bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Structure Adds Power to Detect Schizophrenia Susceptibility at SLIT3 in the Chinese Han Population
Authors: Shi YongYong , Zhao XinZhi , Yu Lan , Tao Ran , Tang JunXia , La YuJuan , Duan Yun , Gao Bo , Gu NiuFan , Xu YiFeng , Feng GuoYin , Zhu ShaoMin , Liu HuiJun , Salter Hugh , He Lin
Published: July 2004

The Chinese Han population, the largest population in the world, has traditionally been geographically divided into two parts, the Southern Han and Northern Han. In practice, however, these commonly used ethnic labels are both insufficient and inaccurate as descriptors of inferred genetic clustering, and can lead to the observation of “spurious association” as well as the concealment of real association. In this study, we attempted to address this problem by using 14 microsatellite markers to reconstruct the population genetic structure in 768 Han Chinese samples, including 384 Southern Han and 384 Northern Han, and in samples from Chinese minorities including 48 Yao and 48 BouYei subjects. Furthermore, with a dense set of markers around the region 5q34–35, we built fine-scale haplotype networks for each population/subpopulation and tested for association to schizophrenia susceptibility. We found that more variants in SLIT3 tend to associate with schizophrenia susceptibility in the genetically structured samples, compared to geographically structured samples and samples without identified population substructure. Our results imply that identifying the hidden genetic substructure adds power when detecting association, and suggest that SLIT3 or a nearby gene is associated with schizophrenia.
Transcript Level Alterations Reflect Gene Dosage Effects Across Multiple Tissues in a Mouse Model of Down Syndrome
Authors: Kahlem Pascal , Sultan Marc , Herwig Ralf , Steinfath Matthias , Balzereit Daniela , Eppens Barbara , Saran Nidhi G. , Pletcher Mathew T. , South Sarah T. , Stetten Gail , Lehrach Hans , Reeves Roger H. , Yaspo Marie-Laure
Published: July 2004

Human trisomy 21, which results in Down syndrome (DS), is one of the most complicated congenital genetic anomalies compatible with life, yet little is known about the molecular basis of DS. It is generally accepted that chromosome 21 (Chr21) transcripts are overexpressed by about 50% in cells with an extra copy of this chromosome. However, this assumption is difficult to test in humans due to limited access to tissues, and direct support for this idea is available for only a few Chr21 genes or in a limited number of tissues. The Ts65Dn mouse is widely used as a model for studies of DS because it is at dosage imbalance for the orthologs of about half of the 284 Chr21 genes. Ts65Dn mice have several features that directly parallel developmental anomalies of DS. Here we compared the expression of 136 mouse orthologs of Chr21 genes in nine tissues of the trisomic and euploid mice. Nearly all of the 77 genes which are at dosage imbalance in Ts65Dn showed increased transcript levels in the tested tissues, providing direct support for a simple model of increased transcription proportional to the gene copy number. However, several genes escaped this rule, suggesting that they may be controlled by additional tissue-specific regulatory mechanisms revealed in the trisomic situation.
A Protein Interaction Framework for Human mRNA Degradation
Authors: Lehner Ben , Sanderson Christopher M.
Published: July 2004

The degradation of mRNA is an important regulatory step in the control of gene expression. However, mammalian RNA decay pathways remain poorly characterized. To provide a framework for studying mammalian RNA decay, a two-hybrid protein interaction map was generated using 54 constructs from 38 human proteins predicted to function in mRNA decay. The results provide evidence for interactions between many different proteins required for mRNA decay. Of particular interest are interactions between the poly(A) ribonuclease and the exosome and between the Lsm complex, decapping factors, and 5′→3′ exonucleases. Moreover, multiple interactions connect 5′→3′ and 3′→5′ decay proteins to each other and to nonsense-mediated decay factors, providing the opportunity for coordination between decay pathways. The interaction network also predicts the internal organization of the exosome and Lsm complexes. Additional interactions connect mRNA decay factors to many novel proteins and to proteins required for other steps in gene expression. These results provide an experimental insight into the organization of proteins required for mRNA decay and their coupling to other cellular processes, and the physiological relevance of many of these interactions are supported by their evolutionary conservation. The interactions also provide a wealth of hypotheses to guide future research on mRNA degradation and demonstrate the power of exhaustive protein interaction mapping in aiding understanding of uncharacterized protein complexes and pathways.
Regulog Analysis: Detection of Conserved Regulatory Networks Across Bacteria: Application to Staphylococcus aureus
Authors: Alkema Wynand B.L. , Lenhard Boris , Wasserman Wyeth W.
Published: July 2004

