bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Event-B to construct instruction set architectures
Authors: Wright Stephen , Eder Kerstin
Published: January 2010

The instruction set architecture (ISA) of a computing machine is the definition of the binary instructions, registers, and memory space visible to an executable binary image. ISAs are typically implemented in hardware as microprocessors, but also in software running on a host processor, i.e. virtual machines (VMs). Despite there being many ISAs in existence, all share a set of core properties which have been tailored to their particular applications. An abstract model may capture these generic properties and be subsequently refined to a particular machine, providing a reusable template for development of robust ISAs by the formal construction of all normal and exception conditions for each instruction. This is a task to which the Event-B (Metayer et al. in Rodin deliverable 3.2 Event-B language,
http://rodin.cs.ncl.ac.uk
, 2005; Schneider in The B-method an introduction, Palgrave, Basingstoke, 2001) formal notation is well suited. This paper describes a project to use the Rodin tool-set (Abrial in Formal methods and software engineering, Springer, Berlin, 2006) to perform such a process, ultimately producing two variants of the MIDAS (Microprocessor Instruction and Data Abstraction System) ISA (Wright in Abstract state machines, B and Z, Springer, Berlin, 2007; Wright in MIDAS machine specification, Bristol University,
http://www.cs.bris.ac.uk/Publications
, 2009) as VMs. The abstract model is incrementally refined to variant models capable of automatic translation to C source code, which this is compiled to create useable VMs. These are capable of running binary executables compiled from high-level languages such as C (Kernighan and Ritchie in The C programming language, Prentice-Hall, Englewood Cliffs, 1988), and compilers targeted to each variant allow demonstration programs to be executed on them.
Randomized Controlled Trial between Perineal and Anal Repairs of Rectocele in Obstructed Defecation
Authors: Farid Mohamed , Madbouly Khaled M. , Hussein Ahmed , Mahdy Tarik , Moneim Hesham A. , Omar Waleed
Published: January 2010

Objective

The present study was designed to evaluate functional outcome of perineal repair with and without levatorplasty versus transanal repair of rectocele in obstructed defecation.

Methods and patients

A total of 48 multiparous women with obstructed defecation caused by a rectocele were randomly allocated to three groups: transperineal repair with levatorplasty (TPR‐LP; n = 16); transperineal repair without levatorplasty (TPR; n = 16); and transanal repair (TAR; n = 16). The study included defecographic assessment, anal manometry, symptom improvement, sexual function, and score on a function questionnaire. Assessments were done preoperatively and 6 months postoperatively.

Results

Defecography showed significant reduction in size of rectocele in all groups. Constipation improved significantly in both groups with transperineal repair but not in the group with transanal repair. Significant reductions in mean anal resting pressure, maximum reflex volume, and urge‐to‐defecate volume were observed only with the transperineal approach (with and without levatorplasty). Functional score improved significantly in the transperineal groups (with levatorplasty, P < 0.001; without levatorplasty, P < 0.01), but not in the transanal group (P = 0.142). Levatorplasty added to transperineal repair significantly improved the overall functional score compared with transperineal repair alone (P < 0.01) and transanal repair TAR (P < 0.001).

Conclusions

Rectocele repair appears to improve anorectal function by improving rectal urge sensitivity. Transperineal repair of rectocele is superior to transanal repair in both structural and functional outcome. Levatorplasty improves functional outcome, but potential effects on dyspareunia should be discussed with the patient.
Diagnostic Utility of Fine‐Needle Aspiration Cytology in Pediatric Differentiated Thyroid Cancer
Authors: Bargren Anna E. , Meyer‐Rochow Goswin Y. , Sywak Mark S. , Delbridge Leigh W. , Chen Herbert , Sidhu Stan B.
Published: January 2010

Background

Pediatric patients present with thyroid nodules less often than adults, but the rate of malignancy is much higher. This study was designed to determine the ability of fine‐needle aspiration cytology (FNA) to diagnose accurately and facilitate management of thyroid neoplasms in pediatric patients.

Methods

A retrospective study revealed 110 patients <19 years old who had undergone thyroid surgery and FNA biopsy at two academic institutions over the last 28 years. FNA sensitivity for diagnosing papillary thyroid cancer (PC) and follicular neoplasm (FN) was investigated.

Results

Of 110 patients who presented for surgery, 27 had PC and 33 had a FN: 4 follicular carcinomas (FCs) and 29 follicular adenomas (FAs). Among the PCs patients, the FNA results were as follows: 1 (4%) nondiagnostic, 6 (22%) atypical, 2 (7%) benign, and 18 (67%) malignant lesions. The sensitivity of a malignant FNA was 90% for diagnosing a PC. Sensitivity of an atypical FNA was 75% for FCs and 69% for FAs, giving an overall FN sensitivity of 70%. Of the atypical FNA readings, 60% had confirmed histological atypical features, and 19% were malignant. In 95% of the malignant FNA reports, final histology confirmed PC, resulting in a positive predictive value of 95%.

