bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of chronic intra‐peritoneally administered chimeric peptide of met‐enkephalin and FMRFa‐[d‐Ala2]YFa‐on antinociception and opioid receptor regulation
Authors: Vats Ishwar Dutt , Snehlata  , Nath Mahendra , Pasha M.A. Qadar , Pasha Santosh
Published: June 2009

The physiological role of NPFF/FMRFa family of peptides is complex and exact mechanism of action of these peptides is not yet completely understood. In same line of scrutiny, previously we reported an enzymatically stable chimeric analog of YGGFMKKKFMRFamide (YFa) i.e., [d‐Ala2]YAGFMKKKFMRFamide ([d‐Ala2]YFa) which have a role in antinociception and modulatory effect on opioid analgesia. In continuation, presently we investigated using tail‐flick test whether [d‐Ala2]YFa on systemic administration induced any antinociception in rats and if so then which specific opioid receptor(s) μ, δ or κ mediated it. Further, the antinociceptive effect of [d‐Ala2]YFa on 6 days chronic intra‐peritoneal (i.p.) treatment in rats was examined and finally, effect of this chronic treatment on the differential expression of opioid receptors was assessed.

[d‐Ala2]YFa on i.p. administration induced dose dependent antinociception which was mainly mediated by δ (DOR) and partially by μ (MOR) and κ (KOR) opioid receptors. Moreover, its antinociceptive effect remained comparable throughout the chronic treatment even during insufficient availability of DOR1. Importantly, during this treatment the mRNA expression of all three opioid receptors (MOR1, KOR1 and DOR1) was increased as assessed by real‐time RTPCR though subsequent western blot analysis revealed a selective increase in the protein level of DOR1, only.

Thus, pharmacological behavior of [d‐Ala2]YFa suggests that competency of an opioid agonist to bind with multiple opioid receptors may enhance its potency to induce tolerance free analgesia.
Apolipoprotein E allele 4 is not a sufficient or a necessary predictor of the development of Mild Cognitive Impairment
Authors: Heun R. , Gühne U. , Luck T. , Angermeyer M.C. , Ueberham U. , Potluri R. , Natalwala A. , Arendt T. , Riedel-Heller S.G.
Published: June 2009

The presence of Mild Cognitive Impairment (MCI) and of an apolipoprotein E (apoE) ε4 allele both predict the development of Alzheimer's disease. However, the extent to which this allele also predicts the development of MCI is unclear even though MCI is an early transitional stage in the development of Alzheimer's disease. The present study investigates the prevalence of the apoE ε4 allele in incipient MCI. Participants were recruited from the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). All subjects who were initially cognitively healthy, i.e. did not meet MCI criteria described by Petersen [Petersen RC. Mild cognitive impairment. J Intern Med 2004; 256(3): 183–94], and whose apoE status could be determined were followed-up. After 4.5 years, 15.5% of the cognitively healthy target population had developed MCI. The frequencies of the apoE ε4 genotype did not differ between individuals with incipient MCI (12.9%) and individuals who remained cognitively healthy during the study (18.4%, p > 0.5). Consequently, the apoE ε4 genotype is not a necessary or sufficient risk factor for MCI. Further studies need to investigate the influence of the whole range of genetic and environmental risk factors on the course of Alzheimer's disease including the initial development of MCI and the later conversion to Alzheimer's disease.
A contact‐waiting‐time metric and RNA folding rates
Authors: Nkwanta Asamoah , Ndifon Wilfred
Published: June 2009

Metrics for indirectly predicting the folding rates of RNA sequences are of interest. In this letter, we introduce a simple metric of RNA structural complexity, which accounts for differences in the energetic contributions of RNA base contacts toward RNA structure formation. We apply the metric to RNA sequences whose folding rates were previously determined experimentally. We find that the metric has good correlation (correlation coefficient: −0.95, ) with the logarithmically transformed folding rates of those RNA sequences. This suggests that the metric can be useful for predicting RNA folding rates. We use the metric to predict the folding rates of bacterial and eukaryotic group II introns. Future applications of the metric (e.g., to predict structural RNAs) could prove fruitful.
Syndecan‐4 promotes the retention of phosphatidylinositol 4,5‐bisphosphate in the plasma membrane
Authors: Kwon Soojin , Son Hyowon , Choi Youngsil , Lee Jung-hyun , Choi Sojoong , Lim Yangmi , Han Inn-Oc , Oh Eok-Soo
Published: June 2009

Although phosphatidylinositol 4,5‐bisphosphate (PIP2) regulates syndecan‐4 function, the potential influence of syndecan‐4 on PIP2 remains unknown. GFP containing PIP2‐binding‐PH domain of phospholipase Cδ (GFP‐PHδ) was used to monitor PIP2. Syndecan‐4 overexpression in COS‐7 cells enhanced membrane translocation of GFP‐PHδ, while the opposite was observed when syndecan‐4 was knocked‐down. PIP2 levels were higher in total phospholipids extracted from rat embryo fibroblasts expressing syndecan‐4. Syndecan‐4‐induced membrane targeting of GFP‐PHδ was further enhanced by phosphoinositide‐3‐kinase inhibitor, but not by phospholipase C (PLC) inhibitor. Besides, both ionomycin and epidermal growth factor caused dissociation of GFP‐PHδ from plasma membrane, an effect that was significantly delayed by syndecan‐4 over‐expression. Collectively, these data suggest that syndecan‐4 promotes plasma membrane retention of PIP2 by negatively regulating PLC‐dependent PIP2 degradation.
Large‐scale purification of ribosome‐nascent chain complexes for biochemical and structural studies
Authors: Rutkowska Anna , Beerbaum Monika , Rajagopalan Nandhakishore , Fiaux Jocelyne , Schmieder Peter , Kramer Günter , Oschkinat Hartmut , Bukau Bernd
Published: June 2009

