bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer‐related mutations in BRCA1‐BRCT cause long‐range structural changes in protein–protein binding sites: A molecular dynamics study
Authors: Gough Craig A. , Gojobori Takashi , Imanishi Tadashi
Published: October 2006

Cancer‐associated mutations in the BRCT domain of BRCA1 (BRCA1‐BRCT) abolish its tumor suppressor function by disrupting interactions with other proteins such as BACH1. Many cancer‐related mutations do not cause sufficient destabilization to lead to global unfolding under physiological conditions, and thus abrogation of function probably is due to localized structural changes. To explore the reasons for mutation‐induced loss of function, the authors performed molecular dynamics simulations on three cancer‐associated mutants, A1708E, M1775R, and Y1853ter, and on the wild type and benign M1652I mutant, and compared the structures and fluctuations. Only the cancer‐associated mutants exhibited significant backbone structure differences from the wild‐type crystal structure in BACH1‐binding regions, some of which are far from the mutation sites. Backbone differences of the A1708E mutant from the liganded wild type structure in these regions are much larger than those of the unliganded wild type X‐ray or molecular dynamics structures. These BACH1‐binding regions of the cancer‐associated mutants also exhibited increases in their fluctuation magnitudes compared with the same regions in the wild type and M1562I mutant, as quantified by quasiharmonic analysis. Several of the regions of increased fluctuation magnitude correspond to correlated motions of residues in contact that provide a continuous path of fluctuating amino acids in contact from the A1708E and Y1853ter mutation sites to the BACH1‐binding sites with altered structure and dynamics. The increased fluctuations in the disease‐related mutants suggest an increase in vibrational entropy in the unliganded state that could result in a larger entropy loss in the disease‐related mutants upon binding BACH1 than in the wild type. To investigate this possibility, vibrational entropies of the A1708E and wild type in the free state and bound to a BACH1‐derived phosphopeptide were calculated using quasiharmonic analysis, to determine the binding entropy difference ΔΔS between the A1708E mutant and the wild type. ΔΔS was determined to be −4.0 cal mol−1 K−1, with an uncertainty of 2 cal mol−1 K−1; that is, the entropy loss upon binding the peptide is 4.0 cal mol−1 K−1 greater for the A1708E mutant, corresponding to an entropic contribution to the ΔΔG of binding (−TΔΔS) 1.1 kcal mol−1 more positive for the mutant. The observed differences in structure, flexibility, and entropy of binding likely are responsible for abolition of BACH1 binding, and illustrate that many disease‐ related mutations could have very long‐range effects. The methods described here have potential for identifying correlated motions responsible for other long‐range effects of deleterious mutations. Proteins 2007. © 2006 Wiley‐Liss, Inc.
A fast liquid chromatographic/mass spectrometric screening method for the simultaneous detection of synthetic glucocorticoids, some stimulants, anti‐oestrogen drugs and synthetic anabolic steroids
Authors: Mazzarino Monica , Botrè Francesco
Published: October 2006

A fast liquid chromatographic/mass spectrometric (LC/MS/MS) screening method for the detection, in urine, of synthetic glucocorticoids, stimulants (formoterol, modafinil and mesocarb), anti‐oestrogens (finasteride, exemestane, anastrozole, letrozole and formestane) and synthetic anabolic steroids (stanozolol, gestrinone and tetrahydrogestrinone) is described. All these drugs (and/or their urinary metabolites) can be simultaneously extracted by a single liquid/liquid extraction step, at alkaline pH, after enzymatic hydrolysis with β‐glucuronidase, and assayed in 7 min by LC/MS/MS using electrospray ionization in positive ion mode and multiple reaction monitoring as the acquisition mode. All compounds show good reproducibility of both the retention times (CV% <2%) and the relative abundances (CV% <10%). The limits of detection for the anti‐oestrogens, glucocorticoids and steroids are in the range of 1–30 ng/mL, and for the stimulants are in the range of 100–200 ng/mL, thus satisfying the minimum required performance limits of the World Anti‐Doping Agency. Copyright © 2006 John Wiley & Sons, Ltd.
A high‐throughput liquid chromatography/tandem mass spectrometry method for simultaneous quantification of a hydrophobic drug candidate and its hydrophilic metabolite in human urine with a fully automated liquid/liquid extraction
Authors: Wang Perry G. , Zhang Jun , Gage Eric M. , Schmidt Jeffrey M. , Rodila Ramona C. , Ji Qin C. , El‐Shourbagy Tawakol A.
Published: October 2006

ABT‐869 (A‐741439) is an investigational new drug candidate under development by Abbott Laboratories. ABT‐869 is hydrophobic, but is oxidized in the body to A‐849529, a hydrophilic metabolite that includes both carboxyl and amino groups. Poor solubility of ABT‐869 in aqueous matrix causes simultaneous analysis of both ABT‐869 and its metabolite within the same extraction and injection to be extremely difficult in human urine. In this paper, a high‐performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) method has been developed and validated for high‐speed simultaneous quantitation of the hydrophobic ABT‐869 and its hydrophilic metabolite, A‐849529, in human urine. The deuterated internal standards, A‐741439D4 and A‐849529D4, were used in this method. The disparate properties of the two analytes were mediated by treating samples with acetonitrile, adjusting pH with an extraction buffer, and optimizing the extraction solvent and mobile phase composition. For a 100 µL urine sample volume, the lower limit of quantitation was approximately 1 ng/mL for both ABT‐869 and A‐849529. The calibration curve was linear from 1.09 to 595.13 ng/mL for ABT‐869, and 1.10 to 600.48 ng/mL for A‐849529 (r2 > 0.9975 for both ABT‐869 and A‐849529). Because the method employs simultaneous quantification, high throughput is achieved despite the presence of both a hydrophobic analyte and its hydrophilic metabolite in human urine. Copyright © 2006 John Wiley & Sons, Ltd.
Determination of fourteen non‐steroidal anti‐inflammatory drugs in animal serum and plasma by liquid chromatography/mass spectrometry
Authors: Vinci Floriana , Fabbrocino Serena , Fiori Maurizio , Serpe Luigi , Gallo Pasquale
Published: October 2006

