bluuebunny/crossref_metadata_2025 huggingface dataset:
A field study of effects of road traffic and railway noise on polysomnographic sleep parameters
Authors: Aasvang Gunn Marit , Øverland Britt , Ursin Reidun , Moum Torbjørn
Published: June 2011

The aim of this study was to explore and compare the effect of noise from railway and road traffic on sleep in subjects habitually exposed to nocturnal noise. Forty young and middle aged healthy subjects were studied with polysomnography (PSG) during two consecutive nights in their own bedroom. Noise measurements and recordings were conducted concurrently outside of the bedroom façade as well as inside the bedroom of each participant. Different noise exposure parameters were calculated (Lp,A,eq,night, Lp,A,Fmax,night, and LAF5,night) and analyzed in relation to whole-night sleep parameters. The group exposed to railway noise had significantly less Rapid eye movement, (REM) sleep than the group exposed to road traffic noise. A significant association was found between the maximum level (Lp,A,Fmax,night) of railway noise and time spent in REM sleep. REM sleep was significantly shorter in the group exposed to at least a single railway noise event above 50 dB inside the bedroom. These results, obtained in an ecological valid setting, support previous laboratory findings that railway noise has a stronger impact than road traffic noise on physiological parameters during sleep, and that the maximum noise level is an important predictor of noise effects on sleep assessed by PSG, at least for railway noise.
The influence of different segments of the ongoing envelope on sensitivity to interaural time delays
Authors: Klein-Hennig Martin , Dietz Mathias , Hohmann Volker , Ewert Stephan D.
Published: June 2011

The auditory system is sensitive to interaural timing disparities in the fine structure and the envelope of sounds, each contributing important cues for lateralization. In this study, psychophysical measurements were conducted with customized envelope waveforms in order to investigate the isolated effect of different segments of a periodic, ongoing envelope on lateralization. One envelope cycle was composed of the four segments attack flank, hold duration, decay flank, and pause duration, which were independently varied to customize the envelope waveform. The envelope waveforms were applied to a 4-kHz sinusoidal carrier, and just noticeable envelope interaural time differences were measured in six normal hearing subjects. The results indicate that attack durations and pause durations prior to the attack are the most important stimulus characteristics for processing envelope timing disparities. The results were compared to predictions of three binaural lateralization models based on the normalized cross correlation coefficient. Two of the models included an additional stage to mimic neural adaptation prior to binaural interaction, involving either a single short time constant (5 ms) or a combination of five time constants up to 500 ms. It was shown that the model with the single short time constant accounted best for the data.
Calibration of pressure-velocity probes using a progressive plane wave reference field and comparison with nominal calibration filters
Authors: Stanzial Domenico , Sacchi Giorgio , Schiffrer Giuliano
Published: June 2011

A procedure for calibrating pressure-velocity (p-v) sound intensity probes using a progressive plane wave as reference field is presented here. The procedure has been checked for a microelectromechanical system technology-based Microflown® match-size probe by comparing the calibration results with the nominal correction curves available from the manufacturer. The reference field was generated along a wave guide by means of a dual cone loudspeaker supplying acoustic energy in the range 20 Hz–20 kHz through an impedance adaptor. Different from the current in-field procedures, the one proposed here allows the calibration of probes under test to be executed at once up to 10 kHz without any change in the experimental setup. After a detailed review of the general principles of calibration, the procedure has been finalized with three main stages: (a) determination of the full coherence calibration bandwidth of the probe, (b) comparison calibration of the probe built-in pressure microphone over the full coherence frequency range, and (c) relative calibration of the velocity sensor over the calibrated pressure one. Calibration results for the probe under test have been best fitted against the calibration filters modeled by the manufacturer and the direct comparison of the obtained data with the factory ones has been reported.
AMPK Is a Direct Adenylate Charge-Regulated Protein Kinase
Authors: Oakhill Jonathan S. , Steel Rohan , Chen Zhi-Ping , Scott John W. , Ling Naomi , Tam Shanna , Kemp Bruce E.
Published: June 2011

The cellular energy sensor adenosine monophosphate–activated protein kinase also binds and is regulated by adenosine diphosphate.
A Possible Relativistic Jetted Outburst from a Massive Black Hole Fed by a Tidally Disrupted Star
Authors: Bloom Joshua S. , Giannios Dimitrios , Metzger Brian D. , Cenko S. Bradley , Perley Daniel A. , Butler Nathaniel R. , Tanvir Nial R. , Levan Andrew J. , O' Brien Paul T. , Strubbe Linda E. , De Colle Fabio , Ramirez-Ruiz Enrico , Lee William H. , Nayakshin Sergei , Quataert Eliot , King Andrew R. , Cucchiara Antonino , Guillochon James , Bower Geoffrey C. , Fruchter Andrew S. , Morgan Adam N. , van der Horst Alexander J.
Published: June 2011

