

Abstract

We present the full numerical solution for the 15-dimensional space of linearized deformations of the Klebanov-Strassler background which preserve the SU(2) × SU(2) ×
$ {{\mathbb{Z}}_2} $
symmetries. We identify within this space the solution corresponding to anti-D3 branes, (modulo the presence of a certain “subleading” singularity in the infrared). All the 15 integration constants of this solution are fixed in terms of the number of anti-D3 branes, and the solution differs in the UV from the supersymmetric solution into which it is supposed to decay by a mode corresponding to a rescaling of the field theory coordinates. Deciding whether two solutions that differ in the UV by a rescaling mode are dual to the same theory is involved even for supersymmetric Klebanov-Strassler solutions, and we explain in detail some of the subtleties associated to this.
Actors and strategies in translating global conservation narratives to Vietnam: An agency perspective
Authors: Mukhtarov Farhad , Brock Andrea , Janssen Sanne , Guignier Armelle
Published: June 2013

With the increasing influence of New Public Management, such narratives as payments for ecosystem services and ecological networks are gaining global popularity in natural resource management. Promoted by transnational actors, these narratives have been introduced in Vietnam and have inspired a number of projects. The ensuing politics of multi-level governance triggered conflict and cooperation in adversarial policy process and deserve greater attention from environmental policy scholars. In this paper we advance a framework to analyze such processes from an agency perspective and contend that policy actors engage in three types of strategies in their policy work: (1) scale-based strategies of seeking support across governance scales; (2) meaning-based strategies of linking narratives to other concepts and discourses; and (3) context- based strategies of engaging with the policy context at multiple sites of governance. We illustrate these strategies with examples from the Ba Be and Na Hang protected areas in Vietnam.
Synthesis of a Thermostable Polymer-supported Strongly Basic Catalyst and its Catalytic Activity
Authors: Zan Huining , Hou Zhiai , Shi Rongfu , Wang Chunhong
Published: June 2013

A novel strongly basic polymer-supported catalyst with guanidine groups has been synthesized and its thermal stability has been investigated. To obtain a thermally stable, cross-linked structure, guanidine groups bound to a polystyrene matrix were allowed to react in a nucleophilic manner with p-xylylene dichloride. Compared with the conventional strongly basic anion-exchange resin 201, it possesses higher thermal stability when placed in deionized water at 95°C for 60 h. This was confirmed by thermogravimetric analysis. The excellent thermal stability can be attributed to the unique structure of guanidine and the cross-linking connection mode between this base and the polymeric matrix. The obtained resin was found to efficiently catalyze Knoevenagel condensation reactions with remarkably high yields. Furthermore, the catalytic efficiency of the resin was found to remain unaffected for seven cycles, whereas that of 201 resin was reduced by 25 % owing to degradation of the strongly basic groups.
Enhancement in Detection of Glucose Based on a Nickel Hexacyanoferrate–Reduced Graphene Oxide-modified Glassy Carbon Electrode
Authors: Lu Pan , Liu Suqin , Dai Gaopeng , Lei Yuting , Liang Ying
Published: June 2013

A new kind of electrode modified by depositing nickel hexacyanoferrate (NiHCF) and reduced graphene oxide (RGO) onto the surface of a glassy carbon electrode is proposed. Electrochemical property investigation demonstrated NiHCF nanoparticles formed on the surface of RGO retain their excellent electrochemical activity and the RGO can enhance the electron transfer between NiHCF nanoparticles and the glassy carbon electrode owing to the large surface of the RGO. The morphology of the NiHCF/RGO film was characterized by scanning electron microscopy. The electrochemical behaviour and electrocatalytic performance of the NiHCF/RGO glassy carbon electrode towards the oxidation of glucose were evaluated by cyclic voltammograms. Results showed that the NiHCF/RGO-modified electrode exhibits a pair of well-defined redox peaks. The linear range for the detection of glucose was 1.0 × 10–6 to 1.7 × 10–2 M and the detection limit was as low as 2.8 × 10–7 M based on a signal-to-noise ratio of 3. The as-made sensor was applied to determine glucose levels in human blood serum with satisfactory results. In addition, the effects of common interfering species, including ascorbic acid, uric acid, dopamine, and some carbohydrates are discussed in detail.
Joint analysis of expression profiles from multiple cancers improves the identification of microRNA–gene interactions
Authors: Chen Xiaowei , Slack Frank J. , Zhao Hongyu
Published: June 2013