Here we present a method to purify large amounts of highly pure and stably arrested ribosome‐nascent chain complexes (RNCs) from Escherichia coli cells. It relies on the combined use of translation‐arrest sequences to generate nascent polypeptides of specified length and subsequent tag purification of the RNCs. Moreover, we adapted this method for the in vivo production of RNCs with specific isotope labeling of the nascent chains for nuclear magnetic resonance (NMR) studies. This method opens therefore possibilities for a wide range of biochemical and structural studies exploring conformations of nascent chains during the early steps of protein folding and targeting.
Methylene blue and dimebon inhibit aggregation of TDP‐43 in cellular models
Authors: Yamashita Makiko , Nonaka Takashi , Arai Tetsuaki , Kametani Fuyuki , Buchman Vladimir L. , Ninkina Natalia , Bachurin Sergey O. , Akiyama Haruhiko , Goedert Michel , Hasegawa Masato
Published: June 2009

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD‐U) are major neurodegenerative diseases with TDP‐43 pathology. Here we investigated the effects of methylene blue (MB) and dimebon, two compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer's disease (AD), on the formation of TDP‐43 aggregates in SH‐SY5Y cells. Following treatment with 0.05 μM MB or 5 μM dimebon, the number of TDP‐43 aggregates was reduced by 50% and 45%, respectively. The combined use of MB and dimebon resulted in a 80% reduction in the number. These findings were confirmed by immunoblot analysis. The results indicate that MB and dimebon may be useful for the treatment of ALS, FTLD‐U and other TDP‐43 proteinopathies.
Altered levels of synapsin I, dopamine transporter, dynorphin A, and neuropeptide Y in the nucleus accumbens and striatum at post‐puberty in rats treated neonatally with pregnenolone or DHEA
Authors: Muneoka Katsumasa , Iwata Masaaki , Shirayama Yukihiko
Published: June 2009

It is well documented that neonatal neurosteroid administration influences brain development. In our previous studies, administration of pregnenolone, the precursor of neurosteroids, during the neonatal period altered the activity of dopamine (DA) in the striatum. Furthermore, neonatal treatment with pregnenolone or dehydroepiandrosterone (DHEA) increased synapse‐related protein synapsin I as well as neuropeptide Y (NPY) in the hippocampus. The present study examined the effects of neonatal treatment with pregnenolone or DHEA on synapsin I, DA transporter (DAT), dynorphin A, and NPY in the striatum and the core and shell of the nucleus accumbens at post‐puberty. Administration of pregnenolone or DHEA during the neonatal period increased immunodensity of synapsin I in the dorsomedial or ventrolateral striatum. DAT immunodensity in the striatum and the nucleus accumbens core as well as dynorphin A immunodensity in the nucleus accumbens core were increased in DHEA‐treated but not in pregnenolone‐treated rats. In addition, the size, but not numbers, of NPY‐positive cells in the nucleus accumbens core was increased in pregnenolone‐ and DHEA‐treated rats. The results suggest that neurosteroid levels during the neonatal period have larger impact on synaptic formation, development of DA and NPY systems in the nigrostriatal rather than the mesolimbic pathway.
Serum Feline Pancreatic Lipase Immunoreactivity Concentration and Seroprevalences of Antibodies Against Toxoplasma Gondii and Bartonella Species in Client-Owned Cats
Authors: Bayliss Danielle B. , Steiner Jörg M. , Sucholdolski Jan S. , Radecki Steven V. , Brewer Melissa M. , Morris Arianne K. , Lappin Michael R.
Published: June 2009

Feline pancreatitis is a commonly suspected illness and it has been proposed that some cases of feline pancreatitis may be caused by infection with Toxoplasma gondii or Bartonella species. Feline pancreatic lipase immunoreactivity (fPLI) is a test performed on serum that is commonly combined with other clinical findings as an indirect aid in the diagnosis of pancreatitis. The purpose of this study was to determine if there are associations between fPLI concentration and the presence of serum antibodies against T gondii or Bartonella species. Serum samples from 458 cats, for which serum fPLI concentrations had already been determined, were assayed by enzyme-linked immunosorbent assay for the presence of T gondii immunoglobulin (Ig) G (IgG) and IgM antibodies, and Bartonella species IgG antibodies. The association between fPLI concentration and T gondii or Bartonella species antibodies was determined. No statistically significant association was found between fPLI concentration and T gondii or Bartonella species antibodies, suggesting that serological tests for the organisms are not useful in cases with increased fPLI concentration.
Two cases of feline ectromelia: Autopodium ectromelia associated with humero-ulnar synostosis and zeugopodium ectromelia
Authors: Macrì Francesco , De Majo Massimo , Rapisarda Giuseppe , Mazzullo Giuseppe
Published: June 2009

