bluuebunny/crossref_metadata_2025 huggingface dataset:
New guideline for tramadol usage following adverse drug reactions reported to the Iranian pharmacovigilance center
Authors: Gholami K. , Shalviri G. , Zarbakhsh A. , Daryabari N. , Yousefian S.
Published: October 2006

Background

Tramadol was introduced as injection and oral form to Iranian Pharmaceutical Market in 2002. Shortly after, the injection form of the drug was observed at the top of suspected drug list of Adverse Drug Reactions (ADRs) received monthly by Iranian Pharmacovigilance Center (IPC).

Objectives

To detect, assess and report total number of Tramadol‐induced ADRs received by IPC.

To assess the frequency of reported Tramadol‐induced ADRs before and after interventions.

To design a guideline for prevention of probable ADRs due to Tramadol injection.

Methods

A descriptive study was conducted on spontaneous reporting received by IPC from April 2002 to February 2005. All ADRs suspected to be induced by Tramadol registered in the database during mentioned period were analysed. To assess the effect of different interventions based on Spontaneous Reporting System, the trend of reporting frequency of Tramadol‐induced ADRs was evaluated before and after interventions.

Results

There were 337 cases of Tramadol‐induced ADRs describing 939 reactions, reported to IPC during the study period.

Although causal relationship had not been established, three cases of deaths appeared among the reports.

The severity of reactions led to implementation of limitations on injectable Tramadol distribution to community pharmacies and the restriction of its use to hospitals only.

Since most adverse reactions were dose‐dependent, the drug potency of injectable Tramadol available in the country changed from 100 mg to 50 mg.

The assessment of ADR reports received by IPC showed that the frequency of adverse reactions registered in the centre was reduced considerably following these interventions.

Conclusion

Designing a detailed programme by Pharmacovigilance Centres and closely monitoring of newly marketed pharmaceutical products is highly recommended. Copyright © 2006 John Wiley & Sons, Ltd.
A single proline substitution is critical for the thermostabilization of Clostridium beijerinckii alcohol dehydrogenase
Authors: Goihberg Edi , Dym Orly , Tel‐Or Shoshana , Levin Inna , Peretz Moshe , Burstein Yigal
Published: October 2006

Analysis of the three‐dimensional structures of three closely related mesophilic, thermophilic, and hyperthermophilic alcohol dehydrogenases (ADHs) from the respective microorganisms Clostridium beijerinckii (CbADH), Entamoeba histolytica (EhADH1), and Thermoanaerobacter brockii (TbADH) suggested that a unique, strategically located proline residue (Pro100) might be crucial for maintaining the thermal stability of EhADH1. To determine whether proline substitution at this position in TbADH and CbADH would affect thermal stability, we used site‐directed mutagenesis to replace the complementary residues in both enzymes with proline. The results showed that replacing Gln100 with proline significantly enhanced the thermal stability of the mesophilic ADH: ΔT = + 8°C (temperature of 50% inactivation after incubation for 60 min), ΔT = +11.5°C (temperature at which 50% of the original CD signal at 218 nm is lost upon heating between 30° and 98°C). A His100 → Pro substitution in the thermophilic TbADH had no effect on its thermostability. An analysis of the three‐dimensional structure of the crystallized thermostable mutant Q100P‐CbADH suggested that the proline residue at position 100 stabilized the enzyme by reinforcing hydrophobic interactions and by reducing the flexibility of a loop at this strategic region. Proteins 2007. © 2006 Wiley‐Liss, Inc.
Routes are trees: The parsing perspective on protein folding
Authors: Hockenmaier Julia , Joshi Aravind K. , Dill Ken A.
Published: October 2006

An important puzzle in structural biology is the question of how proteins are able to fold so quickly into their unique native structures. There is much evidence that protein folding is hierarchic. In that case, folding routes are not linear, but have a tree structure. Trees are commonly used to represent the grammatical structure of natural language sentences, and chart parsing algorithms efficiently search the space of all possible trees for a given input string. Here we show that one such method, the CKY algorithm, can be useful both for providing novel insight into the physical protein folding process, and for computational protein structure prediction. As proof of concept, we apply this algorithm to the HP lattice model of proteins. Our algorithm identifies all direct folding route trees to the native state and allows us to construct a simple model of the folding process. Despite its simplicity, our model provides an account for the fact that folding rates depend only on the topology of the native state but not on sequence composition. Proteins 2007. © 2006 Wiley‐Liss, Inc.
Two alternative substrate paths for compound I formation and reduction in catalase–peroxidase KatG from Burkholderia pseudomallei
Authors: Deemagarn Taweewat , Wiseman Ben , Carpena Xavier , Ivancich Anabella , Fita Ignacio , Loewen Peter C.
Published: October 2006