The European Union has regulated the use of non‐steroidal anti‐inflammatory drugs (NSAIDs) in animal production and requires its member states to detect their residues in different matrices. In this work, a detailed MS and MS/MS study by ion‐trap mass spectrometry of fourteen NSAIDs is described. Two multi‐residue reversed‐phase LC/ESI‐MS/MS methods were developed, one for the determination of salicylic acid, naproxen, carprofen, flurbiprofen, ibuprofen, niflumic acid and meclofenamic acid in the negative ion mode, and the other for the determination of ketoprofen, suxibutazone, diclofenac, mefenamic acid, tolfenamic acid, phenylbutazone and its metabolite oxyphenbutazone in the positive ion mode. It was thus possible to confirm up to 14 different NSAID residues in serum and plasma samples of farmed animals, after chromatographic separation by a linear gradient. These substances were chosen as representative of different chemical subclasses of NSAIDs. The two methods were also validated in‐house at three contamination levels, evaluating specificity and calculating mean recoveries, repeatability and within‐laboratory reproducibility. The MS/MS product ion spectra were successfully used for the qualitative identification of all the drugs tested. All the NSAIDs, apart from salicylic acid, were recovered in high amounts, ranging between 71.6% and 100.9%. Copyright © 2006 John Wiley & Sons, Ltd.
Collision‐induced dissociation of protonated tetrapeptides containing β‐alanine, γ‐aminobutyric acid, ϵ‐aminocaproic acid or 4‐aminomethylbenzoic acid residues
Authors: Talaty Erach R. , Cooper Travis J. , Osburn Sandra , Van Stipdonk Michael J.
Published: October 2006

The influence of the presence and position of a single β‐alanine, γ‐aminobutyric acid, ϵ‐aminocaproic acid or 4‐aminomethylbenzoic acid residue on the tendency to form b‐ and y‐type product ions was determined using a group of protonated tetrapeptides with general sequence XAAG, AXAG and AAXG (where X refers to the position of amino acid substitution). The hypothesis tested was that the ‘alternative’ amino acids would influence product ion signal intensities by inhibiting or suppressing either the nucleophilic attack or key proton transfer steps by forcing the adoption of large cyclic intermediates or blocking cyclization altogether. We found that specific b ions are diminished or eliminated completely when βA, γAbu, Cap or 4AMBz residues are positioned such that they should interfere with the intramolecular nucleophilic attack step. In addition, differences in the relative proton affinities of the alternative amino acids influence the competition between complementary bn and yn ions. For both the AXAG and the XAAG series of peptides, collision‐induced dissociation (CID) generated prominent b ions despite potential inhibition or suppression of intramolecular proton migration by the βA, γAbu, Cap or 4AMBz residues. The prominent appearance of b ions from the AXAG and XAAG peptide is noteworthy, and suggests either that proton migration occurs through larger, ‘whole’ peptide cyclic intermediates or that fragmentation proceeds through a population of [M+H]+ isomers that are initially protonated at amide O atoms. Copyright © 2006 John Wiley & Sons, Ltd.
Bayesian evaluation of group sequential clinical trial designs
Authors: Emerson Scott S. , Kittelson John M. , Gillen Daniel L.
Published: October 2006

Clinical trial designs often incorporate a sequential stopping rule to serve as a guide in the early termination of a study. When choosing a particular stopping rule, it is most common to examine frequentist operating characteristics such as type I error, statistical power, and precision of confidence intervals (Statist. Med. 2005, in revision). Increasingly, however, clinical trials are designed and analysed in the Bayesian paradigm. In this paper, we describe how the Bayesian operating characteristics of a particular stopping rule might be evaluated and communicated to the scientific community. In particular, we consider a choice of probability models and a family of prior distributions that allows concise presentation of Bayesian properties for a specified sampling plan. Copyright © 2006 John Wiley & Sons, Ltd.
Statistical methods for active extension trials
Authors: Hu Zonghui , Follmann Dean
Published: October 2006

This paper develops methods of analysis for active extension clinical trials. Under this design, patients are randomized to treatment or placebo for a period of time (period 1), and then all patients receive treatment for an additional period of time (period 2). We assume a continuous outcome is measured at baseline and at the end of the two consecutive periods. If only period 1 data is available, classic estimators of the treatment effect include the change score, analysis of covariance, and maximum likelihood (ML). We show how to extend these estimators by incorporating period 2 data which we refer to as the period 2 estimators. Under the assumption that the mean responses for treatment and placebo arms are the same at the end of period 2, the new estimators are unbiased and more efficient than estimators that ignore period 2 data. If this assumption is not met, the period 2 tests may be more powerful than period 1 tests, but the estimators are biased downward (upward) if the treatment effect during period 2 is larger (smaller) in treatment arm than the placebo arm. In general, the proposed period 2 procedure can provide an efficient way to supplement but not supplant the usual period 1 analysis. Copyright © 2006 John Wiley & Sons, Ltd.
The Oxidation of the Aldehyde Groups in Dialdehyde Starch
Authors: Haaksman Ingrid K. , Besemer Arie C. , Jetten Jan M. , Timmermans Johan W. , Slaghek Ted M.
Published: October 2006