Conclusions

FNA biopsy can reliably diagnose malignancy in pediatric thyroid patients and should be used as a standard technique to indicate surgical treatment. Atypical or suspicious FNA results do not predict cancer effectively, confirming the current accepted practice for adults that diagnostic excision is required to exclude malignancy in pediatric patients.
Effect of Transoral Incisionless Fundoplication on Symptoms, PPI Use, and pH‐Impedance Refluxes of GERD Patients
Authors: Testoni Pier Alberto , Corsetti Maura , Di Pietro Salvatore , Castellaneta Antonio Gianluca , Vailati Cristian , Masci Enzo , Passaretti Sandro
Published: January 2010

Background

Three previous studies from the same institution have reported that transoral incisionless fundoplication (TIF) with the EsophyX device is effective for creating a continent gastroesophageal valve and for good functional results as measured only by pH‐metry in patients with gastroesophageal reflux disease (GERD). The objective of the present study was to evaluate the effect of TIF on symptoms, use of proton pump inhibitors (PPI), esophageal motility, and pH‐impedance in patients with symptomatic GERD.

Methods

Twenty consecutive patients were enrolled to complete the GERD‐HRQL and GERD‐QUAL questionnaires while on and off PPI. They were also examined by upper gastrointestinal (GI) endoscopy to determine Hill grade and Jobe length of the gastroesophageal valve, and to check for hiatal hernia and esophagitis, esophageal manometry, and pH‐impedance before and 6 months after TIF.

Results

Six months after TIF, the GERD‐HRLQ and GERD‐QUAL scores off‐PPI therapy and the number of total and acid pH‐impedance refluxes were significantly reduced (p < 0.05). The PPI had been completely stopped in 55% of the patient and was reduced in 22% of the patients.

Conclusions

At 6‐month follow‐up, TIF performed using the EsophyX device reduces symptoms and pH‐impedance refluxes, allowing interruption or reduction of PPI use in 78% of patients with GERD.
Theory of mind in obsessive-compulsive disorder: Comparison with healthy controls
Authors: Sayın A. , Oral N. , Utku Ç. , Baysak E. , Candansayar S.
Published: January 2010

Aim

Theory of mind (ToM) is the ability to represent one's own or another's mental states and has been found to be impaired in many psychiatric disorders. Our objective was to compare ToM abilities of patients with obsessive-compulsive disorder (OCD) with healthy controls and to investigate the relation between some illness features, other cognitive functions and ToM abilities of patients.

Method

Thirty OCD patients and age, sex and education matched 30 healthy controls were compared according to their performances on ToM tasks (including first and second order false belief, hinting task and double-bluff task), verbal memory processes test, Weschler memory test (WMT) (logical memory, visual reproduction and digit span sub-tests), stroop test.

Results

Patients’ performances were worse than healthy controls on all of the ToM tasks, but the results were significant for only for double-bluff task (t= −3.992,df= 36.157,p< 0.01). Performance on double-bluff task was significantly and positively correlated with visual reproduction-immediate recall (r= −0.411,p< 0.05) and visual reproduction-delayed recall (r= 0.478,p< 0.05), hinting task was significantly and positively correlated with verbal memory (r= 0.481,p< 0.05).

Conclusion

These results show “basic” ToM abilities of OCD patients are generally preserved, but they show significant reduction in their “advanced” ToM abilities, which seem to be related to their reduced memory capacities. The possible reasons for the relation between memory and ToM impairments, as well as the clinical significance of ToM deficits in OCD are discussed.
NMR characterization of the interactions between lyso‐GM1 aqueous micelles and amyloid β
Authors: Yagi-Utsumi Maho , Kameda Tomoshi , Yamaguchi Yoshiki , Kato Koichi
Published: January 2010

Gangliosides are targets for a variety of pathologically relevant proteins, including amyloid β (Aβ), an important component implicated in Alzheimer's disease (AD). To provide a structural basis for this pathogenic interaction associated with AD, we conducted NMR analyses of the Aβ interactions with gangliosides using lyso‐GM1 micelles as a model system. Our NMR data revealed that the sugar–lipid interface is primarily perturbed upon binding of Aβ to the micelles, underscoring the importance of the inner part of the ganglioside cluster for accommodating Aβ in comparison with the outer carbohydrate branches that provide microbial toxin‐ and virus‐binding sites.
Expanding uterotonic protection following childbirth through community‐based distribution of misoprostol: Operations research study in Nepal
Authors: Rajbhandari Swaraj , Hodgins Stephen , Sanghvi Harshad , McPherson Robert , Pradhan Yasho V. , Baqui Abdullah H. ,   Misoprostol Study Group
Published: January 2010

Objective

To determine feasibility of community‐based distribution of misoprostol for preventing postpartum hemorrhage (PPH) to pregnant woman through community volunteers working under government health services.

Methods

Implemented in one district in Nepal. The primary measure of performance was uterotonic protection after childbirth, measured using pre‐ and postintervention surveys (28 clusters, each with 30 households). Maternal deaths were ascertained through systematic health facility and community‐based surveillance; causes of death were assigned based on verbal autopsy.

Results

Of 840 postintervention survey respondents, 73.2% received misoprostol. The standardized proportion of vaginal deliveries protected by a uterotonic rose from 11.6% to 74.2%. Those experiencing the largest gains were the poor, the illiterate, and those living in remote areas.