A recent bright emission observed by the Swift satellite is due to the sudden accretion of a star onto a massive black hole.
De-AMPylation of the Small GTPase Rab1 by the Pathogen
Legionella pneumophila
Authors: Neunuebel M. Ramona , Chen Yang , Gaspar Andrew H. , Backlund Peter S. , Yergey Alfred , Machner Matthias P.
Published: June 2011

A bacterial pathogen reverses the modification of a host cell protein involved in membrane trafficking.
Detecting Intruders on the Nanoscale
Authors: Sönnichsen Carsten
Published: June 2011

Changes in position within a complex stack of gold nanorods can be detected optically and may enable more precise position sensing of biomolecules.
Autophagy's Top Chef
Authors: Cuervo Ana Maria
Published: June 2011

The transcription factor EB both controls lysosome formation and increases autophagy in cells experiencing starvation.
Making Translation Work
Authors: Williams R. Sanders , Desmond-Hellmann Susan
Published: June 2011

Biotechnology's largest global event, The Bio International Convention, convenes at the end of this month in Washington, DC. BIO is a key forum for exploring partnering opportunities and discussing industry trends, investments, and policies meant to better the world. The gathering is timely because there is an increasing need for new therapies for relentless illnesses. In the United States, cardiovascular disease accounts for 34% of all deaths, and Alzheimer's disease afflicts one of eight Americans at age 65 (and nearly half of 85-year-olds). Treatments for these and other conditions are needed, but the U.S. Food and Drug Administration (FDA) approved only 21 new drugs last year, about half of the more than 40 drugs approved annually in the 1990s. New creative partnerships and regulatory procedures are needed if this is to change.
Citizens Find Radiation Far From Fukushima
Authors: Normile Dennis
Published: June 2011

Civic groups and individuals monitoring radiation released from the ravaged Fukushima nuclear power plant have produced a worrisome picture of contamination throughout eastern Japan.
Who Was
Homo habilis
—And Was It Really
Homo
?
Authors: Gibbons Ann
Published: June 2011

A report in press finds that
Homo habilis
's dietary range was more like that of an australopithecine than
H. erectus
, suggesting that the handyman had yet to make the key adaptations associated with our genus.
'Origami Engineer' Flexes to Create Stronger, More Agile Materials
Authors: Merali Zeeya
Published: June 2011

A latecomer to the Japanese art of paper folding helps harness the mathematics behind it to make medical devices, disaster shelters, and, possibly, rockets.
Enzyme E2 from Chinese White Shrimp Inhibits Replication of White Spot Syndrome Virus and Ubiquitinates Its RING Domain Proteins
Authors: Chen An-Jing , Wang Shuai , Zhao Xiao-Fan , Yu Xiao-Qiang , Wang Jin-Xing
Published: June 2011

Recent studies have shown that the ubiquitin (Ub) proteasome pathway (UPP) is closely related to immune defense. We have identified a ubiquitin-conjugating enzyme, E2, from the Chinese white shrimp,
Fenneropenaeus chinensis
(FcUbc). Injection of recombinant FcUbc protein (rFcUbc) reduced the mortality of shrimp infected with white spot syndrome virus (WSSV) and inhibited replication of WSSV. rFcUbc, but not a mutant FcUbc (mFcUbc), bound to WSSV RING domains (WRDs) from four potential E3 ligase proteins of WSSV
in vitro
. Importantly, rFcUbc could ubiquitinate the RING domains (named WRD2 and WRD3) of WSSV277 and WSSV304 proteins
in vitro
and the two proteins in WSSV-infected
Drosophila melanogaster
Schneider 2 (S2) cells. Furthermore, overexpression of FcUbc increased ubiquitination of WSSV277 and WSSV304 during WSSV infection. In summary, our study demonstrates that FcUbc from Chinese white shrimp inhibited WSSV replication and could ubiquitinate WSSV RING domain-containing proteins. This is the first report about antiviral function of Ubc E2 in shrimp.
Analysis of Rab GTPase-Activating Proteins Indicates that Rab1a/b and Rab43 Are Important for Herpes Simplex Virus 1 Secondary Envelopment
Authors: Zenner Helen L. , Yoshimura Shin-ichiro , Barr Francis A. , Crump Colin M.
Published: June 2011