Motivation: MicroRNAs (miRNAs) play a crucial role in tumorigenesis and development through their effects on target genes. The characterization of miRNA–gene interactions will lead to a better understanding of cancer mechanisms. Many computational methods have been developed to infer miRNA targets with/without expression data. Because expression datasets are in general limited in size, most existing methods concatenate datasets from multiple studies to form one aggregated dataset to increase sample size and power. However, such simple aggregation analysis results in identifying miRNA–gene interactions that are mostly common across datasets, whereas specific interactions may be missed by these methods. Recent releases of The Cancer Genome Atlas data provide paired expression profiling of miRNAs and genes in multiple tumors with sufficiently large sample size. To study both common and cancer-specific interactions, it is desirable to develop a method that can jointly analyze multiple cancers to study miRNA–gene interactions without combining all the data into one single dataset.

Results: We developed a novel statistical method to jointly analyze expression profiles from multiple cancers to identify miRNA–gene interactions that are both common across cancers and specific to certain cancers. The benefit of this joint analysis approach is demonstrated by both simulation studies and real data analysis of The Cancer Genome Atlas datasets. Compared with simple aggregate analysis or single sample analysis, our method can effectively use the shared information among different but related cancers to improve the identification of miRNA–gene interactions. Another useful property of our method is that it can estimate similarity among cancers through their shared miRNA–gene interactions.

Availability and implementation: The program, MCMG, implemented in R is available at http://bioinformatics.med.yale.edu/group/.

Contact:  hongyu.zhao@yale.edu
Single modification at position 14 of siRNA strand abolishes its gene‐silencing activity by decreasing both RISC loading and target degradation
Authors: Zheng Jie , Zhang Lei , Zhang Junbin , Wang Xiaoxia , Ye Keqiong , Xi Zhen , Du Quan , Liang Zicai
Published: June 2013

Normally siRNA has to be chemically stabilized in therapeutic applications. It is a challenge to obtain optimal stabilizing effects while maintaining full silencing activity due to a lack of understanding of how different chemical modifications would influence the efficacy of siRNA. In the current study, the effect of single 2‘‐sugar modifications was profiled across the length of the siRNA guide strand. This led to the surprising finding that a single 2‘‐OMe modification at position 14 of the siRNA guide strand substantially compromised its gene‐silencing activity in a manner that was independent of the nucleotide identity at this site or the sequence context around it. We found that modification at position 14 of the siRNA guide strand reduced its RNA‐induced silencing complex (RISC) loading tremendously, whereas the loading of the siRNA sense strand was only marginally affected. When comparing the silencing potency of 14th position‐modified siRNA (transfected at 16.7 nM) and native control (transfected at 1 nM) at equivalent Ago2 loading levels, the silencing potency of modified siRNA was much lower, even lower than the level of native siRNA transfected at 0.1 nM. These data indicated that modification at position 14 of the siRNA guide strand abolishes its gene‐silencing activity by decreasing both RISC loading and target degradation. Using a computational modeling approach, we demonstrated an intimate interaction between the 14th nucleotide of guide strand and the amino acid Q675 in the AGO protein, which is located in a highly conserved loop of PIWI domain. In addition to gaining insights into siRNA‐AGO interactions, this study of structure‐activity relationship further established a general principle for siRNA modification in siRNA drug development.— Zheng, J., Zhang, L., Zhang, J., Wang, X., Ye, K., Xi, Z., Du, Q., Liang, Z., Single modification at position 14 of siRNA strand abolishes its gene‐silencing activity by decreasing both RISC loading and target degradation. FASEBJ. 27, 4017‐4026 (2013). www.fasebj.org
Thermoanaerobaculum aquaticum gen. nov., sp. nov., the first cultivated member of Acidobacteria subdivision 23, isolated from a hot spring
Authors: Losey Nathaniel A. , Stevenson Bradley S. , Busse Hans-Jürgen , Damsté Jaap S. Sinninghe , Rijpstra W. Irene C. , Rudd Stephen , Lawson Paul A.
Published: June 2013