Conclusion

Community‐based distribution of misoprostol for PPH prevention can be successfully implemented under government health services in a low‐resource, geographically challenging setting, resulting in much increased population‐level protection against PPH, with particularly large gains among the disadvantaged.
Radiation therapy for feline cutaneous squamous cell carcinoma using a hypofractionated protocol
Authors: Cunha Simone CS , Carvalho Luis Alfredo V. , Canary Paulo Cesar , Reisner Marcio , Corgozinho Katia B. , Souza Heloisa J.M. , Ferreira Ana Maria R.
Published: January 2010

The objective of this paper was to evaluate the efficacy of a hypofractionated radiation protocol for feline facial squamous cell carcinoma (SCC). Twenty-five histologically confirmed SCCs in 15 cats were treated with four fractions of 7.6–10 Gy each, with 1 week intervals. The equipment used was a linear accelerator Clinac 2100 delivering electron beam of 4 or 6 MeV, and a bolus of 5 or 10 mm was used in all lesions. Of the lesions, 44% were staged as T4, 16% as T3, 8% as T2 and 32% as T1. Of the irradiated lesions, 40% had complete response, 12% had partial response and 48% had no response (NR) to the treatment. For T1 tumors, 62.5% had complete remission. Mean overall survival time was 224 days. Owners requested euthanasia of cats having NR to the treatment. Mean disease free time was 271 days. Side effects observed were skin erythema, epilation, ulceration and conjunctivitis, which were graded according to Veterinary Radiation Therapy Oncology Group (VRTOG) toxicity criteria. Response rates found in this study (52%) were lower when compared to other protocols, probably due to technique differences, such as fractionation schedule, bolus thickness and energy penetration depth. However, the hypofractionated radiation protocol was considered safe for feline facial SCC. Modifications of this protocol are being planned with the objective of improving the cure rates in the future.
The Cambridge Companion to the African Novel
Authors: Irele F. Abiola
Published: January 2010

Africa's strong tradition of storytelling has long been an expression of an oral narrative culture. African writers such as Amos Tutuola, Naguib Mahfouz, Wole Soyinka and J. M. Coetzee have adapted these older forms to develop and enhance the genre of the novel, in a shift from the oral mode to print. Comprehensive in scope, these new essays cover the fiction in the European languages from North Africa and Africa south of the Sahara, as well as in Arabic. They highlight the themes and styles of the African novel through an examination of the works that have either attained canonical status - an entire chapter is devoted to the work of Chinua Achebe - or can be expected to do so. Including a guide to further reading and a chronology, this is the ideal starting-point for students of African and world literatures.
Emotional Beliefs
Authors: Mercer Jonathan
Published: January 2010

A belief in alien abduction is an emotional belief, but so is a belief that Iran intends to build nuclear weapons, that one's country is good, that a sales tax is unjust, or that French decision makers are irresolute. Revolutionary research in the brain sciences has overturned conventional views of the relationship between emotion, rationality, and beliefs. Because rationality depends on emotion, and because cognition and emotion are nearly indistinguishable in the brain, one can view emotion as constituting and strengthening beliefs such as trust, nationalism, justice or credibility. For example, a belief that another's commitment is credible depends on one's selection (and interpretation) of evidence and one's assessment of risk, both of which rely on emotion. Observing that emotion and cognition co-produce beliefs has policy implications: how one fights terrorism changes if one views credibility as an emotional belief.
Nonstate Actors and the Diffusion of Innovations: The Case of Suicide Terrorism
Authors: Horowitz Michael C.
Published: January 2010

Studies of terrorism in general and suicide terrorism in particular tend to view terrorist groups independently. However, what if the propensity for a terrorist group to adopt suicide tactics depends in part on its external linkages and the relationship between the organizational capabilities required to adopt the innovation and the organizational capabilities of the group? This article shows that the organizational change requirements for adopting an innovation significantly influence the overall adoption pattern, along with interlinkages between groups. Additionally, evaluating the universe of terrorist groups, not only those groups that adopted suicide terrorism but those that did not, shows that Pape's key variable of interest, occupation, does not significantly predict the adoption of suicide terrorism. Thinking about suicide terrorism as a special case of diffusion in the military area—an innovation for nonstate groups—can help bring the study of suicide terrorism further into the mainstream and highlight how the phenomenon has not just differences, but similarities, to other innovations.
Toward Internationally Regulated Goods: Controlling the Trade in Small Arms and Light Weapons
Authors: Efrat Asif
Published: January 2010

Contrary to the general trend of trade liberalization, specific goods—such as small arms, drugs, and antiquities—have come under increasing international control in recent decades through a set of international regulatory agreements. This article offers a theoretical framework of government preferences on the international regulation of these goods. Departing from conventional models of trade policy, the theoretical framework introduces negative externalities, rather than protection, as the motivation for restricting trade; it also takes moral concerns into account. I test this framework empirically through an original survey of government views on international small-arms regulation. Based on interviewing officials from 118 countries, the survey reveals a large variation in government preferences that conforms to the theoretical expectations. I employ this variation to explain why the international regulation of small arms is weak, despite the fact that these are the deadliest weapons of all in terms of actual death toll.
What is a mental/psychiatric disorder? From DSM-IV to DSM-V
Authors: Stein D. J. , Phillips K. A. , Bolton D. , Fulford K. W. M. , Sadler J. Z. , Kendler K. S.
Published: January 2010

The distinction between normality and psychopathology has long been subject to debate. DSM-III and DSM-IV provided a definition of mental disorder to help clinicians address this distinction. As part of the process of developing DSM-V, researchers have reviewed the concept of mental disorder and emphasized the need for additional work in this area. Here we review the DSM-IV definition of mental disorder and propose some changes. The approach taken here arguably takes a middle course through some of the relevant conceptual debates. We agree with the view that no definition perfectly specifies precise boundaries for the concept of mental/psychiatric disorder, but in line with a view that the nomenclature can improve over time, we aim here for a more scientifically valid and more clinically useful definition.
A systematic review of the effects of antipsychotic drugs on brain volume
Authors: Moncrieff J. , Leo J.
Published: January 2010

Background

People with schizophrenia are often found to have smaller brains and larger brain ventricles than normal, but the role of antipsychotic medication remains unclear.

