bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure and evolution of Apetala3, a sex-linked gene in Silene latifolia
Authors: Cegan Radim , Marais Gabriel AB , Kubekova Hana , Blavet Nicolas , Widmer Alex , Vyskot Boris , Doležel Jaroslav , Šafář Jan , Hobza Roman
Published: August 2010

Background

The evolution of sex chromosomes is often accompanied by gene or chromosome rearrangements. Recently, the gene AP3 was characterized in the dioecious plant species Silene latifolia. It was suggested that this gene had been transferred from an autosome to the Y chromosome.

Results

In the present study we provide evidence for the existence of an X linked copy of the AP3 gene. We further show that the Y copy is probably located in a chromosomal region where recombination restriction occurred during the first steps of sex chromosome evolution. A comparison of X and Y copies did not reveal any clear signs of degenerative processes in exon regions. Instead, both X and Y copies show evidence for relaxed selection compared to the autosomal orthologues in S. vulgaris and S. conica. We further found that promoter sequences differ significantly. Comparison of the genic region of AP3 between the X and Y alleles and the corresponding autosomal copies in the gynodioecious species S. vulgaris revealed a massive accumulation of retrotransposons within one intron of the Y copy of AP3. Analysis of the genomic distribution of these repetitive elements does not indicate that these elements played an important role in the size increase characteristic of the Y chromosome. However, in silico expression analysis shows biased expression of individual domains of the identified retroelements in male plants.

Conclusions

We characterized the structure and evolution of AP3, a sex linked gene with copies on the X and Y chromosomes in the dioecious plant S. latifolia. These copies showed complementary expression patterns and relaxed evolution at protein level compared to autosomal orthologues, which suggests subfunctionalization. One intron of the Y-linked allele was invaded by retrotransposons that display sex-specific expression patterns that are similar to the expression pattern of the corresponding allele, which suggests that these transposable elements may have influenced evolution of expression patterns of the Y copy. These data could help researchers decipher the role of transposable elements in degenerative processes during sex chromosome evolution.
Interaction of silver nanoparticles with Tacaribe virus
Authors: Speshock Janice L , Murdock Richard C , Braydich-Stolle Laura K , Schrand Amanda M , Hussain Saber M
Published: August 2010

Background

Silver nanoparticles possess many unique properties that make them attractive for use in biological applications. Recently they received attention when it was shown that 10 nm silver nanoparticles were bactericidal, which is promising in light of the growing number of antibiotic resistant bacteria. An area that has been largely unexplored is the interaction of nanomaterials with viruses and the possible use of silver nanoparticles as an antiviral agent.

Results

This research focuses on evaluating the interaction of silver nanoparticles with a New World arenavirus, Tacaribe virus, to determine if they influence viral replication. Surprisingly exposing the virus to silver nanoparticles prior to infection actually facilitated virus uptake into the host cells, but the silver-treated virus had a significant reduction in viral RNA production and progeny virus release, which indicates that silver nanoparticles are capable of inhibiting arenavirus infection in vitro. The inhibition of viral replication must occur during early replication since although pre-infection treatment with silver nanoparticles is very effective, the post-infection addition of silver nanoparticles is only effective if administered within the first 2-4 hours of virus replication.

Conclusions

Silver nanoparticles are capable of inhibiting a prototype arenavirus at non-toxic concentrations and effectively inhibit arenavirus replication when administered prior to viral infection or early after initial virus exposure. This suggests that the mode of action of viral neutralization by silver nanoparticles occurs during the early phases of viral replication.
Profiling alumni of a Brazilian public dental school
Authors: Nunes Maria F , Silva Erica T , Santos Laura B , Queiroz Maria G , Leles Cláudio R
Published: August 2010

Background

Follow-up studies of former students are an efficient way to organize the entire process of professional training and curriculum evaluation. The aim of this study was to identify professional profile subgroups based on job-related variables in a sample of former students of a Brazilian public dental school.

Methods

A web-based password-protected questionnaire was sent to 633 registered dentists who graduated from the Federal University of Goias between 1988 and 2007. Job-related information was retrieved from 14 closed questions, on subjects such as gender, occupational routine, training, profits, income status, and self-perception of professional career, generating an automatic database for analysis. The two-step cluster method was used for dividing dentists into groups on the basis of minimal within-group and maximal between-group variation, using job-related variables to represent attributes upon which the clustering was based.

Results

There were 322 respondents (50.9%), predominantly female (64.9%) and the mean age was 34 years (SD = 6.0). The automatic selection of an optimal number of clusters included 289 cases (89.8%) in 3 natural clusters. Clusters 1, 2 and 3 included 52.2%, 30.8% and 17.0% of the sample respectively. Interpretation of within-group rank of variable importance for cluster segmentation resulted in the following characterization of clusters: Cluster 1 - specialist dentists with higher profits and positive views of the profession; Cluster 2 - general dental practitioners in small cities; Cluster 3 - underpaid and less motivated dentists with negative views of the profession. Male dentists were predominant in cluster 1 and females in cluster 3. One-way Anova showed that age and time since graduation were significantly lower in Cluster 2 (P < 0.001). Alternative solutions with 4 and 5 clusters revealed specific discrimination of Cluster 1 by gender and dental education professionals.