This paper describes the difference in relative reactivity of the aldehyde groups present in dialdehyde starch towards different oxidising agents. The oxidation of dialdehyde starch with peracetic acid and sodium bromide leads to only partial oxidation to give mono‐aldehyde‐carboxy starch, while oxidation with sodium chlorite results in dicarboxy derivatives. In order to obtain a more in depth insight into this phenomenon, the products obtained after partial oxidation via both routes were isolated and characterised. The results showed a pronounced difference in preferences between the two carbonyl groups towards the different oxidising agents.
Detecting spurious timeouts in wireless cellular networks using DS‐Agent
Authors: Xin Fei , Jamalipour Abbas
Published: October 2006

Large and sudden variations in packet transmission delays are often unavoidable in wireless networks. Such large delays, refer to as delay spikes (DSs), are likely to exceed several times the typical network round‐trip‐time figures, which can cause TCP spurious timeouts. The spurious timeouts lead to unnecessary retransmissions and reduction of the TCP sender's transmission rate, and degradation of TCP throughput. In this paper we propose a new scheme called DS‐Agent. The spurious timeout is detected by a DS‐Agent and thus TCP sender can response to this spurious timeout accordingly. The simulation results show the better performance of DS‐Agent scheme compared with F‐RTO and TCP Reno in the presence of DSs which is caused by mobility. Copyright © 2006 John Wiley & Sons, Ltd.
Monitoring left ventricular function in adults receiving anthracycline‐containing chemotherapy
Authors: Belham Mark , Kruger Anton , Mepham Sophie , Faganello Giorgio , Pritchard Colin
Published: October 2006

Aims:

To assess prospectively (1) the incidence of early anthracycline‐induced cardiotoxicity; (2) the best predictor for identifying individuals at risk of developing functional cardiotoxicity; and (3) the most sensitive standard echocardiographic measure for the detection of anthracycline‐induced changes in left ventricular (LV) function.

Methods:

Sixty‐seven consecutive patients (45 male, mean age 50±18 years) requiring doxorubicin‐containing chemotherapy were enrolled. Clinical and echocardiographic assessments occurred before they received any anthracycline, after low‐dose anthracyclines and 1–3 months after completion of their chemotherapy.

Results:

Twenty six percent of patients without significant pre‐existing cardiac disease developed cardiotoxicity. The parameter that best predicted the development of functional cardiotoxicity was the change in EF between baseline and low dose with an area under the curve of 0.92. The Tei index detected declines in LV function earlier in the course of treatment with anthracyclines and to a greater significance than any other standard echocardiographic measurement but did not predict functional cardiotoxicity.

Conclusions:

All patients receiving potential cardiotoxic chemotherapy should be under the care of a cardiologist and have their EF monitored closely.
Sphingosine kinase‐1 is cleaved by cathepsin B in vitro: Identification of the initial cleavage sites for the protease
Authors: Taha Tarek A. , El-Alwani Mazen , Hannun Yusuf A. , Obeid Lina M.
Published: October 2006

Previous work has identified sphingosine kinase‐1 (SK1) as a substrate for the cysteine protease cathepsin B in vitro. In this study, the mechanism of SK1 cleavage by cathepsin B was investigated. We identified two initial cleavage sites for the protease, the first at histidine 122 and the second at arginine 199. Mutation analysis showed that replacement of histidine 122 with a tyrosine maintained the activity of SK1 while significantly reducing cleavage by cathepsin B at the initial cleavage site. The efficacy of cleavage of SK1 at arginine 199, however, was not affected. These studies demonstrate that SK1 is cleaved by cathepsin B in a sequential manner after basic amino acids, and that the initial cleavages at the two identified sites occur independently of each other.
Mass spectrometry studies of demetallation of haemin by recombinant horse L chain apoferritin and its mutant (E 53,56,57,60 Q)
Authors: de Val Natalia , Herschbach Haiko , Potier Noëlle , Dorsselaer Alain Van , Crichton Robert R.
Published: October 2006

In this paper, we report the mass spectrometry studies of L‐chain apoferritin and its mutant incubated with haemin and analysed after different times of incubation: 15 days, 2 months, 6 months, 9 months and 12 months. These studies show that the recombinant L‐chain apoferritin and its mutant are able to demetallate haemin to give a hydroxyethyl protoporphyrin IX derivative in a dimeric form [Macieira, S., Martins, B. M. and Huber, R. (2003) Oxygen‐dependent coproporphyrinogen IX oxidase from Escherichia coli: one‐step purification and biochemical characterization. FEMS. Microbiology Letters 226, 31–37].
Was Heracleon a Valentinian? A New Look at Old Sources
Authors: Kaler Michael , Bussières Marie-Pierre
Published: October 2006

Heracleon was a great second-century Christian thinker, and the author of the first known commentary on a New Testament text, the Gospel of John. Although we do not have Heracleon's commentary itself, Origen integrated a great deal of it into his own commentary on the fourth gospel.
Factualizing the Folklore: Stephen Carlson's Case against Morton Smith
Authors: Brown Scott G.
Published: October 2006