Method

We conducted a systematic review of magnetic resonance imaging (MRI) studies. We included longitudinal studies of brain changes in patients taking antipsychotic drugs and we examined studies of antipsychotic-naive patients for comparison purposes.

Results

Fourteen out of 26 longitudinal studies showed a decline in global brain or grey-matter volume or an increase in ventricular or cerebrospinal fluid (CSF) volume during the course of drug treatment, including the largest studies conducted. The frontal lobe was most consistently affected, but overall changes were diffuse. One large study found different degrees of volume loss with different antipsychotics, and another found that volume changes were associated with taking medication compared with taking none. Analyses of linear associations between drug exposure and brain volume changes produced mixed results. Five out of 21 studies of patients who were drug naive, or had only minimal prior treatment, showed some differences from controls in volumes of interest. No global differences were reported in three studies of drug-naive patients with long-term illness. Studies of high-risk groups have not demonstrated differences from controls in global or lobar brain volumes.

Conclusions

Some evidence points towards the possibility that antipsychotic drugs reduce the volume of brain matter and increase ventricular or fluid volume. Antipsychotics may contribute to the genesis of some of the abnormalities usually attributed to schizophrenia.
Religious fictionalism defended: reply to Cordry
Authors: ESHLEMAN ANDREW
Published: January 2010

In his paper, ‘A critique of religious fictionalism’, Benjamin Cordry raises a series of objections to a fictionalist form of religious non-realism that I proposed in my earlier paper, ‘Can an atheist believe in God?’. They fall into two main categories: those alleging that an atheist would be unjustified in adopting fictionalism, and those alleging that fictionalism could not be successfully implemented, or practised communally. I argue that these objections can be met.
Intermanueller Transfer und Händigkeit
Authors: Fries Udo , Panzer Stefan , Shea Charles H. , Grützmacher Nicole , Krüger Melanie
Published: January 2010

Zusammenfassung. In dem Experiment wurde der intermanuelle Transfer auf eine neue dynamische Anforderung und Händigkeit untersucht. Gegenstand ist das Lernen einer Bewegungssequenz. Die Aufgabe der Lerner bestand in dem Erwerb einer 16-Elementigen Bewegungssequenz. Nach einem anfänglichen Training einer Bewegungssequenz für Rechts- und Linkshänder in Abhängigkeit der Starthand (dominante, nicht-dominante Hand) wurden nach einem Intervall von 24 Stunden ein Behaltenstest und zwei Transfertests appliziert. In dem Behaltenstest musste die gelernte Sequenz mit der trainierten Hand ohne Zusatzlast (0 kg) reproduziert werden. In den beiden ausbalancierten Transfertests sollte sowohl mit der trainierten als auch mit der untrainierten kontralateralen Hand eine zusätzliche Masse von 1 kg bewegt werden. Die Ergebnisse zeigen, dass sowohl Rechts- als auch Linkshänder auf unterschiedliche dynamische Eigenschaften mit ihrer dominanten Hand transferieren können. Rechtshänder können sowohl mit der rechten als auch der linken Hand unabhängig von ihrer Starthand auf neue dynamische Anforderungen transferieren (Symmetrie). Eine Asymmetrie in dem Übertrag zeigt sich bei den Linkshändern, die unabhängig von ihrer trainierten Hand nicht auf ihre rechte Hand und auf eine veränderte dynamische Anforderung transferieren können.
Joint retrieval of surface reflectance and aerosol optical depth from MSG/SEVIRI observations with an optimal estimation approach: 1. Theory
Authors: Govaerts Y. M. , Wagner S. , Lattanzio A. , Watts P.
Published: January 2010

An original method is presented in this paper for the joint retrieval of the mean daily total column aerosol optical depth and surface BRF from the daily accumulated Meteosat Second Generation–Spinning Enhanced Visible and Infrared Imager (MSG/SEVIRI) observations in the solar channels. The proposed algorithm is based on the optimal estimation (OE) theory, a one‐dimensional variational retrieval scheme that seeks an optimal balance between information that can be derived from the observations, and the one that is derived from prior knowledge of the system. The forward radiative transfer model explicitly accounts for the surface anisotropy and its coupling with the atmosphere. The low rate of change in the surface reflectance is used to derive the prior information on the surface state variables. The reliable estimation of the measurement system error is one of the most critical aspects of the OE method as it strongly determines the likelihood of the solution. An important effort in the proposed method has thus been dedicated to this issue, where the actual radiometric performances of SEVIRI are dynamically taken into account.
Ice mélange dynamics and implications for terminus stability, Jakobshavn Isbræ, Greenland
Authors: Amundson J. M. , Fahnestock M. , Truffer M. , Brown J. , Lüthi M. P. , Motyka R. J.
Published: January 2010