Conclusions

Cluster analysis was a valuable method for identifying natural grouping with relatively homogeneous cases, providing potentially meaningful information for professional orientation in dentistry in a variety of professional situations and environments.
Does pleural fluid appearance really matter? The relationship between fluid appearance and cytology, cell counts, and chemical laboratory measurements in pleural effusions of patients with cancer
Authors: Ozcakar Bulent , Martinez Carlos H , Morice Rodolfo C , Eapen Georgie A , Ost David , Sarkiss Mona G , Chiu Hsienchang T , Jimenez Carlos A
Published: August 2010

Background

Previous reports have suggested that the appearance of pleural effusions (i.e., the presence or absence of blood) might help to establish the etiology of the effusions. This study explores the relationship between pleural fluid appearance and the results of chemical and cytological analyses in a group of patients with recurrent symptomatic pleural effusions and a diagnosis of cancer.

Methods

Medical records were reviewed from all 390 patients who were diagnosed with cancer, who underwent thoracentesis before placement of an intrapleural catheter (IPC) between April 2000 and January 2006. Adequate information for data analysis was available in 365 patients. The appearance of their pleural fluid was obtained from procedure notes dictated by the pulmonologists who had performed the thoracenteses. The patients were separated into 2 groups based on fluid appearance: non-bloody and bloody. Group differences in cytology interpretation were compared by using the chi square test. Cellular counts, chemical laboratory results, and survival after index procedure were compared by using the student's t test.

Results

Pleural fluid cytology was positive on 82.5% of the non-bloody effusions and on 82.4% of the bloody ones. The number of red blood cells (220.5 × 103/μL vs. 12.3 × 103/μL) and LDH values (1914 IU/dl vs. 863 IU/dl) were statistically higher in bloody pleural effusions.

Conclusion

The presence or absence of blood in pleural effusions cannot predict their etiology in patients with cancer and recurrent symptomatic pleural effusions.
Atypical presentation of acute pancreatitis in a man with pancreatic insufficiency and cystic fibrosis: a case report
Authors: Turner Malcolm , Jackson Hugh , Harle Robin , Bohmer Rob , Reid David W
Published: August 2010

Introduction

Whether acute pancreatitis can occur in pancreatically insufficient individuals with cystic fibrosis remains a matter of debate.

Case presentation

We describe a case of acute pancreatitis occurring in a 52-year-old Caucasian Australian man with moderately severe cystic fibrosis lung disease and pancreatic insufficiency. An inflammatory mass within the head of his pancreas was confirmed using computed tomography, magnetic resonance imaging and pancreatic biopsy, but serum amylase and lipase remained normal throughout the acute phase of his illness. His symptoms and the pancreatic mass resolved following the insertion of a biliary stent and the introduction of ursodeoxycholic acid.

Conclusion

Our case report highlights the potential for acute pancreatitis to occur in patients with pancreatic insufficiency and cystic fibrosis. We further demonstrate that conventional biochemical markers that are normally assessed to confirm the diagnosis may not be of particular use. As patients with cystic fibrosis survive into their fourth and fifth decades of life, atypical presentations of acute pancreatitis may become more common.
Metabolic syndrome, dyslipidemia, hypertension and type 2 diabetes in youth: from diagnosis to treatment
Authors: Halpern Alfredo , Mancini Marcio C , Magalhães Maria Eliane C , Fisberg Mauro , Radominski Rosana , Bertolami Marcelo C , Bertolami Adriana , de Melo Maria Edna , Zanella Maria Teresa , Queiroz Marcia S , Nery Marcia
Published: August 2010

Overweight and obesity in youth is a worldwide public health problem. Overweight and obesity in childhood and adolescents have a substantial effect upon many systems, resulting in clinical conditions such as metabolic syndrome, early atherosclerosis, dyslipidemia, hypertension and type 2 diabetes (T2D). Obesity and the type of body fat distribution are still the core aspects of insulin resistance and seem to be the physiopathologic links common to metabolic syndrome, cardiovascular disease and T2D. The earlier the appearance of the clustering of risk factors and the higher the time of exposure, the greater will be the chance of developing coronary disease with a more severe endpoint. The age when the event may occur seems to be related to the presence and aggregation of risk factors throughout life.

The treatment in this age-group is non pharmacological and aims at promoting changes in lifestyle. However, pharmacological treatments are indicated in special situations.

The major goals in dietary treatments are not only limited to weight loss, but also to an improvement in the quality of life. Modification of risk factors associated to comorbidities, personal satisfaction of the child or adolescent and trying to establish healthy life habits from an early age are also important. There is a continuous debate on the best possible exercise to do, for children or adolescents, in order to lose weight. The prescription of physical activity to children and adolescents requires extensive integrated work among multidisciplinary teams, patients and their families, in order to reach therapeutic success.