Stephen C. Carlson's The Gospel Hoax sets out to validate the long-standing suspicion that Professor Morton Smith, late of Columbia University, forged his famous discovery of aletter of Clement of Alexandria, which quotes from a longer(“secret”)Gospel of Mark. This academic folklore has been passed on like an esoteric tradition since 1975, when Quentin Quesnell called on Smith to make the manuscript of this letter available for forensic testing in order to rule out the possibility of a recent hoax. Quesnell had difficulty substantiating his concerns. In his article in the Catholic Biblical Quarterly, he postulated that a modern scholar might have devised the letter as “a controlled experiment” in order to examine how scholars react to new evidence. Yet the manuscript of this letter, which Smith found in 1958, was inscribed on the last pages of a seventeenth-century book that purportedly was kept in a locked room of a monastery in the Judean desert. What modern forger would leave his creation there and gamble that someone would discover it in his lifetime? For this scenario to seem at all plausible, Quesnell needed to imply what he personally suspected, namely, that Smith forged it himself for this purpose. Accordingly, Quesnell described his hypothetical modern “mystifier” as someone who shared Smith's abilities, opportunities, resources, and interest in what people make of the document.
Barré–Lieou syndrome and the problem of the obsolete eponym
Authors: Foster C A , Jabbour P
Published: October 2006

Background: Eponym lists in major sources can give an aura of legitimacy to discredited diagnoses, as exemplified by the case of Barré–Lieou syndrome, a ‘rare’ vestibular disorder.

Methods: A literature review for information on the posterior cervical syndrome of Barré–Lieou.

Results: Barré–Lieou syndrome includes very common symptoms – tinnitus, dizziness, and head or neck pain – attributed to ischaemia caused by cervical sympathetic nerve compression. Its original description brings together many unrelated disorders, and its causative mechanism has been discredited. However, it appears credulously in a number of eponym lists, and references to the syndrome are steadily increasing on the internet in general and on alternative medicine and legal profession websites in particular.

Conclusion: By inclusion in eponym lists, without a disclaimer, a syndrome can be given legitimacy before the general public. A syndrome, such as Barré–Lieou syndrome, that is useless to the medical profession can unfortunately prove to be very useful for litigants and disability claimants.
ENT in general practice: training, experience and referral rates
Authors: Clamp P J , Gunasekaran S , Pothier D D , Saunders M W
Published: October 2006

A postal survey of 500 general practitioners (GPs) in south-west England was undertaken to evaluate the levels of undergraduate and postgraduate otolaryngology training and/or experience received by GPs in that area. Most GPs had received two weeks of undergraduate training in ENT, which had involved no formal assessment. Three-quarters of GPs considered this inadequate. A quarter of GPs had completed a hospital post in ENT prior to entering general practice, most of which lasted three months. Sixty-one per cent of GPs had received some formal postgraduate training in ENT, in the form of courses, lectures or hospital training sessions. Almost half of the GPs considered this inadequate. Seventy-five per cent of GPs stated they would like further training in ENT. Subjective estimates of referral rates to hospital ENT specialist clinics varied considerably.

This study illustrates the variability and level of dissatisfaction regarding ENT training amongst GPs at both undergraduate and postgraduate levels.
Subglottic haemangioma in children: experience with open surgical excision
Authors: Bajaj Y , Hartley B E J , Wyatt M E , Albert D M , Bailey C M
Published: October 2006

Subglottic haemangioma is a potentially life-threatening condition for which various treatment modalities are available. The objective of this study was to evaluate our results for open excision of subglottic haemangioma. The study assessed 18 patients who had been treated at a paediatric tertiary referral centre. Most of these patients (83.3 per cent) had undergone open surgical excision without post-operative tracheostomy and had been intubated for several days post-operatively (single-stage procedure). In most of these patients (66.7 per cent), an anterior cartilage graft had been used for reconstruction. The average follow up in this study was 25 months. All the patients in this series had achieved an adequate airway after the procedure. One patient had developed a recurrence of haemangioma in the trachea at a later date. The results of open surgical excision in this study were very encouraging. Seventeen out of 18 (94.4 per cent) patients had avoided tracheostomy or had been decannulated as a direct result of surgery. One of these 18 patients (5.6 per cent) had required a temporary post-operative tracheostomy for 13 months as the subglottis cleared; this was classed as a partial success. Our experience is that open excision is a highly successful ‘one stop’ treatment for subglottic haemangioma, which avoids prolonged use of steroids and multiple endoscopic procedures. No patient in this series developed subglottic stenosis, which can be a significant complication of laser application.
Differentiation between cholesteatoma and inflammatory process of the middle ear, based on contrast-enhanced computed tomography imaging
Authors: Trojanowska A , Trojanowski P , Olszanski W , Klatka J , Drop A
Published: October 2006

Objective: to assess the usefulness of delayed post-contrast computed tomography (CT) examination for the detection of residual or recurrent cholesteatoma after canal wall up tympanoplasty.

Study design and setting: This prospective, non-randomized study, set within an academic medical centre, included 17 consecutive patients who had undergone canal wall up tympanoplasty for cholesteatoma, with possible recurrence. Pre-contrast CT scans and delayed post-contrast images were compared with second look surgical findings.

