bluuebunny/crossref_metadata_2025 huggingface dataset:
Energy Recovering in Active Vibration Isolation System — Results of Experimental Research
Authors: Kowal Janusz , Pluta Janusz , Konieczny Jarosław , Kot Andrzej
Published: June 2008

Studies of systems with energy regeneration have been carried out for years, because they primarily cover the assemblies with electrodynamic actuators. This paper addresses the issue of active reduction of mechanical vibration using an electrohydraulic actuator. The testing procedure aims to assess the potential use of those assemblies in a different frequency band and force range than in electrodynamic actuators. The paper explains the operating principle of the system, and the findings of laboratory tests are presented. The tested vibration reducing system is the physical model of a 2 degree-of-freedom (DOF) suspension. An initial analysis has been conducted to explore the potential use of the energy produced by the vibration of unsprung mass in the first degree of the suspension system, for power supply to the active component incorporated in the second suspension degree.

The energy recuperated from the first suspension DOF is transferred by a dedicated hydraulic system and stored in an accumulator. Results of the experiments revealed that the mechanical parameters of the system can be selected in such a way that for specific interfering signals the accumulated energy should be at least equal to the energy used up by the system.
The Design of a Project to Assess Bilateral Versus Unilateral Hearing Aid Fitting
Authors: Arlinger Stig , Gatehouse Stuart , Kiessling Jürgen , Naylor Graham , Verschuure Hans , Wouters Jan
Published: June 2008

Binaural hearing provides advantages over monaural in several ways, particularly in difficult listening situations. For a person with bilateral hearing loss, the bilateral fitting of hearing aids thus seems like a natural choice. However, surprisingly few studies have been reported in which the additional benefit of bilateral versus unilateral hearing aid use has been investigated based on real-life experiences. Therefore, a project has been designed to address this issue and to find tools to identify people for whom the drawbacks would outweigh the advantages of bilateral fitting. A project following this design is likely to provide reliable evidence concerning differences in benefit between unilateral and bilateral fitting of hearing aids by evaluating correlations between entrance data and outcome measures and final preferences.
Stuart Gatehouse: The International Perspective
Authors: Van Tasell Dianne J. , Levitt Harry
Published: June 2008

The international contributions of Stuart Gatehouse are reviewed in three areas: as a scientist, as an advisor to health policy makers, and as a participant in international conferences. He was able, as no other auditory scientist of his time, to bridge the gap between scientific and clinical research. His ability to apply sound scientific principles to issues of clinical importance was most apparent in his work in three main areas of his research: acclimatization to amplified speech, auditory disability and hearing aid benefit, and candidature for linear and nonlinear signal processing.
Stuart Gatehouse: A Personal Appreciation
Authors: Haggard Mark
Published: June 2008

Stuart Gatehouse worked in the MRC Institute of Hearing Research Scottish Section for 29 years until his untimely death in 2007. The former director records a personal appreciation but also an explanation, for those who did not know him well, of the mixture of qualities that made him an outstanding applied scientist.
Analysis of academic attitudes and existing processes to inform the design of teaching and learning material repositories
Authors: King Melanie , Loddington Steve , Manuel Sue , Oppenheim Charles
Published: June 2008

The last couple of years have brought a rise in the number of institutional repositories throughout the world and within UK Higher Education institutions, with the majority of these repositories being devoted to research output. Repositories containing teaching and learning material are less common and the workflows and business processes surrounding these types of repositories were unclear. The user motivations to contributing to and downloading from repositories were also unknown. This article reports on two studies: a wide-scale survey carried out with HE staff to identify barriers and incentives to contributing to teaching material repositories; and interviews carried out as part of a workflow study at Loughborough University, to identify existing practice in the creation and sharing of teaching material. Confusion is reported with regard to the difference between a Virtual Learning Environment (VLE) and a repository. However, many different purposes of a teaching and learning material repository are highlighted. This article discusses how repositories could successfully interoperate with other institutional applications and highlights the benefits of teaching material repositories to the user, through scenarios. Recommendations relating to the key aspects of the design and implementation of a repository service are outlined.
Summative and formative assessment
Authors: Taras Maddalena
Published: June 2008

Assessment is critically important to education both for accreditation and to support learning. Yet the literature dealing with formative and summative assessment definitions and terminology is not aligned. This article reports an empirical small-scale study of lecturers in Education at an English university. The research posits that these lecturers, owing to the inconsistencies and infelicities in the literature, will have an incomplete and unharmonious understanding of summative and formative assessment and the relationship between the two. The results show that lecturers' understanding of assessment terminology and relationships reflects the fragmented theoretical and practical frameworks available. This study would seem to signal the need for us all to examine our assessment processes in order to (i) be clear and explicit on what we do, (ii) understand how assessment processes relate to each other, and (iii) evaluate how they impact on our practice and our students.
Young Men’s Vulnerability in Constituting Hegemonic Masculinity in Sexual Relations
Authors: Hyde Abbey , Drennan Jonathan , Howlett Etaoine , Brady Dympna
Published: June 2008

