bluuebunny/crossref_metadata_2025 huggingface dataset:
Anatomic Analysis of the Genial Bone Advancement Trephine System's Effectiveness at Capturing the Genial Tubercle and its Muscular Attachments
Authors: Hennessee Jennifer , Miller Frank R.
Published: August 2005

Objective:

The Genial Bone Advancement Trephine (GBAT) System (Stryker Leibinger Inc, Kalamazoo, MI) is a 1‐step system that advances the genial tubercle for treatment of retrolingual obstruction in obstructive sleep apnea. The purpose of this project was to anatomically analyze the effectiveness of the GBAT System to capture the genial tubercle and its muscular attachments in the circular trephine.

Methods:

Eight cadaveric heads (ages 54‐89 years; 3 female and 5 male) were examined, and Panorex radiographs (Stryker Leibinger Inc, Kalamazoo, MI) were obtained. Seven specimens were selected on the basis of mandibular height and dentition to undergo the procedure. The procedure was performed using the GBAT system with the 14‐mm trephine according to the stepwise instructions. The mandibles were dissected, and analysis of the location of the osteotomy with respect to the genial tubercle, genioglossus muscles, geniohyoid muscles, and mandibular dentition was performed.

Results:

All 7 of the specimens had complete capture of the genial tubercle. The mean percentage of the genioglossus muscle captured in the circular trephine was 85% (50%‐100%). All specimens had preservation of the posterior muscle fibers. The mean percentage of the geniohyoid muscle captured was 78% (15%‐100%). No tooth roots were transected or contained in the bone plug.

Conclusions:

The GBAT System is an effective 1‐step system for capturing and advancing the genial tubercle and its muscular attachments in the treatment of OSA.
Standard Anesthetic Technique for Middle Ear Surgical Procedures: A Comparison of Desflurane and Sevoflurane
Authors: Jellish W. Scott , Owen Kevin , Edelstein Steven , Fluder Elaine , Leonetti John P.
Published: August 2005

Objective:

This study was designed to compare desflurane and sevoflurane anesthesia for middle ear microsurgery.

Study Design:

One hundred healthy adults undergoing middle ear surgery were assigned to receive either desflurane or sevoflurane as their anesthetic. Intraoperative hemodynamics and BIS numbers were recorded. Hemodynamics, pain, nausea/vomiting, discharge readiness, and other parameters were compared postoperatively and 24 hours later.

Results:

No intraoperative differences were noted except in BIS scores which trended lower with desflurane. PACU blood pressures were higher after desflurane but pain scores, nausea/vomiting, rescue anti‐emetics, recovery scores, and discharge times were similar. A significant difference was noted in anesthetic costs (desflurane > sevoflurane), and in patients with the lowest BIS scores associated with more nausea/vomiting.

Conclusions:

Both anesthetics may be used for ototic surgery but propofol anesthesia should still be considered in patients with a history of emetic sequelae.

Significance:

Short‐acting inhalational anesthetics produce excellent operating conditions and reduce costs for otologic surgery.
What is the Relationship Between Chronic Sinus Disease and Isolated Nasal Septal Deviation?
Authors: Yasan Hasan , Doĝru Harun , Baykal Bahattin , Döner Fehmi , Tüz Mustafa
Published: August 2005

Objective

The aim of this retrospective study is to examine the role of isolated nasal septal deviation (NSD) in the pathogenesis of chronic rhinosinusitis (CRS).

Study Design and Setting

The interaction between isolated NSD and chronic sinus disease were retrospectively evaluated in 1452 patients. Out of 1452 patients, 152 patients were included in the study. Patients with anatomical variants other than NSD were excluded from the study. Patients with NSD were enrolled in the study group and patients without NSD were enrolled in the control group.

Results

There was no statistically significant difference between NSD group and non‐NSD group with respect to the CRS.

Conclusions

The mild to moderate degree of NSD was not a risk factor for chronic sinus disease. Only gross deviation of the nasal septum itself is a risk factor for the development of CRS.

Significance

Excluding the subjects with ostiomeatal anatomic variations has differentiated this study from the previously reported researches (isolated NSD).
Radiofrequency Versus Injection Snoreplasty in Simple Snoring
Authors: Iseri Mete , Balcioğlu Okan
Published: August 2005

Objective:

To compare the efficacy and tolerance of controlled temperature radiofrequency (RF) and injection snoreplasty (IS) for the treatment of simple snoring.

Study Design:

The study was a nonrandomized, prospective study conducted on 70 simple snorers. Efficacy of the operations was subjectively evaluated by the bed partners and after 6 weeks of the last treatment. Tolerance was evaluated by the patient during first 10 postoperative days. Postoperative pain and discomfort level were assessed.

Results:

Satisfaction in terms of snoring severity was reported by 87.5% of the cases with RF and by 76.7% of the patients with IS. Discomfort levels also were similar for both groups

Conclusions:

Controlled‐temperature RF and IS were both effective on snoring and well tolerated by the patients. This allows retreatments if necessary.
Prevalence of Pus in Radiologically Diseased Sinuses in Patients Undergoing Surgery For Chronic Rhinosinusitis
Authors: Robinson Simon , Der‐Haroutian Vanik , Grove David , Rees Guy , Wormald Peter John
Published: August 2005

OBJECTIVE

To establish the prevalence of pus in radiologically diseased sinuses in patients undergoing sinus surgery and to correlate this with the bacterial load in the sinuses.

