bluuebunny/crossref_metadata_2025 huggingface dataset:
An empirical study of state university students' perceived service quality
Authors: Sumaedi Sik , Mahatma Yuda Bakti Gede , Metasari Nur
Published: April 2012

Purpose

This paper aims to identify: university students' perceived service quality dimensions; the dimensions contributing most towards overall students' perceived service quality; and whether there is a difference in perceived quality level of each dimension based on students' year of study and gender in the context of undergraduate students of state universities in Indonesia.

Design/methodology/approach

The study uses a quantitative approach through a survey method. The respondents of this study are 155 state university students from two state universities in Indonesia. Both multiple regression analysis and t‐test analysis are used to analyze the data.

Findings

Research results show that there are seven perceived service quality dimensions considered important to university students, i.e. curriculum, facilities, contact personnel, social activities, education counselors, assessment, and instruction medium. The perceived service quality dimensions contributing most towards overall perceived service quality of a state university is facilities. Furthermore, the research also shows that university students with a different study period have a different perceived quality level on the social activities dimension, while university students with different gender have a different perceived quality level on two dimensions, i.e. social activities and facilities.

Research limitations/implications

The research was only conducted at two universities in the same geographic area and at a single point of time. Hence, there is a need for further research in terms of a longitudinal study with different geographic samples in order to generalize the research result.

Practical implications

The students' perceived quality dimensions resulting from this research can be used by universities to measure their performance according to students' perspectives. As a result, feedback will be gained by the university, so that the university can identify its weaknesses.

Originality/value

The research was conducted in a developing country context, while most previous research has been conducted in developed country contexts. This research also provides a new insight into quality management, since the university objects are state universities, not private universities. The paper also takes students' personal characteristics (gender and year of study) variables into account.
Measuring the productivity impacts of new ways of working
Authors: Laihonen Harri , Jääskeläinen Aki , Lönnqvist Antti , Ruostela Jenna
Published: April 2012

Purpose

“New ways of working” refers to non‐traditional work practices, settings and locations with information and communication technologies (ICT) to supplement or replace traditional ways of working. They are being deployed in knowledge work context in order to increase employees working motivation, job satisfaction and productivity. However, these benefits are not self‐evident. This paper aims to examine the task of measuring the expected benefits.

Design/methodology/approach

This paper synthesizes the existing literature on measurement of knowledge work productivity and identifies some key prerequisites and restrictions that should be taken into account when measuring the impacts of organizational change.

Findings

The paper proposes a measurement approach for evaluating the impacts of a new ways of working initiative in a knowledge work context.

Originality/value

Previous literature has focused on studying whether facilities and ICT solutions are appropriate from the viewpoint of an individual knowledge worker. However, there is a lack of studies focused on the actual business impacts of different working arrangements.
Phase I and pharmacokinetic study of the oral histone deacetylase inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T‐cell lymphoma
Authors: WADA Hidefumi , TSUBOI Ryoji , KATO Yukihiko , SUGAYA Makoto , TOBINAI Kensei , HAMADA Toshihisa , SHIMAMOTO Takashi , NOGUCHI Kazuo , IWATSUKI Keiji
Published: April 2012

A phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of the oral histone deacetylase (HDAC) inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T‐cell lymphoma (CTCL). Six patients received vorinostat (400 mg p.o., once daily). Dose‐limiting toxicities (DLT) were evaluated in all six patients during the 28 days of the first cycle. One of the six patients who received vorinostat developed a DLT (grade 4 thrombocytopenia). The most common drug‐related adverse events included nausea (4/6, 67%), thrombocytopenia (4/6, 67%), hyperbilirubinemia (3/6, 50%) and vomiting (3/6, 50%). Most of these events were reversible and were resolved by supportive care and/or the interruption of vorinostat treatment. The safety and PK profiles of vorinostat in Japanese patients with CTCL did not appear to differ from those previously observed in non‐Japanese and Japanese patients with advanced solid tumors. None of the patients achieved an objective response in this study. However, one unconfirmed partial response and two cases of sustained stable disease for 12 weeks or longer were observed among the six patients in the study. One of the three evaluable patients experienced pruritus relief. Vorinostat was well tolerated at a dose of 400 mg p.o. once daily and showed potential efficacy in Japanese patients with CTCL, warranting further investigation.
Overexpression of DNA polymerase iota (Polι) in esophageal squamous cell carcinoma
Authors: Zhou Jundong , Zhang Shuyu , Xie Ling , Liu Pengfei , Xie Fang , Wu Jinchang , Cao Jianping , Ding Wei‐Qun
Published: April 2012