This article reports on a qualitative analysis of the accounts of young men on their experiences of heterosexual encounters. Based on data collected in Ireland using 17 focus groups with 124 young men aged between 14 and 19 years (a subsection of a wider study), the manner in which intricate peer group mechanisms acted as surveillance strategies in regulating the young men toward presenting themselves in ways consistent with hegemonic manifestations of masculinity is explored. However, there were also elements of resistance to such a culture in the way in which sexual pleasure for some young men was derived relationally through giving pleasure rather than merely through mechanical, emotionally detached sexual acts that characterize hegemonic masculinity. In emphasizing male vulnerabilities such as uncertainty, fear, and rejection in the realm of sexuality, it is proposed that one must not lose sight of the broader context of male sexual dominance for which, as data indicate, men themselves pay a price.
DNA hypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication
Authors: Whitman Susan P. , Hackanson Björn , Liyanarachchi Sandya , Liu Shujun , Rush Laura J. , Maharry Kati , Margeson Dean , Davuluri Ramana , Wen Jing , Witte Tatiana , Yu Li , Liu Chunhui , Bloomfield Clara D. , Marcucci Guido , Plass Christoph , Caligiuri Michael A.
Published: June 2008

Posttranslationally modified histones and DNA hypermethylation frequently interplay to deregulate gene expression in cancer. We report that acute myeloid leukemia (AML) with an aberrant histone methyltransferase, the mixed lineage leukemia partial tandem duplication (MLL-PTD), exhibits increased global DNA methylation versus AML with MLL-wildtype (MLL-WT; P = .02). Among the differentially methylated genes, the SLC5A8 tumor suppressor gene (TSG) was more frequently hypermethylated (P = .003). In MLL-PTD+ cell lines having SLC5A8 promoter hypermethylation, incubation with decitabine activated SLC5A8 expression. Ectopic SLC5A8 expression enhanced histones H3 and H4 acetylation in response to the histone deacetylase inhibitor, valproate, consistent with the encoded protein—SMCT1—short-chain fatty acid transport function. In addition, enhanced cell death was observed in SMCT1-expressing MLL-PTD+ AML cells treated with valproate. Within the majority of MLL-PTD AML is a mechanism in which DNA hypermethylation silences a TSG that, together with MLL-PTD, can contribute further to aberrant chromatin remodeling and altered gene expression.
Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector–mediated gene therapy
Authors: Velazquez Victoria M. , Bowen David G. , Walker Christopher M.
Published: June 2008

Recombinant adeno-associated virus (rAAV) vectors are considered promising for human gene replacement because they facilitate stable expression of therapeutic proteins in transduced tissues. Whether the success of gene therapy will be influenced by cellular immune responses targeting transgene-encoded proteins that are potentially immunogenic is unknown. Here we characterized CD8+ T-cell activity against β-galactosidase and enhanced green fluorescent protein, model antigens containing major histocompatibility complex (MHC) class I epitopes that are constitutively produced in murine skeletal muscle after rAAV vector transduction. Antigen-specific CD8+ T cells were detected in the spleen and liver of mice within 7 days of muscle transduction. CD8+ T-cell frequencies in these organs were stable, and effector functions were intact for months despite ongoing antigen production in muscle. CD8+ T cells also infiltrated transduced muscle, where frequencies were at least 5-fold higher than in untransduced spleen and liver. Significantly, the majority of antigen-specific CD8+ T cells in vector-transduced muscle were not functional. Loss of function in the muscle was associated with programmed death of the effector cells. Stable gene expression therefore depended on selective death of CD8+ T cells at the site of antigen production, an effective mechanism for subverting immunity that is also potentially reversible.
The natural history and treatment outcome of blast phase BCR-ABL− myeloproliferative neoplasms
Authors: Tam Constantine S. , Nussenzveig Roberto M. , Popat Uday , Bueso-Ramos Carlos E. , Thomas Deborah A. , Cortes Jorge A. , Champlin Richard E. , Ciurea Stefan E. , Manshouri Taghi , Pierce Sherry M. , Kantarjian Hagop M. , Verstovsek Srdan
Published: June 2008

We analyzed the outcomes of 74 patients diagnosed with BCR-ABL− myeloproliferative neoplasms in blast phase receiving induction chemotherapy (55%), low-intensity therapy (16%), stem cell transplantation (SCT; 3%), or supportive care (26%). Median survival from the date of blastic transformation was 5 months. Patients receiving supportive therapy had a median survival of 6 weeks. Complete remission with or without blood recovery was achieved in 46% of patients receiving induction chemotherapy, but remissions were not durable with a median progression-free survival of only 5 months. Eight patients received SCT either as first therapy or after responding to antileukemia therapy. These patients had a markedly superior survival, with 73% alive at a median follow-up of 31 months. JAK2V617F kinetics were assessed in 16 patients: 0 of 4 negative patients became positive at transformation, and among 12 positive patients, 1 had an increase in JAK2V617F% at transformation, 7 had a substantial decrease, and 4 had stable levels. Myeloproliferative neoplasm blast phase is associated with a dismal prognosis. Responses to chemotherapy can be achieved but are not durable. Long-term survivors had all received SCT either as first therapy or in first remission.
Successful treatment of progressive cutaneous mastocytosis with imatinib in a 2-year-old boy carrying a somatic KIT mutation
Authors: Hoffmann Karl M. , Moser Andrea , Lohse Peter , Winkler Andreas , Binder Barbara , Sovinz Petra , Lackner Herwig , Schwinger Wolfgang , Benesch Martin , Urban Christian
Published: June 2008