A novel bacterium was isolated from a freshwater hot spring, the Hale House Spring, located at Hot Springs National Park, Hot Springs, AR, USA. Cells of strain MP-01T stained Gram-negative, were rod-shaped, non-motile, strictly anaerobic and chemo-organotrophic and did not form spores. Growth occurred at 50–65 °C, with an optimum at 60 °C, at pH 6.0–8.0, with an optimum at pH 6.5–7.0, and at NaCl concentrations up to 0.5 % (w/v), with optimum growth in the absence of NaCl. Strain MP-01T was capable of fermentative growth on pyruvate or proteinaceous substrates as well as reducing Fe(III) and Mn(IV). Major fatty acids were iso-C15 : 0, iso-C16 : 0, anteiso-C17 : 0 and iso-C17 : 0. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine and the major isoprenoid quinone was MK-10. In the polyamine pattern, sym-homospermidine was the predominant compound. The DNA G+C content was 62.7 mol%. Analysis of the 16S rRNA gene sequence of the isolate indicated that strain MP-01T represents the first reported cultivated member of subdivision 23 of the

Acidobacteria

. It is proposed that strain MP-01T represents a novel genus and species, for which the name Thermoanaerobaculum aquaticum gen. nov., sp. nov. is proposed. The type strain of Thermoanaerobaculum aquaticum is MP-01T ( = DSM 24856T = JCM 18256T).
Coprobacter fastidiosus gen. nov., sp. nov., a novel member of the family

Porphyromonadaceae

isolated from infant faeces
Authors: Shkoporov Andrei N. , Khokhlova Ekaterina V. , Chaplin Andrei V. , Kafarskaia Lyudmila I. , Nikolin Alexei A. , Polyakov Vladimir Yu. , Shcherbakova Victoria A. , Chernaia Zoya A. , Efimov Boris A.
Published: June 2013

A novel obligately anaerobic, non-spore-forming, rod-shaped, non-motile Gram-reaction-negative bacterium was isolated from infant faeces. The strain, designated NSB1T, was able to grow on rich media at 30–37 °C, in the presence of up to 2 % (w/v) Oxgall and 2 % (w/v) NaCl. Cells of strain NSB1T produced catalase, but not urease and indole. Aesculin was not hydrolysed. The strain was able to utilize d-glucose, lactose, maltose, mannose and raffinose as electron donors. When grown on d-glucose, the main metabolic end products were propionic and acetic acids, with a minor product being succinic acid. The major cellular fatty acids, iso-C15 : 0 and anteiso-C15 : 0, were present at a 1 : 1 molar ratio. The major menaquinone was MK-11. The DNA G+C content was found to be 38.5 mol%. According to 16S rRNA gene sequence analysis strain NSB1T is a member of the family

Porphyromonadaceae

, phylum

Bacteroidetes

. The closest relatives of the strain were

Barnesiella viscericola

(88.2 % identity) and

Barnesiella intestinihominis

(87.4 % identity). On the basis of phenotypic and genotypic properties of strain NSB1T we conclude that this strain represent a novel species in a new genus within the family of

Porphyromonadaceae

for which the name Coprobacter fastidiosus gen. nov., sp. nov. is proposed. The type strain of the species is NSB1T ( = DSM 26242T, = VKM B-2743T).
Rhizobium

freirei sp. nov., a symbiont of Phaseolus vulgaris that is very effective at fixing nitrogen
Authors: Dall’Agnol Rebeca Fuzinatto , Ribeiro Renan Augusto , Ormeño-Orrillo Ernesto , Rogel Marco Antonio , Delamuta Jakeline Renata Marçon , Andrade Diva Souza , Martínez-Romero Esperanza , Hungria Mariangela
Published: June 2013

