bluuebunny/crossref_metadata_2025 huggingface dataset:
Elastic analysis of 3D woven orthogonal composites
Authors: Mahmood Ansar , Wang Xinwei , Zhou Chuwei
Published: November 2011

Purpose

The purpose of this paper is to present an analytical modelling approach to predict engineering elastic constants of 3D woven orthogonal composites (3DWOCs) at representative volume element (RVE) level using a volume averaging method.

Design/methodology/approach

The present analytical modeling approach uses a more realistic internal geometry representation of the 3DWOC. A RVE which is a repeating element at macroscopic level is first identified and volume proportions and engineering elastic constants of various constituents (matrix and family of constituent tows; warp, weft and z‐fibers) which contribute to the global stiffness of RVE/composite are next determined. For accurate predictions, emphasis is given to accurate measurements of micro‐structural data such as fiber volume fraction and fiber volume proportion of constituent tows and internal geometry of the 3DWOC structure‐in particular, undulation of z‐fibers. Microscopic study has been conducted in this regard.

Findings

The predicted engineering elastic constants are compared against experimental data, showing a strong correlation between predicted and experimental values.

Practical implications

The methodology presented in the paper can be used for accurate computation of the engineering elastic constants of 3DWOCs. The method can also be used for other types of 2D or 3D textile composites such as 2D woven composites, 2D braided composites, 3D woven angle interlock composites and 3D braided composites.

Originality/value

The paper succeeds in relating the micro‐structural properties and analytical model for the accurate prediction of engineering elastic constants.
The optimal interval combination forecasting model based on closeness degree and IOWHA operator under the uncertain environment
Authors: Chen Huayou , Jin Lei , Li Xiang , Yao Mengjie
Published: November 2011

Purpose

The purpose of this paper is to propose the optimal combination forecasting model based on closeness degree and induced ordered weighted harmonic averaging (IOWHA) operator under the uncertain environment in which the raw data are provided by interval numbers.

Design/methodology/approach

Starting from maximizing the closeness degree of combination forecasting, which is different from minimizing absolute errors, weighted coefficient vectors of combination forecasting methods are obtained. The new concepts of closeness degree for the center and radius of interval numbers sequences are put forward and the optimal interval combination forecasting model is constructed by maximizing the sum of convex combination with closeness degree of interval center and closeness degree of interval radius. The solution to the model is discussed.

Findings

The results show that this model can improve the combination forecasting accuracy efficiently compared with that of each single forecasting method.

Practical implications

The method proposed in the paper can be used to forecast future tendency in a wide ranges of fields, such as engineering, economics and management. In particular, the raw data are provided in the form of interval numbers under the uncertain environment.

Originality/value

The combination forecasting model proposed in this paper is based on closeness degree and IOWHA operator, which is a new kind of combination forecasting model with variant weights.
Correlation of L‐type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis
Authors: Furuya Mio , Horiguchi Jun , Nakajima Hiroki , Kanai Yoshikatsu , Oyama Tetsunari
Published: November 2011

Triple negative breast cancer (TNBC) is a heterogeneous, aggressive cancer for which there is no effective chemotherapy or targeted therapy. We aimed to evaluate L‐type amino acid transporter (LAT) 1 and CD98 expression immunohistochemically in patients with breast cancer, especially TNBC. Out of 129 patients, LAT1 was positive in 56 patients (43.4%), and CD98 was positive in 41 patients (31.8%). The positive ratio of LAT1 expression in luminal A cases was 7.9%, 30.0% in luminal B cases, 71.4% in HER2 cases and 64.0% in TN cases. HER2 and TN subtypes expressed LAT1 and CD98 at higher levels than luminal A and B subtypes (both P < 0.001). LAT1 and CD98 expression correlated with tumor size (LAT1, P = 0.010; CD98, P = 0.007), nuclear grade (LAT1, P < 0.001; CD98, P < 0.001) and Ki67 labeling index (LAT1, P < 0.001; CD98, P = 0.001). LAT1 and CD98 expression was negatively associated with ER and PgR (both P < 0.001). In TNBC, the 5‐year disease‐free rate of CD98+ (63.6%) or LAT1+/CD98+ (61.9%) patients was significantly worse than that of CD98− (89.3%) patients or those with no co‐expression of LAT1 and CD98 (89.7%), respectively (P = 0.014, P = 0.009). The 5‐year survival rates of CD98 positive/negative patients were 77.3% and 100% (P = 0.050), respectively, whereas that of patients with LAT1+/CD98+ (76.2%) was significantly worse (100%) (P = 0.040). Multivariate analysis confirmed that CD98+ or LAT1+/CD98+ expression were risk factors for relapse in TNBC (P = 0.023, P = 0.019). Thus, in the present study we show that LAT1 and CD98 expression are prognostic factors. Inhibition of these proteins might provide a new therapeutic strategy in TNBC. (Cancer Sci 2012; 103: 382–389)
Current strategies in the diagnosis of diffuse large B‐cell lymphoma of the central nervous system
Authors: Baraniskin Alexander , Deckert Martina , Schulte‐Altedorneburg Gernot , Schlegel Uwe , Schroers Roland
Published: November 2011