Cutaneous mastocytosis (CM) in children is a usually benign skin disorder caused by mast cell proliferation. Progressive disease leading to systemic involvement and fatal outcomes has been described. C-kit receptor mutations have been identified as causative for CM, some of which potentially respond to imatinib treatment as described for patients with systemic mastocytosis. We report successful therapy of progressive CM with imatinib in a 23-month-old boy. KIT gene analysis revealed not only a somatic deletion of codon 419 in exon 8 (c.1255_1257delGAC) which responds to imatinib therapy, but also a novel germ line p. Ser840Asn substitution encoded by exon 18 in the c-kit kinase domain. Family history suggests this exchange does not affect receptor function or cause disease. Imatinib therapy was well tolerated, stopped symptoms and disease progression, and appeared to shorten the course of the disease. Imatinib could possibly represent a novel therapeutic option in patients with progressive CM.
Double feature selection and cluster analyses in mining of microarray data from cotton
Authors: Alabady Magdy S , Youn Eunseog , Wilkins Thea A
Published: June 2008

Background

Cotton fiber is a single-celled seed trichome of major biological and economic importance. In recent years, genomic approaches such as microarray-based expression profiling were used to study fiber growth and development to understand the developmental mechanisms of fiber at the molecular level. The vast volume of microarray expression data generated requires a sophisticated means of data mining in order to extract novel information that addresses fundamental questions of biological interest. One of the ways to approach microarray data mining is to increase the number of dimensions/levels to the analysis, such as comparing independent studies from different genotypes. However, adding dimensions also creates a challenge in finding novel ways for analyzing multi-dimensional microarray data.

Results

Mining of independent microarray studies from Pima and Upland (TM1) cotton using double feature selection and cluster analyses identified species-specific and stage-specific gene transcripts that argue in favor of discrete genetic mechanisms that govern developmental programming of cotton fiber morphogenesis in these two cultivated species. Double feature selection analysis identified the highest number of differentially expressed genes that distinguish the fiber transcriptomes of developing Pima and TM1 fibers. These results were based on the finding that differences in fibers harvested between 17 and 24 day post-anthesis (dpa) represent the greatest expressional distance between the two species. This powerful selection method identified a subset of genes expressed during primary (PCW) and secondary (SCW) cell wall biogenesis in Pima fibers that exhibits an expression pattern that is generally reversed in TM1 at the same developmental stage. Cluster and functional analyses revealed that this subset of genes are primarily regulated during the transition stage that overlaps the termination of PCW and onset of SCW biogenesis, suggesting that these particular genes play a major role in the genetic mechanism that underlies the phenotypic differences in fiber traits between Pima and TM1.

Conclusion

The novel application of double feature selection analysis led to the discovery of species- and stage-specific genetic expression patterns, which are biologically relevant to the genetic programs that underlie the differences in the fiber phenotypes in Pima and TM1. These results promise to have profound impacts on the ongoing efforts to improve cotton fiber traits.
Gait analysis does not correlate with clinical and MR imaging parameters in patients with symptomatic lumbar spinal stenosis
Authors: Zeifang Felix , Schiltenwolf Marcus , Abel Rainer , Moradi Babak
Published: June 2008

Background

Parameters of MR imaging play a pivotal role in diagnosing lumbar spinal stenosis (LSS), and serve as an important tool in clinical decision-making. Despite the importance of MR imaging, little is known about the correlation between MRI parameters, objective gait analysis, and clinical presentation of patients with lumbar spinal stenosis.

Methods

Sixty-three patients from our clinic with symptomatic lumbar spinal stenosis leading to neurogenic claudication were included in this study in accordance with clearly defined inclusion and exclusion criteria. Clinical parameters, the depression status (CES-D), the subjective functional back capacity (FFbH-R), and the absolute walking distance (treadmill gait analysis) were quantitatively evaluated in correlation with morphological data from radiographs and MRI scans, in order to determine the coherence of spinal canal narrowing and clinical affliction.

Results

Sixty-three consecutive paents with a median age of 68 years and a mean Body Mass Index (BMI) of 28 were included in the study. The mean FFbH-R score displayed a value of 44 percent. The depression status scored an average of 13.6. Objectively measured walking distances showed a mean value of 172 m until patients stopped due to leg pain. A significant difference was found between the objectively measured and the subjectively estimated walking distance. The mean cross-sectional area of the dural tube at L1/2 was 113 mm2, at L2/3 94 mm2, at L3/4 73 mm2, at L4/5 65 mm2, and at L5/S1 93 mm2. The mean overall cross sectional area of the dural tube of all segments did not correlate with the objectively measured walking distance. However, bivariate analysis found that the BMI (tau b = -0.194), functional back capacity (tau b = -0.225), and the cross sectional area of the dural tube at L1/2 (tau b = -0.188) correlated significantly with the objectively measured walking distance.