A transcriptional regulatory network encompasses sets of genes (regulons) whose expression states are directly altered in response to an activating signal, mediated by trans-acting regulatory proteins and cis-acting regulatory sequences. Enumeration of these network components is an essential step toward the creation of a framework for systems-based analysis of biological processes. Profile-based methods for the detection of cis-regulatory elements are often applied to predict regulon members, but they suffer from poor specificity. In this report we describe Regulogger, a novel computational method that uses comparative genomics to eliminate spurious members of predicted gene regulons. Regulogger produces regulogs, sets of coregulated genes for which the regulatory sequence has been conserved across multiple organisms. The quantitative method assigns a confidence score to each predicted regulog member on the basis of the degree of conservation of protein sequence and regulatory mechanisms. When applied to a reference collection of regulons from Escherichia coli, Regulogger increased the specificity of predictions up to 25-fold over methods that use cis-element detection in isolation. The enhanced specificity was observed across a wide range of biologically meaningful parameter combinations, indicating a robust and broad utility for the method. The power of computational pattern discovery methods coupled with Regulogger to unravel transcriptional networks was demonstrated in an analysis of the genome of Staphylococcus aureus. A total of 125 regulogs were found in this organism, including both well-defined functional groups and a subset with unknown functions.
Functional Proteomics Mapping of a Human Signaling Pathway
Authors: Colland Frédéric , Jacq Xavier , Trouplin Virginie , Mougin Christelle , Groizeleau Caroline , Hamburger Alexandre , Meil Alain , Wojcik Jérôme , Legrain Pierre , Gauthier Jean-Michel
Published: July 2004

Access to the human genome facilitates extensive functional proteomics studies. Here, we present an integrated approach combining large-scale protein interaction mapping, exploration of the interaction network, and cellular functional assays performed on newly identified proteins involved in a human signaling pathway. As a proof of principle, we studied the Smad signaling system, which is regulated by members of the transforming growth factor β (TGFβ) superfamily. We used two-hybrid screening to map Smad signaling protein–protein interactions and to establish a network of 755 interactions, involving 591 proteins, 179 of which were poorly or not annotated. The exploration of such complex interaction databases is improved by the use of PIMRider, a dedicated navigation tool accessible through the Web. The biological meaning of this network is illustrated by the presence of 18 known Smad-associated proteins. Functional assays performed in mammalian cells including siRNA knock-down experiments identified eight novel proteins involved in Smad signaling, thus validating this integrated functional proteomics approach.
Recovery of a Function Involving Gene Duplication by Retroposition in Saccharomyces cerevisiae
Authors: Schacherer Joseph , Tourrette Yves , Souciet Jean-Luc , Potier Serge , de Montigny Jacky
Published: July 2004

The duplication of DNA sequences contributes to genomic plasticity and is known to be one of the key factors responsible for evolution. The mechanisms underlying these rare events, which have been frequently mentioned by authors performing genomic analysis, have not yet been completely elucidated. These mechanisms were approached here in the yeast Saccharomyces cerevisiae, using a positive selection screen based on a particular mutated allele of the URA2 gene. Spontaneous revertants containing a duplication of the terminal part of the URA2 gene were selected and analyzed. Some important features of the duplicated regions, such as their chromosome location, size, and insertion sites, were characterized. The events selected correspond to a single inter- or intrachromosomal gene duplication process. The duplicated ATCase sequence is generally punctuated by a poly(A) tract and is always located in Ty1 sequences. In addition, the activation of a Ty1 transcription process increased the frequency of the duplication events. All in all, these data suggest that the duplication mechanism involves the reverse transcription of mRNA and the subsequent integration of the cDNA into a Ty1 area. The Ty1 elements and the retrotransposon-encoded function are key factors contributing to chromosomal reshaping. The genomic rearrangements described constitute experimental evidence for the recovery of a function involving duplication by retroposition.
A Phylogeny of Caenorhabditis Reveals Frequent Loss of Introns During Nematode Evolution
Authors: Cho Soochin , Jin Suk-Won , Cohen Adam , Ellis Ronald E.
Published: July 2004

Since introns were discovered 26 years ago, people have wondered how changes in intron/exon structure occur, and what role these changes play in evolution. To answer these questions, we have begun studying gene structure in nematodes related to Caenorhabditis elegans. As a first step, we cloned a set of five genes from six different Caenorhabditis species, and used their amino acid sequences to construct the first detailed phylogeny of this genus. Our data indicate that nematode introns are lost at a very high rate during evolution, almost 400-fold higher than in mammals. These losses do not occur randomly, but instead, favor some introns and do not affect others. In contrast, intron gains are far less common than losses in these genes. On the basis of the sequences at each intron site, we suggest that several distinct mechanisms can cause introns to be lost. The small size of C. elegans introns should increase the rate at which each of these types of loss can occur, and might account for the dramatic difference in loss rate between nematodes and mammals.
Considerations on educating engineers in sustainability
Authors: Boyle Carol
Published: July 2004