The most important conclusion drawn from this symposium was that if the growing prevalence of overweight and obesity continues at this pace, the result will be a population of children and adolescents with metabolic syndrome. This would lead to high mortality rates in young adults, changing the current increasing trend of worldwide longevity. Government actions and a better understanding of the causes of this problem must be implemented worldwide, by aiming at the prevention of obesity in children and adolescents.
New concept for quantification of similarity relates entropy and energy of objects: First and Second Law entangled, group behavior of micro black holes expected
Authors: Zimak Petr , Terenzi Silvia , Strazewski Peter
Published: August 2010

When the free energy of similar but distinct molecule-sized objects is plotted against the temperature at which their energy and entropy contributions cancel, a highly significant linear dependence results from which the degree of similarity between the distinctly different members within the group of objects can be quantified and a relationship between energy and entropy is derived. This energy-entropy relationship entirely reflects the mathematical structure of thermodynamic equations, is in this sense fundamental and therefore does probably not dependent on material nor scale. The energy-entropy relationship is likely to be of general interest in molecular biology, population biology, synthetic biology, biophysics, chemical thermodynamics, systems chemistry and physics, most notably in particle physics and cosmology. In physics we predict a consistent and perhaps testable way of classifying micro black holes, to be generated in future Large Hadron Collider experiments, by their gravitational energy and area entropy.
Evolution of metabolic networks: a computational frame-work
Authors: Flamm Christoph , Ullrich Alexander , Ekker Heinz , Mann Martin , Högerl Daniel , Rohrschneider Markus , Sauer Sebastian , Scheuermann Gerik , Klemm Konstantin , Hofacker Ivo L , Stadler Peter F
Published: August 2010

Background

The metabolic architectures of extant organisms share many key pathways such as the citric acid cycle, glycolysis, or the biosynthesis of most amino acids. Several competing hypotheses for the evolutionary mechanisms that shape metabolic networks have been discussed in the literature, each of which finds support from comparative analysis of extant genomes. Alternatively, the principles of metabolic evolution can be studied by direct computer simulation. This requires, however, an explicit implementation of all pertinent components: a universe of chemical reactions upon which the metabolism is built, an explicit representation of the enzymes that implement the metabolism, a genetic system that encodes these enzymes, and a fitness function that can be selected for.

Results

We describe here a simulation environment that implements all these components in a simplified way so that large-scale evolutionary studies are feasible. We employ an artificial chemistry that views chemical reactions as graph rewriting operations and utilizes a toy-version of quantum chemistry to derive thermodynamic parameters. Minimalist organisms with simple string-encoded genomes produce model ribozymes whose catalytic activity is determined by anad hocmapping between their secondary structure and the transition state graphs that they stabilize. Fitness is computed utilizing the ideas of metabolic flux analysis. We present an implementation of the complete system and first simulation results.

Conclusions

The simulation system presented here allows coherent investigations into the evolutionary mechanisms of the first steps of metabolic evolution using a self-consistent toy universe.
Spontaneous absolute asymmetric synthesis promoted by achiral amines in conjunction with asymmetric autocatalysis
Authors: Suzuki Kenta , Hatase Kunihiko , Nishiyama Daisuke , Kawasaki Tsuneomi , Soai Kenso
Published: August 2010

The origin of homochirality of organic compounds such as L-amino acids and D-sugars have intrigued many scientists, and several hypotheses regarding its homochirality have been proposed. According to the statistical theory, small fluctuations in the ratio of the two enantiomers are present in a racemic mixture obtained from the reaction of achiral molecules.

We report herein the reaction of pyrimidine-5-carbaldehyde and diisopropylzinc in the presence of achiral amine such as N,N'-dimethylpiperazine, N,N'-diethylpiperazine or N-methylmorpholine but in the absence of a chiral substance. The stochastic formation of (S)- and (R)-pyrimidyl alkanols with detectable ee was observed. This study shows that the slight fluctuation of the enantiomeric ratio of pyrimidyl alkanol produced at the initial reaction step can be enhanced significantly in conjunction with asymmetric autocatalysis with amplification of enantiomeric excess. We believe that the stochastic behavior in the formation of pyrimidyl alkanol constitutes one of the conditions necessary for spontaneous absolute asymmetric synthesis.
Deconvolution of a multi-component interaction network using systems chemistry
Authors: Ghosh Soumyadip , Mukhopadhyay Pritam , Isaacs Lyle
Published: August 2010

We describe the stepwise construction of an 8-component self-sorted system (1 - 8) by the sequential addition of components. This process occurs via a large number of states (28 = 256) and even a larger number of pathways (8! = 40320). A pathway (5, 6, 7, 8, 4, 3, 2, then 1) that is self-sorted at every step along the way has been demonstrated experimentally. Another pathway (1, 8, 3, 5, 4, 7, 2, then 6) resembles a game of musical chairs and exhibits interesting shuttling of guest molecules among hosts. The majority of pathways - unlike the special ones described above - proceed through several non self-sorted states. We characterized the remainder of the 40320 pathways by simulation using Gepasi and describe the influence of concentration and binding constants on the fidelity of the self-sorting pathways.
Using the value of the crosscorrelation coefficient to locate microseismic events
Authors: Kummerow J.
Published: August 2010