Congenital limb deformities are rarely reported in cats. This paper describes the radiographic findings of congenital forelimb malformations in two cats. The radiographic changes were suggestive of an autopodium ectromelia associated with humero-ulnar synostosis in one case and zeugopodium ectromelia in the other case. Congenital feline limb deformities are poorly documented and, to the authors' knowledge, this is the first time that humero-ulnar synostosis has been reported in cats.
Dermoid Cysts Presenting as Enlarged Thyroid Glands in a Cat
Authors: Tolbert Katherine , Brown Holly M. , Rakich Pauline M. , Radlinsky Mary Ann G. , Ward Cynthia R.
Published: June 2009

A 5-year-old spayed female cat was evaluated for hyperthyroidism based on an elevated free thyroxine (T4) measurement and bilaterally enlarged symmetric subcutaneous masses in the area of the thyroid glands. Physical examination revealed bilateral subcutaneous masses on either side of the cervical trachea. Blood was obtained for serum biochemical profile and thyroid function analysis. Mild hyperalbuminemia, mild hypercalcemia, and mildly increased alanine aminotransferase activity were identified. Serum concentrations of total and free thyroxine were within the reference interval. Cytologic analysis of fine-needle aspirates from one of the masses was suspicious for neoplasia. Nuclear scintigraphy revealed no abnormalities. Surgically obtained excisional biopsies of both masses were submitted for histopathology and diagnosed as bilateral dermoid cysts. After excisional biopsy, the patient recovered without incident. The histopathologic diagnosis of completely excised bilateral dermoid cysts indicated that no further medical or surgical intervention was required. This is the first report of a cat presenting with bilateral dermoid cysts in the area of the thyroid glands. Histopathologic examination was necessary to make a definitive diagnosis. Practitioners should include cysts in their list of differential diagnoses for ventral neck masses in cats.
Prevalence of feline coronavirus antibodies in cats in Bursa province, Turkey, by an enzyme-linked immunosorbent assay
Authors: Pratelli Annamaria , Yesilbag Kadir , Siniscalchi Marcello , Yalçm Ebru , Yilmaz Zeki
Published: June 2009

Feline sera from Bursa province (Turkey) were assayed for coronavirus antibody using an enzyme-linked immunosorbent assay (ELISA). The study was performed on 100 sera collected from cats belonging to catteries or community shelters and to households. The serum samples were initially tested with the virus neutralisation (VN) test and the results were then compared with the ELISA. The VN yielded 79 negative and 21 positive sera but the ELISA confirmed only 74 as negative. The ELISA-negative sera were also found to be free of feline coronoviruses-specific antibodies by Western blotting. Using the VN as the gold standard test, ELISA had a sensitivity of 100% and a specificity of 93.6%, with an overall agreement of 95%. The Kappa (κ) test indicated high association between the two tests (κ=0.86, 95% confidence interval (CI) 0.743–0.980). The positive predictive value (PPV) was 0.8, and the negative predictive value (NPV) was 0.93. The prevalence of FCoV II antibodies in the sampled population based on the gold standard was 62% (95% CI 0.44–0.77) among multi-cat environments, and 4% (95% CI 0.01–0.11) among single cat households.
HER-2/neu (c-erbB-2) oncoprotein in hyperplastic endometrial polyps detected in two cats
Authors: Misirlioglu Deniz , Nak Deniz , Ozyigit Musa Ozgur , Nak Yavuz , Akkoc Ahmet
Published: June 2009

The presence of HER-2/neu (c-erbB-2) oncoprotein, oestrogen-α receptor (ER), and progesterone receptor (PR) in hyperplastic endometrial polyps (EPs) of two cats with cystic endometrial hyperplasia-pyometra (CEH-P) complex was investigated. Immunohistochemistry assay for ER, PR and c-erbB-2 oncoprotein in the glandular and stromal tissue of the EPs was performed. ER and c-erbB-2 immunoreactivity was observed in the glandular epithelium of the EPs whereas PR immunoreactivity was detected only in the stromal fibroblasts. The c-erbB-2 oncoprotein may play a role with the ER in the pathogenesis of the hyperplastic EPs, although the role of this oncoprotein in the pathogenesis of EPs has yet to be determined.
Ras/MAPK signaling from endomembranes
Authors: Fehrenbacher Nicole , Bar-Sagi Dafna , Philips Mark
Published: June 2009

Signal transduction along the Ras/MAPK pathway has been generally thought to take place at the plasma membrane. It is now evident that the plasma membrane is not the only platform capable of Ras/MAPK signal induction. Fusion of Ras with green fluorescent protein and the development of genetically encoded fluorescent probes for Ras activation have revealed signaling events on a variety of intracellular membranes including endosomes, the Golgi apparatus and the endoplasmic reticulum. Thus, the Ras/MAPK pathway is spatially compartmentalized within cells and this may afford greater complexity of signal output.
Exploratory Analysis of the Relationships between Aerobic Capacity and Self‐Reported Fatigue in Patients with Rheumatoid Arthritis, Polymyositis, and Chronic Fatigue Syndrome
Authors: Weinstein Ali A. , Drinkard Bart M. , Diao Guoqing , Furst Gloria , Dale Janet K. , Straus Stephen E. , Gerber Lynn H.
Published: July 2009

Objective

To determine if self‐reported levels of physical activity and fatigue are related to peak oxygen uptake (VO2peak) and whether these relationships differ among the patient groups (rheumatoid arthritis [RA], polymyositis [PM], and chronic fatigue syndrome [CFS]).

Design

Correlational investigation.

Setting

Two ambulatory research clinics at the National Institutes of Health, Clinical Center, Bethesda, MD.