Common bean (Phaseolus vulgaris L.) can establish symbiotic associations with several

Rhizobium

species; however, the effectiveness of most strains at fixing nitrogen under field conditions is very low. PRF 81T is a very effective strain, usually referred to as

Rhizobium tropici

and used successfully in thousands of doses of commercial inoculants for the common bean crop in Brazil; it has shown high rates of nitrogen fixation in all areas representative of the crop in the country. Here, we present results that indicate that PRF 81T, although it belongs to the ‘

R. tropici

group’, which includes 10

Rhizobium

species,

R. tropici

,

R. leucaenae

,

R. lusitanum

,

R. multihospitium

,

R. miluonense

,

R. hainanense

,

R. calliandrae

,

R. mayense

,

R. jaguaris

and

R. rhizogenes

, represents a novel species. Several morpho-physiological traits differentiated PRF 81T from related species. Differences were also confirmed in the analysis of rep-PCR (sharing less than 45 % similarity with the other species), MLSA with recA, atpD and rpoB genes, and DNA–DNA hybridization. The novel species, for which we propose the name

Rhizobium

freirei sp. nov., is able to establish effective root nodule symbioses with Phaseolus vulgaris, Leucaena leucocephala, Leucaena esculenta, Crotalaria juncea and Macroptilium atropurpureum. The type strain is PRF 81T ( = CNPSo 122T = SEMIA 4080T = IPR-Pv81T = WDCM 440T).
Mice overexpressing type 1 adenylyl cyclase show enhanced spatial memory flexibility in the absence of intact synaptic long-term depression
Authors: Zhang Ming , Wang Hongbing
Published: June 2013

There is significant interest in understanding the contribution of intracellular signaling and synaptic substrates to memory flexibility, which involves new learning and suppression of obsolete memory. Here, we report that enhancement of Ca2+-stimulated cAMP signaling by overexpressing type 1 adenylyl cyclase (AC1) facilitated long-term potentiation (LTP) but impaired long-term depression (LTD) at the hippocampal Shaffer collateral-CA1 synapses. However, following the induction of LTP, low-frequency stimulation caused comparable synaptic depotentiation in both wild type and AC1 transgenic (AC1 TG) mice. Although previous studies have suggested the function of LTD in spatial memory flexibility, AC1 TG mice showed not only better initial learning in the Morris water maze, but also faster acquisition and increased ratio of new memory formation to old memory retention during the reversal platform training. In the memory extinction test, which requires suppression of old memory without involving the acquisition of the new platform information, AC1 TG and wild type mice showed comparable performance. Our results demonstrate new functions of Ca2+-stimulated AC1, and also suggest that certain aspects of hippocampus-dependent behavioral flexibility may not require intact LTD.
Cerebellar deep nuclei involvement in cognitive adaptation and automaticity
Authors: Callu Delphine , Lopez Joëlle , El Massioui Nicole
Published: June 2013

To determine the role of the interpositus nuclei of cerebellum in rule-based learning and optimization processes, we studied (1) successive transfers of an initially acquired response rule in a cross maze and (2) behavioral strategies in learning a simple response rule in a T maze in interpositus lesioned rats (neurotoxic or electrolytic lesions). Even though lesioned animals showed no impairment in learning the initial stimulus–response association, they had difficulties in transferring the acquired adapted response rule, and in optimizing their response strategy. These results add information on the role of interpositus nuclei in adaptation to environmental changes.
The response of plant diversity to grazing varies along an elevational gradient
Authors: Speed James D. M. , Austrheim Gunnar , Mysterud Atle
Published: June 2013

Species richness of plants generally decreases along elevational gradients or peaks at intermediate elevations. Land use including grazing by wild and domestic herbivores also affects plant communities and diversity, but how grazing affects plant diversity along elevational gradients is less clear.