Study Deign and Setting

A prospective study performed on adult patients with the diagnosis of chronic sinusitis undergoing endoscopic sinus surgery at an Adelaide group of academic hospitals. In 45 consecutive and unselected patients, a radiologically diseased sinus was surgically opened, and a specially designed suction aspirator was placed into the sinus under endoscopic control. These aspirates were Gram stained and cultured to quantify the polymorphonuclear neutrophil count, bacterial flora, and bacterial colony count. The CT scans of all patients were graded by using the Lund‐Mackay scoring system.

Results

A variety of bacteria, most commonly staphylococci, were cultured from a radiologically diseased sinus in 88% of patients. There was no correlation between the bacterial colony count and presence of pus, and only 11% of patients had microscopic evidence of inflammation in sinus aspirates. There was no correlation between the Lund‐Mackay CT score and the presence of pus in the sinus.

Conclusions

The majority of patients undergoing surgery for chronic sinusitis did not have a purulent exudate, and there was no correlation with the bacterial load. The usefulness of antibiotics in the treatment of chronic rhinosinusitis, in the absence of macroscopic pus, is questionable.
Efficacy and Safety of a Novel, Single‐dose Azithromycin Microsphere Formulation Versus 10 Days of Levofloxacin for the Treatment of Acute Bacterial Sinusitis in Adults
Authors: Murray John J. , Emparanza Paz , Lesinskas Eugenijus , Tawadrous Margaret , Breen Jeanne D.
Published: August 2005

Objective

To compare the efficacy and safety of a single 2.0‐g dose of a novel azithromycin microsphere formulation with that of 10 days of levofloxacin, 500 mg/d, when used to treat adults with uncomplicated acute bacterial maxillary sinusitis (ABS).

Study Design and Setting

An international, multicenter, randomized, double‐blind, double‐dummy trial. Eligible outpatients ≥18 years of age with clinical and radiographic evidence of ABS underwent maxillary sinus aspiration before randomization. Primary endpoint was clinical efficacy at the test‐of‐cure visit (day 17‐24).

Results

Clinical success rates were 94.5% (242/256) in azithromycin‐microspheres‐treated patients and 92.8% (233/251) in the levofloxacin group. In patients with documented Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis, clinical cure rates were 97.3% (36/37), 96.3% (26/27), and 100% (8/8), respectively, for the azithromycin group and 92.3% (36/39), 100% (30/30), and 90.9% (10/11), respectively, for the levofloxacin group.

Conclusions

Single‐dose azithromycin microspheres provided clinical and bacteriologic efficacy and safety comparable to 10 days of levofloxacin.

Significance

A novel microsphere formulation of azithromycin given as a single dose was safe and effective for the treatment of ABS.
Dexamethasone Inner Ear Perfusion by Intratympanic Injection in Unilateral Ménière's Disease: A Two‐year Prospective, Placebo‐Controlled, Double‐blind, Randomized Trial
Authors: Garduño‐Anaya Marco Antonio , De Toledo Heloísa Couthino , Hinojosa‐González Ramón , Pane‐Pianese Carlo , Ríos‐Castañeda Luis Camilo
Published: August 2005

Objective:

To investigate the efficacy of dexamethasone inner ear perfusion by intratympanic injection in hearing loss, tinnitus, aural fullness, and vertigo in the treatment of unilateral Ménière's disease and compare it with the control group.

Study Design and Setting:

A prospective, randomized, double‐blind study with 2‐year follow‐up comparing changes secondary to dexamethasone inner ear perfusion versus placebo consisting of saline solution.

Patients:

Twenty‐two patients having definite Ménière's disease as outlined by the 1995 American Academy of Otolaryngology‐Head and Neck Surgery Committee on Hearing and Equilibrium. All the patients were older than 18 years of age and were not receiving any other form of treatment with steroids for their Ménière's disease.

Method:

Five consecutive daily intratympanic injections of dexamethasone or placebo to the involved ear.

Results:

In the dexamethasone group at 2‐year follow‐up, complete control of vertigo (class A) was achieved in 9 of 11 patients (82%) and substantial control of vertigo (class B) in the remaining 2 patients (18%.) In the control group only 7 of 11 patients (64%) finished the 2‐year follow‐up because in the other 4 patients (36%) we had to give another treatment for the continuing vertigo and thus they were classified as failure (class F.) From the 7 patients who have finished the follow‐up of 2 years in the control group, 4 patients (57%) achieved class A, 2 patients (29%) achieved class C, and 1 patient (14%) class F.

Conclusions:

Dexamethasone (4 mg/mL) inner ear perfusion in a group of patients with unilateral Ménière's disease (Shea's stage III) showed 82% of complete control of vertigo over placebo (57%). There was also a subjective improvement in tinnitus (48%), hearing loss (35%), and aural fullness (48%) in the dexamethasone group compared with 20%, 10%, and 20% respectively in the control group.

EBM Rating: A
Spectrum of Middle and Inner Ear Abnormalities in Infants With Congenital Heart Defects
Authors: Ulualp Seckin O. , Wright Charles G. , Roland Peter S.
Published: August 2005

Objective:

To evaluate temporal bone histopathology in infants with congenital heart defects (CHD).

Study Design and Setting:

A retrospective review of our temporal bone collection was conducted to identify temporal bones acquired from infants with CHD. Subjects were divided into nonsyndromic and syndromic CHD groups. The presence of temporal bone abnormalities and the incidence of abnormalities that may result in hearing impairment were determined.