We used time‐lapse imagery, seismic and audio recordings, iceberg and glacier velocities, ocean wave measurements, and simple theoretical considerations to investigate the interactions between Jakobshavn Isbræ and its proglacial ice mélange. The mélange behaves as a weak, granular ice shelf whose rheology varies seasonally. Sea ice growth in winter stiffens the mélange matrix by binding iceberg clasts together, ultimately preventing the calving of full‐glacier‐thickness icebergs (the dominant style of calving) and enabling a several kilometer terminus advance. Each summer the mélange weakens and the terminus retreats. The mélange remains strong enough, however, to be largely unaffected by ocean currents (except during calving events) and to influence the timing and sequence of calving events. Furthermore, motion of the mélange is highly episodic: between calving events, including the entire winter, it is pushed down fjord by the advancing terminus (at ∼40 m d−1), whereas during calving events it can move in excess of 50 × 103 m d−1 for more than 10 min. By influencing the timing of calving events, the mélange contributes to the glacier's several kilometer seasonal advance and retreat; the associated geometric changes of the terminus area affect glacier flow. Furthermore, a force balance analysis shows that large‐scale calving is only possible from a terminus that is near floatation, especially in the presence of a resistive ice mélange. The net annual retreat of the glacier is therefore limited by its proximity to floatation, potentially providing a physical mechanism for a previously described near‐floatation criterion for calving.
Vimentin-mediated signalling is required for IbeA+ E. coli K1 invasion of human brain microvascular endothelial cells
Authors: Chi Feng , Jong Timothy D. , Wang Lin , Ouyang Yannan , Wu Chunhua , Li Wei , Huang Sheng-He
Published: January 2010

IbeA in meningitic Escherichia coli K1 strains has been described previously for its role in invasion of BMECs (brain microvascular endothelial cells). Vimentin was identified as an IbeA-binding protein on the surface of HBMECs (human BMECs). In the present study, we demonstrated that vimentin is a primary receptor required for IbeA+ E. coli K1-induced signalling and invasion of HBMECs, on the basis of the following observations. First, E44 (IbeA+ E. coli K1 strain) invasion was blocked by vimentin inhibitors (withaferin A and acrylamide), a recombinant protein containing the vimentin head domain and an antibody against the head domain respectively. Secondly, overexpression of GFP (green fluorescent protein)–vimentin and GFP–VDM (vimentin head domain deletion mutant) significantly increased and decreased bacterial invasion respectively. Thirdly, bacterial invasion was positively correlated with phosphorylation of vimentin at Ser82 by CaMKII (Ca2+/calmodulin-dependent protein kinase II) and IbeA+ E. coli-induced phosphorylation of ERK (extracellular-signal-regulated kinase). Blockage of CaMKII by KN93 and inhibition of ERK1/2 phosphorylation by PD098059 resulted in reduced IbeA+ E. coli invasion. Fourthly, IbeA+ E. coli and IbeA-coated beads induced the clustering of vimentin that was correlated with increased entry of bacteria and beads. Lastly, IbeA+ E. coli K1 invasion was inhibited by lipid-raft-disrupting agents (filipin and nystatin) and caveolin-1 siRNA (small interfering RNA), suggesting that caveolae/lipid rafts are signalling platforms for inducing IbeA–vimentin-mediated E. coli invasion of HBMECs. Taken together, the present studies suggest that a dynamic and function-related interaction between IbeA and its primary receptor vimentin at HBMEC membrane rafts leads to vimentin phosphorylation and ERK-mediated signalling, which modulate meningitic E. coli K1 invasion.
Stimulation of GLUT4 (glucose transporter isoform 4) storage vesicle formation by sphingolipid depletion
Authors: Cheng Zhi-Jie , Singh Raman Deep , Wang Teng-ke , Holicky Eileen L. , Wheatley Christine L. , Bernlohr David A. , Marks David L. , Pagano Richard E.
Published: January 2010

Insulin stimulates glucose transport in fat and skeletal muscle cells primarily by inducing the translocation of GLUT4 (glucose transporter isoform 4) to the PM (plasma membrane) from specialized GSVs (GLUT4 storage vesicles). Glycosphingolipids are components of membrane microdomains and are involved in insulin-regulated glucose transport. Cellular glycosphingolipids decrease during adipocyte differentiation and have been suggested to be involved in adipocyte function. In the present study, we investigated the role of glycosphingolipids in regulating GLUT4 translocation. We decreased glycosphingolipids in 3T3-L1 adipocytes using glycosphingolipid synthesis inhibitors and investigated the effects on GLUT4 translocation using immunocytochemistry, preparation of PM sheets, isolation of GSVs and FRAP (fluorescence recovery after photobleaching) of GLUT4–GFP (green fluorescent protein) in intracellular structures. Glycosphingolipids were located in endosomal vesicles in pre-adipocytes and redistributed to the PM with decreased expression at day 2 after initiation of differentiation. In fully differentiated adipocytes, depletion of glycosphingolipids dramatically accelerated insulin-stimulated GLUT4 translocation. Although insulin-induced phosphorylation of IRS (insulin receptor substrate) and Akt remained intact in glycosphingolipid-depleted cells, both in vitro budding of GLUT4 vesicles and FRAP of GLUT4–GFP on GSVs were stimulated. Glycosphingolipid depletion also enhanced the insulin-induced translocation of VAMP2 (vesicle-associated membrane protein 2), but not the transferrin receptor or cellubrevin, indicating that the effect of glycosphingolipids was specific to VAMP2-positive GSVs. Our results strongly suggest that decreasing glycosphingolipid levels promotes the formation of GSVs and, thus, GLUT4 translocation. These studies provide a mechanistic basis for recent studies showing that inhibition of glycosphingolipid synthesis improves glycaemic control and enhances insulin sensitivity in animal models of Type 2 diabetes.
Searching for the boundaries: unlimited expansion of ubiquitin and ubiquitin-like signals in multiple cellular functions
Authors: Crosas Bernat , Farràs Rosa , Marfany Gemma , Rodríguez Manuel S. , Thomson Timothy M.
Published: January 2010