Five residues in the multifunctional catalase–peroxidase KatG of Burkholderia pesudomallei are essential for catalase, but not peroxidase, activity. Asp141 is the only one of these catalase‐specific residues not related with the covalent adduct found in KatGs that when replaced with a nonacidic residue reduces catalase activity to 5% of native levels. Replacing the nearby catalytic residue Arg108 causes a reduction in catalase activity to 35% of native levels, whereas a variant with both Asp141 and Arg108 replaced exhibits near normal catalase activity (82% of native), suggesting a synergism in the roles of the two residues in support of catalase activity in the enzyme. Among the Asp141 variants, D141E is unique in retaining normal catalase activity but with modified kinetics, suggesting more favorable compound I formation and less favorable compound I reduction. The crystal structure of the D141E variant has been determined at 1.8‐Å resolution, revealing that the carboxylate of Glu141 is moved only slightly compared with Asp141, but retains its hydrogen bond interaction with the main chain nitrogen of Ile237. In contrast, the low temperature ferric Electron Paramagnetic Resonance spectra of the D141A, R108A, and R108A/D141A variants are consistent with modifications of the water matrix and/or the relative positioning of the distal residue side chains. Such changes explain the reduction in catalase activity in all but the double variant R108A/D141A. Two pathways of hydrogen bonded solvent lead from the entrance channel into the heme active site, one running between Asp141 and Arg108 and the second between Asp141 and the main chain atoms of residues 237–239. It is proposed that binding of substrate H2O2 to Asp141 and Arg108 controls H2O2 access to the heme active site, thereby modulating the catalase reaction. Proteins 2007. © 2006 Wiley‐Liss, Inc.
A ToxR‐based dominant‐negative system to investigate heterotypic transmembrane domain interactions
Authors: Lindner Eric , Langosch Dieter
Published: October 2006

The ToxR transcription activator system is a genetic tool widely used to examine homotypic interactions of α‐helical transmembrane domains that drive or support oligomerization of integral membrane proteins. Here, we present a variant of this system that was developed to investigate heterotypic interactions. In this system, a homotypically interacting transmembrane domain within the ToxR protein is coexpressed with a potential competitor that is embedded within an inactivated ToxR mutant. Successful heterotypic interaction competes with homotypic interaction in a dominant‐negative fashion as revealed by reduced reporter gene transcription. We expect that this system will be useful for the characterization of transmembrane domains whose homotypic and heterotypic interactions compete with each other. Proteins 2006. © 2006 Wiley‐Liss, Inc.
Estimation of the mediation effect with a binary mediator
Authors: Li Yan , Schneider Julie A. , Bennett David A.
Published: October 2006

A mediator acts as a third variable in the causal pathway between a risk factor and an outcome. In this paper, we consider the estimation of the mediation effect when the mediator is a binary variable. We give a precise definition of the mediation effect and examine asymptotic properties of five different estimators of the mediation effect. Our theoretical developments, which are supported by a Monte Carlo study, show that the estimators that account for the binary nature of the mediator are consistent for the mediation effect defined in this paper while other estimators are inconsistent. We use these estimators to study the mediation effect of chronic cerebral infarction in the causal relationship between the apolipoprotein E ε4 allele and cognitive function among 233 deceased participants from the Religious Orders Study, a longitudinal, clinical‐pathologic study of aging and Alzheimer's disease. Copyright © 2006 John Wiley & Sons, Ltd.
Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability
Authors: Maltsev Victor A. , Silverman Norman , Sabbah Hani N. , Undrovinas Albertas I.
Published: October 2006

Background:

Late Na+ current (INaL) in human and dog hearts has been implicated in abnormal repolarization associated with heart failure (HF). HF slows inactivation gating of late Na+ channels, which could contribute to these abnormalities.

Aims:

To test how altered gating affects INaL time course, Na+ influx, and action potential (AP) repolarization.

Methods:

INaL and AP were measured by patch clamp in left ventricular cardiomyocytes from normal and failing hearts of humans and dogs. Canine HF was induced by coronary microembolization.

Results:

INaL decay was slower and INaL density was greater in failing hearts than in normal hearts at 24 °C (human hearts: τ659±16 vs. 529±21ms; n=16 and 4 hearts, respectively; mean±SEM; p<0.002; dog hearts: 561±13 vs. 420±17ms; and 0.307±0.014 vs. 0.235±0.019pA/pF; n=25 and 14 hearts, respectively; p<0.005) and at 37°C this difference tended to increase. These INaL changes resulted in much greater (53.6%) total Na+ influx in failing cardiomyocytes. INaL was sensitive to cadmium but not to cyanide and exhibited low sensitivity to saxitoxin (IC50=62nM) or tetrodotoxin (IC50=1.2 μM), tested in dogs. A 50% INaL inhibition by toxins or passing current opposite to INaL, decreased beat‐to‐beat AP variability and eliminated early afterdepolarizations in failing cardiomyocytes.

Conclusions:

Chronic HF leads to larger and slower INaL generated mainly by the cardiac‐type Na+ channel isoform, contributing to larger Na+ influx and AP duration variability. Interventions designed to reduce/normalize INaL represent a potential cardioprotective mechanism in HF via reduction of related Na+ and Ca2+ overload and improvement of repolarization.
Hyperuricaemia and long‐term outcome after hospital discharge in acute heart failure patients
Authors: Pascual‐Figal Domingo A. , Hurtado‐Martínez Jose A. , Redondo Belen , Antolinos Maria J. , Ruiperez Juan A. , Valdes Mariano
Published: October 2006

Background

Uric acid (UA) may be involved in chronic heart failure (HF) pathogenesis, entailing a worse outcome. The purpose of this study was to examine the role of hyperuricaemia as a prognostic marker after hospital discharge in acute HF patients.

Methods

We studied 212 patients consecutively discharged after an episode of acute HF with LVEF<40%. Blood samples for UA measurement were extracted in the morning prior to discharge. The evaluated endpoints were death and new HF hospitalization.