Results:

Thirty‐eight temporal bones obtained from 16 infants with nonsyndromic CHD and 4 with syndromic CHD were evaluated. Nonsyndromic CHD cases had abnormalities such as a mesenchymal remnant, malformed stapes, persistent stapedial artery, shallow round window, dehiscent facial nerve canal, short cochlea, strial basophilic deposits, deformity of the spiral ligament, bulging Reissner's membrane, hypoplastic lateral semicircular canal, and cupular deposits. Syndromic CHD cases had abnormalities including narrow round window niche, facial canal dehiscence, strial basophilic deposits and cysts, and outer hair cell loss. Middle and inner ear abnormalities that may impair hearing were observed in 6 subjects with nonsyndromic CHD and in 1 subject with syndromic CHD.

Conclusions:

A wide variety of temporal bone defects were documented in infants with CHD. Congenital middle and inner ear abnormalities should be anticipated in the hearing assessment and otologic surgery of infants with CHD.
Intratympanic Steroid Injection for Treatment of Idiopathic Sudden Hearing Loss
Authors: Slattery William H. , Fisher Laurel M. , Iqbal Zarina , Friedman Rick A. , Liu Nancy
Published: August 2005

Objective.

To conduct a clinical trial of intratympanic steroid injection for idiopathic sudden sensorineural hearing loss in subjects who failed oral steroid therapy.

Study Design and Setting.

Open‐label methylprednisolone injection clinical trial in a tertiary neurotologic referral center. Twenty subjects (14 males; 6 females) received 4 injections within a 2‐week period (4 days apart). Hearing, dizziness/p, and tinnitus were evaluated before and after treatment.

Results.

There were no serious unexpected adverse events and 2 types of expected adverse events (tympanic membrane perforation, nausea after injection). No increases in dizziness or tinnitus lasting longer than 24 hours were observed after injections. One of 20 (5%) improved to near‐normal hearing. In addition, there was statistically significant improvement in 4‐frequency pure‐tone average and speech discrimination score at 1 month after treatment.

Conclusion.

Four intratympanic injections of methylprednisolone improved pure‐tone average or speech discrimination scores for a subset of sudden hearing loss subjects that failed to benefit from oral steroids.

Significance.

A clinical trial of intratympanic injections for idiopathic sudden hearing loss was successfully completed and promising results were found.
More data on major depression as an antecedent risk factor for first onset of chronic back pain
Authors: CURRIE SHAWN R. , WANG JIANLI
Published: August 2005

Background. Few epidemiological studies have examined the temporal relationship between chronic pain and depression using longitudinal data. In the present study, we examined major depression as both an antecedent risk factor and consequence of chronic back pain (CBP) in the general population.

Method. Data on 9909 pain-free individuals 15 years and older with no history of back problems were drawn from cycle 1 of the National Population Health Survey and followed up 24 months later. Major depression was assessed using a structured diagnostic interview.

Results. At cycle 2, the rate of new cases of CBP in persons who were depressed at cycle 1 was 3·6% compared to 1·1% in non-depressed persons. Compared to pain-free individuals, new cases of CBP were more likely to perceive their health status as poor or fair at cycle 1, were less likely to be working, reported more chronic health problems, and sustained a back or neck injury in the preceding 12 months. After controlling for other factors, pain-free individuals diagnosed as major depressed at cycle 1 were almost three times more likely (OR 2·9, 95% CI 1·2–7·0) to develop CBP at cycle 2.

Conclusions. Consistent with other longitudinal studies major depression increases the risk of developing future chronic pain. The causal mechanism linking these conditions is unknown however depression may represent a modifiable risk factor in the development of CBP.
Genetic and environmental influences on illicit drug use and tobacco use across birth cohorts
Authors: KENDLER KENNETH S. , GARDNER CHARLES , JACOBSON KRISTEN C. , NEALE MICHAEL C. , PRESCOTT CAROL A.
Published: August 2005

Background. The prevalence of use of many psychoactive substances has changed considerably in recent years. While genetic factors impact on overall risk for substance use, we know little about whether the etiological importance of these factors differs across birth cohorts. One theory, which postulates that heritability of deviant traits increases in permissive environments, predicts a positive relationship across cohorts between prevalence and heritability of substance use.

Method. The lifetime history of use of tobacco, cannabis, cocaine, sedatives and stimulants were assessed in 4826 twins from male–male and female–female pairs born in Virginia from 1934 to 1974. Using empirical methods based on prevalence by birth year, these twins were divided into three cohorts for each substance (e.g. for cannabis 1934–1953, 1954–1968 and 1969–1974). Structural equation modeling was performed using the Mx software package.

Results. Prevalence rates for psychoactive substance use differed substantially across cohorts, most markedly for cocaine, sedatives and stimulants, which were highest in the 1958–1963 cohort. However, for all substances, the best-fit model constrained estimates of the etiological role of genetic and environmental risk factors to be equal across both sex and cohort.

Conclusions. We found no evidence in this sample for any systematic relationship between heritability and prevalence of psychoactive substance use – which should be a rough index of drug availability and/or acceptability. This sample had reasonable power to detect large changes in heritability across cohorts and at least moderate power to detect relatively small changes.
Rat Neonatal Immune Challenge Alters Adult Responses to Cerebral Ischaemia
Authors: Spencer Sarah J , Auer Roland N , Pittman Quentin J
Published: August 2005