The present study investigated the transcriptional regulation of low‐fidelity translesion DNA synthesis (TLS) polymerases in human esophageal carcinoma. Significantly higher mRNA expression of polymerase zeta (Polξ), RAD18, polymerase iota (Polι), and polymerase kappa (Polκ) was found in esophageal carcinomas. The increased expression of Polι in tumor samples was further confirmed by immunohistochemistry. The promoter of POLI that encodes Polι was found to be hypomethylated, although the overexpression of this gene was unlikely to be associated with methylation in tumors. We further identified Sp1 and Oct‐1 binding sites present in the POLI promoter. We observed that the binding affinity of Sp1 to the POLI promoter was significantly increased in cancerous tissues and that Sp1 activated POLI gene transcription in cultured cell lines. The present study demonstrates overexpression of the TLS genes in esophageal carcinoma and identifies a key role for Sp1 in upregulating POLI gene expression. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02309.x, 2012)
Renal tubular dysfunction during long‐term adefovir or tenofovir therapy in chronic hepatitis B
Authors: Gara N. , Zhao X. , Collins M. T. , Chong W. H. , Kleiner D. E. , Jake Liang T. , Ghany M. G. , Hoofnagle J. H.
Published: April 2012

Background

Adefovir and tenofovir are nucleotide analogues used as long‐term therapy of chronic hepatitis B. Side effects are few, but prolonged and high‐dose therapy has been associated with proximal renal tubular dysfunction (RTD).

Aim

To assess the incidence of RTD during long‐term nucleotide therapy of chronic hepatitis B.

Methods

A total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria.

Results

Among 51 patients treated for 1–10 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10‐year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.0–3.0 mg/dL), creatinine (1.6–1.1 mg/dL), uric acid (2.7–3.8 mg/dL) and proteinuria.

Conclusions

Renal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 2–9 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long‐term adefovir and tenofovir therapy.
Detecting population structure and recent demographic history in endangered livestock breeds: the case of the Italian autochthonous donkeys
Authors: Colli L. , Perrotta G. , Negrini R. , Bomba L. , Bigi D. , Zambonelli P. , Verini Supplizi A. , Liotta L. , Ajmone‐Marsan P.
Published: April 2012

Since its domestication, about 5000 years ago, the donkey (Equus asinus) has been extensively used as a work or draft animal in agricultural activities and for the transportation of people and goods. In the last century, technology improvement and growing mechanization strongly affected agriculture and the management and use of this livestock species in the industrialized countries. Nowadays, the use of donkeys for work or transport has almost disappeared, together with the need for mules or hinny breeding. During the last five decades, Italian autochthonous donkey populations suffered from a severe reduction in population size, which led to the extinction of several breeds. At present, eight breeds remain, all classified by FAO as critically endangered or endangered: Asinara, Pantesco, Grigio Siciliano, Romagnolo, Amiatino, Sardo Grigio, Martina Franca, and Ragusano. To evaluate the extant genetic variability of Italian donkeys, we typed 16 microsatellite loci in 258 individuals from these breeds. The results highlighted moderate levels of inbreeding (
F

IS = 0.127) and a significant partition of genetic variation into breeds, as suggested by fixation index (
F

ST = 0.109) and analysis of molecular variance (10.86% of total variation assigned to the between‐breeds level) analyses. This was confirmed by a Bayesian clustering procedure that also highlighted a further partitioning at lower hierarchical levels corresponding to the farms of origin. This evidence suggests that an effective management strategy for Italian donkey populations should focus on breeds as conservation units. However, this requires a synergic management strategy at the farm level to maintain diversity and avoid inbreeding.
Androgens and doping tests: genetic variation and pit‐falls
Authors: Rane Anders , Ekström Lena
Published: April 2012

The large variation in disposition known for most drugs is also true for anabolic androgenic steroids. Genetic factors are probably the single most important cause of this variation. Further, there are reasons to believe that there is a corresponding variation in efficacy of doping agents. Doped individuals employ a large variety of doping strategies in respect of choice of substance, dose, dose interval, duration of treatment and use of other drugs for enforcement of effects or correction of side effects.

Metabolic steps up‐stream and down‐stream of testosterone are genetically variable and contribute substantially to the variation in disposition of testosterone, the most common doping agent in sports and in society. Large inter‐ and intra‐ethnic variation in testosterone glucuronidation and excretion is described as well as the pit‐falls in evaluation of testosterone doping test results. The hydrolysis and bioactivation of testosterone enanthate is also genetically variable yielding a 2–3 fold variation in excretion rate and serum concentration, thereby implicating a substantial variation in ‘efficacy’ of testosterone.

Given this situation it is logical to adopt the new findings in the doping control programme. The population based cut‐off level for the testosterone : epitestosterone ratio should be replaced by a Bayesian interpretation of consecutive tests in the same individual. When combined with the above genetic information the sensitivity of the test is considerably improved. The combination of the three approaches should reduce the rate of falsely negative or positive results and the number of expensive follow‐up tests, stipulated by the World Anti‐Doping Agency.
Pre‐culturing human adipose tissue mesenchymal stem cells under hypoxia increases their adipogenic and osteogenic differentiation potentials
Authors: Valorani M. G. , Montelatici E. , Germani A. , Biddle A. , D'Alessandro D. , Strollo R. , Patrizi M. P. , Lazzari L. , Nye E. , Otto W. R. , Pozzilli P. , Alison M. R.
Published: April 2012

Objectives

Hypoxia is an important factor in many aspects of stem‐cell biology including their viability, proliferation, differentiation and migration. We evaluated whether low oxygen level (2%) affected human adipose tissue mesenchymal stem‐cell (hAT‐MSC) phenotype, population growth, viability, apoptosis, necrosis and their adipogenic and osteogenic differentiation potential.