Conclusion

According to the results of this study MRI findings failed to show a major clinical relevance when evaluating the walking distance in patients with lumbar spinal stenosis and, therefore, should be treated with some caution as a predictor of walking distance. In determining the disease pattern of spinal stenosis functional back capacity and BMI might play a more active role than previously thought.
A model-based time-reversal of left ventricular motion improves cardiac motion analysis using tagged MRI data
Authors: Alrefae Tareq , Smirnova Irina V , Cook Larry T , Bilgen Mehmet
Published: June 2008

Background

Myocardial motion is an important observable for the assessment of heart condition. Accurate estimates of ventricular (LV) wall motion are required for quantifying myocardial deformation and assessing local tissue function and viability. Harmonic Phase (HARP) analysis was developed for measuring regional LV motion using tagged magnetic resonance imaging (tMRI) data. With current computer-aided postprocessing tools including HARP analysis, large motions experienced by myocardial tissue are, however, often intractable to measure. This paper addresses this issue and provides a solution to make such measurements possible.

Methods

To improve the estimation performance of large cardiac motions while analyzing tMRI data sets, we propose a two-step solution. The first step involves constructing a model to describe average systolic motion of the LV wall within a subject group. The second step involves time-reversal of the model applied as a spatial coordinate transformation to digitally relax the contracted LV wall in the experimental data of a single subject to the beginning of systole. Cardiac tMRI scans were performed on four healthy rats and used for developing the forward LV model. Algorithms were implemented for preprocessing the tMRI data, optimizing the model parameters and performing the HARP analysis. Slices from the midventricular level were then analyzed for all systolic phases.

Results

The time-reversal operation derived from the LV model accounted for the bulk portion of the myocardial motion, which was the average motion experienced within the overall subject population. In analyzing the individual tMRI data sets, removing this average with the time-reversal operation left small magnitude residual motion unique to the case. This remaining residual portion of the motion was estimated robustly using the HARP analysis.

Conclusion

Utilizing a combination of the forward LV model and its time reversal improves the performance of motion estimation in evaluating the cardiac function.
Myasthenia Gravis and the Tops and Bottoms of AChRs
Authors: Lindstrom Jon , Luo Jie , Kuryatov Alexander
Published: June 2008

The main immunogenic region (MIR), against which half or more of the autoantibodies to acetylcholine receptors (AChRs) in myasthenia gravis (MG) or experimental autoimmune MG (EAMG) are directed, is located at the extracellular end of α1 subunits. Rat monoclonal antibodies (mAbs) to the MIR efficiently compete with MG patient autoantibodies for binding to human muscle AChRs. Antibodies bound to the MIR do not interfere with cholinergic ligand binding or AChR function, but target complement and trigger antigenic modulation. Rat mAbs to the MIR also bind to human ganglionic AChR α3 subunits, but MG patient antibodies do not. By making chimeras of α1 subunits with α7 subunits or ACh binding protein, the structure of the MIR and its functional effects are being investigated. Many mAbs to the MIR bind only to the native conformation of α1 subunits because they bind to sequences that are adjacent only in the native structure. The MIR epitopes recognized by these mAbs are not recognized by most patient antibodies whose epitopes must be nearby. The presence of the MIR epitopes in α1/α7 chimeras greatly promotes AChR expression and sensitivity to activation. EAMG can be suppressed by treatment with denatured, bacterially expressed mixtures of extracellular and cytoplasmic domains of human α1, β1, γ, δ, and ɛ subunits. A mixture of only the cytoplasmic domains not only avoids the potential liability of provoking formation antibodies to pathologically significant epitopes on the extracellular surface, but also potently suppresses the development of EAMG.
Response to Therapy in Myasthenia Gravis with Anti‐MuSK Antibodies
Authors: Evoli Amelia , Bianchi Maria R. , Riso Raffaella , Minicuci Giacomo M. , Batocchi Anna P. , Servidei Serenella , Scuderi Flavia , Bartoccioni Emanuela
Published: June 2008

Myasthenia gravis (MG) with antibodies against the muscle‐specific tyrosine kinase (MuSK abs) is often a severe disease requiring aggressive treatment. Various immunosuppressive (IS) regimens have been employed; the efficacy of plasma exchange is unanimously recognized, while the indication for thymectomy is controversial. We evaluated the response to therapy in 57 MuSK‐positive patients (12 M/45 F) comparing our experience with other authors' results. Disease severity and response to treatment were graded according to MG Foundation of America; follow‐up ranged from 0.5–29 years. Owing to both MG severity and the unsatisfactory response to cholinesterase inhibitors, most patients (54/57) needed IS treatment, and 35 received one or more courses of plasma exchange and intravenous immunoglobulin. At the end of follow‐up, the rate of complete remission was 8.8%, and IS treatment had been withdrawn in only 10/54 patients. The extent of therapeutic response varied considerably. With conventional IS therapy (prednisone alone or in combination with azathioprine or cyclosporine), most patients achieved good control of their disease, but 30% of them were left with permanent facial and bulbar weakness. In patients with refractory disease, the use of mycophenolate mofetil and rituximab proved very effective, as also reported by other authors. In our and others' experience, MuSK‐positive MG markedly improves with IS therapy, although, in comparison with the AChR‐positive disease, it is characterized by a lower remission rate, as a higher proportion of patients remain dependent on treatment. Thymectomy is mostly considered scarcely effective; however, at present, no firm conclusions can be drawn on its role in the treatment of this form of MG.
Peptide‐Toxin Tools for Probing the Expression and Function of Fetal and Adult Subtypes of the Nicotinic Acetylcholine Receptor
Authors: Teichert Russell W. , Garcia Carmen C. , Potian Joseph G. , Schmidt James J. , Witzemann Veit , Olivera Baldomero M. , McArdle Joseph J.
Published: June 2008