Infection, inflammation, and hyperthermia associated with cerebral ischaemia are known to contribute to enhanced neuronal cell loss and more severe behavioural deficits. Because neonatal exposure to an immune challenge has been shown to alter the severity of inflammatory and febrile responses to a further immune challenge experienced in adulthood, we hypothesised that this could also alter temperature responses and neuronal survival after ischaemia. Thus, male Sprague–Dawley rats were treated at postnatal day 14 with a single injection of the bacterial endotoxin lipopolysaccharide (LPS) and were examined as adults for temperature changes, behavioural deficits, and neuronal cell loss associated with global cerebral ischaemia after a two-vessel occlusion (2 VO). Neonatally LPS-treated rats showed behavioural differences in a novel object exploration paradigm, as well as altered temperature responses to the 2 VO compared with neonatally salinetreated controls. Interestingly, these neonatally LPS-treated rats also showed increased cell loss in the central nucleus of the amygdala, a region that is important in the processing of emotional responses, but that is not usually examined in animal models of cerebral ischaemia. No differences were seen in the CA1, CA3, or dentate gyrus regions of the hippocampus. This work shows the importance of examining brain regions other than the hippocampus in association with global ischaemia. We also highlight the importance of the early period of development in programming an animal's ability to deal with injury such as cerebral ischaemia in adulthood.
Estradiol Alters Only GAD67 mRNA Levels in Ischemic Rat Brain with No Consequent Effects on GABA
Authors: Joh Hung-Dong , Searles Robin V , Selmanoff Michael , Alkayed Nabil J , Koehler Raymond C , Hurn Patricia D , Murphy Stephanie J
Published: August 2005

The present study tested the hypothesis that estradiol reduces tissue infarction after middle cerebral artery occlusion (MCAO) in estradiol-deficient females by augmenting glutamic acid decarboxylase (GAD) expression and thus activity, leading to increases in γ-amino-butyric acid (GABA) tissue levels. Glutamic acid decarboxylase is the principal enzyme for GABA synthesis and has two isoforms, GAD65 and GAD67, which differ in size and cellular distribution. Rats were ovariectomized 7 to 8 days before receiving no hormone, placebo, or 25 μg estradiol via subcutaneous implant 7 to 10 days before harvesting tissue in either ischemic cohorts after 2 h of MCAO (end-ischemia) or in nonischemic cohorts. Selected cortical and striatal regions were microdissected from harvested brains. GAD65/67 mRNA levels were determined by microlysate ribonuclease protection assay. End-ischemic GABA concentrations were determined by HPLC. Steroid treatment selectively decreased ischemic cortical GAD67 mRNA levels. In most brain regions evaluated, regional GABA concentrations increased with ischemia regardless of treatment. Estradiol blocked MCAO-induced increases in GABA concentration only in dorsomedial cortex. These data suggest that estradiol repletion in ischemic rat brain selectively decreases GAD67 mRNA levels but does not alter steady-state GABA concentrations. It may be that estradiol under ischemic conditions is attenuating GABA metabolism rather than enhancing synthesis or is augmenting other aspects of GABAergic transmission such as GABA transporters and receptors.
Role of the vitamin D receptor in FGF23 action on phosphate metabolism
Authors: Inoue Yoshio , Segawa Hiroko , Kaneko Ichiro , Yamanaka Setsuko , Kusano Kenichiro , Kawakami Eri , Furutani Junya , Ito Mikiko , Kuwahata Masashi , Saito Hitoshi , Fukushima Naoshi , Kato Shigeaki , Kanayama Hiro-omi , Miyamoto Ken-ichi
Published: August 2005

FGF23 (fibroblast growth factor 23) is a novel phosphaturic factor that influences vitamin D metabolism and renal re-absorption of Pi. The goal of the present study was to characterize the role of the VDR (vitamin D receptor) in FGF23 action using VDR(−/−) (VDR null) mice. Injection of FGF23M (naked DNA encoding the R179Q mutant of human FGF23) into VDR(−/−) and wildtype VDR(+/+) mice resulted in an elevation in serum FGF23 levels, but had no effect on serum calcium or parathyroid hormone levels. In contrast, injection of FGF23M resulted in significant decreases in serum Pi levels, renal Na/Pi co-transport activity and type II transporter protein levels in both groups when compared with controls injected with mock vector or with FGFWT (naked DNA encoding wild-type human FGF23). Injection of FGF23M resulted in a decrease in 25-hydroxyvitamin D 1α-hydroxylase mRNA levels in VDR(−/−) and VDR(+/+) mice, while 25-hydroxyvitamin D 24-hydroxylase mRNA levels were significantly increased in FGF23M-treated animals compared with mock vector control- or FGF23WT-treated animals. The degree of 24-hydroxylase induction by FGF23M was dependent on the VDR, since FGF23M significantly reduced the levels of serum 1,25(OH)2D3 [1,25-hydroxyvitamin D3] in VDR(+/+) mice, but not in VDR(−/−) mice. We conclude that FGF23 reduces renal Pi transport and 25-hydroxyvitamin D 1α-hydroxylase levels by a mechanism that is independent of the VDR. In contrast, the induction of 25-hydroxyvitamin D 24-hydroxylase and the reduction of serum 1,25(OH)2D3 levels induced by FGF23 are dependent on the VDR.
Cancer cell injury by cytotoxins from cobra venom is mediated through lysosomal damage
Authors: Feofanov Alexei V. , Sharonov George V. , Astapova Maria V. , Rodionov Dmitriy I. , Utkin Yuriy N. , Arseniev Alexander S.
Published: August 2005