Lymphomas can arise within the central nervous system (CNS) as primary CNS lymphoma (PCNSL) typically involving the brain and less often the leptomeninges, eyes, and spinal cord. In contrast to PCNSL, secondary CNS lymphoma (SCNSL) is considered to originate as quasi metastasis from systemic lymphoma spreading to the CNS. Both types of CNS lymphomas are predominantly tumours of the diffuse large B‐cell type and represent aggressive diseases necessitating a rapid diagnosis. Following neuroimaging based on magnetic resonance imaging, stereotaxy and histopathological diagnosis of CNS lymphoma currently remain obligatory to plan treatment. However, progress in cytopathological, immunophenotypic, and molecular genetic analyses of the cerebrospinal fluid (CSF) has been achieved recently and potentially will facilitate lymphoma diagnosis in the future. This review describes the diagnostic procedures in patients with suspected CNS lymphomas, primarily PCNSL. In addition to a summary of the standard diagnostic work‐up, an overview and discussion of current data on different techniques for evaluation of the CSF in CNS lymphoma are given.
Temperature and precipitation controls over leaf‐ and ecosystem‐level CO2 flux along a woody plant encroachment gradient
Authors: Barron‐Gafford Greg A. , Scott Russell L. , Jenerette G. Darrel , Hamerlynck Erik P. , Huxman Travis E.
Published: November 2011

Conversion of grasslands to woodlands may alter the sensitivity of CO2 exchange of individual plants and entire ecosystems to air temperature and precipitation. We combined leaf‐level gas exchange and ecosystem‐level eddy covariance measurements to quantify the effects of plant temperature sensitivity and ecosystem temperature responses within a grassland and mesquite woodland across seasonal precipitation periods. In so doing, we were able to estimate the role of moisture availability on ecosystem temperature sensitivity under large‐scale vegetative shifts. Optimum temperatures (Topt) for net photosynthetic assimilation (A) and net ecosystem productivity (NEP) were estimated from a function fitted to A and NEP plotted against air temperature. The convexities of these temperature responses were quantified by the range of temperatures over which a leaf or an ecosystem assimilated 50% of maximum NEP (Ω50). Under dry pre‐ and postmonsoon conditions, leaf‐level Ω50 in C3 shrubs were two‐to‐three times that of C4 grasses, but under moist monsoon conditions, leaf‐level Ω50 was similar between growth forms. At the ecosystems‐scale, grassland NEP was more sensitive to precipitation, as evidenced by a 104% increase in maximum NEP at monsoon onset, compared to a 57% increase in the woodland. Also, woodland NEP was greater across all temperatures experienced by both ecosystems in all seasons. By maintaining physiological function across a wider temperature range during water‐limited periods, woody plants assimilated larger amounts of carbon. This higher carbon‐assimilation capacity may have significant implications for ecosystem responses to projected climate change scenarios of higher temperatures and more variable precipitation, particularly as semiarid regions experience conversions from C4 grasses to C3 shrubs. As regional carbon models, CLM 4.0, are now able to incorporate functional type and photosynthetic pathway differences, this work highlights the need for a better integration of the interactive effects of growth form/functional type and photosynthetic pathway on water resource acquisition and temperature sensitivity.
A genome‐wide phylogenetic reconstruction of family 1 UDP‐glycosyltransferases revealed the expansion of the family during the adaptation of plants to life on land
Authors: Caputi Lorenzo , Malnoy Mickael , Goremykin Vadim , Nikiforova Svetlana , Martens Stefan
Published: November 2011

For almost a decade, our knowledge on the organisation of the family 1 UDP‐glycosyltransferases (UGTs) has been limited to the model plant A. thaliana. The availability of other plant genomes represents an opportunity to obtain a broader view of the family in terms of evolution and organisation. Family 1 UGTs are known to glycosylate several classes of plant secondary metabolites. A phylogeny reconstruction study was performed to get an insight into the evolution of this multigene family during the adaptation of plants to life on land. The organisation of the UGTs in the different organisms was also investigated. More than 1500 putative UGTs were identified in 12 fully sequenced and assembled plant genomes based on the highly conserved PSPG motif. Analyses by maximum likelihood (ML) method were performed to reconstruct the phylogenetic relationships existing between the sequences. The results of this study clearly show that the UGT family expanded during the transition from algae to vascular plants and that in higher plants the clustering of UGTs into phylogenetic groups appears to be conserved, although gene loss and gene gain events seem to have occurred in certain lineages. Interestingly, two new phylogenetic groups, named O and P, that are not present in A. thaliana were discovered.
An assessment of transgenomics as a tool for identifying genes involved in the evolutionary differentiation of closely related plant species
Authors: Correa Raul , Stanga John , Larget Bret , Roznowski Aaron , Shu Guoping , Dilkes Brian , Baum David A.
Published: November 2011

Transgenomics is the process of introducing genomic clones from a donor species into a recipient species and then screening the resultant transgenic lines for phenotypes of interest. This method might allow us to find genes involved in the evolution of phenotypic differences between species as well as genes that have the potential to contribute to reproductive isolation: potential speciation genes.

More than 1100 20‐kbp genomic clones from Leavenworthia alabamica were moved into Arabidopsis thaliana by transformation. After screening a single primary transformant for each line, clones associated with mutant phenotypes were tested for repeatability and co‐segregation.

We found 84 clones with possible phenotypic effects, of which eight were repeatedly associated with the same phenotype. One clone, 11_11B, co‐segregated with a short fruit phenotype. Further study showed that 11_11B affects seed development, with as much as one‐third of the seeds aborted in some fruit.