Although the neuromuscular nicotinic acetylcholine receptor (nAChR) is one of the most intensively studied ion channels in the nervous system, the differential roles of fetal and adult subtypes of the nAChR under normal and pathological conditions are still incompletely defined. Until recently, no pharmacological tools distinguished between fetal and adult subtypes. Waglerin toxins (from snake venom) and αAS‐conotoxins (from cone‐snail venom) have provided such tools. Because these peptides were characterized by different research groups using different methods, we have: 1) more extensively tested their subtype selectivity, and 2) begun to explore how these peptides may be used in concert to elucidate expression patterns and functions of fetal and adult nAChRs. In heterologous expression systems and native tissues, Waglerin‐1 and an αAS‐conotoxin analog, αA‐OIVA[K15N], are high‐affinity, highly selective inhibitors of the adult and fetal muscle nAChRs, respectively. We have used the peptides and their fluorescent derivatives to explore the expression and function of the fetal and adult nAChR subtypes. While fluorescent derivatives of these peptides indicated a gradual transition from fetal to adult muscle nAChRs in mice during the first 2 weeks postnatal, we unexpectedly observed a steeper transition in functional expression in the mouse diaphragm muscle using electrophysiology. As a toolkit of pharmacological agents with complementary specificity, αA‐OIVA[K15N] and Waglerin‐1 should have further utility in determining the roles of fetal and adult nAChR subtypes in development, in mature tissues, and under pathological conditions.
Myasthenia Gravis Seronegative for Acetylcholine Receptor Antibodies
Authors: Vincent Angela , Leite Maria Isabel , Farrugia Maria Elena , Jacob Saiju , Viegas Stuart , Shiraishi Hiro , Benveniste Olivier , Morgan B. Paul , Hilton‐Jones David , Newsom‐Davis John , Beeson David , Willcox Nick
Published: June 2008

Antibodies to muscle‐specific kinase (MuSK) are found in a variable proportion of patients with myasthenia without typical acetylcholine receptor (AChR) antibodies, but their characteristics and pathogenic mechanisms are not fully understood. We discuss the incidence and pathogenicity of MuSK antibodies and how clinical studies, animal models, and cultured cell lines can be used to elucidate their pathogenic mechanisms. Patients without either AChR or MuSK antibodies (seronegative myasthenia) appear to present another disease subtype that is highly similar to that of typical myasthenia gravis. We demonstrate a new method that detects AChR antibodies in these patients and show that these low‐affinity AChR antibodies are predominantly IgG1 and can activate complement C3b deposition. Similarly MuSK antibodies, although mainly IgG4, are partially IgG1 and can activate C3b deposition. Overall, these results suggest that complement‐activation may be an important pathogenic mechanism even in patients without conventional AChR antibodies.
Rules of Evidence for Clinical Trials
Authors: Cutter Gary , Aban Inmaculada
Published: June 2008

Clinical research must address the vagaries of human variation in disease presentation, course, and response. The therapeutic relationship between the physician and patient, along with their role expectations and outcome expectations, also clouds the conduct and evaluation of clinical research. Today's milieu of hyper‐vigilance in ethics has an impact on subject selection, subject continuance, and ultimately generalizability of results. With multiple stakeholders looking more and more to so‐called evidence‐based medicine, the quality of trials and their evaluations is growing in importance. This paper is organized along the lines of how we receive the news—a series of short sound bites on cautions important in clinical trials. Educated readers, consumers of trial information, and practitioners, as well as subjects participating in clinical trials, require thoughtful participation. This is often lacking in our sound‐bite approach to science and results.
Treatment of Myasthenia Gravis by Preventing Acetylcholine Receptor Modulation
Authors: Losen Mario , Martínez‐Martínez Pilar , Phernambucq Marko , Schuurman Janine , Parren Paul W.H.I. , De Baets Marc H.
Published: June 2008

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies mainly directed to the acetylcholine receptor (AChR) of the neuromuscular junction. Induction of antigenic modulation and complement activation by such autoantibodies leads to ultrastructural damage of the postsynaptic membrane and loss of AChR and associated proteins. Reduction of antigenic modulation by increasing the expression of the receptor‐associated anchor protein, rapsyn, or by functionally monovalent competing IgG4 anti‐AChR antibodies was shown to prevent MG disease activity. We propose that preventing antigenic modulation can be used as a treatment strategy for MG.
Suppression of Extravillous Trophoblast Vascular Endothelial Growth Factor Expression and Uterine Spiral Artery Invasion by Estrogen during Early Baboon Pregnancy
Authors: Bonagura Thomas W. , Pepe Gerald J. , Enders Allen C. , Albrecht Eugene D.
Published: June 2008