Cytotoxins from cobra venom are known to manifest cytotoxicity in various cell types. It is widely accepted that the plasma membrane is a target of cytotoxins, but the mechanism of their action remains obscure. Using the confocal spectral imaging technique, we show for the first time that cytotoxins from cobra venom penetrate readily into living cancer cells and accumulate markedly in lysosomes. Cytotoxins CT1 and CT2 from Naja oxiana, CT3 from Naja kaouthia and CT1 from Naja haje are demonstrated to possess this property with respect to human lung adenocarcinoma A549 and promyelocytic leukaemia HL60 cells. Immobilized plasma membrane binding accompanies the internalization of CT3 from Naja kaouthia in the HL60 cells, but it is very weak for other cytotoxins. Detectable membrane binding is not a property of any of the cytotoxins tested in A549 cells. The kinetics and concentration-dependence of cytotoxin accumulation in lysosomes correlate well with their cytotoxic effects. On the basis of the results obtained, we propose that lysosomes are a primary target of the lytic action of cytotoxins. Plasma membrane permeabilization seems to be a downstream event relative to lysosome rupture. Direct damage to the plasma membrane may be a complementary mechanism, but its relative contribution to the cytotoxic action depends on the cytotoxin structure and cell type.
Unusual compactness of a polyproline type II structure
Authors: Zagrovic Bojan , Lipfert Jan , Sorin Eric J. , Millett Ian S. , van Gunsteren Wilfred F. , Doniach Sebastian , Pande Vijay S.
Published: August 2005

Polyproline type II (PPII) helix has emerged recently as the dominant paradigm for describing the conformation of unfolded polypeptides. However, most experimental observables used to characterize unfolded proteins typically provide only short-range, sequence-local structural information that is both time- and ensemble-averaged, giving limited detail about the long-range structure of the chain. Here, we report a study of a long-range property: the radius of gyration of an alanine-based peptide, Ace-(diaminobutyric acid)2-(Ala)7-(ornithine)2-NH2. This molecule has previously been studied as a model for the unfolded state of proteins under folding conditions and is believed to adopt a PPII fold based on short-range techniques such as NMR and CD. By using synchrotron radiation and small-angle x-ray scattering, we have determined the radius of gyration of this peptide to be 7.4 ± 0.5 Å, which is significantly less than the value expected from an ideal PPII helix in solution (13.1 Å). To further study this contradiction, we have used molecular dynamics simulations using six variants of the AMBER force field and the GROMOS 53A6 force field. However, in all cases, the simulated ensembles underestimate the PPII content while overestimating the experimental radius of gyration. The conformational model that we propose, based on our small angle x-ray scattering results and what is known about this molecule from before, is that of a very flexible, fluctuating structure that on the level of individual residues explores a wide basin around the ideal PPII geometry but is never, or only rarely, in the ideal extended PPII helical conformation.
Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways
Authors: Watanabe Nobumoto , Arai Harumi , Iwasaki Jun-ichi , Shiina Masaaki , Ogata Kazuhiro , Hunter Tony , Osada Hiroyuki
Published: August 2005

At the onset of M phase, the activity of somatic Wee1 (Wee1A), the inhibitory kinase for cyclin-dependent kinase (CDK), is down-regulated primarily through proteasome-dependent degradation after ubiquitination by the E3 ubiquitin ligase SCF
β-TrCP
. The F-box protein β-TrCP (β-transducin repeat-containing protein), the substrate recognition component of the ubiquitin ligase, binds to its substrates through a conserved binding motif (phosphodegron) containing two phosphoserines, DpSGXXpS. Although Wee1A lacks this motif, phosphorylation of serines 53 and 123 (S53 and S123) of Wee1A by polo-like kinase 1 (Plk1) and CDK, respectively, are required for binding to β-TrCP. The sequence surrounding phosphorylated S53 (DpSAFQE) is similar to the conserved β-TrCP-binding motif; however, the role of S123 phosphorylation (EEGFGSSpSPVK) in β-TrCP binding was not elucidated. In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to β-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of β-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2), to create two phosphodegrons on Wee1A. In the case of Plk1, S123 phosphorylation created a polo box domain-binding motif (SpSP) on Wee1A to accelerate phosphorylation of S53 by Plk1. CK2 could phosphorylate S121, but only if S123 was phosphorylated first, thereby generating the second β-TrCP-binding site (EEGFGpS121). Using a specific inhibitor of CK2, we showed that the phosphorylation-dependent degradation of Wee1A is important for the proper onset of mitosis.
Caenorhabditis elegans
CNK-1 promotes Raf activation but is not essential for Ras/Raf signaling
Authors: Rocheleau Christian E. , Rönnlund Agneta , Tuck Simon , Sundaram Meera V.
Published: August 2005

Connector enhancer of Ksr (CNK) is a conserved multidomain protein essential for Ras signaling in
Drosophila melanogaster
and thought to be involved in Raf kinase activation. However, the precise role of CNK in Ras signaling is not known, and mammalian CNKs are proposed to have distinct functions.
Caenorhabditis elegans
has a single CNK homologue,
cnk-1
. Here, we describe the role of
cnk-1
in
C. elegans
Ras signaling and its requirements for LIN-45 Raf activation. We find that
cnk-1
positively regulates multiple Ras signaling events during development, but, unlike
Drosophila
CNK,
cnk-1
does not appear to be essential for signaling.
cnk-1
mutants appear to be normal but show cell-type-specific genetic interactions with mutations in two other Ras pathway scaffolds/adaptors
ksr-1
and
sur-8
. Genetic epistasis using various activated LIN-45 Raf transgenes shows that CNK-1 promotes LIN-45 Raf activation at a step between the dephosphorylation of inhibitory sites in the regulatory domain and activating phosphorylation in the kinase domain. Our data are consistent with a model in which CNK promotes Raf phosphorylation/activation through membrane localization, oligomerization, or association with an activating kinase.
Egr3 stimulation of
GABRA4
promoter activity as a mechanism for seizure-induced up-regulation of GABA
A
receptor α4 subunit expression
Authors: Roberts D. S. , Raol Y. H. , Bandyopadhyay S. , Lund I. V. , Budreck E. C. , Passini M. J. , Wolfe J. H. , Brooks-Kayal A. R. , Russek S. J.
Published: August 2005