Materials and methods

hAT‐MSCs from four human donors were cultured in growth medium under either normoxic or hypoxic conditions for 7 days and were then transferred to normoxic conditions to study their differentiation potential.

Results

Hypoxia enhanced hAT‐MSC expansion and viability, whereas expression of mesenchymal markers such as CD90, CD73 and endothelial progenitor cell marker CD34, remained unchanged. We also found that pre‐culturing hAT‐MSCs under hypoxia resulted in their enhanced ability to differentiate into adipocytes and osteocytes.

Conclusions

This protocol could be useful for maximizing hAT‐MSC potential to differentiate in vitro into the adipogenic and osteogenic lineages, for use in plastic and reconstructive surgery, and in tissue engineering strategies.
Subthreshold desensitization of human basophils re‐capitulates the loss of Syk and FcεRI expression characterized by other methods of desensitization
Authors: MacGlashan D.
Published: April 2012

Background

Clinical desensitization of patients to drugs involves progressive exposure to escalating doses of drug over a period of 24 h. In prior studies, this method was re‐capitulated in vitro to also demonstrate loss of mast cell or basophil responsiveness. However, most signalling studies of human basophils have identified changes in signalling by using other methods of inducing cellular desensitization.

Objective

This study examined two well‐described endpoints of basophil desensitization, loss of syk or FcεRI expression, under conditions of subthreshold desensitization.

Methods

The loss of FcεRI and syk was examined in human basophils.

Results

It was shown that both loss of syk and FcεRI/IgE occurred during an escalating series of stimulation (anti‐IgE Ab) and that expression loss occurred despite the presence of little histamine release. If basophils were first cultured for 3 days in 10 ng/mL IL‐3, the concentration‐dependence of histamine release shifted to 100‐fold lower concentrations of stimulus. However, loss of syk did not show any change in its EC50 while loss of FcεRI also shifted 100‐fold. From the perspective of early signal element activation, the marked shift in the EC50 for histamine release was not accompanied by similar shifts in the EC50s for several signalling elements. The EC50s for phospho‐Src, phospho‐SHIP1, phospho‐Syk, or phospho‐Cbl did not change while the EC50s for phospho‐Erk and the cytosolic calcium response did shift 100‐fold.

Conclusions

These studies show that under normal conditions, subthreshold desensitization leads to loss of two critical signalling molecules (FcεRI and syk) but under at least one condition, treatment with IL‐3, it is possible to markedly blunt the loss of syk, but not FcεRI, while executing a proper subthreshold titration. These data also suggest that IL‐3 modifies only the sensitivity of signalling elements that are downstream of syk activation.
GH levels and insulin sensitivity are differently associated with biomarkers of cardiovascular disease in active acromegaly
Authors: Boero L. , Manavela M. , Meroño T. , Maidana P. , Gómez Rosso L. , Brites F.
Published: April 2012

Context

Acromegaly is characterized by GH excess and insulin resistance. It is not known which of these disorders is responsible for the increased atherogenic risk in these patients.

Objective

To analyse the associations of GH and homoeostasis model assessment (HOMA) with biomarkers of cardiovascular disease and to compare the above‐mentioned variables between patients with active acromegaly and controls.

Design and setting

This open cross‐sectional study was conducted at a University Hospital.

Patients

Twenty‐two outpatients were compared with sex‐ and age‐matched control subjects.

Main outcomes

Included clinical features, hormonal status, markers of insulin resistance, lipoprotein profile and biomarkers of cardiovascular disease.

Results

Patients presented higher triglyceride (median [IQR]) (1·2[1·1–1·6] vs 0·9[0·6–1·1] mm, P < 0·05), low‐density lipoprotein‐cholesterol (LDL‐C) (mean ± SD) (3·5 ± 0·9 vs 3·0 ± 0·7mm, P < 0·05), apoB (0·98 ± 0·23 vs 0·77 ± 0·22 g/l, P < 0·05), free fatty acid (0·69 ± 0·2 vs 0·54 ± 0·2 mM, P < 0·05), oxidized‐LDL (120 ± 22 vs 85 ± 19 U/l, P < 0·05) and endothelin‐1 (0·90 ± 0·23 vs 0·72 ± 0·17 ng/l, P < 0·05) levels, increased cholesteryl ester transfer protein (CETP) activity (179 ± 27 vs 138 ± 30%/ml/h, P < 0·01) and lower C reactive protein (CRP) (0·25[0·1–0·9] vs 0·85[0·4–1·4] mg/l; P < 0·05) levels than control subjects. Vascular cell adhesion molecule (VCAM‐1) concentration was not different. By multiple linear regression analyses, HOMA explained the variability of triglycerides (25%), high‐density lipoprotein‐cholesterol (HDL‐C) (30%) and CETP activity (28%), while GH independently predicted LDL‐C (18%), oxidized‐LDL (40%) and endothelin‐1 levels (19%).