Transgenomics is a viable strategy for discovering genes of evolutionary interest. We identify methods to reduce false positives and false negatives in the future. 11_11B can be viewed as a potential speciation gene, illustrating the value of transgenomics for studying the molecular basis of reproductive isolation.
Short‐Lasting Unilateral Neuralgiform Headache With Autonomic Symptoms Syndrome as the Initial Manifestation of Idiopathic Hypertrophic Cranial Pachymeningitis
Authors: Chan Jane W.
Published: November 2011

This is the first report of 2 patients presenting with short‐lasting unilateral neuralgiform headache with autonomic symptoms as the initial manifestation of idiopathic hypertrophic cranial pachymeningitis. They both had acute retro‐orbital pain ipsilateral to the dural thickening on magnetic resonance imaging of brain, and one had transient miosis as an additional parasympathetic feature. Short‐lasting unilateral neuralgiform headache with autonomic symptoms syndrome may be associated with secondary central nervous system pathology, and neuroimaging should be considered in all patients with trigeminal autonomic cephalalgia.
Rizatriptan for Treatment of Acute Migraine in Patients Taking Topiramate for Migraine Prophylaxis
Authors: Seeburger Jeffrey L. , Cady Roger K. , Winner Paul , MacGregor Anne , Valade Dominique , Ge Yang , Zhang Ying , Hustad Carolyn M. , Strickler Nancy , Schaefer Eleanor , Connor Kathryn M. , Ho Tony W.
Published: November 2011

Objective.— To assess efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treatment of acute migraine in patients using topiramate for migraine prophylaxis.

Background.— There are limited data from prospective controlled trials demonstrating the benefit of triptans in patients who experience migraine attacks while taking prophylactic medication.

Methods.— This was a worldwide, randomized, placebo‐controlled, double‐blind, multiple‐attack study in adults with a >1‐year history of migraine taking a stable dose of topiramate for migraine prophylaxis and experiencing ≥2 moderate/severe attacks per month. Participants treated 3 moderate/severe attacks in crossover fashion (2 with rizatriptan 10‐mg ODT, 1 with placebo) following random assignment to 1 of 3 treatment sequences. The primary end point was 2‐hour pain relief.

Results.— Two‐hour pain relief was significantly greater with rizatriptan compared with placebo (55.0% vs 17.4%, P < .001). Response rates also favored rizatriptan for sustained pain relief from 2‐24 hours (32.6% vs 11.1%, P < .001), 2‐hour pain freedom (36.0% vs 6.5%, P < .001), normal functional ability at 2 hours (42.2% vs 12.7%, P < .001), and overall treatment satisfaction at 24 hours (60.8% vs 33.6%, P < .001). Few participants reported adverse experiences (16 [15.8%] with rizatriptan, 3 [3.2%] with placebo); none were serious.

Conclusion.— Rizatriptan 10‐mg ODT was superior to placebo at all pain end points for treatment of acute migraine in patients using topiramate for migraine prophylaxis. Rizatriptan was generally well tolerated in this population. These results are comparable with those from clinical trials in patients not using prophylaxis, suggesting that the use of topiramate does not affect the efficacy or tolerability of rizatriptan for acute migraine treatment.
Anarchy as a Model for Network Governance
Authors: Wachhaus T. Aaron
Published: November 2011

This article centers on two interconnected ideas that have garnered increasing attention in public administration: (1) a shift away from centralized institutional authority structures and (2) the concomitant rise of networks in the public sector. While network theories have been viewed as ushering in a new paradigm for understanding governance, they remain rooted in the language and framework of hierarchical bureaucratic systems. The author suggests that embracing an approach not grounded in a centralized institutional perspective may clarify network theories in public administration. Specifically, the author argues that anarchism has much to add to our understanding of networks and illustrates how an anarchist perspective may advance our understanding of networks in three areas—network formation, network stability, and accountability in networks—in which the hierarchical perspective has generated persistent questions.
Globalizing Public Administration: Today's Research and Tomorrow's Agenda
Authors: Gulrajani Nilima , Moloney Kim
Published: November 2011

What is the relationship between public administration scholarship and the study of developing countries? This article answers this question by presenting the intellectual history of administrative studies of the global South and by examining recent empirical studies of developing country administration. The results suggest that administrative research on the developing world published in leading international publications has become a small‐scale, disparate, descriptive, qualitative, and noncomparative subfield dominated by researchers from the global North. This empirical finding provides a platform to end a false North–South administrative dichotomy and advance a vision for public administration as a global social science.
A randomised controlled trial of the efficacy of supported employment
Authors: Hoffmann H. , Jäckel D. , Glauser S. , Kupper Z.
Published: November 2011

Hoffmann H, Jäckel D, Glauser S, Kupper Z. A randomised controlled trial of the efficacy of supported employment.

Objective:  Although numerous randomised controlled trials indicated the superiority of supported employment (SE), we still have too little evidence that SE is more effective than traditional vocational rehabilitation programmes (TVR) in Western European countries with highly developed social security and welfare systems, sophisticated rehabilitation programmes and high thresholds to the open labour market. The aim of this study is to prove the efficacy of SE in Switzerland.

Method:  Following a 2‐week intake assessment, 100 unemployed persons with stabilised severe mental illness (SMI) were randomly assigned to either the SE programme (n = 46) or to the most viable locally available TVR (n = 54). Follow‐up lasted 24 months.

Results:  After the first year, the rate of competitive employment reached a mean level of 48.2% in the SE group and of 18.5% in the TVR group. 58.7% of the SE group were ever competitively employed as opposed to 25.9% of the TVR group. In the second year, SE group participants were competitively employed for 24.5 weeks as compared with 10.2 in the TVR group. The groups showed no significant differences in the non‐vocational outcome criteria.

Conclusion:  The SE programme in Switzerland also proved more effective than TVR and seems to be applicable to the socio‐economic context of Western European countries.
Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry identification of Archaea: towards the universal identification of living organisms
Authors: DRIDI BÉDIS , RAOULT DIDIER , DRANCOURT MICHEL
Published: November 2011

Dridi B, Raoult D, Drancourt M. Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry identification of Archaea: towards the universal identification of living organisms. APMIS 2012; 120: 85–91.

Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF‐MS) identification of Archaea has been limited to some environmental extremophiles belonging to distant taxa. We developed a specific protocol for MALDI‐TOF‐MS identification of Archaea and applied it to seven environmental human‐associated Methanobrevibacter smithii, Methanobrevibacter oralis, Methanosphaera stadtmanae, and the recently described Methanomassiliicoccus luminyensi Archaea. After mechanical lyse, we observed a unique protein profile for each organisms comprising 7–24 peaks ranging from 3 015 to 10 632 Da with a high quality score of 7.38 ± 1.26. Profiles were reproducible over successive experiments performed at 1, 2, and 3‐week growth durations and unambiguously distinguished the Archaea from all of the 3 995 bacterial spectra in the Brüker database. After the incorporation of the determined profiles into a local database, archaeal isolates were blindly identified within 10 min with an identification score of 1.9–2.3. The MALDI‐TOF‐MS‐based clustering of these archaeal organisms was consistent with their 16S rDNA sequence‐based phylogeny. These data prove that MALDI‐TOF‐MS profiling could be used as a first‐line technique for the identification of human Archaea. In complement to previous reports for animal cells, Bacteria and giant viruses, MALDI‐TOF‐MS therefore appears as a universal method for the identification of living unicellular and multicellular organisms.
Hybrid schwannoma/perineurioma: a report of two cases including a possible radiation‐induced case
Authors: Ohata Chika , Imai Naho , Hinogami Haruna , Akamatsu Kana , Sumimura Yukiko
Published: November 2011

Hybrid schwannoma/perineurioma represents a recently characterized dermal or subdermal tumor showing schwannian cytomorphology and a perineurioma‐like architecture composed of an admixture of both cell types. We report two additional cases of hybrid schwannoma/ perineurioma, one of which occurred after irradiation. Patient 1 was that of a 33‐year‐old man presented with a 2.8‐cm dermal tumor on his left lower leg. Patient 2 was that of an 89‐year‐old woman with a history of uterine carcinoma treated by surgery and radiation therapy at the age of 35. She presented with a 1.2 × 1.0 cm dermal tumor on her left mons pubis with multiple coincidental basal‐cell carcinomas around it. Both tumors were microscopically well circumscribed but unencapsulated and situated in the dermis and adipose tissue and showed a vague storiform and lamellar pattern. Cytologically, both tumors contained two‐cell populations, i.e. spindled cells with plump nuclei, which were positive for S‐100 protein and negative for epithelial membrane antigen (EMA), claudin‐1 and CD34, as well as cells with very slender nuclei and elongated cytoplasmic processes, which were negative for S‐100 protein yet expressed EMA, claudin‐1 and CD34. Claudin‐1 was a better marker to highlight cells with very slender nuclei than EMA. Both tumors lacked expression of neurofilament.

Ohata C, Imai N, Hinogami H, Akamatsu K and Sumimura Y. Hybrid schwannoma/perineurioma: a report of two cases including a possible radiation‐induced case.
Spiradenocarcinoma with low‐grade basal cell adenocarcinoma pattern: report of a case with varied morphology and wild type TP53
Authors: Petersson Fredrik , Nga Min En
Published: November 2011

We present a patient with a 2‐cm spiradenocarcinoma of the left arm resembling low‐grade salivary gland basal cell adenocarcinoma. In addition to showing attributes of conventional spiradenoma, the benign component showed prominent areas of cystic change with focal apocrine differentiation, glands with and without mucinous differentiation, clear cell change and focal adenoid cystic carcinoma‐like areas. The malignant component was composed of nodules of basaloid cells arranged in sheets with variable tendency to luminal differentiation. The nuclear atypia was low‐grade, and the mitotic index was high in the malignant component (to 8/10 high power fields). Immunohistochemically, there was diffuse but variable positivity for cytokeratin 7 in both the benign and malignant components. Epithelial membrane antigen was focally positive, highlighting cells with ductal (luminal) differentiation. Expression of p63 was observed in 50 and 80% of the cells in the benign and malignant components, respectively. Calponin was negative. The proliferative index (MIB‐1/Ki‐67) was <3% in the benign component and up to 10% in the malignant component. Although the malignant component displayed patchy areas with nuclear p53 immunoreactivity with variable intensity, no mutation in the TP53 gene was identified.

Petersson F, Nga ME. Spiradenocarcinoma with low‐grade basal cell adenocarcinoma pattern: report of a case with varied morphology and wild type TP53.
Barotrauma‐associated posterior tension pneumomediastinum, a rare cause of cardiac tamponade in a ventilated neonate: a case report and review of the literature
Authors: Kyle Anna , Veldtman Gruschen , Stanton Michael , Weeden David , Baral Vijay
Published: November 2011

Ventilation‐associated neonatal barotrauma comprises a spectrum of conditions including pneumothorax, pulmonary interstitial emphysema, pneumopericardium and pneumomediastinum. Whilst pneumothorax is common, mediastinal and particularly posterior mediastinal air collections are rare. We report the case of a neonate, presenting with life threatening pericardial tamponade secondary to posterior tension pneumomediastinum. The infant was successfully resuscitated with an emergency left lateral thoracotomy and chest drain insertion. We believe this to be the first such case reported in the literature. We discuss aspects of pathophysiology, diagnosis and management relating to posterior pneumomediastinum.