Results: A residual or recurrent cholesteatoma was found in eight of the 17 patients at revision surgery and was correctly diagnosed on post-contrast CT images in six patients (75 per cent). In the two misdiagnosed cases, cholesteatoma pearls smaller than 2.5 mm were not seen on post-contrast CT. The sensitivity of the imaging test was 75 per cent, the specificity was 60.1 per cent, the positive predictive value was 88.1 per cent and the negative predictive value was 81.8 per cent.

Conclusion: Computed tomography with delayed post-contrast images is a sensitive imaging modality for the detection of residual cholesteatoma. If proven reliable, this method of non-invasive imaging could spare the patient unnecessary revision surgery.
Religion and spirituality among patients with localized prostate
cancer
Authors: HAMRICK NATALIE , DIEFENBACH MICHAEL A.
Published: October 2006

Objective: To examine: (1) daily religious and spiritual
experiences among localized prostate cancer patients as compared to a
national age and race-matched male sample; (2) cognitive-affective and
clinical predictors of prostate cancer diagnosis-related increases in
religiosity and spirituality; (3) short-term impact of daily religious and
spiritual experiences on cancer recurrence worry.

Methods: Analyses of data from a longitudinal questionnaire
study among patients (N = 254) diagnosed with localized prostate
cancer and data from a random sample (N = 238) of respondents to
the national General Social Survey.

Results: Compared to the national sample, prostate cancer
patients reported higher levels of daily spiritual experiences. Patients
with higher worry about prostate cancer and elevated levels of
prostate-related symptoms around diagnosis were more likely to report a
diagnosis-related increase in religiosity and spirituality. Positive
benefits (reduced recurrence worry) of religious coping/practices were
restricted to those patients with higher versus lower level of
postdiagnosis increase in religiosity; patients not reporting
postdiagnosis increases in religion who are not engaging in religious
coping/practice adjusted equally well. Results suggest that the
development of religious/spiritual interventions is premature.

Significance of results: This is the first prospective study
to report on the prevalence and influence of daily spiritual and religious
experiences among prostate cancer patients.
Requests for euthanasia and physician-assisted suicide and the
availability and application of palliative options
Authors: JANSEN-VAN DER WEIDE, MARIJKE C. , ONWUTEAKA-PHILIPSEN BREGJE D. , VAN DER WAL GERRIT
Published: October 2006

Objective: This study investigated the palliative options
available when a patient requested euthanasia or physician-assisted
suicide (EAS), the extent to which the options were applied, and changes
in the patient's wishes.

Methods: In an observational study, 3614 general
practitioners (GPs) filled in a questionnaire and described their most
recent request for EAS (if any) (n = 1,681).

Results: Palliative options were still available in 25% of
cases. In these cases options were applied in 63%; in 46% of these cases
patients withdrew their request. Medication other than antibiotics, which
was most frequently mentioned as a palliative option (67%), and applied
most frequently (79%), together with radiotherapy, most frequently
resulted in patients withdrawing their request.

Significance of results: GPs include the availability of
palliative options in their decision making when considering EAS. The fact
that not all options are applied or, if applied, the patient persists in
the request is related to autonomy of the patient, the burden on the
patient, and medical futility of the option.
Autonomy, paternalism, and the doctor's duty of care
Authors: WEIN SIMON
Published: October 2006

Medicine constantly holds the tensions of contrasts. Of life and of death. Of fighting and of folding. Of truth and of deceit. Herein lies the art of medicine. Holding the balance of the rational advance of science against the relative world of values and attitudes. This tension, in turn, reflects the human condition, wherein man is both symbolic and physical.
PROGNOSIS
Authors: GRANET ROGER B.
Published: October 2006

Prognosis.
GENTLE FLUTTERED PARTINGS
Authors: RAINGRUBER BONNIE
Published: October 2006

Gentle fluttered partings.
Ligamentäre Knieverletzungen in der Praxis
Authors: Behrend  , Stutz  , Bäthis  , Kuster
Published: October 2006

Das Kniegelenk ist wie kein anderes Gelenk auf einen intakten Bandapparat angewiesen. Bandinsuffizienzen führen zu einer Dissoziation der Roll-Gleit-Bewegung zwischen Tibia und Femur und auf lange Sicht mit grosser Wahrscheinlichkeit zu Sekundärschäden. Die Diagnose von Kapselbandverletzungen ergibt sich zum einen aus der genauen Anamnese mit oft typischen Unfallmechanismen und aus der klinischen Untersuchung mit spezifischen Tests. Zusätzlich kommen bildgebende Verfahren zur Anwendung. Das Spektrum der Kapselbandverletzungen ist gross. Es reicht von einer isolierten Innenbandruptur, welche unter konservativer Therapie i.d.R. folgenlos ausheilt bis zur Knieluxation, einem traumatologischen Notfall der einer sofortigen Diagnostik und Therapie bedarf und mit einer hohen Komplikationsrate verbunden ist. Ziel der rekonstruktiven Massnahmen ist die möglichst anatomiegerechte Wiederherstellung der Kapselbandstrukturen unter Gewährleistung einer dauerhaft stabilen Gelenkführung.
Tidal flushing and eddy shedding in Mount Hope Bay and Narragansett Bay: An application of FVCOM
Authors: Zhao Liuzhi , Chen Changsheng , Cowles Geoff
Published: October 2006