The teaching of sustainability to engineers will follow similar paths to that of environmental engineering. There is a strong feeling that environmental engineering is a discipline unto itself, requiring knowledge of chemistry, physics, biology, hydrology, toxicology, modelling and law. However, environmental engineering can also be encompassed within other disciplines; for example, solar and wind power are often taught in electrical or mechanical engineering; pollution control is taught in chemical engineering; and recycling technologies are taught in both chemical and mechanical engineering. The understanding of sustainability engineering, however, requires a greater maturity than that of most engineering disciplines. Although the basics of this concept can be understood by anyone, the ability to understand the complex systems which exist within the environment and society as well as the constraints on those systems is only beginning to emerge at the fourth year or graduate level. Moreover, the elements necessary to achieve sustainability are derived from all aspects of engineering and, like environmental engineering, all engineering disciplines have strong roles to play in achieving sustainability. However, there is also a fundamental discourse that can be taught as a discipline in sustainability engineering. Discusses aspects of such a programme and outlines the requirements for educating engineers in sustainability.
Assessing the educational opportunities from a solar powered cultivator at Slippery Rock University of Pennsylvania
Authors: Borsari Bruno , Elder Timothy , Reynolds Thomas
Published: July 2004

The need to develop alternatives for fossil fuel energy consumption is mandated by the limit of world oil reserves and the environmental costs associated with their continued use. The purpose of this study was to demonstrate to local farmers the environmental benefits provided by a modified farm implement and to enhance interest in alternative energy systems. The investigators wanted also to evaluate the attitudes among students and the general public in studying energy in lower power applications at Slippery Rock University. This was accomplished through the administration of a purposefully designed survey to 72 subjects who were introduced to alternative energy systems by the investigators at the farmers' fairs. Presents a discussion about every indicator proposed by the research instrument with implications for colleges and universities in gearing curricula toward sustainability. The acquisition of solar powered equipment remains inaccessible for a majority of Pennsylvania farmers. However, this initial evaluation study demonstrates a sincere interest toward solar energy, in an attempt to pursue sustainability a step further, at an institution of higher education, in this prominent agrarian region of the USA.
EcoCity Columbus
Authors: Manta Conroy Maria
Published: July 2004

Attention in US literature and practice addressing sustainable development has focused on a limited number of communities such as Seattle, Washington, and Portland, Oregon. These communities have been identified as making difficult decisions and ground‐breaking policies to advance sustainability initiatives. However, these communities are considered by some to be atypical and their experiences do not relate to the typical US city. The US landscape is dominated by more “average” places. Explores the use of a graduate level planning class to help bring sustainability concepts to a more typical US city, Columbus, Ohio. Examines impediments and opportunities that were encountered in the process, and identifies three key factors that have characterized the Columbus experience: timing, leadership, and a non‐continuously successful process.
The use and safety of transoesophageal echocardiography in the general ICU – a minireview
Authors: Hüttemann E. , Schelenz C. , Kara F. , Chatzinikolaou K. , Reinhart K.
Published: July 2004

Background:  The efficacy of transoesophageal echocardiography (TEE) has been evaluated predominantly in medical and cardiac surgical ICUs. This article reviews the pertinent literature and evaluates the impact of TEE in a general surgical ICU.

Methods:  Twenty studies on TEE in the ICU were evaluated for complications, indications, diagnostic, therapeutic, and surgical impact on patient management. Diagnostic impact was defined as identification of the underlying cardiovascular pathology, therapeutic impact as changes in patient management and surgical impact as indication for operative procedures. In addition, we reviewed the TEE reports and patient charts of 216 critically ill patients in a 16‐bed multidisciplinary surgical ICU at our university hospital, who underwent a TEE for differential diagnosis of hemodynamic instability from July 1995 to December 1998 to assess the impact of TEE on patient management in a general surgical ICU.

Results:  The diagnostic, therapeutic and surgical impact in a total of 2,508 patients ranged from 44 to 99% (weighted mean 67.2%), 10–69% (36.0%), and 2–29% (14.1%), respectively. The complication rate was 2.6%, with no examination related mortality. In our series in a general surgical ICU, a diagnostic, therapeutic and surgical impact was inferred in 191 (88.4%), 148 (68.5%) and 12 (5.6%) patients, respectively. Adverse effects were observed in 5.6%.

Conclusion:  TEE is safe, well‐tolerated and useful in the management of critically ill patients. This applies as well for hemodynamically unstable patients in a general surgical ICU.
Rapid reversal of global left ventricular dysfunction after accidental injection of 0.75 mg epinephrine in a 20‐year‐old patient
Authors: Meaudre E. , Barbou F. , Sallaberry M. , Cantais E. , Petit D. , Palmier B.
Published: July 2004

We report an accidental injection of epinephrine before spinal anaesthesia in a 20‐year‐old patient who subsequentely developed immediate myocardial ischemia and global left ventricular dysfunction (ejection fraction of 20%). Hemodynamic status dramatically improved after nitroglycerin, calcium antagonists, acetyl salicylic acid and unfractionated heparin injections. Over 24 h, patient's ejection fraction fully recovered without kinetic abnormality.
Aminotransferases after experimental pneumoperitoneum in dogs
Authors: Nesek‐Adam V. , Rašic Z. , Kos J. , Vnuk D.
Published: July 2004

Background:  Laparoscopic surgery has rapidly become a popular and widely used technique. Elevated intra abdominal pressure due to gas insufflation for laparoscopic surgery may result in a number of local and systemic effects on the organism. The effects of pneumoperitoneum on the cardiovascular and respiratory system are well known today, but very few studies have been carried out on the consequences of pneumoperitoneum on hepatic integrity. The aim of the present study was to assess changes in aminotransferases, bilirubin and prothrombin time after pneumoperitoneum in dogs.