Conclusion:  Posterior pneumomediastinum is rare, but can potentially cause fatal tamponade. Such cases must be managed in a tertiary centre where cardiology and surgical expertize are available.
The Role of Cholesterol in UV Light B‐induced Apoptosis†
Authors: George Kimberly S. , Elyassaki Walid , Wu Qiong , Wu Shiyong
Published: November 2011

Modification of major lipid raft components, such as cholesterol and ceramide, plays a role in regulation of programmed cell death under various stimuli. However, the relationship between cholesterol level modification and the activation of apoptotic signaling cascades upon UVB light has not been established. In this report, we demonstrate that upon UVB irradiation cholesterol levels in membrane rafts of skin cells increase, which leads to Fas‐receptor (Fas) aggregation in the rafts. Utilizing a continuous velocity floatation technique, we show that Fas accumulated in the lipid rafts of human melanoma M624 cells after UVB irradiation. The subsequent events of death‐inducing signaling complex formation were also detected in the lipid raft fractions. Depletion of cholesterol by methyl‐β‐cyclodextrin reduces Fas aggregation, while overloading increases. Disruption of lipid rafts also prevents Fas death domain‐associated protein (Daxx) from dissociating from Fas in the lipid rafts, which is accompanied with a reduced apoptotic, but increased nonapoptotic death of UVB‐irradiated human keratinocytes, HaCaT cells. Results indicate that cholesterol located in the plasma membrane of skin cells is required for lipid raft domain formation and activation of UVB‐induced apoptosis.
Miconazole Induces Fungistasis and Increases Killing of Candida albicans Subjected to Photodynamic Therapy†
Authors: Snell Sara B. , Foster Thomas H. , Haidaris Constantine G.
Published: November 2011

Cutaneous and mucocutaneous Candida infections are considered to be important targets for antimicrobial photodynamic therapy (PDT). Clinical application of antimicrobial PDT will require strategies that enhance microbial killing while minimizing damage to host tissue. Increasing the sensitivity of infectious agents to PDT will help achieve this goal. Our previous studies demonstrated that raising the level of oxidative stress in Candida by interfering with fungal respiration increased the efficiency of PDT. Therefore, we sought to identify compounds in clinical use that would augment the oxidative stress caused by PDT by contributing to reactive oxygen species (ROS) formation themselves. Based on the ability of the antifungal miconazole to induce ROS in Candida, we tested several azole antifungals for their ability to augment PDT in vitro. Although miconazole and ketoconazole both stimulated ROS production in Candida albicans, only miconazole enhanced the killing of C. albicans and induced prolonged fungistasis in organisms that survived PDT using the porphyrin TMP‐1363 and the phenothiazine methylene blue as photosensitizers. The data suggest that miconazole could be used to increase the efficacy of PDT against C. albicans, and its mechanism of action is likely to be multifactorial.
Multiple forms of DNA Damage Caused by UVA Photoactivation of DNA 6‐Thioguanine
Authors: Brem Reto , Karran Peter
Published: November 2011

Thiopurines are prescribed frequently as medication for cancer and for inflammatory disorders. One of them, azathioprine, has been the immunosuppressant of choice for organ transplant recipients for many years. Thiopurine use is associated with elevated sun sensitivity and skin cancer risk. Skin sensitization is selective for UVA. 6‐TG integrates into DNA and unlike the canonical DNA bases, it is a strong UVA chromophore with an absorbance maximum at 342 nm. DNA 6‐TG is a photosensitizer and a source of reactive oxygen species. Reactive oxygen that is generated from the photochemical activation of DNA 6‐TG causes extensive damage to DNA and proteins. This damage is mutagenic and extremely toxic to cultured human cells. Here we describe some of the lesions that are known to be generated from UVA irradiation of DNA 6‐TG. We discuss how this photochemical damage might contribute to the toxic effect of thiopurine/UVA treatment on cultured cells and to the high risk of skin cancer in thiopurine‐treated patients.
Serum Carbohydrate Antigen 125 Levels in Nonischemic Dilated Cardiomyopathy: A Useful Biomarker for Prognosis and Functional Mitral Regurgitation
Authors: Karaca Oguz , Guler Gamze B. , Guler Ekrem , Gunes H. Murat , Alizade Elnur , Agus Hicaz Z. , Gol Gokhan , Kahveci Gokhan , Esen Ozlem , Esen A. Metin , Turkmen Muhsin
Published: November 2011

The authors investigated the prognostic relevance of serum carbohydrate antigen 125 (CA125) levels in nonischemic dilated cardiomyopathy (NICMP) and assessed whether increased levels relate to the degree of functional mitral regurgitation (FMR). Seventy‐seven patients with NICMP were enrolled and followed‐up for 10±2 months in this prospective study. Receiver‐operating characteristic analysis established a cutoff CA125 value of 25 U/mL for predicting mortality. Patients were divided into two groups according to their CA125 levels (CA125 <25 U/mL [n=58] and CA125 ≥25 U/mL [n=19]). Patients with high CA125 values had statistically worse functional status, higher B‐type natriuretic peptide (BNP) levels, higher left ventricular volumes, lower ejection fraction, higher E/Em ratio, higher pulmonary artery systolic pressure, and more severe FMR. On the multivariate analysis, serum CA125 (P=.002) and severe FMR (P=.04) were identified as the independent predictors of mortality. Serum CA125 levels also correlated with BNP levels and FMR severity (P<.001). Serum CA125 is a powerful prognostic biomarker that is associated with the severity of heart failure, serum BNP levels and several echocardiographic parameters including left ventricular volumes, systolic and diastolic functions, pulmonary artery pressure, and the degree of FMR. Serum CA125 was also shown as an independent predictor of mortality during 10±2 months of follow‐up. ©2011 Wiley Periodicals, Inc.
Acinetobacter Insertion Sequence IS
Aba11
Belongs to a Novel Family That Encodes Transposases with a Signature HHEK Motif
Authors: Rieck Barbara , Tourigny David S. , Crosatti Marialuisa , Schmid Ralf , Kochar Mandira , Harrison Ewan M. , Ou Hong-Yu , Turton Jane F. , Rajakumar Kumar
Published: November 2011