GABA is the major inhibitory transmitter at CNS synapses. Changes in subunit composition of the pentameric GABA
A
receptor, including increased levels of α4 subunit in dentate granule cells and associated functional alterations such as increased zinc blockade of GABA currents, are hypothesized to be critical components of epileptogenesis. Here, we report that the minimal promoter of the human α4 subunit gene (
GABRA4p
), when used to drive reporter gene expression from adeno-associated viral vectors, controls condition-specific up-regulation in response to status epilepticus, defining a transcriptional mechanism for seizure-induced changes in levels of α4 subunit containing GABA
A
receptors. Transfection studies in primary hippocampal neurons show that inducible early growth response factor 3 (Egr3) up-regulates
GABRA4p
activity as well as the levels of endogenous α4 subunits. Given that Egr3 knockout mice display ≈50% less
GABRA4
mRNAs in the hippocampus and that increases in α4 and Egr3 mRNAs in response to pilocarpine-induced status epilepticus are accompanied by increased binding of Egr3 to
GABRA4
in dentate granule cells, our findings support a role for Egr3 as a major regulator of
GABRA4
in developing neurons and in epilepsy.
Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by
O
-GlcNAc in diabetes-associated erectile dysfunction
Authors: Musicki Biljana , Kramer Melissa F. , Becker Robyn E. , Burnett Arthur L.
Published: August 2005

Impaired endothelial nitric oxide synthase (eNOS) function is associated with erectile dysfunction in diabetes mellitus, but the exact molecular basis for the eNOS defect in the diabetic penis remains unclear. We investigated whether hyperglycemia increases
O
-GlcNAc modification of eNOS in the penis, preventing phosphorylation at the primary positive regulatory site on the enzyme and hampering mechanisms of the erectile response. Type I diabetes mellitus was induced in male rats by alloxan (140 mg/kg, i.p.). After 5 wk, the diabetic rat penis exhibited increased
O
-GlcNAc modification of eNOS and decreased eNOS phosphorylation at Ser-1177 at baseline compared with the control rat penis; eNOS phosphorylation at Thr-495, Ser-615, and Ser-633 was not affected. In addition, eNOS phosphorylation at Ser-1177 was impaired in the diabetic rat penis in response to penile blood flow (shear stress) elicited by electrical stimulation of the cavernous nerve (ES) and to recombinant human VEGF165. Phosphorylation of Akt, a mediator of shear stress-induced eNOS phosphorylation at Ser-1177, was decreased in the diabetic penis at baseline, but it was restored by ES. Erectile response to shear stress elicited by ES and to VEGF was decreased in diabetic compared with control rats. This work demonstrates that eNOS inactivation occurs in the diabetic penis by a glycosylation mechanism specifically at Ser-1177, by which the enzyme is rendered incapable of activation by fluid shear stress stimuli and VEGF signaling.
In vivo
penile erection paradigm supports the physiologic relevance of
O
-GlcNAc modification in vascular disorders associated with diabetes.
The vast majority of bone-marrow-derived cells integrated into
mdx
muscle fibers are silent despite long-term engraftment
Authors: Wernig Gerlinde , Janzen Viktor , Schäfer Ralf , Zweyer Margit , Knauf Ulrich , Hoegemeier Oliver , Mundegar Rustam R. , Garbe Stefan , Stier Sebastian , Franz Thomas , Wernig Marius , Wernig Anton
Published: August 2005

Bone-marrow-derived cells can contribute nuclei to skeletal muscle fibers. However, serial sectioning of muscle in
mdx
mice implanted with GFP-labeled bone marrow reveals that only 20% of the donor nuclei chronically incorporated in muscle fibers show dystrophin (or GFP) expression, which is still higher than the expected frequency of “revertant” fibers, but there is no overall increase above controls over time. Obviously, the vast majority of incorporated nuclei either never or only temporarily turn on myogenic genes; also, incorporated nuclei eventually loose the activation of the β-actin::GFP transgene. Consequently, we attempted to enhance the expression of dystrophin.
In vivo
application of the chromatin-modifying agents 5-azadeoxycytidine and phenylbutyrate as well as local damage by cardiotoxin injections caused a small increase in dystrophin-positive fibers without abolishing the appearance of “silent” nuclei. The results thus confirm that endogenous repair processes and epigenetic modifications on a small-scale lead to dystrophin expression from donor nuclei. Both effects, however, remain below functionally significant levels.
Asynchronous extinction of late Quaternary sloths on continents and islands
Authors: Steadman David W. , Martin Paul S. , MacPhee Ross D. E. , Jull A. J. T. , McDonald H. Gregory , Woods Charles A. , Iturralde-Vinent Manuel , Hodgins Gregory W. L.
Published: August 2005

Whatever the cause, it is extraordinary that dozens of genera of large mammals became extinct during the late Quaternary throughout the Western Hemisphere, including 90% of the genera of the xenarthran suborder Phyllophaga (sloths). Radiocarbon dates directly on dung, bones, or other tissue of extinct sloths place their “last appearance” datum at ≈11,000 radiocarbon years before present (yr BP) or slightly less in North America, ≈10,500 yr BP in South America, and ≈4,400 yr BP on West Indian islands. This asynchronous situation is not compatible with glacial–interglacial climate change forcing these extinctions, especially given the great elevational, latitudinal, and longitudinal variation of the sloth-bearing continental sites. Instead, the chronology of last appearance of extinct sloths, whether on continents or islands, more closely tracks the first arrival of people.
Blood–testis barrier dynamics are regulated by an engagement/disengagement mechanism between tight and adherens junctions via peripheral adaptors
Authors: Yan Helen H. N. , Cheng C. Yan
Published: August 2005