Results

Mean UA levels were 7.4±2.4 mg/dl (range 1.6 to 16 mg/dl), with 127 (60%) of patients being within the range of hyperuricaemia. Hyperuricaemia was associated with a higher risk of death (n=48) (HR 2.0, 95% CI 1.1–3.9,p=0.028), new HF readmission (n=67) (HR 1.8, 95% CI 1.1–3.1,p=0.023) and the combined event (n=100) (HR 1.9, 95% CI 1.2–2.9,p=0.004). At 24 months, cumulative event‐free survival was lower in the two higher UA quartiles (36.9% and 40.7% vs. 63.5% and 59.5%, log rank=0.006). After adjustment for potential confounders, hyperuricaemia remains an independent risk factor for adverse outcomes (HR 1.6, 95% CI 1.1–2.6,p=0.02).

Conclusions

In hospitalized patients with acute HF and LV systolic dysfunction, hyperuricaemia is a long‐term prognostic marker for death and/or new HF readmission.
PKA modulates GSK‐3β‐ and cdk5‐catalyzed phosphorylation of tau in site‐ and kinase‐specific manners
Authors: Liu Fei , Liang Zhihou , Shi Jianhua , Yin Dongmei , El-Akkad Ezzat , Grundke-Iqbal Inge , Iqbal Khalid , Gong Cheng-Xin
Published: October 2006

Phosphorylation of tau protein is regulated by several kinases, especially glycogen synthase kinase 3β (GSK‐3β), cyclin‐dependent protein kinase 5 (cdk5) and cAMP‐dependent protein kinase (PKA). Phosphorylation of tau by PKA primes it for phosphorylation by GSK‐3β, but the site‐specific modulation of GSK‐3β‐catalyzed tau phosphorylation by the prephosphorylation has not been well investigated. Here, we found that prephosphorylation by PKA promotes GSK‐3β‐catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. These studies reveal the nature of the inter‐regulation of tau phosphorylation by the three major tau kinases.
THE CONDITIONS OF ISLAMIST MODERATION: UNPACKING CROSS-IDEOLOGICAL COOPERATION IN JORDAN
Authors: Clark Janine A.
Published: October 2006

In 1989, Jordan suspended marshal law, lifted media restrictions, expanded freedoms of association, and reintroduced parliamentary elections. Although these steps ushered in a dramatic, albeit limited, political opening, by 1997, many of these measures had been reversed. Indeed, today throughout most of the Middle East, the incipient democratization processes of the 1990s are labeled as “stalled” at best. However, as Jillian Schwedler states, these structural openings and closings do not provide the whole story of these Throughout the region, Islamists, liberals, leftists, and conservatives frequently sit together in opposition blocs and coordinate activities against the state—activities on which they did not cooperate a decade earlier—while remaining bitter rivals in other areas. The Higher Committee for the Coordination of National Opposition Parties (HCCNOP) in Jordan, founded in the mid-1990s in response to normalization efforts by Jordan with Israel, is one such example. A committee of thirteen opposition parties, it includes the Communist and Baءthist parties and the Muslim Brotherhood's Islamic Action Front (IAF). The IAF is very proud of its participation in the HCCNOP and claims that it is a democratic model for the Arab world. It points to the fact that it coordinates deals and “shakes hands” with secularists as evidence of the Party's moderation. The IAF's participation in the HCCNOP raises a variety of questions regarding the relationship between cooperation and democratization. What is the significance of cross-ideological cooperation for political liberalization and democratization? What are the conditions and mechanisms of cooperation? Finally, to what extent do Islamists moderate as a result of cooperation?
Rolled auricular cartilage grafts for dorsal augmentation rhinoplasty
Authors: Gane S , East C , Jayaraj S , Andrews P
Published: October 2006

We present a technique, which has not been previously described in the literature, of using rolled autogenous conchal cartilage for dorsal augmentation via an endonasal or external rhinoplasty approach. This technique gives greater dorsal height compared with the more common layering techniques. It is most appropriate in the minimally or moderately saddled nose.
Nonattendance of adult otolaryngology patients for scheduled appointments
Authors: Cohen A D , Kaplan D M , Kraus M , Rubinshtein E , Vardy D A
Published: October 2006

Background: Nonattendance for appointments is an impediment to otolaryngology patient care worldwide. In a previous study of children attending an otolaryngology clinic, we observed that attendance was determined by the waiting time for an appointment and the timing of the appointment within the day. However, the factors that affect nonattendance in adults have not been well studied.

Objective: We aimed to investigate factors associated with nonattendance in adults visiting an otolaryngology clinic.

Methods: Nonattendance was observed for a period of one year in adult patients visiting an ambulatory otolaryngology clinic. The following parameters were also noted: age, gender, treating physician, waiting time and timing of the appointment. The chi-square test was used to analyse differences between categorical variables. The t-test was used to analyse differences between continuous variables. Logistic regression was used for multivariate analyses.

Results: The study assessed 8071 visits to the otolaryngology clinic. The overall proportion of nonattendance was 27.7 per cent. A multivariate logistic regression model demonstrated that nonattendance was significantly associated with the following factors: female gender, younger age, long waiting time for an appointment, timing of the appointment within the day and the treating physician.