Using a field experiment along an elevational gradient in Norway, we tested whether the impact of grazing on plant diversity interacts with elevation. Vascular plant communities were sampled following 10 years of experimental sheep grazing (decreased/ceased, maintained and increased densities of 0, 25 and 80 sheep km−2) and compared with pre‐experimental baseline data.

The impact of grazing on species richness (alpha diversity) was investigated at the species level, and temporal community variance was used to investigate community stability (temporal beta diversity). Spatial community variance (spatial beta diversity) at the enclosure level was used to test whether community homogenization differed between treatments.

Species richness and temporal stability varied between treatments and along the elevational gradient. Where grazing was ceased, species richness declined by up 3.7 species at low elevations and increased by up to 3.5 species at high elevations, whilst where grazing was maintained or increased, changes were less extreme along the elevational gradient.

Temporal stability of plant communities was highest at low elevations and lowest at high elevations where grazing was reduced. There were no clear differences in spatial homogenization between grazing treatments, although spatial species turnover increased in heathlands where grazing decreased.

Synthesis. This study shows that the effect of grazing on plant diversity varies with elevation, and grazing herbivores can thus directly affect elevational patterns of plant diversity. Grazing can buffer changes in plant communities and species richness, even in the face of other environmental drivers such as climatic warming.
Effects of nutrient enrichment on seagrass population dynamics: evidence and synthesis from the biomass–density relationships
Authors: Cabaço Susana , Apostolaki Eugenia T. , García‐Marín Patricia , Gruber Renee , Hernández Ignacio , Martínez‐Crego Begoña , Mascaró Oriol , Pérez Marta , Prathep Anchana , Robinson Cliff , Romero Javier , Schmidt Allison L. , Short Fred T. , van Tussenbroek Brigitta I. , Santos Rui
Published: June 2013

The available data from experimental and descriptive studies on seagrass biomass and density responses to nutrient enrichment were analysed to assess the intraspecific mechanisms operating within seagrass populations and whether biomass–density relationships can provide relevant metrics for monitoring seagrasses.

The response of shoot biomass and density to nutrient enrichment was dependent on the type of study; the short‐term positive response of biomass and density in experimental studies reveals context‐specific nutrient limitation of seagrasses. The long‐term negative response of descriptive studies probably results from ecosystem‐scale events related to nutrient enrichment such as increased turbidity, algal blooms, epiphyte loads and anoxia.

Most seagrass species analysed lie in the nonthinning part of the theoretical biomass–density curves. A simultaneous increase in biomass and decrease in density, evidence of self‐thinning, were only observed in 4 of 28 studies. The analysis of both the static and the dynamic biomass–density relationships revealed that the slopes increase under nutrient enrichment. Surprisingly, the species‐specific slopes (log B‐log D) were higher than one, revealing that the B/D ratio, that is, the average shoot biomass, increases with density in all seagrass species analysed. Nutrient enrichment further enhanced this effect as biomass–density slopes increased to even higher values. The main drivers behind the increasing biomass–density slopes under nutrient enrichment were the increase in shoot biomass at densities above a species‐specific threshold and/or its decrease below that threshold.

Synthesis. Contrasting short‐ and long‐term responses of both biomass and density of seagrasses to nutrient enrichment suggest that the former, positive ones result from nutrient limitation, whereas the later, negative ones are mediated by whole ecosystem responses. In general, shoot biomass of seagrasses increases with density, and nutrient enrichment enhances this effect. Experimental testing of facilitation processes related to clonal integration in seagrasses needs to be done to reveal whether they determine the low incidence of self‐thinning and the intriguing biomass–density relationships of seagrass species. The increasing slopes and decreasing intercepts of the species‐specific dynamic biomass–density relationships of seagrasses and the decreasing coefficients of variation of both biomass and density constitute relevant, easy‐to‐collect metrics that may be used in environmental monitoring.
Microbial survey of the mummies from the Capuchin Catacombs of Palermo, Italy: biodeterioration risk and contamination of the indoor air
Authors: Piñar Guadalupe , Piombino-Mascali Dario , Maixner Frank , Zink Albert , Sterflinger Katja
Published: June 2013