In the mammalian testis, the blood–testis barrier (BTB), unlike the blood–brain and blood–retina barriers, is composed of coexisting tight junctions (TJs) and adherens junctions (AJs). Yet these junctions must open (or disassemble) to accommodate the migration of preleptotene and leptotene spermatocytes across the BTB during spermatogenesis while maintaining its integrity. In this report, we show that the BTB utilizes a unique “engagement” and “disengagement” mechanism to permit the disruption of AJ that facilitates germ cell movement without compromising the BTB integrity. For instance, both TJ (e.g., occludin and JAM-1) and AJ (e.g., N-cadherin) integral membrane proteins were colocalized to the same site at the BTB. Although these TJ- and AJ-integral membrane proteins did not physically interact with each other, they were structurally linked by means of peripheral adaptors (e.g., ZO-1 and α- and γ-catenins). As such, these proteins are structurally “engaged” under physiological conditions to reinforce the BTB. When rats were exposed to Adjudin to induce AJ restructuring that eventually led to germ cell loss from the epithelium, this structural interaction between occludin and N-cadherin by means of their adaptors became “disengaged” while their protein levels were significantly induced. In short, when the epithelium is under assault, such as by Adjudin or plausibly at the time of germ cell migration across the BTB during spermatogenesis, the TJ- and AJ-integral membrane proteins can be disengaged. Thus, this mechanism is used by the testis to facilitate AJ restructuring to accommodate germ cell migration while maintaining the BTB integrity.
Ligand migration pathway and protein dynamics in myoglobin: A time-resolved crystallographic study on L29W MbCO
Authors: Schmidt Marius , Nienhaus Karin , Pahl Reinhard , Krasselt Angela , Anderson Spencer , Parak Fritz , Nienhaus G. Ulrich , Šrajer Vukica
Published: August 2005

By using time-resolved x-ray crystallography at room temperature, structural relaxations and ligand migration were examined in myoglobin (Mb) mutant L29W from nanoseconds to seconds after photodissociation of carbon monoxide (CO) from the heme iron by nanosecond laser pulses. The data were analyzed in terms of transient kinetics by fitting trial functions to integrated difference electron density values obtained from select structural moieties, thus allowing a quantitative description of the processes involved. The observed relaxations are linked to other investigations on protein dynamics. At the earliest times, the heme has already completely relaxed into its domed deoxy structure, and there is no photodissociated CO visible at the primary docking site. Initial relaxations of larger globin moieties are completed within several hundred nanoseconds. They influence the concomitant migration of photodissociated CO to the Xe1 site, where it appears at ≈300 ns and leaves again at ≈1.5 ms. The extremely long residence time in Xe1 as compared with wild-type MbCO implies that, in the latter protein, the CO exits the protein from Xe1 predominantly via the distal pocket. A well-defined deligated state is populated between ≈2 μs and ≈1 ms; its structure is very similar to the equilibrium deoxy structure. Between 1.5 and 20 ms, no CO is visible in the protein interior; it is either distributed among many sites within the protein or has escaped to the solvent. Finally, recombination at the heme iron occurs after >20 ms.
A genome-wide transcriptional analysis using
Arabidopsis thaliana
Affymetrix gene chips determined plant responses to phosphate deprivation
Authors: Misson Julie , Raghothama Kashchandra G. , Jain Ajay , Jouhet Juliette , Block Maryse A. , Bligny Richard , Ortet Philippe , Creff Audrey , Somerville Shauna , Rolland Norbert , Doumas Patrick , Nacry Philippe , Herrerra-Estrella Luis , Nussaume Laurent , Thibaud Marie-Christine
Published: August 2005

Phosphorus, one of the essential elements for plants, is often a limiting nutrient because of its low availability and mobility in soils. Significant changes in plant morphology and biochemical processes are associated with phosphate (Pi) deficiency. However, the molecular bases of these responses to Pi deficiency are not thoroughly elucidated. Therefore, a comprehensive survey of global gene expression in response to Pi deprivation was done by using
Arabidopsis thaliana
whole genome Affymetrix gene chip (ATH1) to quantify the spatio-temporal variations in transcript abundance of 22,810 genes. The analysis revealed a coordinated induction and suppression of 612 and 254 Pi-responsive genes, respectively. The functional classification of some of these genes indicated their involvement in various metabolic pathways, ion transport, signal transduction, transcriptional regulation, and other processes related to growth and development. This study is a detailed analysis of Pi starvation-induced changes in gene expression of the entire genome of
Arabidopsis
correlated with biochemical processes. The results not only enhance our knowledge about molecular processes associated with Pi deficiency, but also facilitate the identification of key molecular determinants for improving Pi use by crop species.
Structure of trigger factor binding domain in biologically homologous complex with eubacterial ribosome reveals its chaperone action
Authors: Baram David , Pyetan Erez , Sittner Assa , Auerbach-Nevo Tamar , Bashan Anat , Yonath Ada
Published: August 2005