Participants

There were 9 patients with PM, 10 with RA, and 10 with CFS. All patients met case criteria for their respective diagnoses.

Methods/Main Outcome Measurements

VO2peak during bicycle ergometry and self‐reported fatigability, fatigue, and physical activity. VO2peak was used as the criterion measurement of physiological fatigue with which the self‐reported variables were compared.

Results

The Pearson r revealed that self‐reported physical activity correlated with VO2peak (r = 61, P = .01). However, fatigability and fatigue did not correlate with VO2peak. Linear regression analysis was performed to assess the effects of diagnosis group, self‐reported activity level or fatigue, and their interaction. A trend in the data showed a distinctive relationship between fatigue/fatigability within the 3 groups. In addition, when controlling for group status, self‐reported activity predicted aerobic capacity as measured by VO2peak.

Conclusions

This study confirms that patients with chronic, but stable RA, PM, or CFS are fatigued and have significantly decreased aerobic capacity. Self‐reports of physical activity predicted VO2peak, and may be used as an indicator of activity‐based aerobic capacity. Self‐reports of fatigue, however, did not correlate with VO2peak and hence are assessing something other than an index of aerobic capacity, and provide additional information about patients' perceptions, which will require further investigation.
Inter‐rater Reliability of Three Musculoskeletal Physical Examination Techniques Used to Assess Motion in Three Planes While Standing
Authors: Prather Heidi , Hunt Devyani , Steger‐May Karen , Hayes Marcie Harris , Knaus Evan , Clohisy John
Published: July 2009

Objective

The objective of the study was to measure the reliability between examiners of 3 basic maneuvers of the Total Body Functional Profile physical examination test. The hypothesis was musculoskeletal health care providers of different disciplines could reliably use the 3 basic maneuvers as part of the musculoskeletal physical examination.

Design

A prospective observational study was conducted. Twenty‐eight adult volunteers were measured on both the left and right side by 2 independent raters on a single occasion.

Setting

The subjects were recruited through advertisements placed by the orthopedic department at a tertiary university.

Participants

Twenty‐eight volunteers were recruited and completed the study. The volunteers were between the ages of 18 and 51 years of age, had no symptoms in the lower extremity or spine, had no previous history of surgery or tumor involving the lower extremity, and no medical conditions that would preclude participation.

Methods

On a single occasion, 2 examiners per 1 volunteer were blinded to their own and each others' measurements. Each examiner assessed the distance of frontal and sagittal plane lunge and angle of motion for transverse plane testing.

Main Outcome Measurements

Inter‐rater agreement is expressed with intraclass correlation coefficients (ICCs) and corresponding 95% confidence intervals (CIs). The difference between raters is reported with 95% CIs. Baseline demographics, University of California Los Angeles (UCLA), and Harris hip questionnaires were completed by all participants.

Results

The UCLA and Harris hip scores showed no significant activity restrictions or pain limitations in all participants. The inter‐rater reliability for sagittal, frontal, and transverse plane matrix testing was good with ICCs of 0.86 (95% CI 0.77‐0.91), 0.90 (95% CI 0.84‐0.94), and 0.85 (95% CI 0.75‐0.91), respectively. The rater reliability between disciplines for transverse, sagittal, and frontal plane matrix testing was good with ICCs of 0.89 (95% CI 0.80‐0.94), 0.88 (95% CI 0.79‐0.94), and 0.90 (95% CI 0.81‐0.95), respectively.

Conclusions

The inter‐rater reliability for 3 basic maneuvers of the Total Body Functional Profile is good among musculoskeletal health care providers of different disciplines. These 3 maneuvers may be used consistently as part of the musculoskeletal physical examination.
Maternal diets deficient in folic acid and related methyl donors modify mechanisms associated with lipid metabolism in the fetal liver of the rat
Authors: McNeil Christopher J. , Hay Susan M. , Rucklidge Garry J. , Reid Martin D. , Duncan Gary J. , Rees William D.
Published: July 2009

Previously we have examined the effects of diets deficient in folic acid ( − F) or folate deficient with low methionine and choline ( − F LM LC) on the relative abundance of soluble proteins in the liver of the pregnant rat. In the present study we report the corresponding changes in the fetal liver at day 21 of gestation. The abundance of eighteen proteins increased when dams were fed the − F diet. When dams were fed the − F LM LC diet, thirty-three proteins increased and eight decreased. Many of the differentially abundant proteins in the fetal liver could be classified into the same functional groups as those previously identified in the maternal liver, namely protein synthesis, metabolism, lipid metabolism and proteins associated with the cytoskeleton and endoplasmic reticulum. The pattern was consistent with reduced cell proliferation in the − F LM LC group but not in the − F group. Metabolic enzymes associated with lipid metabolism changed in both the − F and − F LM LC groups. The mRNA for carnitine palmitoyl transferase were up-regulated and CD36 (fatty acid translocase) down-regulated in the − F group, suggesting increased mitochondrial oxidation of fatty acids as an indirect response to altered maternal lipid metabolism. In the − F LM LC group the mRNA for acetyl CoA carboxylase was down-regulated, suggesting reduced fatty acid synthesis. The mRNA for transcriptional regulators including PPARα and sterol response element-binding protein-1c were unchanged. These results suggest that an adequate supply of folic acid and the related methyl donors may benefit fetal development directly by improving lipid metabolism in fetal as well as maternal tissues.
The role of the vestibular assessment
Authors: Phillips J S , FitzGerald J E , Bath A P
Published: July 2009

Objective:

To evaluate the role of vestibular assessment in the management of the dizzy patient.