Methods:  The effects of different levels and duration of intra abdominal pressure and different gases on liver function test were investigated in dogs. The levels of aspartate aminotransferase, alanine aminotransferase, total and direct bilirubin, and prothrombin time, according to the duration and the level of pneumoperitoneum and gas, were measured at 6, 12, 24 and 48 h of desufflation.

Results:  The levels of total bilirubin, direct bilirubin and prothrombin time showed no significant alteration. A statistically significant (P < 0.01) elevation of aspartate aminotrasferase and alanine aminotransferase was recorded in the group of animals with higher intra abdominal pressure and longer duration of pneumoperitoneum. They returned to normal values within 48 h.

Conclusion:  Transient elevation of hepatic transaminases occurred after laparoscopic surgery, but they returned to normal values within 48 h. These increases were more prominent with higher and longer intra abdominal pressures irrespective of the type of insufflated gas. Alteration in aminotransferases was not associated with any clinical signs of hepatic dysfunction in experimental animals.
Can chronic poststernotomy pain after cardiac valve replacement be reduced using thoracic epidural analgesia?
Authors: Jensen M. K. , Andersen C.
Published: July 2004

Background:  The aim of our study was to evaluate the use of thoracic epidural analgesia (TEA) in acute pain management after cardiac valve replacement and determine if the incidence of chronic pain related to the sternotomy was reduced by the use of TEA. This patient group was chosen to exclude pain related to the use of the internal mammary artery and angina pectoris.

Methods:  Patients scheduled for elective cardiac valve replacement were offered TEA. A match‐control group was selected. Epidural catheter placement, complications and postoperative neurological state were noted for both groups. Eighteen months postoperatively, a questionnaire was sent out concerning pain management, wound discomfort and pain.

Results:  Forty‐nine patients were included. The TEA group consisted of 35 patients. At 18 months' follow up, 37% from the TEA group and 21% from the control group had pain or discomfort related to the sternum (NS). Two in the TEA group had severe pain.

Conclusion:  We found in our small material that TEA provided excellent analgesia in the peri‐ and postoperative period, but we did not find a protective effect of TEA on chronic poststernotomy pain, neither weak pain nor severe pain.
Effects of neuromuscular‐blocking drugs in rats in vivo: Direct measurements in the diaphragm and tibialis anterior muscle
Authors: Itoh H. , Shibata K. , Matsumoto T. , Nitta S. , Nishi M. , Kobayashi T. , Yamamoto K.
Published: July 2004

Background:  Effects of neuromuscular‐blocking drugs are often investigated in rodents using both the diaphragm in vitro and the tibialis anterior muscle in vivo. Differences in the properties of these muscles cannot be neglected. We evaluated the neuromuscular effects of drugs on the rat diaphragm in vivo in comparison with the tibialis anterior muscle, directly measuring twitch tension with a force transducer.

Methods:  Respectively using sternotomy and an approach via the gluteal space, transducers were attached to the diaphragm and the tibialis anterior muscle. Phrenic and sciatic nerves were stimulated supramaximally by single square pulses to record isometric contraction of muscles. Pancuronium, vecuronium, or rocuronium was infused continuously at a rate adjusted repeatedly until stable tension was obtained. Effective doses for 50% (ED 50) and 90% (ED 90) depression of tension were calculated, using a cumulative infusion dosing method.

Results:  Isometric contraction of the diaphragm could be recorded despite movements of the heart and lungs. For all three drugs, both mean ED 50 and ED 90 were more than twice as large for the diaphragm as for the tibialis anterior (P<0.05). In addition, slopes of dose–response curves for the diaphragm were significantly less steep than those of the tibialis anterior for the three drugs.

Conclusion:  Neuromuscular‐blocking effects on the diaphragm can be recorded in vivo. According to direct contractile force measurement, the diaphragm is more resistant to non‐depolarizing neuromuscular‐blocking drugs than the tibialis anterior muscle.
Anesthetic management for separation of craniopagus twins
Authors: Huang W. Q. , Fang J. Y. , Xiao L. C. , Jiang X. P. , Xia J. H. , Feng X. , Jiang N.
Published: July 2004

We report the anesthetic management of a case of separation of craniopagus twins with unbalanced cross circulation and one twin with renal dysfunction. After intravenous induction, anesthesia was maintained with isoflurane inhalation and propofol infusion. Twin A survived but Twin B died after the surgery. The anesthetic problems during the operation are discussed.
Anaesthesia in day case laparoscopic female sterilization: a comparison of two anaesthetic methods
Authors: Rognås L. K. , ElkjÆr P.
Published: July 2004

Background:  Laparoscopic sterilization (LS) in women is a procedure frequently carried out in a day case setting. The purpose of the study was to measure postoperative pain, nausea and vomiting (PONV), the incidence of unplanned overnight admissions and patient satisfaction with two different anaesthetic methods.