Assembly of herpes simplex virus 1 (HSV-1) occurs in the cytoplasm, where the capsid and tegument bud into host cell membranes. It is at this point that the viral glycoproteins are incorporated into the virion, as they are located at the assembly site. We investigated the role of the Rab GTPases in coordinating the assembly process by overexpressing 37 human Rab GTPase-activating proteins (GAPs) and assessing infectious titers. Rab GTPases are key cellular regulators of membrane trafficking events that, by their membrane association and binding of effector proteins, ensure the appropriate fusion of membranes. We identified that TBC1D20 and RN-tre and their partner Rabs, Rab1a/b and Rab43, respectively, are important for virion assembly. In the absence of Rab1a/b, the viral glycoproteins are unable to traffic from the endoplasmic reticulum to the assembly compartment, and thus unenveloped particles build up in the cytoplasm. The defect resulting from Rab43 depletion is somewhat more complex, but it appears that the fragmentation and dispersal of the
trans
-Golgi network and associated membranes render these compartments unable to support secondary envelopment.
Identification of a Phosphorylation Site within the P Protein Important for mRNA Transcription and Growth of Parainfluenza Virus 5
Authors: Sun Dengyun , Luthra Priya , Xu Pei , Yoon Haeyoung , He Biao
Published: June 2011

The viral RNA-dependent RNA polymerase (vRdRp) of paramyxovirus consists of the large (L) protein and the phosphoprotein (P). P is heavily phosphorylated, and it is thought that the phosphorylation of P plays a role in regulating viral RNA synthesis. However, no phosphorylation site within the P protein in paramyxovirus has been identified as playing a positive role in viral RNA synthesis in virus infection. Using mass spectrometry analysis, the threonine residue at position 286 of P of parainfluenza virus 5 (PIV5) was found phosphorylated. Mutation of T286 to alanine (T286A), aspartic acid (T286D), or glutamic acid (T286E) reduced minigenome activity. Recombinant virus containing a mutation at the T286 position (rPIV5-P-T286A) grew slower than wild-type virus; viral mRNA synthesis and protein expression of rPIV5-P-T286A were delayed. Biochemical studies showed that the binding of NP or L protein with the P mutants or tetramer formation by the mutant P proteins was unaltered from that for wild-type P. While we failed to rescue rPIV5-P-T286E virus, several revertant viruses were obtained. All non-wild-type revertants had mutations at T286 and showed defects in both minigenome activity and viral growth. This is the first time that a phosphorylation site within the P protein in paramyxovirus has been found to play a positive role in viral mRNA synthesis and virus growth.
Conservation of a Packaging Signal and the Viral Genome RNA Packaging Mechanism in Alphavirus Evolution
Authors: Kim Dal Young , Firth Andrew E. , Atasheva Svetlana , Frolova Elena I. , Frolov Ilya
Published: June 2011

Alphaviruses are a group of small, enveloped viruses which are widely distributed on all continents. In infected cells, alphaviruses display remarkable specificity in RNA packaging by encapsidating only their genomic RNA while avoiding packaging of the more abundant viral subgenomic (SG), cellular messenger and transfer RNAs into released virions. In this work, we demonstrate that in spite of evolution in geographically isolated areas and accumulation of considerable diversity in the nonstructural and structural genes, many alphaviruses belonging to different serocomplexes harbor RNA packaging signals (PSs) which contain the same structural and functional elements. Their characteristic features are as follows. (i) Sindbis, eastern, western, and Venezuelan equine encephalitis and most likely many other alphaviruses, except those belonging to the Semliki Forest virus (SFV) clade, have PSs which can be recognized by the capsid proteins of heterologous alphaviruses. (ii) The PS consists of 4 to 6 stem-loop RNA structures bearing conserved GGG sequences located at the base of the loop. These short motifs are integral elements of the PS and can function even in the artificially designed PS. (iii) Mutagenesis of the entire PS or simply the GGG sequences has strong negative effects on viral genome packaging and leads to release of viral particles containing mostly SG RNAs. (iv) Packaging of RNA appears to be determined to some extent by the number of GGG-containing stem-loops, and more than one stem-loop is required for efficient RNA encapsidation. (v) Viruses of the SFV clade are the exception to the general rule. They contain PSs in the nsP2 gene, but their capsid protein retains the ability to use the nsP1-specific PS of other alphaviruses. These new discoveries regarding alphavirus PS structure and function provide an opportunity for the development of virus variants, which are irreversibly attenuated in terms of production of infectious virus but release high levels of genome-free virions.
Lack of Correlation of Central Nervous System Inflammation and Neuropathology with the Development of Seizures following Acute Virus Infection
Authors: Libbey Jane E. , Kennett Nikki J. , Wilcox Karen S. , White H. Steve , Fujinami Robert S.
Published: June 2011