The Capuchin Catacombs of Palermo contain over 1800 preserved bodies dating from the 16th to 20th centuries AD and showing evidence of biodeterioration. An extensive microbiological and molecular investigation was recently performed. Samples were taken from skin, muscle, hair, bone, stuffing materials, clothes, and surrounding walls as well as from the indoor air. In this study, we witnessed that the different degradation phenomena observed on the variety of materials located at the Capuchin Catacombs of Palermo are biological in origin. Molecular techniques showed the dominance of halophilic species of the domains Bacteria and Archaea on the walls and – as a result of salt emanating from the walls – on the mummies themselves. Nevertheless, specialized microorganisms belonging to taxa well-known for their cellulolytic and proteolytic activities were detected on clothes and stuffing material, and on skin, muscle, hair, and bone, respectively. This specialized microbiota is threatening the conservation of the mummies themselves. Additionally, sequences related to the human skin microbiome and to some pathogenic Bacteria (order Clostridiales) and fungi (genus Phialosimplex) were identified on samples derived from the mummies. Furthermore, a phosphate-reducing fungus, Penicillium radicum, was detected on bone. Finally, the high concentration of airborne fungal spores is not conducive to the conservation of the human remains and is posing a potential health risk for visitors.
Iron status and developmental scores in 6‐year‐olds highlights ongoing need to tackle iron deficiency in infants
Authors: Thorisdottir Asa Vala , Gunnarsdottir Ingibjorg , Palsson Gestur I. , Gretarsson Sigurdur J. , Thorsdottir Inga
Published: June 2013

Aim

To investigate iron status and developmental scores at 6 years of age in a population with decreased prevalence of iron deficiency in infancy. Iron status at 6 years and tracking from 12 months were also studied.

Methods

Children (n = 143) born in Iceland in 2005 were followed up at the age of six. Motor and verbal development was assessed by a parental questionnaire, and iron status was assessed by Hb, MCV and serum ferritin (SF). Iron depletion was defined as SF <15 μg/L and deficiency as MCV <76 fL and SF <15 μg/L.

Results

Iron depletion was observed in 5.6% of 6‐year‐olds, and 1.4% were iron deficient. Self‐help (subset in motor development) differed by −4.14 (95% CI = −7.61, −0.67), between those iron depleted at 12 months (n = 6) and those nondepleted (n = 102), adjusted for maternal education. The combined motor developmental score seemed lower in iron depleted infants, although of borderline significance (p = 0.066). MCV concentration tracked from 12 months to 6 years (r = 0.31, p < 0.002), but Hb and SF did not.

Conclusion

Improved iron status at 12 months and 6 years has diminished the public health threat associated with iron depletion in the population studied, but iron depletion and development still associate weakly. Action to prevent iron depletion in infancy remains important.
Genetics of steroid‐resistant nephrotic syndrome: a review of mutation spectrum and suggested approach for genetic testing
Authors: Joshi S , Andersen R , Jespersen B , Rittig S
Published: June 2013

Identification of genes, associated mutations and genotype–phenotype correlations in steroid‐resistant nephrotic syndrome (SRNS) is being translated to clinical practice through genetic testing. This review provides an update on the genes and mutations associated with SRNS along with a suggested approach for genetic testing in patients with SRNS.

Conclusion

The number of indentified genes associated with SRNS is increasing along with our understanding of their impact on treatment response and risk of recurrence. A systematic approach to genetic testing in patients with SRNS might aid the physician in selecting appropriate treatment.
Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents
Authors: Chen Christine I. , Masih‐Khan Esther , Jiang Haiyan , Rabea Ahmed , Cserti‐Gazdewich Christine , Jimenez‐Zepeda Victor H. , Chu Chia‐Min , Kukreti Vishal , Trudel Suzanne , Tiedemann Rodger , Tsang Richard , Reece Donna E.
Published: June 2013