Conclusion: In adult otolaryngology patients, nonattendance was associated with patient-related factors and healthcare systems related factors alike. It is suggested that managed overbooking could be carefully introduced into otolaryngology patient scheduling.
Sternoclavicular joint pseudo-tumour: a case report and literature review
Authors: Islam S , Walton G M , Hoffman G R
Published: October 2006

This case report describes the development of a post-treatment enlargement of the sternoclavicular joint, diagnosed as a pseudo-tumour, in a patient who had previously undergone radical neck dissection and post-operative radiotherapy for metastatic mucoepidermoid carcinoma. Although pseudo-tumour has been previously reported in the surgical literature, it remains an uncommonly recognized condition. We present a review of the literature and discuss the condition's pathogenesis. We also highlight its importance to both the surgeon and the oncologist when considering the differential diagnosis of a swelling in the clavicular region, typically occurring following radical surgery for malignant disease in the neck.
A qualitative study of the trauma and posttraumatic growth of
multiple myeloma patients treated with peripheral blood stem cell
transplant
Authors: DAHAN JACQUELINE FINE , AUERBACH CARL F.
Published: October 2006

Objective: The study was conducted to understand the
emotional impact of multiple myeloma, as well as the impact of its
principle treatment, peripheral blood stem cell transplant (PBSCT). The
absence of psycho-oncology research literature on this population prompted
the need for a hypothesis-generating investigation. Thus, a qualitative
design was used to construct a theoretical model of the trauma relating to
diagnosis and treatment of myeloma. The study also incorporates the
important period of reflection and growth following treatment.

Methods: The sample consisted of 3 women and 3 men treated
for myeloma at a New York City-based cancer treatment center. Data from
individual interviews were audiotaped and transcribed. After extensive
review, the data were categorized into groups of repeating ideas, themes
and broad theoretical constructs.

Results: A five-construct model emerged from the data
analysis that integrated a model of trauma and growth presented in earlier
work (Auerbach et al., 2006). These constructs
roughly correspond with stages of illness, but do not necessarily imply a
linear process, as suggested by stage models. The first construct is
diagnosis. Patients receive the news that they have multiple myeloma.
Initial reactions are discussed and a treatment plan takes form. In the
second construct, treatment, patients highlight the physical and emotional
hurdles confronted throughout treatment. The third construct, network of
safety, presents social factors that play a role in comforting patients
throughout illness. Patients recognize the importance of a strong support
system during their experiences. In the fourth construct, recuperation,
physical energy is regained after an arduous recovery period. This
contributes to higher spirits and a motivation to reengage with life. The
fifth construct is reflection and new existence. Patients strive to
balance a new reality that relapse and death are inevitable, along with
their need to live a meaningful life. Many do not yet appreciate how their
disease has impacted them, but describe how their interpersonal lives and
perceptions have changed, both positively and negatively.

Significance of results: Limitations of the study, future
directions for research and clinical implications are discussed.
Upon hearing good news.
Authors: SHERMAN RITA
Published: October 2006

Upon hearing good news.
Air‐sea CO2 fluxes and the continental shelf pump of carbon in the Chukchi Sea adjacent to the Arctic Ocean
Authors: Bates Nicholas R.
Published: October 2006

The Chukchi Sea, a shallow sea‐ice covered coastal sea adjacent to the Arctic Ocean, exhibits an intense bloom of phytoplankton each year due to the exposure of nutrient‐laden surface waters during the brief summertime retreat and melting of sea‐ice. The impact of phytoplankton production and other factors on the seasonal dynamics of carbon and air‐sea CO2 fluxes were investigated during two survey cruises (5 May–15 June 2002, and 17 July–26 August 2002), as part of the Western Arctic Shelf‐Basins‐Interactions (SBI) project. In springtime, most of the Chukchi Sea was sea‐ice covered (>95%) and remnant winter water was present across the shelf. Surface layer seawater partial pressure of CO2 (pCO2) ranged from ∼200–320 μatm, indicative of undersaturation with respect to atmospheric pCO2, although sea‐ice cover kept rates of air‐to‐sea CO2 flux generally low (<1 mmoles CO2 m2 d−1). By summertime, after sea‐ice retreat, seawater pCO2 contents had decreased to very low values (<80–220 μatm) in response to high rates of localized primary and net community production (NCP) and biological uptake of dissolved inorganic carbon (DIC). In the seasonally sea‐ice free regions of the Chukchi Sea shelf, rates of air‐to‐sea CO2 fluxes, determined using the quadratic wind speed‐transfer velocity relationships of Wanninkhof (1992), were high, ranging from ∼30–90 mmoles CO2 m−2 d−1. In regions of the Chukchi Sea slope (and western Beaufort Sea shelf and Arctic Ocean basin) where sea‐ice cover remained high (>80%), air‐to‐sea CO2 fluxes remained generally low (<2 mmoles CO2 m−2 d−1). Seasonal (i.e., May to September) and annual net air‐to‐sea CO2 fluxes from the Chukchi Sea shelf were estimated at ∼27 ± 7 Tg C yr−1, and 38 ± 7 Tg C yr−1, respectively. The Chukchi Sea represents the largest oceanic CO2 sink in the marginal coastal seas adjacent to the Arctic Ocean. An active continental shelf pump of carbon, driven by the northward transport of nutrient‐rich water of Pacific Ocean origin, high rates of primary and net community production during the sea‐ice free period, and lateral export of organic carbon, maintains the Chukchi Sea shelf and slope as a perennial ocean CO2 sink.
Development and evaluation of a new catchment‐scale model of floodplain sedimentation
Authors: Nicholas A. P. , Walling D. E. , Sweet R. J. , Fang X.
Published: October 2006