Methods:  From August 1997 to January 1999 the LS patients were anaesthetized with propofol + fentanyl/alfentanil, N2O and atracurium, and from January 1999 to end of 2001 they were given TIVA with propofol + remifentanil. Postoperative pain was managed with standardized high doses of paracetamol and NSAID in both groups. Data were collected from hospital records and from questionnaires given to all the patients.

Results:  Six hundred and eighty‐one women were sterilized. There were no significant differences in postoperative pain between the two groups, with 8.2 and 12.1 per cent, respectively, experiencing severe pain. Significantly fewer patients experienced moderate or severe postoperative nausea after the introduction of remifentanil anaesthesia (3.3 vs. 11.7%, P = 0.001). Eleven patients (1.8%) were admitted overnight, with no difference between the two groups. 94.5% and 96.3% of the patients were either satisfied or very satisfied with their treatment (P = 0.50).

Conclusion:  Both anaesthetic methods provide equally good postoperative pain relief, few unplanned admissions and a high degree of patient satisfaction when combined with postoperative paracetamol and NSAID. Patients anaesthetized with remifentanil and propofol have less postoperative nausea.
Adaptive versus Proactive Behavior in Service Recovery: The Role of Self‐Managing Teams
Authors: Jong Ad de , De Ruyter Ko
Published: July 2004

In this article, we develop a conceptual model of adaptive versus proactive recovery behavior by self‐managing teams (SMTs) in service recovery operations. To empirically test the conceptual model a combination of bank employee, customer, and archival data is collected. The results demonstrate support for independent group‐level effects of intrateam support on adaptive and proactive recovery behavior, indicating that perceptual consensus within service teams has incremental value in explaining service recovery performance. In addition, we provide evidence that adaptive and proactive recovery behavior have differential effects on external performance measures. More specifically, higher levels of adaptive performance positively influence customer‐based parameters (i.e., service recovery satisfaction and loyalty intentions), while employee proactive recovery behavior contributes to higher share of customer rates.
Restaurant Revenue Management at Chevys: Determining the Best Table Mix
Authors: Kimes Sheryl E. , Thompson Gary M.
Published: July 2004

Revenue management has been used in a variety of industries and generally takes the form of managing demand by manipulating length of customer usage and price. Supply mix is rarely considered, although it can have considerable impact on revenue. In this research, we focused on developing an optimal supply mix, specifically on determining the supply mix that would maximize revenue. We used data from a Chevys restaurant, part of a large chain of Mexican restaurants, in conjunction with a simulation model to evaluate and enumerate all possible supply (table) mixes. Compared to the restaurant's existing table mix, the optimal mix is capable of handling a 30% increase in customer volume without increasing waiting times beyond their original levels. While our study was in a restaurant context, the results of this research are applicable to other service businesses.
Evaluating the Deming Management Model of Total Quality in Services*
Authors: Douglas Thomas J. , Fredendall Lawrence D.
Published: July 2004

This article uses the Deming management model developed by Anderson et al. (1994b) as an initial template to analyze total quality in services. While the literatures addressing quality management have developed separately for products and services, the founders of total quality portrayed this management philosophy as universally oriented. Our study first replicates two earlier studies that tested the Deming management model in manufacturing industries. Using hospitals as our unit of analysis, we realized findings similar to the earlier manufacturing studies. Next, we used contributions from the MBNQA literature to test an enhanced model. Our subsequent findings support the MBNQA concept that “leadership drives the system that creates results” and provides evidence of the ubiquitous importance of leadership for ensuring the success of a quality improvement program. Finally, an anomaly of this study and those published earlier is the inability to find support for the relationship between continuous improvement and customer satisfaction. Integrating the substantial work in the service quality literature focused on customer satisfaction measurement is recommended to future researchers to help resolve this issue and further enhance the model.
The Role of Clinical and Process Quality in Achieving Patient Satisfaction in Hospitals
Authors: Marley Kathryn A. , Collier David A. , Meyer Goldstein Susan
Published: July 2004

Managers constantly struggle with where to allocate their resources and efforts in managing the complex service delivery system called a hospital. In the broadest sense, their decisions and actions focus on two important aspects of health care—clinical or technical medical care that emphasizes “what” the patient receives and process performance that emphasizes “how” health care services are delivered to patients. Here, we investigate the role of leadership, clinical quality, and process quality on patient satisfaction. A causal model is hypothesized and evaluated using structural equation modeling for a sample of 202 U.S. hospitals. Statistical results support the idea that leadership is a good exogenous construct and that clinical and process quality are good intermediate outcomes in determining patient satisfaction. Statistical results also suggest that hospital leadership has more influence on process quality than on clinical quality, which is predominantly the doctors' domain. Other results are discussed, such as that hospital managers must be mindful of the fact that process quality is at least as important as clinical quality in predicting patient satisfaction. The article concludes by proposing areas for future research.
A Mathematical Model of Service Failure and Recovery Strategies*
Authors: Zhu Zhen , Sivakumar K. , Parasuraman A.
Published: July 2004