Conclusions

In patients with active acromegaly, GH excess contributes to the development of insulin resistance, and the interaction between both disturbances would be responsible for the appearance of atherogenic pro‐oxidative and pro‐inflammatory factors. Insulin resistance would be preferably associated with an atherogenic lipoprotein profile and to high CETP activity, while high GH levels would independently predict the increase in LDL‐C, ox‐LDL and endothelin‐1.
Climate oscillations and species interactions: large‐scale congruence but regional differences in the phylogeographic structures of an alpine plant and its monophagous insect
Authors: Borer Matthias , Arrigo Nils , Buerki Sven , Naisbit Russell E. , Alvarez Nadir
Published: April 2012

Aim  To predict the fate of alpine interactions involving specialized species, using a monophagous beetle and its host plant as a case study.

Location  The Alps.

Methods  We investigated genetic structuring of the herbivorous beetle Oreina gloriosa and its specific host‐plant Peucedanum ostruthium. We used genome fingerprinting (in the insect and the plant) and sequence data (in the insect) to compare the distribution of the main gene pools in the two associated species and to estimate divergence time in the insect, a proxy for the temporal origin of the interaction. We quantified the similarity in spatial genetic structures by performing a Procrustes analysis, a tool from shape theory. Finally, we simulated recolonization of an empty space analogous to the deglaciated Alps just after ice retreat by two lineages from two species showing unbalanced dependence, to examine how timing of the recolonization process, as well as dispersal capacities of associated species, could explain the observed pattern.

Results  Contrasting with expectations based on their asymmetrical dependence, patterns in the beetle and plant were congruent at a large scale. Exceptions occurred at a regional scale in areas of admixture, matching known suture zones in Alpine plants. Simulations using a lattice‐based model suggested these empirical patterns arose during or soon after recolonization, long after the estimated origin of the interaction c. 0.5 million years ago.

Main conclusions  Species‐specific interactions are scarce in alpine habitats because glacial cycles have limited the opportunities for co‐evolution. Their fate, however, remains uncertain under climate change. Here we show that whereas most dispersal routes are paralleled at a large scale, regional incongruence implies that the destinies of the species might differ under changing climate. This may be a consequence of the host dependence of the beetle, which locally limits the establishment of dispersing insects.
Evolutionary history of Scinax treefrogs on land‐bridge islands in south‐eastern Brazil
Authors: Bell Rayna C. , Brasileiro Cinthia A. , Haddad Célio F. B. , Zamudio Kelly R.
Published: April 2012

Aim  We investigated how Pleistocene refugia and recent (c. 12,000 years ago) sea level incursions shaped genetic differentiation in mainland and island populations of the Scinax perpusillus treefrog group.

Location  Brazilian Atlantic Forest, São Paulo state, south‐eastern Brazil.

Methods  Using mitochondrial and microsatellite loci, we examined population structure and genetic diversity in three species from the S. perpusillus group, sampled from three land‐bridge islands and five mainland populations, in order to understand the roles of Pleistocene forest fragmentation and sea level incursions on genetic differentiation. We calculated metrics of relatedness and genetic diversity to assess whether island populations exhibit signatures of genetic drift and isolation. Two of the three island populations in this study have previously been described as new species based on a combination of distinct morphological and behavioural characters, thus we used the molecular datasets to determine whether phenotypic change is consistent with genetic differentiation.

Results  Our analyses recovered three distinct lineages or demes composed of northern mainland São Paulo populations, southern mainland São Paulo populations, and one divergent island population. The two remaining island populations clustered with samples from adjacent mainland populations. Estimates of allelic richness were significantly lower, and estimates of relatedness were significantly higher, in island populations relative to their mainland counterparts.

Main conclusions  Fine‐scale genetic structure across mainland populations indicates the possible existence of local refugia within São Paulo state, underscoring the small geographic scale at which populations diverge in this species‐rich region of the Atlantic Coastal Forest. Variation in genetic signatures across the three islands indicates that the populations experienced different demographic processes after marine incursions fragmented the distribution of the S. perpusillus group. Genetic signatures of inbreeding and drift in some island populations indicate that small population sizes, coupled with strong ecological selection, may be important evolutionary forces driving speciation on land‐bridge islands.
Computerized detection and segmentation of mitochondria on electron microscope images
Authors: MUMCUOGLU E.U. , HASSANPOUR R. , TASEL S.F. , PERKINS G. , MARTONE M.E. , GURCAN M.N.
Published: April 2012