Fine‐sediment storage within floodplain systems typically represents a significant component of the catchment sediment budget and a primary control on sediment‐associated nutrient and contaminant fluxes at the basin scale. However, quantitative modeling of floodplain sedimentation within whole catchments represents a significant challenge, not least because hydraulic controls on sediment transport and deposition processes operate at fine spatial scales that cannot be resolved by basin‐scale models. This paper outlines a new approach to addressing this problem in order to develop a computationally efficient model of floodplain sedimentation, which retains a strong physical basis. The approach involves two stages. First, a simple theoretical model of overbank sedimentation is presented, which quantifies the relationship between floodplain geometry, overbank discharge, and total sedimentation rate. Second, the precise form that such a relationship should take is established by analysis of the output from high‐resolution flow and suspended sediment transport models applied to 22 floodplain reaches along three U.K. rivers. This analysis supports a simple power law model between discharge in excess of bankfull and sedimentation rate per unit valley floor length per unit sediment concentration. The power law model is then incorporated within a sediment budget framework and implemented using a Monte Carlo approach to allow an assessment of uncertainty in the model parameterization. The relative likelihood of competing model structures is determined using estimates of mean annual floodplain sediment storage derived by analysis of the 137Cs content of floodplain sediment cores. Comparison of 137Cs‐derived sedimentation rates with uncertainty‐bounded model predictions highlights the potential for assessing the significance of overbank sedimentation within catchment sediment budgets using the simple power law model.
Characteristics of the large‐scale traveling atmospheric disturbances during geomagnetically quiet and disturbed periods simulated by a whole atmosphere general circulation model
Authors: Fujiwara Hitoshi , Miyoshi Yasunobu
Published: October 2006

We have investigated characteristics of the large‐scale traveling atmospheric disturbances (LS‐TADs) generated during geomagnetically quiet and disturbed periods using a whole atmosphere general circulation model (GCM). The GCM simulations show that various TADs appear in association with passages of regions with large temperature gradients near the solar terminator, midnight temperature anomaly, and auroral oval which move with the Earth's rotation. These TADs, which are superimposed on each other, appear even when a geomagnetically quiet period. The TADs generated during a geomagnetically quiet period show structures extending in the longitudinal direction at high‐latitude and in the latitudinal direction at mid‐ and low‐latitude. These structures disappear after their short‐range propagations. The TADs generated during a geomagnetically disturbed period show structures extending widely in the longitudinal direction and propagate from high‐ to low‐latitude. These simulation results suggest the different generation mechanisms and features between the TADs generated during geomagnetically quiet and disturbed periods.
Interannual variability in the Indian Ocean using altimeter and IX1‐expendable bathy‐thermograph (XBT) data: Does the 18‐month signal exist?
Authors: Sakova Irina V. , Meyers Gary , Coleman Richard
Published: October 2006

The dominant frequency bands in altimeter sea surface height (SSH) variability over the whole Indian Ocean and in temperature profiles near the Sumatra‐Java coast are identified and analysed using spectral analysis techniques. We find that in most regions of the Indian Ocean, the low‐frequency part of the SSH spectra (corresponding to signals with periods from six months to six years) is concentrated in five frequency bands separated by substantial spectral gaps: semi‐annual, annual, 18–20 months, 3 years, and 4–6 years. The existence of semi‐annual, annual, 2–3‐year, and 4–6‐year periodical signals is well known; however, the 18–20‐month signal has not previously been described. Further investigation of temporal and spatial characteristics of this later signal point to its relationship with the Indian Ocean dipole events: the signal is particularly strong between 1994 and 2000; it develops near the Sumatra coast and propagates to the Bay of Bengal and into the Indonesian Throughflow.
Multiple discontinuities near 660 km beneath Tonga area
Authors: Zang Shao‐Xian , Zhou Yuan‐Ze , Ning Jie‐Yuan , Wei Rong‐Qiang
Published: October 2006

We study the discontinuities beneath Tonga subduction zone using the deep earthquakes recorded by the Pacific Northwest Seismic Network (PNSN). The multiple discontinuities around 660 km beneath Tonga subduction zone are found using converted phase SdP. The amplitude ratios of the converted phase with the direct P wave (Ac/Ap) are also determined. The largest number of robust converted phases with large Ac/Ap comes from the depth range of 660–690 km, its peak is at 680 km; the second one appears in the depth range of 700–745 km, its peak is at 740 km. The two discontinuities are obviously depressed by the subduction slab. According to experimental and numerical studies, a possible explanation of the observation is that the first discontinuity is formed by the transition of γ‐spinel to perovskite and magnesiowüstite and the second is formed by the transition of ilmenite to perovskite.
Scaling of electric field fluctuations associated with the aurora during northward IMF
Authors: Kozelov B. V. , Golovchanskaya I. V.
Published: October 2006