The ubiquitin–proteasome field has matured, as is evident from the wide diversity of systems and mechanisms in which it participates and that are the subject of investigation, presented in the Ubiquitin–Proteasome System, Dynamics and Targeting meeting held in Barcelona, co-sponsored by the Biochemical Society, the Spanish Ministry of Science, the Spanish Research Council and the Catalan Academy of Sciences. Several of the aspects dealt with in the meeting are discussed in detail in the collection of review papers included in this issue of Biochemical Society Transactions. These papers reflect the importance of ubiquitin and ubiquitin-like modifiers as enormously versatile signalling entities that modulate and direct pathways in specific directions through modification-induced interactions. One conclusion from the meeting is that the field has become so rich and dense that, in order to be useful and informative, future meetings may need to focus on particular aspects of the ubiquitin–proteasome system.
Antiviral activity of resveratrol
Authors: Campagna Michela , Rivas Carmen
Published: January 2010

Resveratrol is a natural compound produced by certain plants on various stimuli. In recent years, extensive research on resveratrol has been carried out, demonstrating its capacity to prevent a wide variety of conditions, including cardiovascular diseases and cancer, and to control fungal, bacterial and viral infections. In the present review, we summarize the current knowledge of the activity of resveratrol against viral infection and describe the possible molecular pathways through which resveratrol exerts its antiviral activity.
Diversity of the SUMOylation machinery in plants
Authors: Lois L. Maria
Published: January 2010

In the last decade, SUMOylation has emerged as an essential post-translational modification in eukaryotes. In plants, the biological role of SUMO (small ubiquitin-related modifier) has been studied through genetic approaches that together with recent biochemical studies suggest that the plant SUMOylation system has a high degree of complexity. The present review summarizes our current knowledge on the SUMOylation system in Arabidopsis, focusing on the mechanistic properties of the machinery components identified.
Ubiquitin and SUMO signalling in DNA repair
Authors: Thomson Timothy M. , Guerra-Rebollo Marta
Published: January 2010

The repair of lesions and gaps in DNA follows different pathways, each mediated by specific proteins and complexes. Post-translational modifications in many of these proteins govern their activities and interactions, ultimately determining whether a particular pathway is followed. Prominent among these modifications are the addition of phosphate or ubiquitin (and ubiquitin-like) moieties that confer new binding surfaces and conformational states on the modified proteins. The present review summarizes some of consequences of ubiquitin and ubiquitin-like modifications and interactions that regulate nucleotide excision repair, translesion synthesis, double-strand break repair and interstrand cross-link repair, with the discussion of relevant examples in each pathway.
Parkin-mediated ubiquitin signalling in aggresome formation and autophagy
Authors: Chin Lih-Shen , Olzmann James A. , Li Lian
Published: January 2010

Understanding how cells handle and dispose of misfolded proteins is of paramount importance because protein misfolding and aggregation underlie the pathogenesis of many neurodegenerative disorders, including PD (Parkinson's disease) and Alzheimer's disease. In addition to the ubiquitin–proteasome system, the aggresome–autophagy pathway has emerged as another crucial cellular defence system against toxic build-up of misfolded proteins. In contrast with basal autophagy that mediates non-selective, bulk clearance of misfolded proteins along with normal cellular proteins and organelles, the aggresome–autophagy pathway is increasingly recognized as a specialized type of induced autophagy that mediates selective clearance of misfolded and aggregated proteins under the conditions of proteotoxic stress. Recent evidence implicates PD-linked E3 ligase parkin as a key regulator of the aggresome–autophagy pathway and indicates a signalling role for Lys63-linked polyubiquitination in the regulation of aggresome formation and autophagy. The present review summarizes the current knowledge of the aggresome–autophagy pathway, its regulation by parkin-mediated Lys63-linked polyubiquitination, and its dysfunction in neurodegenerative diseases.
Synthesis of fusogenic lipids through activation of phospholipase D1 by GTPases and the kinase RSK2 is required for calcium-regulated exocytosis in neuroendocrine cells
Authors: Vitale Nicolas
Published: January 2010

Exocytosis of hormones occurs through the fusion of large dense-core secretory vesicles with the plasma membrane. This highly regulated process involves key proteins such as SNAREs (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptors) and also specific lipids at the site of membrane fusion. Among the different lipids required for exocytosis, our recent observations have highlighted the crucial role of PA (phosphatidic acid) in the late stages of membrane fusion in various exocytotic events. An RNAi (RNA interference) strategy coupled with the detection of PA in living cells has pointed to plasma membrane-associated PLD1 (phospholipase D1) as the main producer of PA in response to secretagogue stimulation. We have identified several GTPases which regulate the activation level of PLD1 in neuroendocrine cells. Finally, RSK2 (ribosomal S6 kinase 2) appears to phosphorylate and regulate the activity of PLD1 in a calcium-dependent manner. Altogether our results have unravelled a complex set of regulatory pathways controlling the synthesis of fusogenic lipids at the secretory granule fusion site by PLD1.
Intersectin 1: a versatile actor in the synaptic vesicle cycle
Authors: Pechstein Arndt , Shupliakov Oleg , Haucke Volker
Published: January 2010