Understanding the nature of service failures and their impact on customer responses and designing cost‐effective recovery strategies have been recognized as important issues by both service researchers and practitioners. We first propose a conceptual framework of service failure and recovery strategies. We then transform it into a mathematical model to assist managers in deciding on appropriate resource allocations for outcome and process recovery strategies based on customer risk profiles and the firm's cost structures. Based on this mathematical model we derive optimal recovery strategies, conduct sensitivity analyses of the optimal solutions for different model parameters, and illustrate them through numerical examples. We conclude with a discussion of managerial implications and directions for future research.
Short‐Distance Reanalysis of Middle English Modals: Evidence from Ellipsis
Authors: Gergel Remus
Published: July 2004

Abstract.  This paper argues that the Middle English modals have a shorter distance to diachronically reanalyze to T than traditionally assumed. The claim essentially draws on the analysis of two elliptical constructions in whose licensing the premodals are unexpectedly involved if one assumes the standard account of their full lexical status. Specifically, VP‐ellipsis and directional PPs are investigated. The two phenomena have previously led to contradictory results regarding the status of the premodals. In the present account, an economy driven explanation is proposed, based on an intermediate projection which unifies the two phenomena and gives an account of the patterns of modal complementation.
The Cyclic Generation of Interpretational Semantic Roles
Authors: Minkoff Seth A.
Published: July 2004

Abstract.  This work develops Minkoff (1994)'s proposal that so‐called ‘logophoric’ semantic roles license certain semantic dependencies, and are constrained in their occurrence by an optional semantic interpretation of syntax subject to an abstract structural condition, the ‘Logophoric Role Constraint’ (LRC). I argue that the logophoric roles belong to a broader inventory of interpretational semantic roles; that these roles form two classes, which license distinct sets of semantic dependencies and interact in distinct ways with the lexical semantics of verbs; and that these roles’ distribution is restricted in ways that argue for replacing the LRC with the more natural conclusion that semantic interpretation applies cyclically and generates just one semantic role per cyclic domain.
Enforcing order within a complex locus: current perspectives on the control of V(D)J recombination at the murine T‐cell receptor α/δ locus
Authors: Krangel Michael S. , Carabana Juan , Abbarategui Iratxe , Schlimgen Ryan , Hawwari Abbas
Published: July 2004

Summary:  V(D)J recombination proceeds according to defined developmental programs at T‐cell receptor (TCR) and immunoglobulin loci as a function of cell lineage and stage of differentiation. Although the molecular details are still lacking, such regulation is thought to occur at the level of accessibility of chromosomal recombination signal sequences to the recombinase. The unique and complex organization of the TCRα/δ locus poses intriguing regulatory challenges in this regard: embedded TCRα and TCRδ gene segments rearrange at distinct stages of thymocyte development, there is a highly regulated progression of primary followed by secondary rearrangements involving Jα segments, and there are important developmental constraints on V gene segment usage. The locus therefore provides a fascinating laboratory in which to explore the basic mechanisms underlying developmental control. We provide here a current view of cis‐acting mechanisms that enforce the TCRα/δ locus developmental program, and we emphasize the unresolved issues that command the attention of our and other laboratories.
Regulation of activation and recombination of the murine Igκ locus
Authors: Schlissel Mark S.
Published: July 2004

Summary:  The murine immunoglobulin (Ig) κ locus has been intensively studied in an attempt to understand its developmentally regulated activation for both transcription and V(D)J recombination. A variety of signaling proteins, cis‐acting DNA elements, and trans‐acting DNA‐binding proteins have been discovered and shown to be involved in the regulated changes in chromatin structure, which are associated with recombinase accessibility. In addition, key roles have been suggested for DNA methylation and replication in κ‐locus expression and rearrangement. This review summarizes data in this area and considers what studies of the murine κ locus have revealed about the lineage specificity, order, and allelic exclusion of lymphoid V(D)J recombination.
Monoallelic gene expression: a repertoire of recurrent themes
Authors: Goldmit Maya , Bergman Yehudit
Published: July 2004

Summary:  The development of mature B and T cells in the lymphoid system involves a series of molecular decisions that culminate in the expression of a single antigen receptor on the cell surface, a phenomenon termed allelic exclusion. While feedback inhibition of the recombinase‐activation gene proteins evidently plays an important role in the maintenance of allelic exclusion, the initial restriction of rearrangement to only one allele in each cell seems to be achieved through monoallelic epigenetic changes. Epigenetic mechanisms involved in the establishment of allelic exclusion also play a central role in other types of monoallelic expression, including X‐chromosome inactivation in female cells, and parental imprinting. In all three systems, the inequality of the two alleles seems to be achieved mainly by differential DNA methylation, asynchronous DNA replication, differential chromatin modifications, unequal nuclear localization, and non‐coding RNA. In this review, we discuss the unifying features among these monoallelically expressed systems and the unique characteristics displayed by each of them.
The bounty of RAGs: recombination signal complexes and reaction outcomes
Authors: Swanson Patrick C.
Published: July 2004