We present a statistical study of scaling features of the electric field fluctuations measured by the DE2 satellite in the polar region during positive Bz IMF when the theta‐aurora was observed by the DE1 satellite. It is demonstrated that the power spectra of the fluctuations have a power‐law form at spatial scales from ∼0.5 km (the limit of resolution) to several thousands of kilometers, with a break near 100 km. The scaling properties of the field are studied by examining the generalized structure functions (GSFs) and probability density functions (PDFs) of the fluctuations. The observed PDFs have a non‐Gaussian shape with heavy tails. We also demonstrate a collapse of the re‐scaled PDFs onto a single curve. A relation of PDF shape to solar wind conditions is revealed. The same analysis is performed on the TV observations of the theta‐aurora. The scaling characteristics of the field and auroral fluctuations are compared.
Influence of stream bank seepage during low‐flow conditions on riparian zone hydrology
Authors: Duval T. P. , Hill A. R.
Published: October 2006

We examined the effect of sustained stream bank seepage during base flow conditions on the hydrology of two riparian zones in lowland agricultural areas in southern Ontario, Canada. Hydrometric data and subsurface chloride patterns over a 2‐year period indicated that stream inflow to the riparian zone sustained a reversed water table gradient inland for periods of up to 4 months in summer and autumn at one of the riparian sites. Stream bank seepage occurred throughout the year at the second riparian site where hillslope inflow was restricted by an upslope spur. Despite high evapotranspiration rates in summer, stream inflow maintained a zone of saturated riparian sediments that extended up to 25 m inland. A bromide tracer injection at the stream bank interface indicated that bank seepage occurred along preferential flow paths in a poorly sorted gravel layer at the two riparian sites. Conceptual models of humid temperate riparian zones have focused on hillslope to stream hydrologic flow paths. However, our results suggest that sustained stream bank inflow during low‐flow conditions can exert a dominant control on riparian hydrology in lowland landscapes where level riparian zones bounded by perennial streams receive limited subsurface inflows from adjacent slopes.
Deletion of the c-Jun N-terminal Kinase 3 Gene Protects Neonatal Mice against Cerebral Hypoxic—Ischaemic Injury
Authors: Pirianov Grisha , Brywe Katarina G , Mallard Carina , Edwards A David , Flavell Richard A , Hagberg Henrik , Mehmet Huseyin
Published: October 2006

c-Jun N-terminal kinase 3 (JNK3) is a member of the stress-activated group of mitogen-activated protein kinases. c-Jun N-terminal kinase 3 is a potent mediator of apoptosis and the use of JNK inhibitors or jnk3 gene deletion each protect against brain injury in adults. However, little is known about the role of JNK3 or its mechanism of action in neonatal brain injury. The aim of the present study was to compare the vulnerability of neonatal JNK3 knockout (JNK3 KO) mice and wild-type (WT) mice to cerebral hypoxic—ischaemic injury (HII) using unilateral-carotid occlusion combined with transient hypoxia. The degree of neural tissue loss in JNK3 KO mice was substantially reduced compared with WT mice (JNK3 KO 27.8% ± 2.8% versus WT 48.3% ± 2.0%, P ≤ 0.0001) after HII. Significant attenuation of injury was observed in the cerebral cortex, hippocampus, striatum, and thalamus of JNK3 KO compared with WT mice. Hypoxic—ischaemic injury increased JNK phosphorylation and activity, with JNK3 as the major isoform. Significantly, in JNK3 KO animals there was no difference in the activation of the upstream kinases mitogen-activated protein kinase kinase (MKK4) or MKK7. Downstream of JNK3, HII lead to increased phosphorylation of the transcription factors c-Jun and adenovirus transcription factor-2 (ATF-2), which was attenuated in JNK3 KO mice. c-Jun N-terminal kinase 3 deletion also decrease caspase-3 cleavage and Bim/PUMA expression, coupled with a upregulation of AKT/FOXO3a levels, linking JNK3 to apoptosis. These findings implicate JNK3 involvement in neural cell loss resulting from cerebral HII in the developing brain.
Novel Delivery System Enhances Efficacy of Antiretroviral Therapy in Animal Model for HIV-1 Encephalitis
Authors: Spitzenberger Timothy J , Heilman David , Diekmann Casey , Batrakova Elena V , Kabanov Alexander V , Gendelman Howard E , Elmquist William F , Persidsky Yuri
Published: October 2006

Most potent antiretroviral drugs (e.g., HIV-1 protease inhibitors) poorly penetrate the blood—brain barrier. Brain distribution can be limited by the efflux transporter, P-glycoprotein (P-gp). The ability of a novel drug delivery system (block co-polymer P85) that inhibits P-gp, to increase the efficacy of antiretroviral drugs in brain was examined using a severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE). Severe combined immunodeficiency mice inoculated with HIV-1 infected human monocyte-derived macrophages (MDM) into the basal ganglia were treated with P85, antiretroviral therapy (ART) (zidovudine, lamivudine and nelfinavir (NEL)), or P85 and ART. Mice were killed on days 7 and 14, and brains were evaluated for levels of viral infection. Antiviral effects of NEL, P85, or their combination were evaluated in vitro using HIV-1 infected MDM and showed antiretroviral effects of P85 alone. In SCID mice injected with virus-infected MDM, the combination of ART-P85 and ART alone showed a significant decrease of HIV-1 p24 expressing MDM (25% and 33% of controls, respectively) at day 7 while P85 alone group was not different from control. At day 14, all treatment groups showed a significant decrease in percentage of HIV-1 infected MDM as compared with control. P85 alone and combined ART-P85 groups showed the most significant reduction in percentage of HIV-1 p24 expressing MDM (8% to 22% of control) that were superior to the ART alone group (38% of control). Our findings indicate major antiretroviral effects of P85 and enhanced in vivo efficacy of antiretroviral drugs when combined with P85 in a SCID mouse model of HIVE.
The molecular mechanisms of the mammalian exocyst complex in exocytosis
Authors: Wang S. , Hsu S.C.
Published: October 2006