During neurotransmitter release, SVs (synaptic vesicles) fuse at the active zone and are recovered predominantly via clathrin-mediated endocytosis at the presynaptic compartment surrounding the site of release, referred to as the periactive zone. Exo- and endo-cytosis in synapses are tightly temporarily and spatially coupled to sustain synaptic transmission. The molecular mechanisms linking these two cellular events, which take place in separate compartments of the nerve terminal, remain largely enigmatic. Several lines of evidence indicate that multiple factors may be involved in exocytic–endocytic coupling including SV integral membrane proteins, SV membrane lipids and the membrane-associated actin cytoskeleton. A number of recent studies also indicate that multimodular adaptor proteins shuttling between the active and periactive zones aid the dynamic assembly of macromolecular protein complexes that execute the exo- and endo-cytic limbs of the SV cycle. Here, we discuss recent evidence implicating the multidomain scaffolding and adaptor protein ITSN1 (intersectin 1) as a central regulator of SV cycling.
microRNA in erythrocytes
Authors: Hamilton Andrew J.
Published: January 2010

Mammalian erythrocytes are generally thought to lack RNA and therefore to be unable to translate new proteins in response to internal or external signals. Support for this long-standing view has accumulated from diverse studies, most of which have focused on the total content of RNA or the overall level of translation. However, more recent work on specific types of RNA has shown the presence in human erythrocytes of both Y RNA and microRNA. The latter seem particularly incongruous given that their normal role is to attenuate the translation of mRNA. Y RNA binds the Ro autoantigen which may have a role in cellular RNA quality control. Therefore the presence of both of these non-coding RNAs indicates the possible existence of other cryptic RNAs in erythrocytes. It also suggests either the existence of low levels of translation or new uncharacterized processes involving microRNA in these cells.
Genotype–phenotype correlations in laminopathies: how does fate translate?
Authors: Scharner Juergen , Gnocchi Viola F. , Ellis Juliet A. , Zammit Peter S.
Published: January 2010

A-type laminopathies are a group of diseases resulting from mutations in the intermediate filament proteins lamin A and C (both encoded by the LMNA gene), but for which the pathogenic mechanisms are little understood. In some laminopathies, there is a good correlation between the presence of a specific LMNA mutation and the disease diagnosed. In others however, many different mutations can give rise to the same clinical condition, even though the mutations may be distributed throughout one, or more, of the three functionally distinct protein domains of lamin A/C. Conversely, certain mutations can cause multiple laminopathies, with related patients carrying an identical mutation even having separate diseases, often affecting different tissues. Therefore clarifying genotype–phenotype links may provide important insights into both disease penetrance and mechanism. In the present paper, we review recent developments in genotype–phenotype correlations in laminopathies and discuss the factors that could influence pathology.
Lamin A-linked progerias: is farnesylation the be all and end all?
Authors: Smallwood Dawn T. , Shackleton Sue
Published: January 2010

HGPS (Hutchinson–Gilford progeria syndrome) is a severe childhood disorder that appears to mimic an accelerated aging process. The disease is most commonly caused by gene mutations that disrupt the normal post-translational processing of lamin A, a structural component of the nuclear envelope. Impaired processing results in aberrant retention of a farnesyl group at the C-terminus of lamin A, leading to altered membrane dynamics. It has been widely proposed that persistence of the farnesyl moiety is the major factor responsible for the disease, prompting clinical trials of farnesyltransferase inhibitors to prevent lamin A farnesylation in children afflicted with HGPS. Although there is evidence implicating farnesylation in causing some of the cellular defects of HGPS, results of several recent studies suggest that aberrant lamin A farnesylation is not the only determinant of the disease. These findings have important implications for the design of treatments for this devastating disease.
Lamins: ‘structure goes cycling’
Authors: Boban Mirta , Braun Juliane , Foisner Roland
Published: January 2010

Nuclear intermediate filaments formed by A- and B-type lamins are central components of the nucleoskeleton and are required for the architecture and integrity of the nucleus. There is growing evidence that lamins are also involved in regulatory pathways controlling cell proliferation and differentiation. Lamins affect the activity of several transcription factors, such as retinoblastoma protein and c-Fos, and signalling pathways, such as the ERK1/2 (extracellular-signal-regulated kinase 1/2) and Notch pathways, which are key regulators of cell-cycle progression and differentiation. During mitosis, lamins are dynamically reorganized and play active roles in spindle matrix formation and in post-mitotic nuclear reassembly. Several of the cell-cycle-regulating functions of lamins may be impaired in the diseases linked to mutations in lamins and lamin-associated proteins, including striated muscle diseases, lipodystrophies and premature aging syndromes, and contribute to the tissue-specific disease pathologies.
Ferromagnetism of low-dimensional Mn-doped III-V semiconductor structures in the vicinity of the insulator-metal transition
Authors: Aronzon B. A. , Pankov M. A. , Rylkov V. V. , Meilikhov E. Z. , Lagutin A. S. , Pashaev E. M. , Chuev M. A. , Kvardakov V. V. , Likhachev I. A. , Vihrova O. V. , Lashkul A. V. , Lähderanta E. , Vedeneev A. S. , Kervalishvili P.
Published: January 2010