Mitochondrial function plays an important role in the regulation of cellular life and death, including disease states. Disturbance in mitochondrial function and distribution can be accompanied by significant morphological alterations. Electron microscopy tomography (EMT) is a powerful technique to study the 3D structure of mitochondria, but the automatic detection and segmentation of mitochondria in EMT volumes has been challenging due to the presence of subcellular structures and imaging artifacts. Therefore, the interpretation, measurement and analysis of mitochondrial distribution and features have been time consuming, and development of specialized software tools is very important for high‐throughput analyses needed to expedite the myriad studies on cellular events. Typically, mitochondrial EMT volumes are segmented manually using special software tools. Automatic contour extraction on large images with multiple mitochondria and many other subcellular structures is still an unaddressed problem. The purpose of this work is to develop computer algorithms to detect and segment both fully and partially seen mitochondria on electron microscopy images. The detection method relies on mitochondria's approximately elliptical shape and double membrane boundary. Initial detection results are first refined using active contours. Then, our seed point selection method automatically selects reliable seed points along the contour, and segmentation is finalized by automatically incorporating a live‐wire graph search algorithm between these seed points. In our evaluations on four images containing multiple mitochondria, 52 ellipses are detected among which 42 are true and 10 are false detections. After false ellipses are eliminated manually, 14 out of 15 fully seen mitochondria and 4 out of 7 partially seen mitochondria are successfully detected. When compared with the segmentation of a trained reader, 91% Dice similarity coefficient was achieved with an average 4.9 nm boundary error.
Occlusion on implants – is there a problem?
Authors: KLINEBERG I. J. , TRULSSON M. , MURRAY G. M.
Published: April 2012

Summary  Oral rehabilitation restores form and function and impacts on general health. Teeth provide a discriminating sense of touch and directional specificity for occlusal perception, management of food with mastication and swallowing, and awareness of its texture and hardness. Peripheral feedback for control of jaw muscles includes the enamel–dentine–pulp complex and mechanoreceptors in the periodontal tissues. The implications of feedback from periodontal and other intra‐oral mechanoreceptors as well as changes in central representation are significant for function and adaptation to oral rehabilitation. With implants, in the absence of the periodontium and periodontal mechanoreceptor feedback, fine motor control of mastication is reduced, but patients are still able to function adequately. Further, there is no significant difference in function with full‐arch fixed prostheses on teeth in comparison with implants. Predictable implant outcomes depend on bone support. Optimum restoration design appears to be significant for bone remodelling and bone strains around implants with occlusal loading. Finite element analysis data confirmed load concentrations at the coronal bone around the upper section of the implant where bone loss is commonly observed clinically. Load concentration increased with steeper cusp inclination and broader occlusal table and decreased with central fossa loading and narrower occlusal table size. It is recommended that occlusal design should follow a narrow occlusal table, with central fossa loading in intercuspal contact and low cusp inclination to minimise lateral loading in function and parafunction. Acknowledging these features should address potential problems associated with the occlusion in implant therapy.
Triangulating the genetic basis of adaptation to multifarious selection
Authors: PFRENDER M. E.
Published: April 2012

Understanding how natural populations adapt to their local environments is a major research theme for ecological genomics. This endeavour begins by sleuthing for shared genetic similarities among unrelated natural populations sharing adaptive traits to documented selective pressures. When the selective pressures have low dimensionality, and the genetic response is localized to a few genes of major effect, this detective work is relatively straightforward. However, in the real world, populations face a complex mixture of selective pressures and many adaptive responses are the result of changes in quantitative traits that have a polygenic genetic basis. This complex relationship between environment and adaptation presents a significant challenge. How can we begin to identify drivers of adaptation in natural settings? In this issue of Molecular Ecology, Orsini et al. (2012) take advantage of the biological attributes of the freshwater microcrustacean Daphnia (Fig. 1) to disentangle multidimensional selection’s signature on the genome of populations that have repeatedly evolved adaptive responses to isolated selective pressures including predation, parasitism and anthropogenic changes in land use. Orsini et al. (2012) leverage a powerful combination of spatially structured populations in a geographic mosaic of environmental stressors, the historical archive of past genotypes preserved in lake‐bottom sediments and selection experiments to identify sets of candidate genomic regions associated with adaptation in response to these three environmental stressors. This study provides a template for future investigation in ecological genomics, combining multiple experimental approaches with the genomic investigation of a well‐studied ecological model species.

 Adult Daphnia magna carrying a resting egg in the brood pouch. The water flea Daphnia is a renowned ecological model system and rapidly developing as an ecological and environmental genomics model species. Photo credit Joachim Mergeay.

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Mitogenome sequencing reveals shallow evolutionary histories and recent divergence time between morphologically and ecologically distinct European whitefish (Coregonus spp.)
Authors: JACOBSEN MAGNUS W. , HANSEN MICHAEL M. , ORLANDO LUDOVIC , BEKKEVOLD DORTE , BERNATCHEZ LOUIS , WILLERSLEV ESKE , GILBERT M. THOMAS P.
Published: April 2012