A procedure to locate seismic events uses the value of the crosscorrelation coefficient between waveforms of different events. First, an empirical relation between spatial event separation and maximum crosscorrelation coefficient is established for a subset of a priori located reference events. Then this relation is used to determine the hypocenters of an increasing number of events by a grid-search strategy. Measured arrival-time differences between S- and P-waves also constrain the location. Although the reference events are located by a standard method using the arrival-time measurements at three or more receivers, the correlation-based location requires only one receiver. The method has been applied to microseismic data recorded at a single borehole sensor during the 2004/05 injection experiment at the Continental Deep Drilling Site (KTB) in Germany. With the approach, significantly more weak seismic events were located, compared to the number of events recorded by a near-surface receiver array and by inversion of arrival times. The proposed location method is particularly well suited to locate small-magnitude earthquakes within dense event clouds when too few arrival-time observations for part of the events are available and standard location methods fail. These conditions are frequently met in the case of microseismic monitoring of geothermal or enhanced oil recovery experiments.
Postmodern Repetitions: Parody, Trauma, and the Case of Kara Walker
Authors: Tang Amy
Published: August 2010

There is perhaps no single formal practice more closely associated with contemporary culture than the repetition of images, styles, and forms from the past, and nowhere have these practices been more contentiously debated than in the cultural production of racial subjects. This essay argues that critics consistently interpret such repetitions through the opposing frameworks of either parody or trauma, which consign them to imagining a racial subject who is either entirely in possession of the past or entirely possessed by it; who either stages a cathartic emancipation from historical oppressio or continual subjection to it. These opposing views of postmodern repetitions have collided in an especially contentious way in the reception of the work of visual artist Kara Walker, whose cut-paper silhouettes of antebellum racial stereotypes are seen as either parodically resignifying racist imagery or traumatically reproducing it. This essay argues that by relying only upon these models of repetition, critics inevitably fail to recognize the dynamic of compulsive repetition that permeates Walker's art, a dynamic that dialectically entwines the agency and subjection implied by parody and trauma respectively. For Walker, compulsive repetition becomes a way to elucidate the equivocal logic of contemporary identity politics, which consigns the socially marginalized to the contradictory practice of affirming the very identities on which their historical exclusion has been based. Concerned less with the recuperation of the past than with the contradictions of the present, then, Walker's art offers an incisive account of a contemporary moment that compels iterative repetitions rather than allowing conclusive resolutions.
Control of Notch-ligand endocytosis by ligand-receptor interaction
Authors: Hansson Emil M. , Lanner Fredrik , Das Debashish , Mutvei Anders , Marklund Ulrika , Ericson Johan , Farnebo Filip , Stumm Gabriele , Stenmark Harald , Andersson Emma R. , Lendahl Urban
Published: August 2010

In Notch signaling, cell-bound ligands activate Notch receptors on juxtaposed cells, but the relationship between ligand endocytosis, ubiquitylation and ligand-receptor interaction remains poorly understood. To study the specific role of ligand-receptor interaction, we identified a missense mutant of the Notch ligand Jagged1 (Nodder, Ndr) that failed to interact with Notch receptors, but retained a cellular distribution that was similar to wild-type Jagged1 (Jagged1WT) in the absence of active Notch signaling. Both Jagged1WT and Jagged1Ndr interacted with the E3 ubiquitin ligase Mind bomb, but only Jagged1WT showed enhanced ubiquitylation after co-culture with cells expressing Notch receptor. Cells expressing Jagged1WT, but not Jagged1Ndr, trans-endocytosed the Notch extracellular domain (NECD) into the ligand-expressing cell, and NECD colocalized with Jagged1WT in early endosomes, multivesicular bodies and lysosomes, suggesting that NECD is routed through the endocytic degradation pathway. When coexpressed in the same cell, Jagged1Ndr did not exert a dominant-negative effect over Jagged1WT in terms of receptor activation. Finally, in Jag1Ndr/Ndr mice, the ligand was largely accumulated at the cell surface, indicating that engagement of the Notch receptor is important for ligand internalization in vivo. In conclusion, the interaction-dead Jagged1Ndr ligand provides new insights into the specific role of receptor-ligand interaction in the intracellular trafficking of Notch ligands.
Assortment Planning and Inventory Decisions Under Stockout-Based Substitution
Authors: Honhon Dorothée , Gaur Vishal , Seshadri Sridhar
Published: August 2010

We present an efficient dynamic programming algorithm to determine the optimal assortment and inventory levels in a single-period problem with stockout-based substitution. In our model, total customer demand is random and comprises fixed proportion of customers of different types. Customer preferences are modeled through the definition of these types. Each customer type corresponds to a specific preference ordering among products. A customer purchases the highest-ranked product, according to his type (if any), that is available at the time of his visit to the store (stockout-based substitution). We solve the optimal assortment problem using a dynamic programming formulation. We establish structural properties of the value function of the dynamic program that, in particular, help to characterize multiple local maxima. We use the properties of the optima to solve the problem in pseudopolynomial time. Our algorithm also gives a heuristic for the general case, i.e., when the proportion of customers of each type is random. In numerical tests, this heuristic performs better and faster than previously known methods, especially when the mean demand is large, the degree of substitutability is high, the population is homogeneous, or prices and/or costs vary across products.
Dynamic Supplier Contracts Under Asymmetric Inventory Information
Authors: Zhang Hao , Nagarajan Mahesh , Sošić Greys
Published: August 2010