We have shown that advancing the increase in maternal serum estrogen levels from the second to the first third of baboon pregnancy suppressed extravillous cytotrophoblast (EVT) spiral artery invasion. Because vascular endothelial growth factor (VEGF) promotes EVT invasion, the present study determined whether EVT VEGF expression is altered by prematurely elevating estrogen in early pregnancy. Placental basal plate was obtained on d 60 of gestation (term is 184 d) from baboons treated daily on d 25–59 with estradiol (0.35 mg/d sc), which increased maternal peripheral serum estradiol levels 3-fold above normal. Overall percentage of uterine arteries (25 to more than 100 μm in diameter) invaded by EVT assessed by image analysis in untreated baboons (29.11 ± 5.78%) was decreased 4.5-fold (P < 0.001) by prematurely elevating estrogen (6.55 ± 1.83%). VEGF mRNA levels in EVT isolated by laser capture microdissection from the anchoring villi of untreated baboons (6.77 ± 2.20) were decreased approximately 5-fold (P < 0.05, ANOVA) by estradiol (1.37 ± 0.29). Uterine vein serum levels of the truncated soluble fms-like receptor, which controls VEGF bioavailability, in untreated baboons (403 ± 37 pg/ml) were increased 3-fold (P < 0.01) by estrogen treatment (1127 ± 197 pg/ml). Thus, placental EVT expression of VEGF mRNA was decreased and serum soluble truncated fms-like receptor levels increased in baboons in which EVT invasion of the uterine spiral arteries was suppressed by advancing the rise in estrogen from the second to the first third of pregnancy. We suggest that VEGF mediates the decline in EVT vessel invasion induced by estrogen in early primate pregnancy.
Aldosterone Induces Cardiotrophin-1 Expression in HL-1 Adult Cardiomyocytes
Authors: López-Andrés Natalia , Iñigo Carmen , Gallego Idoia , Díez Javier , Fortuño María Antonia
Published: June 2008

Aldosterone (ALDO) may induce cardiac hypertrophy by nonhemodynamic mechanisms that are not completely defined. Cardiotrophin-1 (CT-1) is a cytokine that exerts hypertrophic actions on isolated cardiomyocytes and promotes cardiac hypertrophy in vivo. We investigated whether ALDO induces CT-1 expression in HL-1 cardiomyocytes aiming at the possibility that the cytokine is involved in ALDO-induced cardiomyocyte hypertrophy. mRNA and protein expression were quantified by RT-PCR and Western blot. Cardiomyocyte area, as an index of hypertrophy, was assayed by image analysis in phalloidin-stained HL-1 cells. ALDO addition to adult HL-1 cardiomyocytes increased (P < 0.01) CT-1 mRNA and protein expression in a concentration-dependent manner. This effect was abrogated by actinomycin D, the mineralocorticoid and glucocorticoid receptor antagonists spironolactone and RU486, respectively, and the p38 MAPK blocker SB203580. CT-1 signaling pathway blockade with specific antibodies against the cytokine and its two receptor subunits avoided (P < 0.01) α-sarcomeric actin and c-fos protein overexpression as well as cell size increase induced by ALDO in HL-1 cells. In vivo, a single ALDO injection acutely increased (P < 0.01) the myocardial expression of CT-1 in C57BJ6 wild-type mice but not CT-1-null mice. The bolus of the mineralocorticoid increased (P < 0.01) ANP and c-fos mRNA expression in the myocardium of wild-type mice, whereas no changes were observed in CT-1-null mice. In summary, ALDO induces CT-1 expression in adult HL-1 cardiomyocytes via genomic and nongenomic mechanisms. CT-1 up-regulation could have relevance in the direct hypertrophic effects of ALDO in cardiomyocytes.
Maturation of Testicular Tissue from Infant Monkeys after Xenografting into Mice
Authors: Rathi Rahul , Zeng Wenxian , Megee Susan , Conley Alan , Meyers Stuart , Dobrinski Ina
Published: June 2008

In juvenile monkeys, precocious puberty can be induced by administration of gonadotropins resulting in testicular somatic cell maturation and germ cell differentiation. It is, however, unknown whether testicular maturation can also be induced in younger monkeys. Here we used testis tissue xenografting to investigate whether infant monkey testis tissue will undergo somatic cell maturation and/or spermatogenesis in response to endogenous adult mouse gonadotropins or exogenous gonadotropins. Testicular tissue pieces from 3- and 6-month-old rhesus monkeys were grafted to immunodeficient, castrated mice. Recipient mice were either left untreated or treated with pregnant mare serum gonadotropin and/or human chorionic gonadotropin twice weekly and were killed 28 weeks after grafting. Testicular maturation in grafted tissue was assessed based on morphology and the most advanced germ cell type present and by immunohistochemistry for expression of proliferating cell nuclear antigen, Mullerian-inhibiting substance, and androgen receptor. Testis grafts, irrespective of donor age or treatment, contained fewer germ cells than donor tissue. Grafts from 6-month-old donors showed tubular expansion with increased seminiferous tubule diameter and lumen formation, whereas those harvested from gonadotropin-treated mice contained elongated spermatids. Grafts from 3-month-old donors recovered from gonadotropin-treated mice contained pachytene spermatocytes, whereas those recovered from untreated mice showed only slight tubular expansion. Immunohistochemistry revealed that exposure to exogenous gonadotropins supported Sertoli cell maturation, irrespective of donor age. These results indicate that sustained gonadotropin stimulation of immature (<12 months old) monkey testis supports Sertoli cell maturation, thereby terminating the unresponsive phase of the germinal epithelium and allowing complete spermatogenesis in testis tissue from infant rhesus monkeys.
A Novel Mouse Model for Acute and Long-Lasting Consequences of Early Life Stress
Authors: Rice Courtney J. , Sandman Curt A. , Lenjavi Mohammed R. , Baram Tallie Z.
Published: June 2008