The structural and transport properties of GaAs/Mn/GaAs/InxGa1−xAs/GaAs quantum wells (x≈0.2) with Mn δ-layer (4–10 at. %), separated from the well by a GaAs spacer, have been studied. The hole mobility in the investigated structures has exceeded the values known for magnetic III-V heterostructures by two orders of magnitude. For structures with the conductivity of the metal type, we have succeeded to observe at low temperatures Shubnikov–de Haas oscillations just confirming the two dimensionality (2D) of the hole energy spectrum. Exactly those 2D holes promote the ferromagnetic ordering of the Mn layer. That has been proven by (i) observing maxima (at 25–40 K) in temperature dependencies of the resistance, which positions agree with calculated values of Curie temperatures (for structures with the indirect interaction of Mn atoms via 2D holes), and (ii) revealing the negative spin-dependent magnetoresistance (NMR) as well as the anomalous Hall effect (AHE), which values are also in good agreement with calculations relating to ferromagnetic 2D III-V systems. As for the structures with the insulator type of the conductivity, their NMR and AHE features evidence the phase separation—the sample fragmentation with the formation of mesoscopic ferromagnetic areas separated by paramagnetic strata of the high tunnel conductivity.
Effects of nonequilibrium particle distributions in deuterium-tritium burning
Authors: Michta David , Graziani Frank , Luu Thomas , Pruet Jason
Published: January 2010

The effects of nonequilibrium particle distributions resulting from rapid deuterium-tritium burning in plasmas are investigated using a Fokker–Planck code that incorporates small-angle Coulomb scattering, bremsstrahlung, Compton scattering, and light-ion fusion. For inertial confinement fusion environments, it is found that deviations away from Maxwellian distributions for either deuterium or tritium ions are small and result in 1% changes in the energy production rates. The deuterium and tritium effective temperatures are not equal, but differ by only about 2.5% near the time of peak burn rate. Simulations with high Z (Xe) dopants show that the dopant temperature closely tracks that of the fuel. On the other hand, fusion product ion distributions are highly non-Maxwellian, and careful treatments of energy-exchange between these ions and other particles is important for determining burn rates.
Note: A combined aerodynamic lens/ambient pressure x-ray photoelectron spectroscopy experiment for the on-stream investigation of aerosol surfaces
Authors: Mysak Erin R. , Starr David E. , Wilson Kevin R. , Bluhm Hendrik
Published: January 2010

We discuss a new approach for the measurement of the surfaces of free aerosol particles with diameters from 50 to 1000 nm. Particles in this size range have significant influence on the heterogeneous chemistry in the atmosphere and affect human health. Interfacing an aerodynamic lens to an ambient pressure x-ray photoelectron spectrometer permits measurement of the surface chemical composition of unsupported aerosol particles in real time. We discuss the basic considerations for the design of such an instrument, its current limitations and potentials for improvement. Results from a proof-of-principle experiment on silicon oxide particles with average diameters of 270 nm are shown.
A bright and long-pulse illumination for ultrahigh-speed microscopy of living specimens
Authors: Nakano Hitoshi , Yokoi Sayoko , Yoshida Shigeru , Yamada Makoto , Takeuchi Takeshi , Takehara Kosei , Etoh T. Goji
Published: January 2010

Ultrahigh-speed microscopy of living specimens requires ultrabright illumination. Moreover, the duration of illumination should be sufficiently long, on the order of at least several tens of milliseconds, in order to investigate the dynamic state of living specimens. However, specimens are exposed to a high risk of damage by the intense illumination. The brightness and pulse duration of illumination have to be continuously controlled for use in the ultrahigh-speed microscopy of living specimens. Commercial or laboratory-made illumination systems do not satisfy the abovementioned requirements. In this paper, the development of a bright and long-pulse illumination system for ultrahigh-speed microscopy of living specimens is presented. A xenon flashlamp with an arc length of 1.5 mm has been used as the light source. The electrical power supply consists of a voltage-regulated circuit, a capacitor bank, and a control circuit including an insulated-gate bipolar transistor as a gating device, which provides a large rectangular current pulse with the duration in the range to the order of several tens of milliseconds. The brightness, pulse duration, and repetition rate can be easily and continuously controlled. The illumination developed in the present study is installed in an inverted fluorescence microscope equipped with a high-speed camera in order to evaluate the performance as an illumination source. A fluorescent image of the living spermatozoa of a mouse obtained at a frame rate of 8 kHz shows good contrast. Such an image cannot be obtained using a commercial illumination system.
Metal-enhanced fluorescence from tin nanostructured surfaces
Authors: Zhang Yongxia , Dragan Anatoliy , Geddes Chris D.
Published: January 2010

The recent surge in interest in the metal-enhanced fluorescence (MEF) phenomenon and its numerous applications in the biosciences has fueled research into identifying alternative metals to silver which have desirable properties, such as enhanced emission and fluorophore photostability. In this paper, we subsequently study and reveal that tin nanodeposits are a suitable metal for MEF with an electric field wavelength dependence somewhat different than silver. An enhanced fluorescence emission coupled with a reduced fluorophore lifetime suggests both an electric field and plasmon-coupling component are the underlying mechanisms for tin-based MEF. In addition, an enhanced fluorophore photostability is observed near-to tin nanodeposits.