Materials and methods:

A retrospective review of case notes and vestibular assessment reports of 100 consecutive patients referred for vestibular assessment.

Results:

Sixty of the 100 patients had an abnormal vestibular assessment. Eleven patients had benign paroxysmal positional vertigo as the sole diagnosis, of whom nine had not had a Dix–Hallpike manoeuvre performed before referral. Of patients referred for vestibular rehabilitation, 76 per cent had an abnormal electrophysiological assessment. After vestibular assessment, 35 patients were discharged with no further follow-up appointments in the ENT department.

Conclusions:

All patients should have a Dix–Hallpike manoeuvre performed prior to referral for vestibular assessment. The majority of our patients undergoing vestibular rehabilitation had abnormal test results, although a significant number did not. Prior to referral, it is worth considering the implication of a ‘normal’ and ‘abnormal’ result for the management of the patient. Careful consideration should be given to the development of dedicated dizziness clinics run by practitioners with a specialist interest in balance disorders, in order to ensure appropriate requests for vestibular assessment.
Findings at exploratory tympanotomy for conductive hearing loss
Authors: Robertson G , Mills R
Published: July 2009

Introduction:

Despite advances in imaging and other diagnostic tests, it is often impossible to establish with confidence a pre-operative diagnosis in a patient with a conductive hearing loss.

Methods:

We studied a series of 340 exploratory tympanotomies for conductive hearing loss carried out by a single surgeon.

Results:

The most common operative diagnosis was otosclerosis (n = 164, 48.2 per cent). Ossicular discontinuity was found more commonly than previously reported (n = 103, 30.3 per cent). A small but significant number of patients were found to have cholesteatoma (n = 7.2 per cent).

Conclusions:

This information is of value when discussing potential findings at surgery for conductive hearing loss. While otosclerosis is the commonest finding in such cases, a significant number of patients have defects of the ossicular chain.
A CHANGE HAS COME
Authors: Bobo Lawrence D. , Dawson Michael C.
Published: July 2009

Has Barack Obama's success transformed the racial divide? Did he somehow transcend or help bring to an end centuries of racial division in the United States? Did he deliberately run a strategically race-neutral, race-evading campaign? Did his race and ingrained American racism constrain the reach of his success? Have we arrived at that postracial moment that has long been the stuff of dreams and high oratory? Or was the outcome of the 2008 presidential election driven entirely by nonracial factors, such as a weak Republican ticket, an incumbent party saddled with defending an unpopular war, and a worsening economic crisis? It is at once too simple and yet entirely appropriate to say that the answers to these questions are, in a phrase, complicated matters. These complexities can, however, be brought into sharper focus.
ECOSYSTEM PERSPECTIVE AND BARACK OBAMA'S CAMPAIGN FOR THE PRESIDENCY
Authors: Crocker Jennifer , Hughes Shayne B.
Published: July 2009

The presidential campaign of Barack Obama was remarkable for the millions of volunteers and donors it inspired. In this article, we argue that the Obama campaign was inspirational because it communicated an ecosystem perspective—a perspective in which people care about something larger than the self. We describe the characteristics of ecosystem perspectives revealed in a program of social psychological research and how these characteristics translate to ecosystem leadership. We then consider Obama's speeches and actions at critical moments in the campaign that suggest to us an ecosystem perspective.
Rapid exhumation of deep crust in an obliquely convergent orogen: The Kaoko Belt of the Damara Orogen
Authors: Foster David A. , Goscombe Ben D. , Gray David R.
Published: July 2009

The exhumation of deep crustal rocks and juxtaposition of structural‐metamorphic domains from different depths in a transpressional orogen may occur during the prograde evolution of the orogen by vertical extrusion or during the retrograde evolution of the orogen via extension. Metamorphic petrology, kinematics, and thermochronology of strike‐slip shear zones in the Kaoko Belt of the Damara Orogen are used to evaluate extrusion and extension processes in this transpressional orogen. Mineral assemblages and deformation mechanisms record shearing at pressures of 4–6 kbar and temperatures of ∼550°C for the Three Palms mylonite zone, 600–650°C for the Purros mylonite zone, and ∼630–700°C for the Village and Khumib mylonite zones. The Three Palms mylonite zone, which separates the accreted Coastal Terrane from the former passive margin of the Congo Craton, exhibits progressive deformation during decreasing temperatures through lower greenschist facies and into the brittle field, with consistent oblique normal shear indicators. Lower‐temperature fabrics and brittle features also overprint the Village mylonite zone. The207Pb‐206Pb (titanite) and40Ar/39Ar (hornblende, muscovite, and biotite) data indicate rapid cooling, at rates of 30–100°C/Ma, of all high‐grade structural domains in the core of the Kaoko Belt between circa 535 and 525 Ma, which is about 20–30 Ma younger then peak metamorphism. The40Ar/39Ar data from synkinematic muscovite fish in the retrograde shear zone assemblages indicate that the Khumib, Village, and Three Palms mylonite zones were actively deforming at temperatures below 350°C at circa 530–524 Ma. These data indicate that the high‐grade metamorphic rocks of the Kaoko were rapidly exhumed and juxtaposed after the main transpressive deformation by oblique extension. Reactivation of the shear zones and tectonic exhumation of high‐grade structural domains from beneath the accreted Coastal Terrane was caused by collision in the Damara Belt and terminal accretion of Gondwana.
Protein Kinase A-Dependent Suppression of Reactive Oxygen Species in Transient Focal Ischemia in Adrenomedullin-Deficient Mice
Authors: Miyamoto Nobukazu , Tanaka Ryota , Shimosawa Tatsuo , Yatomi Yutaka , Fujita Toshiro , Hattori Nobutaka , Urabe Takao
Published: July 2009