Summary:  V(D)J recombination is a form of site‐specific DNA rearrangement through which antigen receptor genes are assembled. This process involves the breakage and reunion of DNA mediated by two lymphoid cell‐specific proteins, recombination activating genes RAG‐1 and RAG‐2, and ubiquitously expressed architectural DNA‐binding proteins and DNA‐repair factors. Here I review the progress toward understanding the composition, assembly, organization, and activity of the protein‐DNA complexes that support the initiation of V(D)J recombination, as well as the molecular basis for the sequence‐specific recognition of recombination signal sequences (RSSs) that are the targets of the RAG proteins. Parallels are drawn between V(D)J recombination and Tn5/Tn10 transposition with respect to the reactions, the proteins, and the protein‐DNA complexes involved in these processes. I also consider the relative roles of the different sequence elements within the RSS in recognition, cleavage, and post‐cleavage events. Finally, I discuss alternative DNA transactions mediated by the V(D)J recombinase, the protein‐DNA complexes that support them, and factors and forces that control them.
Sibling rivalry: competition between Pol X family members in V(D)J recombination and general double strand break repair
Authors: Nick McElhinny Stephanie A. , Ramsden Dale A.
Published: July 2004

Summary:  The nonhomologous end‐joining pathway is a major means for repairing double‐strand breaks (DSBs) in all mitotic cell types. This repair pathway is also the only efficient means for resolving DSB intermediates in V(D)J recombination, a lymphocyte‐specific genome rearrangement required for assembly of antigen receptors. A role for polymerases in end‐joining has been well established. They are a major factor in determining the character of repair junctions but, in contrast to ‘core’ end‐joining factors, typically appear to have a subtle impact on the efficiency of end‐joining. Recent work implicates several members of the Pol X family in end‐joining and suggests surprising complexity in the control of how these different polymerases are employed in this pathway.
V(D)J recombination: how to tame a transposase
Authors: Brandt Vicky L. , Roth David B.
Published: July 2004

Summary:  Since the discovery that the recombination‐activating gene (RAG) proteins were capable of transposition in vitro, investigators have been trying to uncover instances of transposition in vivo and understand how this transposase has been harnessed to do useful work while being inhibited from causing deleterious chromosome rearrangements. How to preserve the capacity of the recombinase to promote a certain class of rearrangements while curtailing its ability to catalyze others is an interesting problem. In this review, we examine the progress that has been made toward understanding the regulatory mechanisms that prohibit transposition in order to formulate a model that takes into account the diverse observations that have been made over the last 15 years. First, we touch on the striking mechanistic similarities between transposition and V(D)J recombination and review evidence suggesting that the RAG proteins may be members of the retroviral integrase superfamily. We then dispense with an old theory that certain standard products of V(D)J recombination called signal joints protect against deleterious transposition events. Finally, we discuss the evidence that target capture could serve a regulatory role and close with an analysis of hairpins as preferred targets for RAG‐mediated transposition. These novel strategies for harnessing the RAG transposase not only shed light on V(D)J recombination but also may provide insight into the regulation of other transposases.
The DNA‐dependent protein kinase: the director at the end
Authors: Meek Katheryn , Gupta Shikha , Ramsden Dale A. , Lees‐Miller Susan P.
Published: July 2004

Summary:  Efficient repair of DNA double‐strand breaks is essential for the maintenance of chromosomal integrity. In higher eukaryotes, non‐homologous end‐joining (NHEJ) DNA is the primary pathway that repairs these breaks. NHEJ also functions in developing lymphocytes to repair strand breaks that occur during V(D)J recombination, the site‐specific recombination process that provides for the assembly of functional antigen‐receptor genes. If V(D)J recombination is impaired, B‐ and T‐lymphocyte development is blocked resulting in severe combined immunodeficiency disease. In the last decade, an intensive research effort has focused on NHEJ resulting in a reasonable understanding of how double‐strand breaks are resolved. Six distinct gene products have been identified that function in this pathway (Ku70, Ku86, XRCC4, DNA ligase IV, Artemis, and DNA‐PKcs). Three of these comprise one complex, the DNA‐dependent protein kinase (DNA‐PK). This protein complex is central during NHEJ, because DNA‐PK initially recognizes and binds to the damaged DNA and then targets the other repair activities to the site of DNA damage. In this review, we discuss recent developments that have provided insight into how DNA‐PK functions, once bound to DNA ends.
Computational tools for understanding sequence variability in recombination signals
Authors: Cowell Lindsay G. , Davila Marco , Ramsden Dale , Kelsoe Garnett
Published: July 2004