The tidal motion in Mt. Hope Bay (MHB) and Narragansett Bay (NB) is simulated using the unstructured grid, finite‐volume coastal ocean model (FVCOM). With an accurate geometric representation of irregular coastlines and islands and sufficiently high horizontal resolution in narrow channels, FVCOM provides an accurate simulation of the tidal wave in the bays and also resolves the strong tidal flushing processes in the narrow channels of MHB‐NB. Eddy shedding is predicted on the lee side of these channels due to current separation during both flood and ebb tides. There is a significant interaction in the tidal flushing process between MHB‐NB channel and MHB‐Sakonnet River (SR) channel. As a result, the phase of water transport in the MHB‐SR channel leads the MHB‐NB channel by 90°. The residual flow field in the MHB and NB features multiple eddies formed around headlands, convex and concave coastline regions, islands, channel exits and river mouths. The formation of these eddies is mainly due to the current separation either at the tip of the coastlines or asymmetric tidal flushing in narrow channels or passages. Process‐oriented modeling experiments show that horizontal resolution plays a critical role in resolving the asymmetric tidal flushing process through narrow passages. With a horizontal resolution of 50 m, FVCOM reproduces the eddy field that is in good agreement in the intensity and spatial scale with the current measurement data.
First whistler observed in the magnetosphere of Saturn
Authors: Akalin F. , Gurnett D. A. , Averkamp T. F. , Persoon A. M. , Santolik O. , Kurth W. S. , Hospodarsky G. B.
Published: October 2006

This paper describes and analyzes the first whistler observed in the magnetosphere of Saturn. The whistler was detected by the Radio and Plasma Wave Science (RPWS) instrument on the Cassini spacecraft during the inbound pass on October 28, 2004, at a radial distance of 6.18 RS (Saturn radii). Based on the measured dispersion, a travel time computation shows that the whistler originated from lightning in the northern hemisphere of Saturn. Using a simple centrifugal potential model for the plasma distribution along the magnetic field line, we have determined the scale height and fractional concentrations of water group ions and protons that give the best fit to the observed dispersion. In addition, a more complex diffusive equilibrium model was also analyzed. The inferred electron density profiles for the two models are very similar. Representative scale heights and equatorial ion fractional concentrations that provided good fits to the dispersion of the whistler were found to be = 0.89 RS and = 0.7 for water group ions, and = 2.67 RS and = 0.3 for protons.
Modulation of the diurnal cycle of tropical deep convective clouds by the MJO
Authors: Tian Baijun , Waliser Duane E. , Fetzer Eric J.
Published: October 2006

The infrared cloud amount with cloud tops above 180 hPa from the International Satellite Cloud Climatology Project D1 cloud product and the Tropical Rainfall Measurement Mission 3B42 precipitation product are employed to study the impact of the Madden‐Julian Oscillation (MJO) on the diurnal cycle of tropical deep convective cloud amount (DCC). Our analysis demonstrates that the diurnal cycle of tropical DCC is enhanced over both land and water during the convectively active phase of the MJO, while it is reduced during the convectively suppressed phase of the MJO. However, the diurnal phase of DCC is not significantly affected by the MJO. The analysis also indicates that the MJO modulation of the diurnal amplitude is much larger over the eastern Indian Ocean (around 50% of the mean diurnal amplitude) than over the western Pacific and the Maritime Continents (around 20% of the mean diurnal amplitude).
Repeated large subduction zone earthquakes in the Nankai‐Suruga trough: Evidence from submarine liquefactions
Authors: Lin Aiming
Published: October 2006

Subduction zones are generally characterized by large earthquakes that contribute about 90% of the total seismic moment worldwide, and can cause great damage from tsunamis such as the 2004 Sumatra Mw9.0 earthquake. Here, we report recurrent large subduction zone earthquakes revealed by extensive submarine liquefactions formed in the Nankai‐Suruga trough where the Philippine Sea plate is subducting beneath the Eurasian plate. Field evidence and grain‐size analysis of liquefied deposits show that the multiple‐liquefactions were repeatedly induced by strong earthquake shaking during the Pleistocene in the eastern Nankai‐Suruga subduction zone. The recognition and analysis of submarine liquefactions provide reliable paleoseismic evidence in the Nankai‐Suruga subduction zone.
Broadband electrostatic wave observations in the auroral region on Polar and comparisons with theory
Authors: Grabbe C. L. , Menietti J. D.
Published: October 2006

Broadband electrostatic wave (BEN) data gathered from Polar for passes through the aurora are analyzed and compared with theoretical predictions for the origin of magnetized solitary waves in BEN. Two passes exhibiting solitary waves were chosen for comparison, and times were selected that show numerous such waves. Examination of the data shows that even for these cases the nonsolitary form of BEN occurs much more commonly than the solitary form that is being particularly examined here. The first pass was for the period of 1430–1550 UT on 7 April 1996 at distances near 7RE, and the second pass was for the period of 0600–0800 UT on 10 May 1996 at distances near 8.8 RE. Four short intervals were chosen from the passes that show interesting solitary waves, each at slightly different radial distance, and the plasma parameters measured are used in developed theory to give predictions for the minimum and maximum electric field for propagation of BGK solitary waves, which have been the focus of theory for the nonlinear form of BEN for over a decade. This predicted minimum is compared to observations for solitary waves observed in these spacecraft time intervals along with parameters of the plasma environment at the time of observation, identified from the HYDRA data for these passes. The actual electric field is found to lie below the predicted minimum for all cases. Our conclusion is that these solitary waves are clearly not BGK waves in their observed form and may possibly have been produced by means other than electron trapping processes for BGK solitary waves. Feasible alternative theories for the solitary waves are discussed.
Photosystem II: an enzyme of global significance
Authors: Barber J.
Published: October 2006