Involvement of the central nervous system (CNS) in multiple myeloma (MM) is a rare complication, with reported survival of <6 months. This report describes 37 MM patients with leptomeningeal and/or parenchymal brain involvement treated at our institution and identifies factors associated with long‐term survival. From January 1999 to December 2010, 37 patients with CNS MM were evaluated at our institution. Clinical characteristics, treatment and survival were retrospectively collected. CNS disease was present at MM diagnosis in 24% and at relapse in 76%. Plasma cell leukemia (40%) and skull plasmacytomas (65%) were common, suggesting haematological and contiguous spread. Intrathecal (IT) chemotherapy was used in 81%, cranial and/or spinal irradiation in 78%, and various systemic therapies [immunomodulatory agents (IMiDs) (51%), cisplatin‐based (DPACE; cisplatin, doxorubicin, cyclophosphamide, etoposide) (27%), bortezomib (19%), alkylators (11%), dexamethasone alone (8%), auto‐transplant (5%)]. Median survival from CNS disease was only 4·6 months [95% confidence interval (CI): 2·8–6·7]; however, nine patients had prolonged survival (median: 17·1 months, 95% CI: 13·2–67·4). In general, these long‐term survivors were treated with radiotherapy, multi‐dosing IT chemotherapy, and IMiD‐containing therapy. CNS MM is a highly aggressive disease but in our experience, long‐term survival can be achieved with the combination of multi‐dosing IT chemotherapy, radiation and IMiD‐based therapy.
Microbiological screening for earlier detection of central venous catheter–related bloodstream infections
Authors: Wagner Jasmin , Schilcher Gernot , Zollner‐Schwetz Ines , Hoenigl Martin , Valentin Thomas , Ribitsch Werner , Horina Joerg , Rosenkranz Alexander R. , Grisold Andrea , Unteregger Matthias , Troppan Katharina , Valentin Angelika , Neumeister Peter , Krause Robert
Published: June 2013

Background

Catheter‐related bloodstream infections (CRBSIs) are currently detected with a reactive diagnostic policy, that is, application of tests to patients with clinically suspected CRBSI. The aim of our study was to evaluate whether CRBSIs could be anticipated in an earlier stage by microbiological screening using peptide nucleic acid fluorescence in situ hybridization (PNA FISH) with universal hybridization probes or acridine‐orange leucocyte cytospin (AOLC) tests in haemodialysis and haematological patients with CVCs in situ compared with routine test.

Materials and methods

Peptide nucleic acid fluorescence in situ hybridization (PNA FISH) and AOLC tests using blood samples from both CVC lines in patients undergoing haemodialysis were performed three times a week and from one CVC line in haematological patients were performed daily. Results were compared with those obtained from routinely performed CRBSI diagnostic tests.

Results

One hundred fifteen patients with 139 catheter periods were investigated. The mean observation time per catheter period was 25 days (IQR 13·5–43·5), resulting in 5615 CVC days with a total of 4839 tested blood samples. Five CRBSI cases were detected by routine measures resulting in a CRBSI rate of 0·9/1000 catheter days. Four of five CRBSIs could be anticipated by positive PNA FISH and AOLC tests 2–8 days before the diagnosis was established with routine measures.

Conclusions

The proactive anticipative strategy using microscopic examination of CVC blood samples to anticipate CRBSI in an earlier stage compared with routine measures is a new diagnostic approach in patients with CVCs and a high risk of developing CRBSI.
A novel RT‐qPCR assay for quantification of the MLL‐MLLT3 fusion transcript in acute myeloid leukaemia
Authors: Abildgaard Lotte , Ommen Hans Beier , Lausen Birgitte , Hasle Henrik , Nyvold Charlotte Guldborg
Published: June 2013

Objectives

Patients with acute myeloid leukaemia (AML) of the monocytic lineage often lack molecular markers for minimal residual disease (MRD) monitoring. The MLL‐MLLT3 fusion transcript found in patients with AML harbouring t(9;11) is amenable to RT‐qPCR quantification but because of the heterogeneity of translocation break points, the MLL‐MLLT3 fusion gene is a challenging target. We hypothesised that MRD monitoring using MLL‐MLLT3 as a RT‐qPCR marker is feasible in the majority of patients with t(9;11)‐positive AML.