Summary:  The recombination signals (RSs) that guide V(D)J rearrangement are remarkably diverse. In mice, fewer than 16% of RSs carry consensus heptamers and nonamers and none also contain a consensus spacer sequence. It is increasingly clear that this variability regulates recombination: genetic variability in RSs may help enforce allelic exclusion, determine the general nature of antigen receptor repertoires, and mitigate autoreactivity in B lymphocytes. The great diversity of RSs has largely precluded, however, empiric determinations of how RS sequence affects recombination. For example, 439 unique 23‐RSs are possible or approximately 3 × 1023 sequences; some 7 × 1013 unique 23‐RSs can be produced just by changes in the spacer. In contrast, the recombination activities of only 100 or so RSs have been measured, and it is unlikely that the activities of even a tiny fraction of extant RSs can be determined. We have addressed the problem of how sequence determines the efficiency of RS templates by generating computational models that describe the correlation structure of mouse RSs. These models successfully predict RS activity and identify functional, cryptic RSs (cRSs). These models permit studies to identify RSs and cRSs for empiric study and constitute a tool useful for understanding RS structure and function.
Reproductive Autonomy Rights and Genetic Disenhancement: Sidestepping the Argument from Backhanded Benefit
Authors: Harvey Martin
Published: July 2004

abstract  John Robertson has famously argued that the right to reproductive autonomy is exceedingly broad in scope. That is, as long as a particular reproductive preference such as having a deaf child is “determinative” of the decision to reproduce then such preferences fall under the protective rubric of reproductive autonomy rights. Importantly, the deafness in question does not constitute a harm to the child thereby wrought since unless the child could be born deaf he or she would otherwise never have existed— his or her prospective parents would simply have chosen to abort. As such, for this child, being born deaf counts as a benefit, albeit of the “backhanded” variety, since the only other practical alternative is nonexistence. In what follows, I want to investigate this argument in detail. The target of my investigation will be the possible future use of gene therapy technology to “disenhance” one's offspring. I intend to show that the apparently unlimited right to reproductive autonomy, that is, the right to choose both the quantity and qualities of future offspring, entailed by the argument from backhanded benefit can in fact be “sidestepped” through considering what sorts of reproductive practices we as a society ought to allow.
The Social Model of Disability: A Philosophical Critique
Authors: Terzi Lorella
Published: July 2004

abstract  Emerging from the political activism of disabled people's movements and mainly theorised by the scholar Michael Oliver, the social model of disability is central to current debates in Disability Studies as well as to related perspectives on inclusive education.

This article presents a philosophical critique of the social model of disability and outlines some of its theoretical problems. It argues that in conceptualising disability as unilaterally socially caused, the social model presents a partial and, to a certain extent, flawed understanding of the relation between impairment, disability and society, thus setting a framework that needs clarifications and extensions and presents limits to the achievement of its own aim of inclusion.

This article concludes by suggesting that, despite its theoretical limits, the social model acts as a powerful and important reminder to face issues of inclusion as fundamental, moral issues.
The Right to Trial by Jury
Authors: Brooks Thom
Published: July 2004

abstract  Recently, the right to trial by jury has attracted a number of vociferous critics with deep reservations about the use of juries, most of whom are in favour of greatly restricting the use of juries with a minority desiring complete abolition. This article offers a justification for the continued use of jury trials. I shall critically examine the ability of juries to render just verdicts, judicial impartiality, and judicial transparency. My contention is that the judicial system that best satisfies these values is most preferable. Of course, these three values are not the only factors relevant for consideration. Empirical evidence demonstrates that juries foster both democratic participation and public legitimation of legal decisions regarding the most serious cases. Nevertheless, juries are costly and, therefore, economically less efficient than competing modes of trial. I do not argue that all human beings possess an inalienable legal right to be tried by a jury. However, it is my hope that this analysis will make clear what we might gainor lose when we propose jury reforms.
Developmental up‐regulation of MnSOD in rat oligodendrocytes confers protection against oxidative injury
Authors: Baud Olivier , Haynes Robin F. , Wang Hong , Folkerth Rebecca D. , Li Jianrong , Volpe Joseph J. , Rosenberg Paul A.
Published: July 2004

Periventricular leukomalacia, the predominant pathological lesion underlying cerebral palsy in premature infants, is thought to be the result of hypoxic–ischemic injury to the cerebral white matter. The main cell type injured is the developing oligodendrocyte (OL), which has been shown to be more sensitive than mature OLs to both excitotoxic and oxidative mechanisms of injury. A maturation dependence of OL vulnerability to cystine deprivation‐induced glutathione depletion has been previously demonstrated in culture. We hypothesized that mitochondria could be involved in this toxicity by generating superoxide and that increased superoxide dismutase (SOD) activity in mature OLs may account for their greater resistance. Cystine deprivation toxicity was found to be associated with mitochondrial dysfunction and intracellular superoxide accumulation in developing OLs. CuZnSOD protein expression and enzyme activity was similar along the OL lineage. In contrast, MnSOD was up‐regulated in mature OLs, as manifested by a 53% increase in its expression and a four‐fold increase in its activity. Overexpressing MnSOD in developing OLs was associated with a protective effect on mitochondrial membrane potential and a decrease in cell death induced by mild cystine deprivation. The greater challenge presented by total cystine deprivation was resistant to MnSOD overexpression and appeared to be related to hydrogen peroxide toxicity. These data suggest a primary involvement of superoxide in glutathione depletion toxicity in developing OLs, and suggest an important role for MnSOD in the resistance observed in mature OLs.