Exocytosis is a highly ordered vesicle trafficking pathway that targets proteins to the plasma membrane for membrane addition or secretion. Research over the years has discovered many proteins that participate at various stages in the mammalian exocytotic pathway. At the early stage of exocytosis, co-atomer proteins and their respective adaptors and GTPases have been shown to play a role in the sorting and incorporation of proteins into secretory vesicles. At the final stage of exocytosis, SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) and SNARE-associated proteins are believed to mediate the fusion of secretory vesicles at the plasma membrane. There are multiple events that may occur between the budding of secretory vesicles from the Golgi and the fusion of these vesicles at the plasma membrane. The most obvious and best-known event is the transport of secretory vesicles from Golgi to the vicinity of the plasma membrane via microtubules and their associated motors. At the vicinity of the plasma membrane, however, it is not clear how vesicles finally dock and fuse with the plasma membrane. Identification of proteins involved in these events should provide important insights into the mechanisms of this little known stage of the exocytotic pathway. Currently, a protein complex, known as the sec6/8 or the exocyst complex, has been implicated to play a role at this late stage of exocytosis.
Rab27 and its effectors in secretory granule exocytosis: a novel docking machinery composed of a Rab27·effector complex
Authors: Fukuda M.
Published: October 2006

A small GTPase Rab27 is present on secretory granules in a wide variety of secretory cells and on melanosomes in melanocytes, and it is involved in controlling the trafficking of these organelles through interaction with a cell-type- or tissue-specific Rab27 effector(s). Slps (synaptotagmin-like proteins) and rabphilin contain an N-terminal Rab27-binding domain and C-terminal tandem C2 domains, and some of the Rab27-binding proteins have recently been shown to promote docking of Rab27-bound organelles to the plasma membrane. This mini-review presents a model for how the Rab27·effector complex controls the docking step in the trafficking of Rab27-bound organelles. Our results indicate that Slp2-a, Slp4-a/granuphilin-a and rabphilin are capable of interacting with the plasma membrane directly or indirectly, and thus that these Rab27 effectors form a bridge between Rab27-bound organelles and the plasma membrane.
Mitotic spindle morphogenesis: Ran on the microtubule cytoskeleton and beyond
Authors: Goodman B. , Zheng Y.
Published: October 2006

Assembly and disassembly of the mitotic spindle are essential for both chromosome segregation and cell division. The small G-protein Ran has emerged as an important regulator of spindle assembly. In this review, we look at the role of Ran in different aspects of spindle assembly, including its effects on microtubule assembly dynamics and microtubule organization. In addition, we examine the possibility of a spindle matrix and the role Ran might play in such a structure.
The aggravating role of the ubiquitin–proteasome system in neurodegenerative disease
Authors: Hung C.-C. , Davison E.J. , Robinson P.A. , Ardley H.C.
Published: October 2006

Intraneuronal inclusion bodies are key pathological features of most age-related neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. These inclusions are commonly characterized both by the presence of ubiquitinated proteins and the sequestration of components of the UPS (ubiquitin–proteasome system). Unfortunately, as we age, the efficiency of the UPS declines, suggesting that the presence of ubiquitinated proteins and UPS components in inclusions may reflect unsuccessful attempts by the (failing) UPS to remove the aggregating proteins. Whether the physical presence of inclusions causes cell death or, conversely, whether they are non-toxic and their presence reflects a cellular protective mechanism remains highly controversial. Animal and in vitro model systems that allow detailed characterization of the inclusions and their effects on the cell have been developed by us and others. Identification of the mechanisms involved in inclusion formation is already aiding the development of novel therapeutic strategies to prevent or alleviate aggregate-associated neurodegenerative diseases.
De-ubiquitinating enzymes: intracellular signalling and disease
Authors: Johnston J.A. , Burrows J.F.
Published: October 2006

Ubiquitination is now accepted as an important process for regulating intracellular signalling and the realization that many known signalling molecules exhibit E3 ligase activity has led to great strides in our understanding of how these pathways are regulated. However, as most of the de-ubiquitinating enzymes have as yet no identified substrate, little is known about their potential role in the regulation of intracellular signalling. Here, we examine what is known about de-ubiquitinating enzymes and signalling, with particular emphasis on their role in the regulation of immune signalling and the initiation of DNA repair. In addition, we look at the evidence implicating these enzymes in the pathogenesis of diseases such as cancer and neurodegenerative diseases.
Nutrient regulation of pancreatic β-cell function in diabetes: problems and potential solutions
Authors: Flatt P.R. , Green B.D.
Published: October 2006