The advent of second‐generation sequencing has made it possible to quickly and economically generate whole mitochondrial genome (mitogenome) sequences. To date, mitogenome studies of nonmodel organisms have demonstrated increased power for resolving interspecies relationships. We explored an alternate use of such data to recover relationships and population history of closely related lineages with a shallow evolutionary history. Using a GS‐FLX platform, we sequenced 106 mitogenomes from the Coregonus lavaretus (Europe) and Coregonus clupeaformis (North America) species complexes to investigate the evolutionary history of the endangered Danish North Sea houting (NSH) and other closely related Danish and Baltic European lake whitefish (ELW). Two well‐supported clades were found within both ELW and NSH, probably reflecting historical introgression via Baltic migrants. Although ELW and NSH are not reciprocally monophyletic, they share no haplotypes, suggesting recent, but strong, reproductive isolation. The divergence time between NSH and the geographically closest ELW population was estimated using IMa, assuming isolation with migration and a new mutation rate estimate chosen to avoid time‐dependency effects. The estimate of c. 2700 bp was remarkably similar to results obtained using microsatellite markers. Within North American C. clupeaformis, the divergence time between the two lineages (Atlantic and Acadian) was estimated as between 20 000 and 60 000 bp. Under the assumption that NSH and ELW colonized Denmark following the last glacial maximum, Bayesian Serial SimCoal analysis showed consistency with a scenario of long‐term stability, resulting from a rapid initial sixfold population expansion. The findings illustrate the utility of mitogenome data for resolving recent intraspecific divergence events and provide evidence for recent reproductive isolation of the phenotypically divergent NSH.
Regulation of proline metabolism in mycobacteria and its role in carbon metabolism under hypoxia
Authors: Berney Michael , Weimar Marion R. , Heikal Adam , Cook Gregory M.
Published: April 2012

Genes with a role in proline metabolism are strongly expressed when mycobacterial cells are exposed to nutrient starvation and hypoxia. Here we show that proline metabolism in mycobacteria is mediated by the monofunctional enzymes Δ1‐pyrroline‐5‐carboxylate dehydrogenase (PruA) and proline dehydrogenase (PruB). Proline metabolism was controlled by a unique membrane‐associated DNA‐binding protein PruC. Under hypoxia, addition of proline led to higher biomass production than in the absence of proline despite excess carbon and nitrogen. To identify the mechanism responsible for this enhanced growth, microarray analysis of wild‐type Mycobacterium smegmatis versus pruC mutant was performed. Expression of the DNA repair machinery and glyoxalases was increased in the pruC mutant. Glyoxalases are proposed to degrade methylglyoxal, a toxic metabolite produced by various bacteria due to an imbalance in intermediary metabolism, suggesting the pruC mutant was under methylglyoxal stress. Consistent with this notion, pruB and pruC mutants were hypersensitive to methylglyoxal. Δ1‐pyrroline‐5‐carboxylate is reported to react with methylglyoxal to form non‐toxic 2‐acetyl‐1‐pyrroline, thus providing a link between proline metabolism and methylglyoxal detoxification. In support of this mechanism, we show that proline metabolism protects mycobacterial cells from methylglyoxal toxicity and that functional proline dehydrogenase, but not Δ1‐pyrroline‐5‐carboxylate dehydrogenase, is essential for this protective effect.
Indoleamine 2,3‐dioxygenase Expression and Functional Activity in Dendritic Cells Exposed to Cholera Toxin
Authors: Slavica L. , Nurkkala‐Karlsson M. , Karlson T. , Ingelsten M. , Nyström J. , Eriksson K.
Published: April 2012

Indoleamine 2,3‐dioxygenase (IDO), a tryptophan‐metabolizing enzyme expressed by dendritic cells (DC), has the potential to inhibit T cell responses and to promote tolerance. In contrast, cholera toxin (CT), the enterotoxin produced by Vibrio cholerae, promotes T cell responses, partly through its ability to induce DC maturation and promote antigen presentation. We hypothesized that the adjuvant activity of CT is associated with a lack of induction of IDO in DC. To test this hypothesis, monocyte‐derived DC were pulsed with CT, and the IDO mRNA expression, IDO functional activity and cytokine production were measured as well as the ability of DC to induce T cell responses in vitro. Cholera toxin exposure induced enhanced levels of IDO mRNA in DC but no functional IDO protein activity. Cholera toxin pulsing however primed DC for CD40L‐induced IDO protein activity. CD40L stimulation of CT‐pulsed DC induced a modest IL‐12p40 production, but not IL‐12p70 or IL‐23 secretion. Furthermore, CT‐pulsed DC induced strong allogeneic and autologous T cell responses in vitro, which were not affected by the IDO‐specific inhibitor 1‐methyl tryptophan. Our results show that CT per se does not induce the expression of functional IDO protein, although it primes DC for CD40L‐mediated IDO production and IL‐12p40 secretion. Furthermore, CT‐treated DC were equally powerful in their T cell stimulatory capacity as cytokine‐matured DC.
Steroid‐free living donor liver transplantation for HCV – a multicenter prospective cohort study in Japan
Authors: Marubashi Shigeru , Umeshita Koji , Asahara Toshimasa , Fujiwara Kenji , Haga Hironori , Hashimoto Takashi , Hatakeyama Katsuyoshi , Ichida Takafumi , Kanematsu Takashi , Kitajima Masaki , Kiyosawa Kendo , Makuuchi Masatoshi , Miyagawa Shinichi , Satomi Susumu , Soejima Yuji , Takada Yasutsugu , Tanaka Noriaki , Teraoka Satoshi , Monden Morito
Published: April 2012

This prospective, non‐randomized, multicenter cohort study analyzed the safety and efficacy of a steroid‐free immunosuppressive (IS) protocol for hepatitis C virus (HCV)‐positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid‐free IS protocol (Fr group) and 29 the traditional steroid‐containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p = 0.013). Preemptive anti‐HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p = 0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p = 0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p = 0.022, p < 0.0001, p = 0.012, respectively). The steroid‐free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post‐transplant period and HCV recurrence in HCV‐positive LDLT recipients.
IL‐31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis
Authors: Raap Ulrike , Weißmantel Sigo , Gehring Manuela , Eisenberg Anna M. , Kapp Alexander , Fölster‐Holst Regina
Published: April 2012

To cite this article: Raap U, Weißmantel S, Gehring M, Eisenberg AM, Kapp A, Fölster‐Holst R. IL‐31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis. Pediatr Allergy Immunol 2012: 23: 285–288.