Infection of C57BL/6 mice by the intracerebral route with the Daniels (DA) strain of Theiler's murine encephalomyelitis virus (TMEV) resulted in acute behavioral seizures in approximately 50% of the mice. By titration, the viral dose correlated with the percentage of mice developing seizures; however, neuropathological changes were similar over the dose range, and viral clearance from the brains occurred uniformly by day 14 postinfection (p.i.). Other TMEV strains and mutants (GDVII, WW, BeAn 8386 [BeAn], DApBL2M, H101) induced seizures in C57BL/6 mice to various degrees. The BeAn strain and DApBL2M mutant were similar to the DA strain in the percentages of mice developing seizures and neuropathological changes and in the extent of infected cells. The GDVII and WW strains caused 100% mortality by days 5 and 6 p.i., respectively, at which time neuropathological changes and neuronal infection were extensive. The H101 mutant induced seizures and caused 100% mortality by day 7 p.i.; however, only minor neuropathological changes and few infected cells were observed. Thus, in H101 mutant infections, it appears that elevated levels of cytokines, rather than neuronal cell death, play the dominant role in seizure induction.
A Recombinant Vesicular Stomatitis Virus Bearing a Lethal Mutation in the Glycoprotein Gene Uncovers a Second Site Suppressor That Restores Fusion
Authors: Stanifer Megan L. , Cureton David K. , Whelan Sean P. J.
Published: June 2011

Vesicular stomatitis virus
(VSV), a prototype of the
Rhabdoviridae
family, contains a single surface glycoprotein (G) that is responsible for attachment to cells and mediates membrane fusion. Working with the Indiana serotype of VSV, we employed a reverse genetic approach to produce fully authentic recombinant viral particles bearing lethal mutations in the G gene. By altering the hydrophobicity of the two fusion loops within G, we produced a panel of mutants, W72A, Y73A, Y116A, and A117F, that were nonfusogenic. Propagation of viruses bearing those lethal mutations in G completely depended on complementation by expression of the glycoprotein from the heterologous New Jersey serotype of VSV. The nonfusogenic G proteins oligomerize and are transported normally to the cell surface but fail to mediate acid pH-triggered membrane fusion. The nonfusogenic G proteins also interfered with the ability of wild-type G to mediate fusion, either by formation of mixed trimers or by inhibition of trimer function during fusion. Passage of one recombinant virus, A117F, identified a second site suppressor of the fusion block, E76K. When analyzed in the absence of the A117F substitution, E76K rendered G more sensitive to acid pH-triggered fusion, suggesting that this compensatory mutation is destabilizing. Our work provides a set of authentic recombinant VSV particles bearing lethal mutations in G, confirms that the hydrophobic fusion loops of VSV G protein are critical for membrane fusion, and underscores the importance of the sequence elements surrounding the hydrophobic tips of the fusion loops in driving fusion. This study has implications for understanding dominant targets for inhibition of G-mediated fusion. Moreover, the recombinant viral particles generated here will likely be useful in dissecting the mechanism of G-catalyzed fusion as well as study steps of viral assembly.
Multiple CCR5 Conformations on the Cell Surface Are Used Differentially by Human Immunodeficiency Viruses Resistant or Sensitive to CCR5 Inhibitors
Authors: Berro Reem , Klasse Per Johan , Lascano Danny , Flegler Ayanna , Nagashima Kirsten A. , Sanders Rogier W. , Sakmar Thomas P. , Hope Thomas J. , Moore John P.
Published: June 2011