Methods

Using a locked nucleic acid probe, we developed a sensitive RT‐qPCR assay for quantification of the most common break point region of the MLL‐MLLT3 fusion gene. Five paediatric patients with t(9;11)‐positive AML were monitored using the MLL‐MLLT3 assay.

Results

A total of 43 bone marrow (BM) and 52 Peripheral blood (PB) samples were collected from diagnosis until follow‐up. Two patients relapsed, and both were MRD positive in BM after first induction course. A total of three relapses occurred, and they were detected by RT‐qPCR 3 wks before haematological relapse was diagnosed.

Conclusion

This MLL‐MLLT3 RT‐qPCR assay could be useful in MRD monitoring of a group of patients with AML who often lack reliable MRD markers.
The kinetic, mechanistic and cytomorphological effects of palytoxin in human intestinal cells (Caco‐2) explain its lower‐than‐parenteral oral toxicity
Authors: Fernández Diego A. , Louzao M. Carmen , Vilariño Natalia , Espiña Begoña , Fraga María , Vieytes Mercedes R. , Román Albina , Poli Mark , Botana Luis M.
Published: June 2013

Palytoxin is one of the most toxic marine toxins known. Distributed worldwide, it poses a potential human health risk linked to the consumption of contaminated seafood. Despite its high parenteral toxicity, the lethal oral dose of palytoxin is several times higher than the intraperitoneal lethal dose. In the present study, we investigated the passage of palytoxin through the human intestinal barrier by employing a well‐characterized and accepted in vitro model of intestinal permeability that uses differentiated Caco‐2 cell monolayers. Trans‐epithelial electric resistance measurements showed that palytoxin disrupts the integrity of Caco‐2 monolayers at concentrations > 0.135 nm. However, confocal microscopy imaging showed that the tight‐junction protein occludin was not affected by palytoxin in the nanomolar range. This finding was supported by transmission electron microscopy imaging, where tight‐junctions appeared to be unaffected by palytoxin treatment. In addition, the nuclear envelope does not appear to be altered by high concentrations of palytoxin. However, palytoxin‐treated cells showed electron‐dense and damaged mitochondria. Toxin exposure also induced the disappearance of the differentiated Caco‐2 microvilli and organelles, as well as chromatin de‐condensation. Permeability assays showed that palytoxin could not significantly pass the Caco‐2 monolayer, despite the lack of epithelium integrity, suggesting that palytoxins would be poorly transported to blood, which may explain its lower oral toxicity. These data can help to achieve a better understanding of palytoxin poisoning. However, more studies regarding its repeated administration and chronic effects are needed.
Adiponectin protects Leydig cells against proinflammatory cytokines by suppressing the nuclear factor‐κB signaling pathway
Authors: Wu Ling , Xu Bufang , Fan Weimin , Zhu Xiaobin , Wang Guangyan , Zhang Aijun
Published: June 2013

Adiponectin is an adipocyte hormone that is predominantly secreted by adipocytes, and has important roles in glucose and lipid homeostasis. Recent studies have shown that adiponectin is also involved in the regulation of many endocrine organs, such as the ovary, adrenal gland, and pituitary. However, its biological role in male testes is largely unexplored. The present findings demonstrate the presence of adeponectin receptors (adiponectin receptor 1 and adiponectin receptor 2) in TM3 cells derived from mouse Leydig cells. Proinflammatory cytokine treatment significantly downregulated mRNA and protein levels of adiponectin receptor 1 and adiponectin receptor 2. However, adiponectin pretreatment successfully inhibited the signaling pathway mediated by proinflammatory cytokines. At the molecular level, we provide compelling evidence that adeponectin achieves this by suppressing nuclear factor‐κB activation through promotion of AMP‐activated protein kinase phosphorylation. Thus, our data clearly indicate that adiponectin plays a protective role in Leydig cells through its anti‐inflammatory actions.