Chronic early-life stress (ES) exerts profound acute and long-lasting effects on the hypothalamic-pituitary-adrenal system, with relevance to cognitive function and affective disorders. Our ability to determine the molecular mechanisms underlying these effects should benefit greatly from appropriate mouse models because these would enable use of powerful transgenic methods. Therefore, we have characterized a mouse model of chronic ES, which was provoked in mouse pups by abnormal, fragmented interactions with the dam. Dam-pup interaction was disrupted by limiting the nesting and bedding material in the cages, a manipulation that affected this parameter in a dose-dependent manner. At the end of their week-long rearing in the limited-nesting cages, mouse pups were stressed, as apparent from elevated basal plasma corticosterone levels. In addition, steady-state mRNA levels of CRH in the hypothalamic paraventricular nucleus of ES-experiencing pups were reduced, without significant change in mRNA levels of arginine vasopressin. Rearing mouse pups in this stress-provoking cage environment resulted in enduring effects: basal plasma corticosterone levels were still increased, and CRH mRNA levels in paraventricular nucleus remained reduced in adult ES mice, compared with those of controls. In addition, hippocampus-dependent learning and memory functions were impaired in 4- to 8-month-old ES mice. In summary, this novel, robust model of chronic early life stress in the mouse results in acute and enduring neuroendocrine and cognitive abnormalities. This model should facilitate the examination of the specific genes and molecules involved in the generation of this stress as well as in its consequences.
The discovery of a source of adult hematopoietic cells in the embryo
Authors: Dzierzak Elaine , Medvinsky Alexander
Published: June 2008

This essay is about the 1975 JEEM paper by Françoise Dieterlen-Lièvre(Dieterlen-Lièvre,1975) and the studies that followed it, which indicated that the adult hematopoietic system in the avian embryo originates, not from the blood islands of the extraembryonic yolk sac as was then believed, but from the body of the embryo itself. Dieterlen-Lièvre's 1975paper created a paradigm shift in hematopoietic research, and provided a new and lasting focus on hematopoietic activity within the embryo body.
Optimization of the hydrotesting sequence in tank farm construction using an adaptive genetic algorithm with stochastic preferential logic
Authors: Lancaster J , Cheng K
Published: June 2008

In the construction of tank farms there is a requirement for the tanks to be hydrotested in order to verify that they are leak proof as well as proving the lack of differential settlement in the foundations. The tanks will be required to be filled to a predetermined level and then to maintain this loaded state for a certain period of time before being drained. In areas such as the Middle East, water for hydrotesting is not freely available as sea water is often not suitable for this purpose, so fresh water needs to be produced or transported to the construction site for this purpose. It is therefore of major benefit to the project to schedule the hydrotesting of the tanks in such a manner as to minimize the utilization of hydrotest water.

This problem is a special case of the resource-constrained project scheduling problem (RCPSP) and in this research the fitness differential adaptive genetic algorithm previously developed by the authors has been modified to enable the solution of this real world problem. The algorithm has been ported from the original MATLAB code into Microsoft Project using Microsoft Visual Basic for Applications in order to provide a more user friendly, practical interface.
Safety of screening with Human papillomavirus testing for cervical cancer at three-year intervals in a high-risk population: experience from the LAMS study
Authors: Derchain S F , Sarian L O , Naud P , Roteli-Martins C , Longatto-Filho A , Tatti S , Branca M , Eržen M , Serpa-Hammes L , Matos J , Gontijo R C , Bragança J F , Lima T P , Maeda M Y S , Lörincz A , Dores G B , Costa S , Syrjänen S , Syrjänen K
Published: June 2008

Objectives

To assess whether human papillomavirus (HPV) testing is a safe enough approach to warrant extension of the screening intervals of baseline Papanicolaou (Pap)−/HPV− women in low-income settings.

Methods

Of the >1000 women prospectively followed up as part of the Latin American Screening (LAMS) Study in São Paulo, Campinas, Porto Alegre) and Buenos Aires, 470 women with both baseline cytology and Hybrid Capture 2 (HC2) results available were included in this analysis. These baseline Pap-negative and HC2− or HC2+ women were controlled at six-month intervals with colposcopy, HC2 and Pap to assess the cumulative risk of incident Pap smear abnormalities and their predictive factors.