In this paper, we examine a supply chain in which a single supplier sells to a downstream retailer. We consider a multiperiod model with the following sequence of events. In period t the supplier offers a contract to the retailer, and the retailer makes her purchasing decision in anticipation of the random demand. The demand then unravels, and the retailer carries over any excess inventory to the next period (unmet demand is lost). In period t+1 the supplier designs a new contract based on his belief of the retailer's inventory, and the game is played dynamically. We assume that short-term contracts are used, i.e., the contracting is dynamically conducted at the beginning of each period. We also assume that the retailer's inventory before ordering is not observed by the supplier. This setting describes scenarios in which the downstream retailer does not share inventory/sales information with the supplier. For instance, it captures the phenomenon of retailers distorting past sales information to secure better contracting terms from their suppliers. We cast our problem as a dynamic adverse-selection problem and show that, given relatively high production and holding costs, the optimal contract can take the form of a batch-order contract, which minimizes the retailer's information advantage. We then analyze the performance of this type of contract with respect to some useful benchmarks and quantify the value of prudent contract design and the value of inventory information to the supply chain. Markovian adverse-selection models, in which the state and action in a period affect the state in the subsequent period, are recognized as theoretically challenging and are relatively less understood. We take a nontrivial step towards a better understanding of such models under short-term contracting.
The cμ/θ Rule for Many-Server Queues with Abandonment
Authors: Atar Rami , Giat Chanit , Shimkin Nahum
Published: August 2010

We consider a multiclass queueing system with multiple homogeneous servers and customer abandonment. For each customer class i, the holding cost per unit time, the service rate, and the abandonment rate are denoted by ci, μi, and θi, respectively. We prove that under a many-server fluid scaling and overload conditions, a server-scheduling policy that assigns priority to classes according to their index ciμi/θi is asymptotically optimal for minimizing the overall long-run average holding cost. An additional penalty on customer abandonment is easily incorporated into this model and leads to a similar index rule.
Biomarker-Based Prediction of Response to Therapy for Colorectal Cancer
Authors: Ross Jeffrey S. , Torres-Mora Jorge , Wagle Nikhil , Jennings Timothy A. , Jones David M.
Published: August 2010

The diagnosis and management of colorectal cancer (CRC) has been impacted by the discovery and validation of a wide variety of biomarkers designed to facilitate a personalized approach for the treatment of the disease. Recently, CRC has been reclassified based on molecular analyses of various genes and proteins capable of separating morphologic types of tumors into molecular categories. At the same time, a number of new prognostic and predictive single genes and proteins have been discovered that are designed to reflect sensitivity and/or resistance to existing therapies. Multigene predictors have also been developed to predict the risk of relapse for intermediate-stage CRC after completion of surgical extirpation. More recently, a number of biomarkers tested by a variety of methods have been proposed as specific predictors of chemotherapy and radiotherapy response. Other markers have been successfully used to predict toxic effects of standard therapies. In this review, a series of novel biomarkers are considered and compared with standard-of-care markers for their potential use as pharmacogenomic and pharmacogenetic predictors of disease outcome.
Country Leadership and Policy Are Critical Factors for Implementing Laboratory Accreditation in Developing Countries
Authors: Opio Alex , Wafula Winnie , Amone Jackson , Kajumbula Henry , Nkengasong John N.
Published: August 2010

Accreditation of laboratories is one means to promote quality laboratory services, underscoring the need to document factors that facilitate laboratory accreditation. A desk review and key informant’s interviews were conducted to determine the roles of country leadership and policies in laboratory accreditation.

Overall, the review revealed that Uganda has enabling factors for laboratory accreditation, putting the country in a state of accreditation-readiness and including strong leadership that provides stewardship and availability of a national health laboratory policy with an explicit statement on laboratory accreditation. A National Laboratory Technical and Policy Committee coordinated the development of the policy. Laboratory training schools provide leadership in training laboratory professionals, while the Association of Medical Laboratory Technologists provides professional leadership. Although there is no national accreditation system, some laboratories are participating in international laboratory accreditation. Key informants expressed strong support for and observed that laboratory accreditation is beneficial and can be implemented in Uganda.

Lessons from this study can benefit countries planning to implement laboratory accreditation. Countries that have not developed national laboratory policies and strategic plans should do so to guide the strengthening of laboratory systems and services as a part of health systems strengthening, which would be a springboard for laboratory accreditation.
CD71 (Transferrin Receptor)
Authors: Marsee Derek K. , Pinkus Geraldine S. , Yu Hongbo
Published: August 2010