This study was designed to examine the effect of adrenomedullin deficiency on cerebral infarction and the relationship between adrenomedullin and cyclic AMP–protein kinase A pathway in regulating reactive oxygen species (ROS). Adrenomedullin heterozygous and wild-type mice were subjected to 60-mins focal ischemia. We used adrenomedullin heterozygous mice because adrenomedullin homozygotes die in utero. Infarct volume, neurologic deficit scores, and immunohistochemical analyses were evaluated at several time points after ischemia. The infarct volume and neurologic deficit scores were significantly worse in adrenomedullin heterozygous mice. Significant accumulation of inducible nitric oxide, oxidative DNA damage, and lipid peroxidation was noted after reperfusion in adrenomedullin heterozygous mice. Treatment of wild-type mice with H89, a protein kinase A inhibitor, resulted in increased infarct size, and worsening of neurologic deficit score and other parameters to levels comparable to those of adrenomedullin heterozygous mice. In contrast, cilostazol, which increases cyclic AMP, rescued neurologic deficit and ROS accumulation in adrenomedullin heterozygous mice. This study showed that adrenomedullin downregulation results in increase in ROS after transient focal ischemia in mice. The results also indicated that adrenomedullin has an important function against ischemic injury through the cyclic AMP–protein kinase A pathway.
Proximity detector circuits: An alternative to tunnel diode oscillators for contactless measurements in pulsed magnetic field environments
Authors: Altarawneh M. M. , Mielke C. H. , Brooks J. S.
Published: July 2009

A radio frequency oscillator circuit based on a proximity detector integrated circuit is described as an alternative for the traditional tunnel diode oscillator used for pulsed magnetic field measurements at low temperatures. The proximity detector circuit design, although less sensitive than tunnel diode oscillator circuits, has a number of essential advantages for measurements in the extreme environments of pulsed magnetic fields. These include the insensitivity of operation to voltages induced in the inductor coil, the elimination of a diode bias circuit and tuning, and a broad dynamic range of resonant frequency variation. The circuit has been successfully applied to measure the superconducting upper critical field in Ba0.55K0.45Fe2As2 single crystals up to 60 T.
Introduction to Controversial Topics in Nonlinear Science: Is the Normal Heart Rate Chaotic?
Authors: Glass Leon
Published: July 2009

In June 2008, the editors of Chaos decided to institute a new section to appear from time to time that addresses timely and controversial topics related to nonlinear science. The first of these deals with the dynamical characterization of human heart rate variability. We asked authors to respond to the following questions: Is the normal heart rate chaotic? If the normal heart rate is not chaotic, is there some more appropriate term to characterize the fluctuations (e.g., scaling, fractal, multifractal)? How does the analysis of heart rate variability elucidate the underlying mechanisms controlling the heart rate? Do any analyses of heart rate variability provide clinical information that can be useful in medical assessment (e.g., in helping to assess the risk of sudden cardiac death)? If so, please indicate what additional clinical studies would be useful for measures of heart rate variability to be more broadly accepted by the medical community. In addition, as a challenge for analysis methods, PhysioNet [A. L. Goldberger et al., “PhysioBank, PhysioToolkit, and PhysioNet: Components of a new research resource for complex physiologic signals,” Circulation 101, e215–e220 (2000)] provided data sets from 15 patients of whom five were normal, five had heart failure, and five had atrial fibrillation (http://www.physionet.org/challenge/chaos/). This introductory essay summarizes the main issues and introduces the essays that respond to these questions.
Escape from cavity through narrow tunnel
Authors: Berezhkovskii Alexander M. , Barzykin Alexander V. , Zitserman Vladimir Yu.
Published: July 2009

The paper deals with a diffusing particle that escapes from a cavity to the outer world through a narrow cylindrical tunnel. We derive expressions for the Laplace transforms of the particle survival probability, its lifetime probability density, and the mean lifetime. These results show how the quantities of interest depend on the geometric parameters (the cavity volume and the tunnel length and radius) and the particle diffusion coefficients in the cavity and in the tunnel. Earlier suggested expressions for the mean lifetime, which correspond to different escape scenarios, are contained in our result as special cases. In contrast to these expressions, our formula predicts correct asymptotic behavior of the mean lifetime in the absence of the cavity or tunnel. To test the accuracy of our approximate theory we compare the mean lifetime, the lifetime probability density, and the survival probability (the latter two are obtained by inverting their Laplace transforms numerically) with corresponding quantities found by solving numerically the three-dimensional diffusion equation, assuming that the cavity is a sphere and that the particle has the same diffusion coefficient in the cavity and in the tunnel. Comparison shows excellent agreement between the analytical and numerical results over a broad range of the geometric parameters of the problem.
Shear thinning in deeply supercooled melts
Authors: Lubchenko Vassiliy
Published: June 2009