Results

Of the 470 women, 324 (68.9%) were high-risk HPV (hrHPV) positive and 146 (31.1%) were negative. Having two or more lifetime sex partners (odds ratio [OR] = 2.63; 95% CI 1.70–3.51) and women using hormonal contraception (OR = 2.21; 95% CI 1.40–3.51) were at increased risk for baseline hrHPV infection. Baseline hrHPV+ women had a significantly increased risk of incident abnormal Pap smears during the follow-up. Survival curves deviate from each other starting at month 24 onwards, when hrHPV+ women start rapidly accumulating incident Pap smear abnormalities, including atypical squamous cells (ASC) or worse (log-rank; P < 0.001), low-grade squamous intraepithelial lesions (LSIL) or worse ( P < 0.001) and high-grade squamous intraepithelial lesions (HSIL) ( P = 0.03). Among the baseline hrHPV− women, the acquisition of incident hrHPV during the follow-up period significantly increased the risk of incident cytological abnormalities (hazard ratio = 3.5; 95% CI 1.1–11.7).

Conclusion

These data implicate that HPV testing for hrHPV types might be a safe enough approach to warrant extension of the screening interval of hrHPV−/Pap−women even in low-resource settings. Although some women will inevitably contract hrHPV, the process to develop HSIL will be long enough to enable their detection at the next screening round (e.g. after three years).
Probabilistic Cross-Species Inference of Orthologous Genomic Regions Created by Whole-Genome Duplication in Yeast
Authors: Conant Gavin C , Wolfe Kenneth H
Published: June 2008

Identification of orthologous genes across species becomes challenging in the presence of a whole-genome duplication (WGD). We present a probabilistic method for identifying orthologs that considers all possible orthology/paralogy assignments for a set of genomes with a shared WGD (here five yeast species). This approach allows us to estimate how confident we can be in the orthology assignments in each genomic region. Two inferences produced by this model are indicative of purifying selection acting to prevent duplicate gene loss. First, our model suggests that there are significant differences (up to a factor of seven) in duplicate gene half-life. Second, we observe differences between the genes that the model infers to have been lost soon after WGD and those lost more recently. Gene losses soon after WGD appear uncorrelated with gene expression level and knockout fitness defect. However, later losses are biased toward genes whose paralogs have high expression and large knockout fitness defects, as well as showing biases toward certain functional groups such as ribosomal proteins. We suggest that while duplicate copies of some genes may be lost neutrally after WGD, another set of genes may be initially preserved in duplicate by natural selection for reasons including dosage.
Post-mating Gene Expression Profiles of Female Drosophila melanogaster in Response to Time and to Four Male Accessory Gland Proteins
Authors: McGraw Lisa A , Clark Andrew G , Wolfner Mariana F
Published: June 2008

In Drosophila melanogaster, the genetic and molecular bases of post-mating changes in the female's behavior and physiology are poorly understood. However, DNA microarray studies have demonstrated that, shortly after mating, transcript abundance of >1700 genes is altered in the female's reproductive tract as well as in other tissues. Many of these changes are elicited by sperm and seminal fluid proteins (Acps) that males transfer to females. To further dissect the transcript-level changes that occur following mating, we examined gene expression profiles of whole female flies at four time points following copulation. We found that, soon after copulation ends, a large number of small-magnitude transcriptional changes occurred in the mated female. At later time points, larger magnitude changes were seen, although these occurred in a smaller number of genes. We then explored how four individual Acps (ovulin, Acp36DE, Acp29AB, and Acp62F) with unique functions independently affected gene expression in females shortly after mating. Consistent with their early and possibly local action within the female, ovulin and Acp36DE caused relatively few gene expression changes in whole bodies of mated females. In contrast, Acp29AB and Acp62F modulated a large number of transcriptional changes shortly after mating.
The Chromosomal Polymorphism Linked to Variation in Social Behavior in the White-Throated Sparrow (Zonotrichia albicollis) Is a Complex Rearrangement and Suppressor of Recombination
Authors: Thomas James W , Cáceres Mario , Lowman Joshua J , Morehouse Caroline B , Short Meghan E , Baldwin Erin L , Maney Donna L , Martin Christa L
Published: June 2008

Variation in social behavior and plumage in the white-throated sparrow (Zonotrichia albicollis) is linked to an inversion polymorphism on chromosome 2. Here we report the results of our comparative cytogenetic mapping efforts and population genetics studies focused on the genomic characterization of this balanced chromosomal polymorphism. Comparative chromosome painting and cytogenetic mapping of 15 zebra finch BAC clones to the standard (ZAL2) and alternative (ZAL2m) arrangements revealed that this chromosome is orthologous to chicken chromosome 3, and that at a minimum, ZAL2 and ZAL2m differ by a pair of included pericentric inversions that we estimate span at least 98 Mb. Population-based sequencing and genotyping of multiple loci demonstrated that ZAL2m suppresses recombination in the heterokaryotype and is evolving as a rare nonrecombining autosomal segment of the genome. In addition, we estimate that the first inversion within the ZAL2m arrangement originated 2.2 ± 0.3 million years ago. Finally, while previously recognized as a genetic model for the evolution of social behavior, we found that the ZAL2/ZAL2m polymorphism also shares genetic and phenotypic features with the mouse t complex and we further suggest that the ZAL2/ZAL2m polymorphism is a heretofore unrecognized model for the early stages of sex chromosome evolution.