Accurate analysis of the erythroid lineage is essential in evaluating bone marrow biopsy specimens and can be particularly challenging in the setting of dyserythropoiesis. Transferrin receptor (CD71) mediates the uptake of transferrin-iron complexes and is highly expressed on the surface of cells of the erythroid lineage. Although CD71 has been used for flow cytometric analysis, its usefulness in paraffin-embedded bone marrow biopsy specimens has not been examined. This study defined the immunohistochemical profile of CD71, as compared with glycophorin A (CD235a) and hemoglobin, in 65 bone marrow biopsy specimens, including normal marrow specimens and cases of myelodysplastic syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, plasma cell neoplasm, and metastatic carcinoma. Immunoreactivity for CD71 was restricted to erythroid precursors in normal and dyspoietic marrow samples and exhibited a membranous and cytoplasmic staining pattern. The vast majority of mature erythrocytes lack expression of CD71, greatly facilitating interpretation. CD71 is a highly effective marker for the detection of cells of erythroid lineage in bone marrow biopsy specimens.
High Serum Thymidine Kinase 1 Level Predicts Poorer Survival in Patients With Chronic Lymphocytic Leukemia
Authors: Konoplev Sergej N. , Fritsche Herbert A. , O’Brien Susan , Wierda William G. , Keating Michael J. , Gornet Terrie G. , St Romain Susan , Wang Xuemei , Inamdar Kedar , Johnson Malisha R. , Medeiros L. Jeffrey , Bueso-Ramos Carlos E.
Published: August 2010

Serum thymidine kinase 1 (TK1) levels have been reported to have prognostic significance in patients with chronic lymphocytic leukemia (CLL). Until recently, serum TK1 levels were assessed using inconvenient radioenzyme assays. In this study, we used a novel chemiluminescence assay to assess serum TK1 levels in patients with CLL at the time of first examination. We show that high serum TK1 levels predict poorer overall survival and correlate with unmutated immunoglobulin variable region genes, CD38 and ZAP-70 expression, and subsequent risk of developing large B-cell lymphoma (Richter syndrome). Similar findings were observed in a subset of patients treated with current fludarabine-based chemotherapy regimens. We suggest that serum TK1 levels analyzed using this convenient chemiluminescence assay may be useful in the risk assessment of patients with CLL.
New Drug Approvals: Milnacipran for Treatment of Fibromyalgia
Authors: Kyle Jeffrey A , Dugan B DeeAnn , Testerman Kristian K
Published: August 2010

Objective:

To review the pharmacology, pharmacokinetics, efficacy, and safety of milnacipran and evaluate relevant clinical trial data.

Data Sources:

MEDLINE, International Pharmaceutical Abstracts, and Google Scholar searches (1966-June 2010) were conducted using the key words fibromyalgia, milnacipran, and serolonin-norepinephrine reuptake inhibitor. Searches were limited to articles published in English.

Study Selection and Data Extraction:

All available English-language articles of human studies were evaluated. One pharmacokinetic study reviewed included animal data. References cited in identified articles were used for additional evaluation.

Data Synthesis:

Milnacipran is a serotonin-norepinephrine reuptake inhibitor with a 3-fotd increased selectivity for norepinephrine compared to serotonin. It is well absorbed with 85-90% bioavailability. Maximum concentrations are achieved 2-4 hours after administration. Milnacipran does not undergo cytochrome P450 metabolism and has a half-life of 6-8 hours. Fifty-five percent of each dose is excreted unchanged in the urine. Dose adjustment is needed in patients with an estimated creatinine clearance of <30 mL/min. Clinical trials indicated that twice-daily dosing at 100 mg/day or 200 mg/day was superior to single-daily dosing. Studies further established the effectiveness of both doses in the treatment of fibromyalgia pain utilizing patient self-reported pain scores, as well as on a visual analog scale, Patient Global Impression of Change scale, and the Short-Form 36 Physical Component Summary, A 6-month extension trial, which evaluated patients continued on milnacipran for up to 1 year, demonstrated continued pain relief. The most common adverse drug reaction associated with milnacipran was nausea, which was reduced with slow-dose titration and administrai ion with food.

Conclusions:

Milnacipran is an effective treatment option for patients with fibromyalgia. More head-to-head clinical trials are necessary to assess its ultimate place in therapy.
The Therapeutic Test: An Ancient Malady in the 21 st Century
Authors: Schmalstieg Frank C , Goldman Armond S
Published: August 2010

The response to treatment was the diagnostic mainstay in ancient times when diseases were poorly understood. Now that the bases of most diseases are known, appropriate diagnostic means are available. However, many physicians still rely on therapeutic tests to establish diagnoses. Since most illnesses are self-limited and because of the placebo effect, many physicians and patients attribute the improvement to (he medication and believe that the correct diagnosis was made. However, inappropriate therapeutic tests often lead to diagnostic delays. rapid emergence of antibiotic-resistant bacterial pathogens, increased risks of adverse drug reactions, and unnecessary expenses. To reduce the frequency of unwarranted therapeutic tests, health-care professionals and educators must take steps to rectify the problem.
Statistical methods for assessment of added usefulness of new biomarkers
Authors: Pencina Michael J. , D'Agostino Ralph B. , Vasan Ramachandran S.
Published: August 2010

The discovery and development of new biomarkers continues to be an exciting and promising field. Improvement in prediction of risk of developing disease is one of the key motivations in these pursuits. Appropriate statistical measures are necessary for drawing meaningful conclusions about the clinical usefulness of these new markers. In this review, we present several novel metrics proposed to serve this purpose. We use reclassification tables constructed on the basis of clinically meaningful disease risk categories to discuss the concepts of calibration, risk separation, risk discrimination, and risk classification accuracy. We discuss the notion that the net reclassification improvement (NRI) is a simple yet informative way to summarize information contained in risk reclassification tables. In the absence of meaningful risk categories, we suggest a ‘category-less’ version of the NRI and integrated discrimination improvement as metrics to summarize the incremental value of new biomarkers. We also suggest that predictiveness curves be preferred to receiver operating characteristic curves as visual descriptors of a statistical model's ability to separate predicted probabilities of disease events. Reporting of standard metrics, including measures of relative risk and the c statistic, is still recommended. These concepts are illustrated with a risk prediction example using data from the Framingham Heart Study.