We compute, on a molecular basis, the viscosity of a deeply supercooled liquid at high shear rates. The viscosity is shown to decrease at growing shear rates, owing to an increase in the structural relaxation rate as caused by the shear. The onset of this non-Newtonian behavior is predicted to occur universally at a shear rate significantly lower than the typical structural relaxation rate, by approximately two orders of magnitude. This results from a large size—up to several hundred atoms—of the cooperative rearrangements responsible for mass transport in supercooled liquids and the smallness of individual molecular displacements during the cooperative rearrangements. We predict that the liquid will break down at shear rates such that the viscosity drops by approximately a factor of 30 below its Newtonian value. These phenomena are predicted to be independent of the liquid's fragility. In contrast, the degree of nonexponentiality and violation of the Stokes–Einstein law, which are more prominent in fragile substances, will be suppressed by shear. The present results are in agreement with existing measurements of shear thinning in silicate melts.
Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo
Authors: Sola Caroline , André Pascale , Lemmers Céline , Fuseri Nicolas , Bonnafous Cécile , Bléry Mathieu , Wagtmann Nicolai R. , Romagné François , Vivier Eric , Ugolini Sophie
Published: June 2009

Natural killer (NK) cells are lymphocytes of the innate immune system able to recognize and kill tumors lacking self-MHC class I molecules. This “missing-self” recognition is mediated by the lack of engagement of MHC class I-specific inhibitory NK cell receptors that include the killer cell Ig-like receptors (KIR) in humans and Ly49 molecules in mice. A promising immunotherapeutic strategy against MHC class I
+
cancer cells is to block NK cell inhibitory receptors using monoclonal antibodies (mAb). However, interactions between MHC class I molecules and their inhibitory receptors are also required for the acquisition of NK cell functional competence, a process referred as to “education.” In addition, inhibitory receptors are involved in self-tolerance on educated NK cells. Here, we developed a preclinical mouse model in which all NK cells are educated by a single transgenic inhibitory receptor, human KIR2DL3, through the engagement with its HLA-Cw3 ligand. This approach revealed that NK cells could be reprogrammed to control the development of mouse syngenic tumors in vivo. Moreover, in vivo anti-KIR mAb treatment induced the killing of HLA
+
target cells without breaking self-tolerance. Finally, the long-term infusion of anti-KIR mAb neither abolished NK cell education nor tumor cell recognition. Therefore, these results strongly support the use of inhibitory receptor blockade in cancer patients.
Chemistry of fast electrons
Authors: Maximoff Sergey N. , Head-Gordon Martin P.
Published: June 2009

A chemicurrent is a flux of fast (kinetic energy ≳ 0.5−1.3 eV) metal electrons caused by moderately exothermic (1−3 eV) chemical reactions over high work function (4−6 eV) metal surfaces. In this report, the relation between chemicurrent and surface chemistry is elucidated with a combination of top-down phenomenology and bottom-up atomic-scale modeling. Examination of catalytic CO oxidation, an example which exhibits a chemicurrent, reveals 3 constituents of this relation: The localization of some conduction electrons to the surface via a reduction reaction, 0.5 O
2
+ δe
−
→ O

δ
−

(Red); the delocalization of some surface electrons into a conduction band in an oxidation reaction, O

δ
−

+ CO → CO
2
δ−
→ CO
2
+ δe
−
(Ox); and relaxation without charge transfer (Rel). Juxtaposition of Red, Ox, and Rel produces a daunting variety of metal electronic excitations, but only those that originate from CO
2
reactive desorption are long-range and fast enough to dominate the chemicurrent. The chemicurrent yield depends on the universality class of the desorption process and the distribution of the desorption thresholds. This analysis implies a power-law relation with exponent 2.66 between the chemicurrent and the heat of adsorption, which is consistent with experimental findings for a range of systems. This picture also applies to other oxidation-reduction reactions over high work function metal surfaces.
Programmed loss of millions of base pairs from a vertebrate genome
Authors: Smith Jeramiah J. , Antonacci Francesca , Eichler Evan E. , Amemiya Chris T.
Published: June 2009

In general, the strict preservation of broad-scale structure is thought to be critical for maintaining the precisely tuned functionality of vertebrate genomes, although nearly all vertebrate species undergo a small number of programmed local rearrangements during development (e.g., remodeling of adaptive immune receptor loci). However, a limited number of metazoan species undergo much more extensive reorganizations as a normal feature of their development. Here, we show that the sea lamprey (
Petromyzon marinus
), a jawless vertebrate, undergoes a dramatic remodeling of its genome, resulting in the elimination of hundreds of millions of base pairs (and at least one transcribed locus) from many somatic cell lineages during embryonic development. These studies reveal the highly dynamic nature of the lamprey genome and provide the first example of broad-scale programmed rearrangement of a definitively vertebrate genome. Understanding the mechanisms by which this vertebrate species regulates such extensive remodeling of its genome will provide invaluable insight into factors that can promote stability and change in vertebrate genomes.
ANO2 is the cilial calcium-activated chloride channel that may mediate olfactory amplification
Authors: Stephan Aaron B. , Shum Eleen Y. , Hirsh Sarah , Cygnar Katherine D. , Reisert Johannes , Zhao Haiqing
Published: June 2009