Increasing prevalence of obesity combined with longevity will produce an epidemic of Type 2 (non-insulin-dependent) diabetes in the next 20 years. This disease is associated with defects in insulin secretion, specifically abnormalities of insulin secretory kinetics and pancreatic β-cell glucose responsiveness. Mechanisms underlying β-cell dysfunction include glucose toxicity, lipotoxicity and β-cell hyperactivity. Defects at various sites in β-cell signal transduction pathways contribute, but no single lesion can account for the common form of Type 2 diabetes. Recent studies highlight diverse β-cell actions of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). These intestinal hormones target the β-cell to stimulate glucose-dependent insulin secretion through activation of protein kinase A and associated pathways. Both increase gene expression and proinsulin biosynthesis, protect against apoptosis and stimulate replication/neogenesis of β-cells. Incretin hormones therefore represent an exciting future multi-action solution to correct β-cell defect in Type 2 diabetes.
Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes
Authors: Fang X. , Sweeney G.
Published: October 2006

Nutritional control of molecular events has become of great interest given the increased incidence of diet-induced obesity, and consequently Type 2 (non-insulin-dependent) diabetes, in recent years. The altered adipose tissue content in obese individuals results in an altered profile of circulating adipokines, and here we focus on adiponectin, whose circulating levels decrease in obese individuals. Adiponectin is a 30 kDa protein but circulates primarily as hexameric, oligomeric and, to a lesser extent, trimeric forms. Full-length adiponectin can also be cleaved to produce a fragment containing the globular domain that exerts potent metabolic effects. Adiponectin has insulin-mimetic and -sensitizing actions including stimulation of glucose uptake in skeletal muscle and suppression of glucose production in liver. Hence, adiponectin has attracted great interest as an antidiabetic agent. Adiponectin acts via two receptor isoforms, AdipoR1 (adiponectin receptor 1) and AdipoR2, which have distinct tissue distributions and affinities for recognition of the various adiponectin forms. Expression of AdipoR isoforms can be regulated by hyperinsulinaemia and hyperglycaemia with the consequence of increased sensitivity or resistance to specific forms of adiponectin. In summary, regulation of adiponectin or AdipoR expression may be of great importance in the development of metabolic perturbations characteristic of Type 2 diabetes in obese individuals.
Regulation of insulin secretion by uncoupling protein
Authors: Chan C.B. , Kashemsant N.
Published: October 2006

UCPs (uncoupling proteins) can regulate cellular ATP production by uncoupling oxidative phosphorylation. UCP2 is expressed in islet β-cells and its induction reduces glucose-stimulated insulin secretion. Under physiological conditions, superoxide, formed as a by-product of respiration, activates UCP2. This leads to reduced ATP production, which impairs closure of the ATP-dependent K+ channels to prevent insulin secretion. It is suggested that the physiological role of UCP2 is to prevent excessive superoxide generation through a feedback loop. UCP2 induction may also alter fatty acid metabolism by altering NAD/NADH or by facilitating cycling of fatty acid anions. Recently, UCP2 has been proposed to keep insulin secretion low during starvation, a function under the control of the transcription co-repressor, surtuin-1, which has been shown to bind to the UCP2 promoter. Pathological UCP2 expression or activation may suppress glucose-stimulated insulin secretion to the extent that diabetes onset is hastened. In ob/ob mice, induction of UCP2 at age 5 weeks precedes development of insulin secretion defects and hyperglycaemia. Activating protein kinase A-dependent pathways can normalize insulin secretion in UCP2-overexpressing islets. Conversely, lowering UCP2 expression may promote increased insulin secretion. UCP2 knockout mice were protected from the diabetogenic effects of a high-fat diet and their islets exhibited increased sensitivity to glucose and elevated ATP/ADP. These results support a role for UCP2 as a gene contributing to the pathogenesis of Type 2 diabetes.
The importance of redox shuttles to pancreatic β-cell energy metabolism and function
Authors: Bender K. , Newsholme P. , Brennan L. , Maechler P.
Published: October 2006

The coupling of cytosolic glycolytic NADH production with the mitochondrial electron transport chain is crucial for pancreatic β-cell function and energy metabolism. The activity of lactate dehydrogenase in the β-cell is low, thus glycolysis-derived electrons are transported towards the mitochondrial matrix by a NADH shuttle system, which in turn regenerates cytosolic NAD+. Mitochondrial electron transport then produces ATP, the main coupling factor for insulin secretion. Aralar1, a Ca2+-sensitive member of the malate–aspartate shuttle expressed in β-cells, has been found to play a significant role in nutrient-stimulated insulin secretion and β-cell function. Increased capacity of Aralar1 enhances the responsiveness of the cell to glucose. Conversely, inhibition of the malate–aspartate shuttle results in impaired glucose metabolism and insulin secretion. Current research investigates potentiating or attenuating activities of various amino acids on insulin secretion, mitochondrial membrane potential and NADH production in Aralar1-overexpressing β-cells. This work may provide evidence for a central role of Aralar1 in the regulation of nutrient metabolism in the β-cells.
Mechanisms of MAPK signalling specificity
Authors: Bardwell L.
Published: October 2006

MAPK (mitogen-activated protein kinase) signalling pathways contribute to the regulation of diverse responses, including normal and pathological aspects of cell growth, division, differentiation and death. Their ubiquity and versatility raise the issue of how they achieve specific coupling of signal with cellular response. How do the kinases in the cascade distinguish their correct substrates from the vast excess of incorrect substrates? Furthermore, how do different signals elicit distinct responses when they are transmitted by the same components? This short review highlights several mechanisms that can promote specificity in MAPK signalling, including tethering interactions between MAPKs and their substrates and regulators mediated by docking sites, feedback loops and cross-pathway regulatory circuits, and the selective activation of scaffold proteins.