Clin Chem Lab Med 2010;48:1703–11.
Repeated Stress Impairs Endocannabinoid Signaling in the Paraventricular Nucleus of the Hypothalamus
Authors: Wamsteeker Jaclyn I. , Kuzmiski J. Brent , Bains Jaideep S.
Published: August 2010

Endocannabinoids (eCBs) are ubiquitous retrograde signaling molecules in the nervous system that are recruited in response to robust neuronal activity or the activation of postsynaptic G-protein-coupled receptors. Physiologically, eCBs have been implicated as important mediators of the stress axis and they may contribute to the rapid feedback inhibition of the hypothalamic–pituitary–adrenal axis (HPA) by circulating corticosteroids (CORTs). Understanding the relationship between stress and eCBs, however, is complicated by observations that eCB signaling is itself sensitive to stress. The mechanisms that link stress to changes in synaptic eCB signaling and the impact of these changes on CORT-mediated negative feedback have not been resolved. Here, we show that repetitive immobilization stress, in juvenile male rats, causes a functional downregulation of CB1receptors in the paraventricular nucleus of the hypothalamus (PVN). This loss of CB1receptor signaling, which requires the activation of genomic glucocorticoid receptors, impairs both activity and receptor-dependent eCB signaling at GABA and glutamate synapses on parvocellular neuroendocrine cells in PVN. Our results provide a plausible mechanism for how stress can lead to alterations in CORT-mediated negative feedback and may contribute to the development of plasticity of HPA responses.
The Muscarinic Long-Term Enhancement of NMDA and AMPA Receptor-Mediated Transmission at Schaffer Collateral Synapses Develop through Different Intracellular Mechanisms
Authors: de Sevilla David Fernández , Buño Washington
Published: August 2010

We had described a muscarinic-mediated long-term synaptic enhancement at Schaffer collateral synapses caused by the insertion of AMPARs in spines of rat hippocampal CA1 pyramidal neurons that requires Ca2+release from IP3-sensitive stores (Fernández de Sevilla et al., 2008). We now show that this AMPA-mediated LTPIP3is precisely matched by an amplification of NMDAR-mediated transmission. The enhanced AMPAR transmission involves SNARE protein activity and CaMKII activation. The amplification of NMDA transmission requires combined CaMKII, PKC, and SRC kinase activity without detectable surface incorporation of NMDARs, suggesting that changes in receptor properties mediate this process. The enhanced AMPAR- and NMDAR-mediated transmission markedly reduce the induction threshold of “Hebbian” LTP. We conclude that both modes of glutamatergic synaptic potentiation may play a critical functional role in the regulation of the learning machinery of the brain by adding flexibility to the demands of the hippocampal network.
Stability of the Visual World during Eye Drift
Authors: Poletti Martina , Listorti Chiara , Rucci Michele
Published: August 2010

We are normally not aware of the microscopic eye movements that keep the retinal image in motion during visual fixation. In principle, perceptual cancellation of the displacements of the retinal stimulus caused by fixational eye movements could be achieved either by means of motor/proprioceptive information or by inferring eye movements directly from the retinal stimulus. In this study, we examined the mechanisms underlying visual stability during ocular drift, the primary source of retinal image motion during fixation on a stationary scene. By using an accurate system for gaze-contingent display control, we decoupled the eye movements of human observers from the changes in visual input that they normally cause. We show that the visual system relies on the spatiotemporal stimulus on the retina, rather than on extraretinal information, to discard the motion signals resulting from ocular drift. These results have important implications for the establishment of stable visual representations in the brain and argue that failure to visually determine eye drift contributes to well known motion illusions such as autokinesis and induced movement.
Nuclear Factor κB Controls Acetylcholine Receptor Clustering at the Neuromuscular Junction
Authors: Wang Jia , Fu Xiu-Qing , Lei Wen-Liang , Wang Tong , Sheng Ai-Li , Luo Zhen-Ge
Published: August 2010