For vertebrate olfactory signal transduction, a calcium-activated chloride conductance serves as a major amplification step. However, the molecular identity of the olfactory calcium-activated chloride channel (CaCC) is unknown. Here we report a proteomic screen for cilial membrane proteins of mouse olfactory sensory neurons (OSNs) that identified all the known olfactory transduction components as well as Anoctamin 2 (ANO2).
Ano2
transcripts were expressed specifically in OSNs in the olfactory epithelium, and ANO2::EGFP fusion protein localized to the OSN cilia when expressed in vivo using an adenoviral vector. Patch-clamp analysis revealed that ANO2, when expressed in HEK-293 cells, forms a CaCC and exhibits channel properties closely resembling the native olfactory CaCC. Considering these findings together, we propose that ANO2 constitutes the olfactory calcium-activated chloride channel.
Functional implications of multistage copper binding to the prion protein
Authors: Hodak Miroslav , Chisnell Robin , Lu Wenchang , Bernholc J.
Published: June 2009

The prion protein (PrP) is responsible for a group of neurodegenerative diseases called the transmissible spongiform encephalopathies. The normal function of PrP has not yet been discovered, but indirect evidence suggests a linkage to its ability to bind copper. In this article, low-copper-concentration bindings of Cu
2+
to PrP are investigated by using a recently developed hybrid density functional theory (DFT)/DFT method. It is found that at the lowest copper concentrations, the binding site consists of 4 histidine residues coordinating the copper through ε imidazole nitrogens. At higher concentrations, 2 histidines are involved in the binding, one of them in the axial position. These results are in good agreement with existing experimental data. Comparison of free energies for all modes of coordination shows that when enough copper is available, the binding sites will spontaneously rearrange to accommodate more copper ions, despite the fact that binding energy per copper ion decreases with concentration. These findings support the hypothesis that PrP acts as a copper buffer in vivo, protecting other proteins from the attachment of copper ions. Using large-scale classical molecular dynamics, we also probe the structure of full-length copper-bound PrP, including its unfolded N-terminal domain. The results show that copper attachment leads to rearrangement of the structure of the Cu-bonded octarepeat region and to development of turns in areas separating copper-bound residues. These turns make the flexible N-terminal domain more rigid and thus more resistant to misfolding. The last result suggests that copper binding plays a beneficial role in the initial stages of prion diseases.
Scaling of strength and lifetime probability distributions of quasibrittle structures based on atomistic fracture mechanics
Authors: Bažant Zdeněk P. , Le Jia-Liang , Bazant Martin Z.
Published: June 2009

The failure probability of engineering structures such as aircraft, bridges, dams, nuclear structures, and ships, as well as microelectronic components and medical implants, must be kept extremely low, typically <10
−6
. The safety factors needed to ensure it have so far been assessed empirically. For perfectly ductile and perfectly brittle structures, the empirical approach is sufficient because the cumulative distribution function (cdf) of random material strength is known and fixed. However, such an approach is insufficient for structures consisting of quasibrittle materials, which are brittle materials with inhomogeneities that are not negligible compared with the structure size. The reason is that the strength cdf of quasibrittle structure varies from Gaussian to Weibullian as the structure size increases. In this article, a recently proposed theory for the strength cdf of quasibrittle structure is refined by deriving it from fracture mechanics of nanocracks propagating by small, activation-energy-controlled, random jumps through the atomic lattice. This refinement also provides a plausible physical justification of the power law for subcritical creep crack growth, hitherto considered empirical. The theory is further extended to predict the cdf of structural lifetime at constant load, which is shown to be size- and geometry-dependent. The size effects on structure strength and lifetime are shown to be related and the latter to be much stronger. The theory fits previously unexplained deviations of experimental strength and lifetime histograms from the Weibull distribution. Finally, a boundary layer method for numerical calculation of the cdf of structural strength and lifetime is outlined.
Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in
Drosophila
features of human Charcot–Marie–Tooth neuropathy
Authors: Storkebaum Erik , Leitão-Gonçalves Ricardo , Godenschwege Tanja , Nangle Leslie , Mejia Monica , Bosmans Inge , Ooms Tinne , Jacobs An , Van Dijck Patrick , Yang Xiang-Lei , Schimmel Paul , Norga Koen , Timmerman Vincent , Callaerts Patrick , Jordanova Albena
Published: June 2009

Dominant-intermediate Charcot–Marie–Tooth neuropathy (DI-CMT) is characterized by axonal degeneration and demyelination of peripheral motor and sensory neurons. Three dominant mutations in the
YARS
gene, encoding tyrosyl-tRNA synthetase (TyrRS), have so far been associated with DI-CMT type C. The molecular mechanisms through which mutations in
YARS
lead to peripheral neuropathy are currently unknown, and animal models for DI-CMTC are not yet available. Here, we report the generation of a
Drosophila
model of DI-CMTC: expression of the 3 mutant—but not wild type—TyrRS in
Drosophila
recapitulates several hallmarks of the human disease, including a progressive deficit in motor performance, electrophysiological evidence of neuronal dysfunction and morphological signs of axonal degeneration. Not only ubiquitous, but also neuron-specific expression of mutant TyrRS, induces these phenotypes, indicating that the mutant enzyme has cell-autonomous effects in neurons. Furthermore, biochemical and genetic complementation experiments revealed that loss of enzymatic activity is not a common feature of DI-CMTC-associated mutations. Thus, the DI-CMTC phenotype is not due to haploinsufficiency of aminoacylation activity, but most likely to a gain-of-function alteration of the mutant TyrRS or interference with an unknown function of the WT protein. Our results also suggest that the molecular pathways leading to mutant TyrRS-associated neurodegeneration are conserved from flies to humans.