Experimental and
in silico
PCR analysis targeting IS
Aba11
and Tn
AbaR
islands in 196 epidemiologically unrelated
Acinetobacter
strains representative of ≥19 species were performed. The first two
Acinetobacter baumannii
IS
Aba11
elements identified had been found to map to the same site on Tn
AbaR
transposons. However, no further evidence of physical linkage between the two elements was demonstrated. Indeed, examination of 25 definite or putative insertion sites suggested limited sequence specificity. Importantly, an
aacC1
-tagged version of IS
Aba11
was shown to actively transpose in
A. baumannii
. Similarity searches identified nine iso-IS
Aba11
elements in
Acinetobacter
and one in
Enhydrobacter
and single representatives of four distant homologs in bacteria belonging to the phyla “
Cyanobacteria
” and
Proteobacteria
. Phylogenetic, sequence, and structural analyses of IS
Aba11
and/or its associated transposase (Tnp

IS
Aba11

) suggested that these elements be assigned to a new family. All five homologs encode transposases with a shared extended signature comprising 16 invariant residues within the N2, N3, and C1 regions, four of which constituted the cardinal IS
Aba11
family HHEK motif that is substituted for the YREK DNA binding motif conserved in the IS
4
family. Additionally, IS
Aba11
family members were associated with either no flanking direct repeat (DR) or an IS
Aba11
-typical 5-bp DR and possessed variable-length terminal inverted repeats that exhibited extensive intrafamily sequence identity. Given the limited pairwise identity among Tnp

IS
Aba11

homologs and the observed restricted distribution of IS
Aba11
, we propose that substantial gaps persist in the evolutionary record of IS
Aba11
and that this element represents a recent though potentially highly significant entrant into the
A. baumannii
gene pool.
Molecular Diversity of the Syndinean Genus Euduboscquella Based on Single-Cell PCR Analysis
Authors: Bachvaroff Tsvetan R. , Kim Sunju , Guillou Laure , Delwiche Charles F. , Coats D. Wayne
Published: November 2011

The genus
Euduboscquella
is one of a few described genera within the syndinean dinoflagellates, an enigmatic lineage with abundant diversity in marine environmental clone libraries based on small subunit (SSU) rRNA. The region composed of the SSU through to the partial large subunit (LSU) rRNA was determined from 40 individual tintinnid ciliate loricae infected with
Euduboscquella
sampled from eight surface water sites in the Northern Hemisphere, producing seven distinct SSU sequences. The corresponding host SSU rRNA region was also amplified from eight host species. The SSU tree of
Euduboscquella
and syndinean group I sequences from environmental clones had seven well-supported clades and one poorly supported clade across data sets from 57 to 692 total sequences. The genus
Euduboscquella
consistently formed a supported monophyletic clade within a single subclade of group I sequences. For most parasites with identical SSU sequences, the more variable internal transcribed spacer (ITS) to LSU rRNA regions were polymorphic at 3 to 10 sites. However, in
E. cachoni
there was variation between ITS to LSU copies at up to 20 sites within an individual, while in a parasite of
Tintinnopsis
spp., variation between different individuals ranged up to 19 polymorphic sites. However, applying the compensatory base change model to the ITS2 sequences suggested no compensatory changes within or between individuals with the same SSU sequence, while one to four compensatory changes between individuals with similar but not identical SSU sequences were found. Comparisons between host and parasite phylogenies do not suggest a simple pattern of host or parasite specificity.
A Flucytosine-Responsive Mbp1/Swi4-Like Protein, Mbs1, Plays Pleiotropic Roles in Antifungal Drug Resistance, Stress Response, and Virulence of Cryptococcus neoformans
Authors: Song Min-Hee , Lee Jang-Won , Kim Min Su , Yoon Ja-Kyung , White Theodore C. , Floyd Anna , Heitman Joseph , Strain Anna K. , Nielsen Judith N. , Nielsen Kirsten , Bahn Yong-Sun
Published: November 2011

Cryptococcosis, caused by the basidiomycetous fungus
Cryptococcus neoformans
, is responsible for more than 600,000 deaths annually in AIDS patients. Flucytosine is one of the most commonly used antifungal drugs for its treatment, but its resistance and regulatory mechanisms have never been investigated at the genome scale in
C. neoformans
. In the present study, we performed comparative transcriptome analysis by employing two-component system mutants (
tco1
Δ and
tco2
Δ) exhibiting opposing flucytosine susceptibility. As a result, a total of 177 flucytosine-responsive genes were identified, and many of them were found to be regulated by Tco1 or Tco2. Among these, we discovered an APSES-like transcription factor, Mbs1 (
Mb
p1- and
S
wi4-like protein 1). Expression analysis revealed that
MBS1
was regulated in response to flucytosine in a Tco2/Hog1-dependent manner. Supporting this,
C. neoformans
with the deletion of
MBS1
exhibited increased susceptibility to flucytosine. Intriguingly, Mbs1 played pleiotropic roles in diverse cellular processes of
C. neoformans
. Mbs1 positively regulated ergosterol biosynthesis and thereby affected polyene and azole drug susceptibility. Mbs1 was also involved in genotoxic and oxidative stress responses. Furthermore, Mbs1 promoted production of melanin and capsule and thereby was required for full virulence of
C. neoformans
. In conclusion, Mbs1 is considered to be a novel antifungal therapeutic target for treatment of cryptococcosis.
Neddylation and CAND1 Independently Stimulate SCF Ubiquitin Ligase Activity in Candida albicans
Authors: Sela Nadine , Atir-Lande Avigail , Kornitzer Daniel
Published: November 2011