At the vertebrate neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is stimulated by motor neuron-derived glycoprotein Agrin and requires a number of intracellular signal or structural proteins, including AChR-associated scaffold protein Rapsyn. Here, we report a role of nuclear factor κB (NF-κB), a well known transcription factor involved in a variety of immune responses, in regulating AChR clustering at the NMJ. We found that downregulating the expression of RelA/p65 subunit of NF-κB or inhibiting NF-κB activity by overexpression of mutated form of IκB (inhibitor κB), which is resistant to proteolytic degradation and thus constitutively keeps NF-κB inactive in the cytoplasma, impeded the formation of AChR clusters in cultured C2C12 muscle cells stimulated by Agrin. In contrast, overexpression of RelA/p65 promoted AChR clustering. Furthermore, we investigated the mechanism by which NF-κB regulates AChR clustering. Interestingly, we found that downregulating the expression of RelA/p65 caused a marked reduction in the protein and mRNA level of Rapsyn and upregulation of RelA/p65 enhanced Rapsyn promoter activity. Mutation of NF-κB binding site on Rapsyn promoter prevented responsiveness to RelA/p65 regulation. Moreover, forced expression of Rapsyn in RelA/p65 downregulated muscle cells partially rescued AChR clusters, suggesting that NF-κB regulates AChR clustering, at least partially through the transcriptional regulation of Rapsyn. In line with this notion, genetic ablation of RelA/p65 selectively in the skeletal muscle caused a reduction of AChR density at the NMJ and a decrease in the level of Rapsyn. Thus, NF-κB signaling controls AChR clustering through transcriptional regulation of synaptic protein Rapsyn.
Motoneurons Dedicated to Either Forward or Backward Locomotion in the NematodeCaenorhabditis elegans
Authors: Haspel Gal , O'Donovan Michael J. , Hart Anne C.
Published: August 2010

Multifunctional motoneurons and muscles, which are active during forward and backward locomotion are ubiquitous in animal models. However, studies in the nematodeCaenorhabditis eleganssuggest that some locomotor motoneurons are necessary only for forward locomotion (dorsal B-motoneurons, DB), while others (dorsal A-motoneurons, DA) are necessary only for backward locomotion. We tested this hypothesis directly by recording the activity of these motoneurons during semirestrained locomotion. For this purpose, we used epifluorescence imaging of the genetically encoded calcium sensor cameleon, expressed in specific motoneurons, while monitoring locomotor behavior through the microscope condenser using a second camera. We found that ventral and dorsal B-motoneurons (DB and VB) were coactive during forward locomotion while ventral A-motoneurons (VA) were only active during backward locomotion. The signals we recorded correlated with the direction of locomotion but not with the faster undulatory cycles. To our knowledge, these are the first recordings of motoneuron activity inC. elegansand the only direction-dedicated motoneurons described to date.
Age-Related Deterioration of Rod Vision in Mice
Authors: Kolesnikov Alexander V. , Fan Jie , Crouch Rosalie K. , Kefalov Vladimir J.
Published: August 2010

Even in healthy individuals, aging leads to deterioration in visual acuity, contrast sensitivity, visual field, and dark adaptation. Little is known about the neural mechanisms that drive the age-related changes of the retina and, more specifically, photoreceptors. According to one hypothesis, the age-related deterioration in rod function is due to the limited availability of 11-cis-retinal for rod pigment formation. To determine how aging affects rod photoreceptors and to test the retinoid-deficiency hypothesis, we compared the morphological and functional properties of rods of adult and aged B6D2F1/J mice. We found that the number of rods and the length of their outer segments were significantly reduced in 2.5-year-old mice compared with 4-month-old animals. Aging also resulted in a twofold reduction in the total level of opsin in the retina. Behavioral tests revealed that scotopic visual acuity and contrast sensitivity were decreased by twofold in aged mice, and rod ERG recordings demonstrated reduced amplitudes of both a- and b-waves. Sensitivity of aged rods determined from single-cell recordings was also decreased by 1.5-fold, corresponding to not more than 1% free opsin in these photoreceptors, and kinetic parameters of dim flash response were not altered. Notably, the rate of rod dark adaptation was unaffected by age. Thus, our results argue against age-related deficiency of 11-cis-retinal in the B6D2F1/J mouse rod visual cycle. Surprisingly, the level of cellular dark noise was increased in aged rods, providing an alternative mechanism for their desensitization.
The Development of the Corpus Callosum in the Healthy Human Brain
Authors: Luders Eileen , Thompson Paul M. , Toga Arthur W.
Published: August 2010

The corpus callosum changes structurally throughout life, but most dramatically during childhood and adolescence. Even so, existing studies of callosal development tend to use parcellation schemes that may not capture the complex spatial profile of anatomical changes. Thus, more detailed mapping of callosal growth processes is desirable to create a normative reference. This will help to relate and interpret other structural, functional, and behavioral measurements, both from healthy subjects and pediatric patients. We applied computational surface-based mesh-modeling methods to analyze callosal morphology at extremely high spatial resolution. We mapped callosal development and explored sex differences in a large and well matched sample of healthy children and adolescents (n= 190) aged 5–18 years. Except for the rostrum in females, callosal thickness increased across the whole surface, with sex- and region-specific rates of growth, and at times shrinkage. The temporally distinct changes in callosal thickness are likely to be a consequence of varying degrees of axonal myelination, redirection, and pruning. Alternating phases of callosal growth and shrinkage may reflect a permanent adjustment and fine-tuning of fibers connecting homologous cortical areas during childhood and adolescence. Our findings emphasize the importance of taking into account sex differences in future studies, as existing developmental effects might remain disguised (or biased toward the effect of the dominant sex in unbalanced statistical designs) when pooling male and female samples.