Photosystem II (PSII) is a multisubunit enzyme embedded in the lipid environment of the thylakoid membranes of plants, algae and cyanobacteria. Powered by light, this enzyme catalyses the chemically and thermodynamically demanding reaction of water splitting. In so doing, it releases dioxygen into the atmosphere and provides the reducing equivalents required for the conversion of CO2 into the organic molecules of life. Recently, a fully refined structure of a 700 kDa cyanobacterial dimeric PSII complex was elucidated by X-ray crystallography which gave organizational and structural details of the 19 subunits (16 intrinsic and three extrinsic) which make up each monomer and provided information about the position and protein environments of 57 different cofactors. The water-splitting site was revealed as a cluster of four Mn ions and a Ca2+ ion surrounded by amino acid side chains, of which six or seven form direct ligands to the metals. The metal cluster was modelled as a cubane-like structure composed of three Mn ions and the Ca2+ linked by oxo-bonds with the fourth Mn attached to the cubane via one of its oxygens. The overall structure of the catalytic site is providing a framework to develop a mechanistic scheme for the water-splitting process, knowledge which could have significant implications for mimicking the reaction in an artificial chemical system.
Signalling through Class I PI3Ks in mammalian cells
Authors: Hawkins P.T. , Anderson K.E. , Davidson K. , Stephens L.R.
Published: October 2006

It is now accepted that activation of Class I PI3Ks (phosphoinositide 3-kinases) is one of the most important signal transduction pathways used by cell-surface receptors to control intracellular events. The receptors which access this pathway include those that recognize growth factors, hormones, antigens and inflammatory stimuli, and the cellular events known to be regulated include cell growth, survival, proliferation and movement. We have learnt a great deal about the family of Class I PI3K enzymes themselves and the structural adaptations which allow a variety of cell-surface receptors to regulate their activity. Class I PI3Ks synthesize the phospholipid PtdIns(3,4,5)P3 in the membranes in which they are activated, and it is now accepted that PtdIns(3,4,5)P3 and its dephosphorylation product PtdIns(3,4)P2 are messenger molecules which regulate the localization and function of multiple effectors by binding to their specific PH (pleckstrin homology) domains. The number of direct PtdIns(3,4,5)P3/PtdIns(3,4)P2 effectors which exist, even within a single cell, creates an extremely complex signalling web downstream of PI3K activation. Some key players are beginning to emerge, however, linking PI3K activity to specific cellular responses. These include small GTPases for the Rho and Arf families which regulate the cytoskeletal and membrane rearrangements required for cell movement, and PKB (protein kinase B), which has important regulatory inputs into the regulation of cell-cycle progression and survival. The importance of the PI3K signalling pathway in regulating the balance of decisions in cell growth, proliferation and survival is clear from the prevalence of oncogenes (e.g. PI3Kα) and tumour suppressors [e.g. the PtdIns(3,4,5)P3 3-phosphatase, PTEN (phosphatase and tensin homologue deleted on chromosome 10)] found in this pathway. The recent availability of transgenic mouse models with engineered defects in Class I PI3K signalling pathways, and the development of PI3K isoform-selective inhibitors by both academic and pharmaceutical research has highlighted the importance of specific isoforms of PI3K in whole-animal physiology and pathology, e.g. PI3Kα in growth and metabolic regulation, PI3Kβ in thrombosis, and PI3Kδ and PI3Kγ in inflammation and asthma. Thus the Class I PI3K signalling pathway is emerging as an exciting new area for the development of novel therapeutics.
The role of myosin Va in secretory granule trafficking and exocytosis
Authors: Eichler T.W. , Kögel T. , Bukoreshtliev N.V. , Gerdes H.-H.
Published: October 2006

It emerges that myosin Va plays multiple roles in the trafficking of SGs (secretory granules). In addition to a function in the capture and transport of newly formed SGs in the F-actin-rich cortex, myosin Va is implicated in late transport events of these organelles, which precede their exocytosis. Consistent with these roles, interactions of myosin Va with an array of well-known proteins involved in regulated protein secretion have been documented.
Fluorescence lifetime imaging microscopy (FLIM) to quantify protein–protein interactions inside cells
Authors: Duncan R.R.
Published: October 2006

Recent developments in cellular imaging spectroscopy now permit the minimally invasive study of protein dynamics inside living cells. These advances are of interest to cell biologists, as proteins rarely act in isolation, but rather in concert with others in forming cellular machinery. Until recently, all protein interactions had to be determined in vitro using biochemical approaches: this biochemical legacy has provided cell biologists with the basis to test defined protein–protein interactions not only inside cells, but now also with high spatial resolution. These techniques can detect and quantify protein behaviours down to the single-molecule level, all inside living cells. More recent developments in TCSPC (time-correlated single-photon counting) imaging are now also driving towards being able to determine protein interaction rates with similar spatial resolution, and together, these experimental advances allow investigators to perform biochemical experiments inside living cells.
The Kaposi's sarcoma-associated herpesvirus ORF57 protein: a pleurotropic regulator of gene expression
Authors: Malik P. , Schirmer E.C.
Published: October 2006