Recently, we could show that IL‐31 serum levels are significantly increased in adult patients with atopic dermatitis compared with skin healthy controls. However, the regulation of IL‐31 in children with atopic dermatitis so far is not clear. Thus, we analyzed IL‐31 serum levels together with IL‐4, IL‐13, ECP, and total IgE levels in 60 children with extrinsic, in five children with intrinsic atopic dermatitis, and 20 non‐atopic healthy children. Further, we determined the SCORAD score, sleeplessness, and pruritus severity in all children with atopic dermatitis. IL‐31 was significantly increased in children with the intrinsic and extrinsic type of atopic dermatitis compared with non‐atopic healthy children (p < 0.05‐0.001). Further, IL‐31 serum levels significantly correlated with SCORAD score (p < 0.01), sleeplessness (p < 0.05), IL‐4, and IL‐13 levels (p < 0.01) in children with extrinsic atopic dermatitis. There was no correlation of IL‐31 with pruritus, total IgE Ab, and ECP levels, whereas ECP levels significantly correlated with the SCORAD score in children with extrinsic atopic dermatitis. Together, IL‐31 represents an interesting cytokine especially with regard to the severity of the inflammatory process indicated by the correlation of IL‐31 with SCORAD score and Th2 cytokines including IL‐4 and IL‐13 in children with extrinsic atopic dermatitis.
Peanut sensitization during the first 5 yr of life is associated with elevated levels of peanut‐specific IgG
Authors: Sverremark‐Ekström E. , Hultgren E. H. , Borres M. P. , Nilsson C.
Published: April 2012

To cite this article: Sverremark‐Ekström E, Hultgren EH, Borres MP, Nilsson C. Peanut sensitization during the first 5 yr of life is associated with elevated levels of peanut‐specific IgG. Pediatr Allergy Immunol 2012: 23: 224–229.

Background:  Allergen‐specific IgE antibodies are implicated in allergic diseases while allergen‐specific IgG antibodies have been proposed to prevent allergic reactions. The objective for this study was to study whether the immune response (IgG and IgG4) to peanut differs in IgE‐sensitized and non‐sensitized young children.

Methods:  A total of 239 children have been followed prospectively from birth to 5 yr of age. The levels of IgG and IgG4 to peanut, Ara h 2, and Ara h 8 were analyzed at 2 and 5 yr of age and related to IgE sensitization and peanut consumption.

Results:  The levels of peanut‐specific IgG and IgG4 were significantly higher in peanut‐sensitized children at 2 and 5 yr of age when compared with non‐sensitized children and children sensitized to other food/inhalant allergens. A strong correlation was seen between levels of peanut‐specific IgG/IgG4‐ratios and peanut‐specific IgE at 5 yr of age. Children avoiding peanuts, a subgroup of the peanut sensitized, had statistically significant higher levels of IgE to peanut and a tendency of higher IgG and IgG4 levels to peanut. In the avoidance group, significant correlations between IgE and IgG/IgG4 to peanut were found compared with children eating peanuts.

Conclusion:  Peanut‐specific IgG or IgG4 levels were elevated in peanut‐sensitized children especially those avoiding peanuts. In our study, IgG and IgG4 do not seem to indicate tolerance or protection from sensitization.
Maintenance therapies in bipolar disorders
Authors: Gitlin Michael , Frye Mark A
Published: April 2012

Gitlin M, Frye MA. Maintenance therapies in bipolar disorders. Bipolar Disord 2012: 14 (Suppl. 2): 51–65. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S.

Objective:  Bipolar disorder is an inherently recurrent disorder, requiring maintenance preventive treatments in the vast majority of patients. The authors review the data on maintenance treatments in bipolar disorder, highlighting the controlled trial literature.

Methods:  Literature review using PubMed, Medline, and a hand search of relevant literature.

Results:  Over the last decade, a number of effective maintenance treatments for bipolar disorder have been developed with an evidence base for second‐generation antipsychotics and some anticonvulsants. Increasing numbers of patients, therefore, are appropriately treated with multiple medications as a maintenance regimen. For some medications, maintenance treatment has been demonstrated in randomized controlled trials for both monotherapy and in combination with other mood stabilizers. Lithium continues as our oldest well‐established maintenance treatment in bipolar disorder with somewhat better efficacy in preventing mania than depression. Lamotrigine, olanzapine, and quetiapine have bimodal efficacy in preventing both mania and depression, although lamotrigine’s efficacy is more robust in preventing depression and olanzapine’s efficacy is greater in preventing mania. Aripiprazole, ziprasidone, and risperidone long‐acting injection all prevent mania, but not depression. Less controlled investigations have suggested some evidence of maintenance mood stabilization with carbamazepine, oxcarbazepine, and adjunctive psychotherapy.