SCF (Skp1–cullin/Cdc53–F-box protein) ubiquitin ligases bind substrates via the variable F-box protein and, in conjunction with the RING domain protein Rbx1 and the ubiquitin-conjugating enzyme Ubc3/Cdc34, catalyze substrate ubiquitination. The cullin subunit can be modified covalently by conjugation of the ubiquitin-like protein Rub1/NEDD8 (neddylation) or bound noncovalently by the protein CAND1 (cullin-associated, neddylation-dissociated). Expression of the
Candida albicans
CAND1 gene homolog Ca
TIP120
in
Saccharomyces cerevisiae
is toxic only in the presence of CaCdc53, consistent with a specific interaction between CaTip120 and CaCdc53. To genetically analyze this system in
C. albicans
, we deleted the homologs of
RUB1
/NEDD8,
TIP120
/CAND1, and the deneddylase gene
JAB1
, and we also generated a temperature-sensitive allele of the essential Ca
CDC53
gene by knock-in site-directed mutagenesis. Deletion of Ca
RUB1
and Ca
TIP120
caused morphological, growth, and protein degradation phenotypes consistent with a reduction in SCF ubiquitin ligase activity. Furthermore, the double Ca
rub1
−/−
Ca
tip120
−/−
mutant was more defective in SCF activity than either individual deletion mutant. These results indicate that CAND1 stimulates SCF ubiquitin ligase activity and that it does so independently of neddylation. Our data do not support a role for CAND1 in the protection of either the F-box protein or cullin from degradation but are consistent with the suggested role of CAND1 in SCF complex remodeling.
Benzoate Mediates Repression of C
4
-Dicarboxylate Utilization in “Aromatoleum aromaticum” EbN1
Authors: Trautwein Kathleen , Grundmann Olav , Wöhlbrand Lars , Eberlein Christian , Boll Matthias , Rabus Ralf
Published: November 2011

Diauxic growth was observed in anaerobic C
4
-dicarboxylate-adapted cells of “
Aromatoleum aromaticum
” EbN1 due to preferred benzoate utilization from a substrate mixture of a C
4
-dicarboxylate (succinate, fumarate, or malate) and benzoate. Differential protein profiles (two-dimensional difference gel electrophoresis [2D DIGE]) revealed dynamic changes in abundance for proteins involved in anaerobic benzoate catabolism and C
4
-dicarboxylate uptake. In the first active growth phase, benzoate utilization was paralleled by maximal abundance of proteins involved in anaerobic benzoate degradation (e.g., benzoyl-coenzyme A [CoA] reductase) and minimal abundance of DctP (EbA4158), the periplasmic binding protein of a predicted C
4
-dicarboxylate tripartite ATP-independent periplasmic (TRAP) transporter (DctPQM). The opposite was observed during subsequent succinate utilization in the second active growth phase. The increased
dctP
(respectively,
dctPQM
) transcript and DctP protein abundance following benzoate depletion suggests that repression of C
4
-dicarboxylate uptake seems to be a main determinant for the observed diauxie.
Perturbation of FliL Interferes with Proteus mirabilis Swarmer Cell Gene Expression and Differentiation
Authors: Cusick Kathleen , Lee Yi-Ying , Youchak Brian , Belas Robert
Published: November 2011

Proteus mirabilis
is a dimorphic, motile bacterium often associated with urinary tract infections. Colonization of urinary tract surfaces is aided by swarmer cell differentiation, which is initiated by inhibition of flagellar rotation when the bacteria first contact a surface. Mutations in
fliL
, encoding a flagellar structural protein with an enigmatic function, result in the inappropriate production of differentiated swarmer cells, called pseudoswarmer cells, under noninducing conditions, indicating involvement of FliL in the surface sensing pathway. In the present study, we compared the
fliL
transcriptome with that of wild-type swarmer cells and showed that nearly all genes associated with motility (flagellar class II and III genes) and chemotaxis are repressed. In contrast, spontaneous motile revertants of
fliL
cells that regained motility yet produced differentiated swarmer cells under noninducing conditions transcribed flagellar class II promoters at consistent levels. Expression of
umoA
(a known regulator of swarmer cells),
flgF
, and
flgI
increased significantly in both swarmer and pseudoswarmer cells, as did genes in a degenerate prophage region situated immediately adjacent to the Rcs phosphorelay system. Unlike swarmer cells, pseudoswarmers displayed increased activity, rather than transcription, of the flagellar master regulatory protein, FlhD
4
C
2
, and analyses of the
fliL
parent strain and its motile revertants showed that they result from mutations altering the C-terminal 14 amino acids of FliL. Collectively, the data suggest a functional role for the C terminus of FliL in surface sensing and implicate UmoA as part of the signal relay leading to the master flagellar regulator FlhD
4
C
2
, which ultimately controls swarmer cell differentiation.
Thiosulfate Reduction in Salmonella enterica Is Driven by the Proton Motive Force
Authors: Stoffels Laura , Krehenbrink Martin , Berks Ben C. , Unden Gottfried
Published: November 2011