Trigger factor (TF), the first chaperone in eubacteria to encounter the emerging nascent chain, binds to the large ribosomal subunit in the vicinity of the protein exit tunnel opening and forms a sheltered folding space. Here, we present the 3.5-Å crystal structure of the physiological complex of the large ribosomal subunit from the eubacterium
Deinococcus radiodurans
with the N-terminal domain of TF (TFa) from the same organism. For anchoring, TFa exploits a small ribosomal surface area in the vicinity of proteins L23 and L29, by using its “signature motif” as well as additional structural elements. The molecular details of TFa interactions reveal that L23 is essential for the association of TF with the ribosome and may serve as a channel of communication with the nascent chain progressing in the tunnel. L29 appears to induce a conformational change in TFa, which results in the exposure of TFa hydrophobic patches to the opening of the ribosomal exit tunnel, thus increasing its affinity for hydrophobic segments of the emerging nascent polypeptide. This observation implies that, in addition to creating a protected folding space for the emerging nascent chain, TF association with the ribosome prevents aggregation by providing a competing hydrophobic environment and may be critical for attaining the functional conformation necessary for chaperone activity.
The Business of Survival: Competition and Cooperation in the Shanghai Flour Milling Industry
Authors: Meissner Daniel J.
Published: August 2005

At the turn of the twentieth century, American and Chinese millers were locked in a fiercely contested battle for control of China’s flour market. Imported American flour had dominated Chinese urban markets since the early 1880s, but the founding of a modern native milling industry in 1900 had initiated a commercial war that pitted the great flour corporations of the Pacific Coast against the independent mill owners near Shanghai. Although the anti-American boycott of 1905 had boosted sales for Chinese mills and sparked growth in the native industry, the period between 1905 and 1909 severely tested the ability of the young industry to survive foreign competition. A high silver/gold rate, low transpacific shipping rates, and bumper wheat harvests in the Pacific Northwest lowered the relative cost and enhanced the market appeal of American flour to Chinese brokers. Conversely, severe flooding in China’s wheat-producing regions forced curtailment or even cessation of production for some native mills. Facing catastrophic reductions in their wheat supplies and markets saturated with American flour, Chinese millers devised alternative business strategies and implemented collaborative measures to ensure the solvency of their mills.
Adolescent Aggression and Differentiation of Self: Guided Mindfulness Meditation in the Service of Individuation
Authors: Birnbaum Liora
Published: August 2005

This paper presents adolescent aggression as mediated by the level of differentiation of self. No research has directly addressed Bowen's notion that level of differentiation impacts child functioning including aggression. Level of differentiation is discussed in conjunction with social, gender and cultural norms as manifested in aggressive behavior. Female adolescent aggression is described as mainly relationship focused and expressed via verbal threats, intimidation and manipulation, while male aggression is described mainly as overt physical violence involving dominance and competitiveness. Research on differentiation focuses mainly on Western cultures that tend to be individualistic. Jewish-Israeli society is in transition from collectivistic to individualistic cultural values in the midst of ongoing hostilities. These processes create conflict regarding togetherness and individuality needs among adolescents, who are exposed to contradictory messages regarding separating and staying close. External as well as internal expressions of aggression (depression, suicide) are presented as coping strategies in the service of a wounded self-negotiating with the world. Guided mindfulness meditation is a powerful technique for facilitating healing and growth toward autonomy by helping adolescents connect to their inner voice. This technique may be especially useful in the adolescent search for self-awareness, meaning and life purpose. Bodily, cognitive and emotional experiences are treated as informative regarding the “self” and facilitate expansion of self-perception and individuality.
The application of fracture mechanics to crack propagation in dry soil
Authors: HALLETT P.D. , DEXTER A.R. , SEVILLE J.P.K.
Published: August 2005

The application of fracture mechanics to dry soil has been investigated. Discs moulded from sand and kaolinite pastes, into which artificial tension cracks were introduced, were fractured using the indirect tension technique. The basic linear elastic fracture mechanics (LEFM) approach was found inadequate to describe the observed relation between the imposed flaw size and the failure stress. Fracture mechanics have been extended to dry soil by adding a crack length increment, Δc, to the imposed flaw size, c, to account for energy dissipation by processes other than the creation of new surfaces. This increment seems to represent the effective size of a ‘process zone’ ahead of the crack tip in which energy is dissipated by micro‐cracking and internal friction. Further experiments done using specimens containing two collinear cracks separated by a variable distance and using samples of different size showed that the two cracks behaved effectively as one for separation distances less than about Δc. For specimen sizes much bigger than Δc fracture testing was found to be scale‐invariant for geometrically similar specimens.
Modelling the solid–solution distributions of protons, aluminium, base cations and humic substances in acid soils
Authors: TIPPING E. , BERGGREN D. , MULDER J. , WOOF C.
Published: August 2005

wham, an equilibrium chemical model for soils, waters and sediments, centred on a discrete‐site/ electrostatic model of humic substances (HS), has been used to analysae batch titration data for organic and mineral horizons of acid soils. In most cases, tolerable fits were obtained by optimizing the soil contents of HS and aluminium, while keeping the model parameters (site densities, equilibrium constants, electrostatic terms) fixed. The optimized contents agreed reasonably with those estimated by chemical extraction. For some mineral soil samples, low in HS and high in aluminium, fitting of the titration data was improved by assuming the formation and dissolution of A1(OH)3 and adjusting its solubility product. Solid‐solution distributions of base cations (Na+, Mg2+, K+, Ca2+, NH+4) could be explained by non‐specific counterion accumulation, with a small degree of selectivity. The WHAM sub‐model for fulvic acid sorption accounted approximately for observed aqueous‐phase concentrations of organic carbon and organically‐complexed aluminium.