Conclusions:  Despite the number of agents with demonstrated efficacy as maintenance treatments in bipolar disorder, optimal treatment regimens are still a combination of evidence‐based therapy in combination with individualized creative treatment algorithms.
Reticular Groove of the Domestic Ruminants: Histochemical and Immunocytochemical Study
Authors: Scala G. , Maruccio L.
Published: April 2012

The reticular groove mucosa of adult cattle, buffalo and sheep was investigated by histochemical and immunocytochemical techniques. Intense NADPH‐d staining was observed in the folds of the epithelium mucosa and at the bottom of the reticular groove in all domestic ruminants studied. The NADPH‐d staining showed that the innervations of the tunica muscularis of the reticular groove lip were composed of nerve corpuscles, nerve fibres and nerve cells of the mucosa epithelium. SEM analysis showed an intense nitric oxide synthase (NOS) I immunoreactivity in deep and medium cellular layers. It is interesting to note that the same morphologies were observed in samples of the mucosa epithelium, and of the tunica muscularis processed by NADPH‐d and in those processed by immunogold techniques. This study has demonstrated that nitric oxide (NO) is involved in the rumination activity and that it plays a double role in this activity in the reticular groove of all domestic ruminants studied: (1) NO plays a role similar to the one it has in the mucosa epithelium of all the other compartments of the ruminant forestomach, (2) The lip sections of the reticular groove has shown abundant innervations that may indirectly coordinate and control the forestomach motility through the direct activation of the nitrergic (nitroxidergic) nerve cells and nerve fibres.
Auditory perception and syntactic cognition: brain activity‐based decoding within and across subjects
Authors: Herrmann Björn , Maess Burkhard , Kalberlah Christian , Haynes John‐Dylan , Friederici Angela D.
Published: April 2012

The present magnetoencephalography study investigated whether the brain states of early syntactic and auditory‐perceptual processes can be decoded from single‐trial recordings with a multivariate pattern classification approach. In particular, it was investigated whether the early neural activation patterns in response to rule violations in basic auditory perception and in high cognitive processes (syntax) reflect a functional organization that largely generalizes across individuals or is subject‐specific. On this account, subjects were auditorily presented with correct sentences, syntactically incorrect sentences, correct sentences including an interaural time difference change, and sentences containing both violations. For the analysis, brain state decoding was carried out within and across subjects with three pairwise classifications. Neural patterns elicited by each of the violation sentences were separately classified with the patterns elicited by the correct sentences. The results revealed the highest decoding accuracies over temporal cortex areas for all three classification types. Importantly, both the magnitude and the spatial distribution of decoding accuracies for the early neural patterns were very similar for within‐subject and across‐subject decoding. At the same time, across‐subject decoding suggested a hemispheric bias, with the most consistent patterns in the left hemisphere. Thus, the present data show that not only auditory‐perceptual processing brain states but also cognitive brain states of syntactic rule processing can be decoded from single‐trial brain activations. Moreover, the findings indicate that the neural patterns in response to syntactic cognition and auditory perception reflect a functional organization that is highly consistent across individuals.
Convergent inputs from electrically and topographically distinct orexin cells to locus coeruleus and ventral tegmental area
Authors: González J. Antonio , Jensen Lise T. , Fugger Lars , Burdakov Denis
Published: April 2012

Orexin/hypocretin (orx/hcrt) neurons are thought to ensure that reward‐seeking is accompanied by alertness, but the underlying circuit organization is unclear. Reports of differential regulation of lateral versus medial orx/hcrt cells produced a hypothesis of ‘efferent dichotomy’, in which lateral orx/hcrt cells innervate the ventral tegmental area (VTA) and control reward, while medial orx/hcrt cells innervate locus coeruleus (LC) and control arousal. Two distinct types of orx/hcrt cells also emerged from analysis of intrinsic and input‐driven single‐cell electrical activity. To examine the projections of these emerging orx/hcrt subtypes to LC and VTA, we injected retrograde tracer into these regions in the mouse brain in vivo, and then examined the properties of tracer‐containing orx/hcrt cells in hypothalamic slices. VTA‐ and LC‐projecting orx/hcrt cells were found across the entire orx/hcrt field, including the zona incerta, perifornical area, dorsomedial/anterior and lateral hypothalamus. Within these areas, orx/hcrt cells had similar probabilities of projecting to VTA or LC. Examination of lateral versus medial sections revealed that VTA and LC received inputs from both lateral and medial orx/hcrt cells, but, unexpectedly, lateral orx/hcrt cells were more likely to project to LC than medial orx/hcrt cells. Finally, patch‐clamp recordings revealed that VTA and LC received projections from both electrical classes of orx/hcrt cells, which had similar likelihoods of projecting to VTA or LC. Contrary to previous predictions, our data suggest that medial and lateral orx/hcrt cells, and the different electrical and morphological subclasses of orx/hcrt cells identified to date, send projections to both LC and VTA.