Thiosulfate respiration in
Salmonella enterica
serovar Typhimurium is catalyzed by the membrane-bound enzyme thiosulfate reductase. Experiments with quinone biosynthesis mutants show that menaquinol is the sole electron donor to thiosulfate reductase. However, the reduction of thiosulfate by menaquinol is highly endergonic under standard conditions (Δ
E
°′ = −328 mV). Thiosulfate reductase activity was found to depend on the proton motive force (PMF) across the cytoplasmic membrane. A structural model for thiosulfate reductase suggests that the PMF drives endergonic electron flow within the enzyme by a reverse loop mechanism. Thiosulfate reductase was able to catalyze the combined oxidation of sulfide and sulfite to thiosulfate in a reverse of the physiological reaction. In contrast to the forward reaction the exergonic thiosulfate-forming reaction was PMF independent. Electron transfer from formate to thiosulfate in whole cells occurs predominantly by intraspecies hydrogen transfer.
A-Type Carrier Protein ErpA Is Essential for Formation of an Active Formate-Nitrate Respiratory Pathway in Escherichia coli K-12
Authors: Pinske Constanze , Sawers R. Gary
Published: November 2011

A-type carrier (ATC) proteins of the Isc (
i
ron-
s
ulfur
c
luster) and Suf (
su
l
f
ur mobilization) iron-sulfur ([Fe-S]) cluster biogenesis pathways are proposed to traffic preformed [Fe-S] clusters to apoprotein targets. In this study, we analyzed the roles of the ATC proteins ErpA, IscA, and SufA in the maturation of the nitrate-inducible, multisubunit anaerobic respiratory enzymes formate dehydrogenase N (Fdh-N) and nitrate reductase (Nar). Mutants lacking SufA had enhanced activities of both enzymes. While both Fdh-N and Nar activities were strongly reduced in an
iscA
mutant, both enzymes were inactive in an
erpA
mutant and in a mutant unable to synthesize the [Fe-S] cluster scaffold protein IscU. It could be shown for both Fdh-N and Nar that loss of enzyme activity correlated with absence of the [Fe-S] cluster-containing small subunit. Moreover, a slowly migrating form of the catalytic subunit FdnG of Fdh-N was observed, consistent with impeded twin arginine translocation (TAT)-dependent transport. The highly related Fdh-O enzyme was also inactive in the
erpA
mutant. Although the Nar enzyme has its catalytic subunit NarG localized in the cytoplasm, it also exhibited aberrant migration in an
erpA iscA
mutant, suggesting that these modular enzymes lack catalytic integrity due to impaired cofactor biosynthesis. Cross-complementation experiments demonstrated that multicopy IscA could partially compensate for lack of ErpA with respect to Fdh-N activity but not Nar activity. These findings suggest that ErpA and IscA have overlapping roles in assembly of these anaerobic respiratory enzymes but demonstrate that ErpA is essential for the production of active enzymes.
Genome Sequences and Phylogenetic Analysis of K88- and F18-Positive Porcine Enterotoxigenic Escherichia coli
Authors: Shepard Sara M. , Danzeisen Jessica L. , Isaacson Richard E. , Seemann Torsten , Achtman Mark , Johnson Timothy J.
Published: November 2011

Porcine enterotoxigenic
Escherichia coli
(ETEC) continues to result in major morbidity and mortality in the swine industry via postweaning diarrhea. The key virulence factors of ETEC strains, their serotypes, and their fimbrial components have been well studied. However, most studies to date have focused on plasmid-encoded traits related to colonization and toxin production, and the chromosomal backgrounds of these strains have been largely understudied. Here, we generated the genomic sequences of K88-positive and F18-positive porcine ETEC strains and examined the phylogenetic distribution of clinical porcine ETEC strains and their plasmid-associated genetic content. The genomes of porcine ETEC strains UMNK88 and UMNF18 were both found to contain remarkable plasmid complements containing known virulence factors, potential novel virulence factors, and antimicrobial resistance-associated elements. The chromosomes of these strains also possessed several unique genomic islands containing hypothetical genes with similarity to classical virulence factors, although phage-associated genomic islands dominated the accessory genomes of these strains. Phylogenetic analysis of 78 clinical isolates associated with neonatal and porcine diarrhea revealed that a limited subset of porcine ETEC lineages exist that generally contain common toxin and fimbrial profiles, with many of the isolates belonging to the ST10, ST23, and ST169 multilocus sequencing types. These lineages were generally distinct from existing human ETEC database isolates. Overall, most porcine ETEC strains appear to have emerged from a limited subset of
E. coli
lineages that either have an increased propensity to carry plasmid-encoded virulence factors or have the appropriate ETEC core genome required for virulence.
Hepatology training in the UK
Authors: Patanwala Imran , Hudson Mark
Published: November 2011

Objectives

To establish the perceived adequacy of the hepatology training component of the unified gastroenterology and hepatology training programme in the UK by assessing the attitudes and experiences of trainees in the programme.

Design and intervention

Online cross-sectional questionnaire survey linked to the annual British Society of Gastroenterology/Trainee in Gastroenterology survey in 2010.

Setting and participants

National survey of all specialist gastroenterology trainees in the UK.

Results

283/489 (58%) trainees responded, 68% were male. 54% of all trainees wanted to deliver liver services as consultants. 25% of trainees complete training without exposure to a liver unit providing comprehensive specialist hepatology services. Median time spent in such a unit for the others was 8 months (IQR 6). Significantly fewer trainees lacked confidence in managing liver-related conditions if they had spent time training in a specialist liver unit and with increasing years in training. One in three trainees is dissuaded from a career in hepatology. One in five trainees wished to work part time as consultants—an option preferred significantly more by women.

Conclusions

Hepatology training in the UK is perceived by trainees as being suboptimal. A national strategy aimed at improving and standardising hepatology training and making specialist liver unit experience available for every trainee is required.