Herpesviridae comprises over 120 viruses infecting a wide range of vertebrates including humans and livestock. Herpesvirus infections typically produce dermal lesions or immune cell destruction, but can also lead to oncogenesis, especially with KSHV (Kaposi's sarcoma-associated herpesvirus). All herpesviruses are nuclear replicating viruses that subvert cellular processes such as nucleocytoplasmic transport for their advantage. For virus replication to take over the cell and produce lytic infection requires that virus gene expression outpace that of the host cell. KSHV ORF57 (open reading frame 57) appears to play a major role in this by (i) serving as a nuclear export receptor to carry intronless viral mRNAs out of the nucleus and (ii) inhibiting expression of intron-containing host mRNAs. As most of the virally encoded mRNAs are intronless compared with host cell mRNAs, these two mechanisms are critical to overcoming host gene expression.
Parkin: a multifaceted ubiquitin ligase
Authors: Moore D.J.
Published: October 2006

Mutations in the parkin gene are a common cause of autosomal recessive early-onset parkinsonism. Parkin functions as an E3 ubiquitin ligase where it can polyubiquitinate a number of its protein substrates, thus targeting them for degradation by the 26 S proteasomal complex. Recent studies have demonstrated that alternative modes of parkin-mediated ubiquitination may serve other non-degradative regulatory roles. In addition, parkin appears to function as a multipurpose neuroprotectant in a number of toxic paradigms. Coupled with these observations, parkin may integrate other gene products associated with parkinsonism, including α-synuclein, LRRK2 (leucine-rich repeat kinase 2), DJ-1 and PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced putative kinase 1], into a common biochemical pathway of potential relevance to disease pathogenesis. Parkin therefore represents a unique multifaceted ubiquitin ligase consistent with an important housekeeping role in maintaining the integrity or survival of dopaminergic neurons.
Control of growth factor receptor dynamics by reversible ubiquitination
Authors: Urbé S. , McCullough J. , Row P. , Prior I.A. , Welchman R. , Clague M.J.
Published: October 2006

Activated tyrosine kinase receptors acquire ubiquitin tags. Ubiquitination governs receptor down-regulation through interaction with components of the endosomal ESCRT (endosomal sorting complexes required for transport) machinery that shepherds receptors into luminal vesicles of multivesicular bodies en route to the lysosome. We have characterized two de-ubiquitinating enzymes that interact with components of this machinery. AMSH [associated molecule with the SH3 domain (Src homology 3 domain) of STAM (signal transducing adapter molecule)] shows specificity for Lys63- over Lys48-linked ubiquitin and may act to rescue receptors from taking the lysosomal pathway. In contrast, UBPY (ubiquitin-specific processing protease Y) does not discriminate between Lys48 and Lys63-linked chains and is required for lysosomal sorting.
The role of ubiquitin in neurotrophin receptor signalling and sorting
Authors: Wooten M.W. , Geetha T.
Published: October 2006

NGF (nerve growth factor) binding to TrkA (tropomyosin receptor kinase A) induces dimerization, autophosphorylation and internalization of the receptor to signalling vesicles for delivery of differentiation signals. TrkA interacts with p75 receptor through the p62–TRAF-6 (tumour-necrosis-factor-receptor-associated factor 6) complex bridging the two receptors. The atypical protein kinase C is activated and recruited to the receptor complex as well. TrkA is Lys63-polyubiquitinated on Lys485 by the E3 (ubiquitin ligase), TRAF-6, and E2 (ubiquitin-conjugating enzyme), UbcH7. Inhibition of polyubiquitination has been observed to interrupt signalling and internalization. Furthermore, an absence of p62 prevents endosomal localization and signalling. Altogether, these findings reveal Lys63-linked polyubiquitin chains and the shuttling protein p62 co-ordinately regulate TrkA internalization, trafficking and sorting.
The lipid second messenger diacylglycerol as a negative regulator of Rac signalling
Authors: Wang H. , Kazanietz M.G.
Published: October 2006

We have established a novel role for the second messenger DAG (diacylglycerol), a product of PtdIns(4,5)P2 hydrolysis by PLC (phospholipase C). In addition to its well-known function as a protein kinase C activator, DAG produced by stimulation of the epidermal growth factor receptor causes the redistribution of the Rac-GAP (GTPase-activating protein) β2-chimaerin to the plasma membrane, where it associates with the active form of Rac1 and promotes the inactivation of this small G-protein. This represents the first example of a Rac-GAP regulated directly by DAG in response to the activation of a tyrosine kinase receptor, and suggests a previously unappreciated role for this lipid as a negative modulator of Rac signalling.
Impact of subunit positioning on GABAA receptor function
Authors: Sigel E. , Baur R. , Boulineau N. , Minier F.
Published: October 2006

The major isoforms of the GABAA (γ-aminobutyric acid type A) receptor are composed of two α, two β and one γ subunit. Thus α and β subunits occur twice in the receptor pentamer. As it is well documented that different isoforms of α and β subunits can co-exist in the same pentamer, the question is raised whether the relative position of a subunit isoform affects the functional properties of the receptor. We have used subunit concatenation to engineer receptors of well-defined subunit arrangement to study this question. Although all five subunits may be concatenated, we have focused on the combination of triple and dual subunit constructs. We review here what is known so far on receptors containing simultaneously α1 and α6 subunits and receptors containing β1 and β2 subunits. Subunit concatenation may not only be used to study receptors containing two different subunit isoforms, but also to introduce a point mutation into a defined position in receptors containing either two α or β subunits, or to study the receptor architecture of receptors containing unconventional GABAA receptor subunits. Similar approaches may be used to characterize other members of the pentameric ligand-gated ion channel family, including nicotinic acetylcholine receptors, glycine receptors and 5-HT3 (5-hydroxytryptamine) receptors.