Resistance to small-molecule CCR5 inhibitors arises when HIV-1 variants acquire the ability to use inhibitor-bound CCR5 while still recognizing free CCR5. Two isolates, CC101.19 and D1/85.16, became resistant via four substitutions in the gp120 V3 region and three in the gp41 fusion peptide (FP), respectively. The binding characteristics of a panel of monoclonal antibodies (MAbs) imply that several antigenic forms of CCR5 are expressed at different levels on the surfaces of U87-CD4-CCR5 cells and primary CD4
+
T cells, in a cell-type-dependent manner. CCR5 binding and HIV-1 infection inhibition experiments suggest that the two CCR5 inhibitor-resistant viruses altered their interactions with CCR5 in different ways. As a result, both mutants became generally more sensitive to inhibition by CCR5 MAbs, and the FP mutant is specifically sensitive to a MAb that stains discrete cell surface clusters of CCR5 that may correspond to lipid rafts. We conclude that some MAbs detect different antigenic forms of CCR5 and that inhibitor-sensitive and -resistant viruses can use these CCR5 forms differently for entry in the presence or absence of CCR5 inhibitors.
Parvovirus B19 Infection of Human Primary Erythroid Progenitor Cells Triggers ATR-Chk1 Signaling, Which Promotes B19 Virus Replication
Authors: Luo Yong , Lou Sai , Deng Xuefeng , Liu Zhengwen , Li Yi , Kleiboeker Steve , Qiu Jianming
Published: June 2011

Human parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells of the human bone marrow. Although the mechanism by which the B19V genome replicates in these cells has not been studied in great detail, accumulating evidence has implicated involvement of the cellular DNA damage machinery in this process. Here, we report that, in
ex vivo
-expanded human erythroid progenitor cells, B19V infection induces a broad range of DNA damage responses by triggering phosphorylation of all the upstream kinases of each of three repair pathways: ATM (ataxia-telangiectasi mutated), ATR (ATM and Rad3 related), and DNA-PKcs (DNA-dependent protein kinase catalytic subunit). We found that phosphorylated ATM, ATR, and DNA-PKcs, and also their downstream substrates and components (Chk2, Chk1, and Ku70/Ku80 complex, respectively), localized within the B19V replication center. Notably, inhibition of kinase phosphorylation (through treatment with either kinase-specific inhibitors or kinase-specific shRNAs) revealed requirements for signaling of ATR and DNA-PKcs, but not ATM, in virus replication. Inhibition of the ATR substrate Chk1 led to similar levels of decreased virus replication, indicating that signaling via the ATR-Chk1 pathway is critical to B19V replication. Notably, the cell cycle arrest characteristic of B19V infection was not rescued by interference with the activity of any of the three repair pathway kinases.
Financially strapped owner with a suffering cat
Authors: McCulloch Steven
Published: June 2011

A two‐year‐old male cat has presented out of hours at a private clinic for depression and straining to urinate. Handling and being picked up in particular causes it to vocalise. Examination reveals a blocked bladder and the signalment, history and clinical presentation together suggest urolithiasis. Unfortunately, the owner does not have the £600 to £1000 required to stabilise, catheterise and hospitalise her pet for the weekend. The owner is upset because if she could afford the treatment, her pet would likely live a full life afterwards. It is also a difficult situation for the veterinary surgeon, who may have to euthanase the animal for these reasons, but what other options could the practitioner consider?
Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype
Authors: Ricardo Sara , Vieira André Filipe , Gerhard Renê , Leitão Dina , Pinto Regina , Cameselle-Teijeiro Jorge F , Milanezi Fernanda , Schmitt Fernando , Paredes Joana
Published: June 2011

Background and Aim

The study of CD44/CD24 and ALDH1 expression is the most accurate method to identify cancer stem cells (CSC) from breast cancer populations. However, the overlap between CD44+CD24−/lowand ALDH1highCSC phenotypes in breast cancer seems to be very small, as well as their distribution among intrinsic breast cancer subtypes. Due to this discrepancy, it is imperative to improve the understanding of breast CSC marker distribution.

Methods

466 invasive breast carcinomas and eight breast cancer cell lines were analysed for the expression of CD44, CD24 and ALDH1, to evaluate their distribution among the distinct molecular subtypes.

Results

Basal-like tumours (76.5%) contained the higher percentage of cells with the CSC phenotype CD44+CD24−/low(p<0.0001). From ALDH1-positive cases, 39.4% were also basal-like tumours (p<0.0001). The analysis of breast cancer cell lines indicated that luminal cell lines are mainly enriched in a CD44−/lowCD24+cell population, basal/mesenchymal breast cancer cell lines are enriched in the CD44+CD24−/lowphenotype, whereas the remaining basal/epithelial cell lines are mainly positive for both markers. ALDH1 activity was mainly found in HER-OE and basal/epithelial breast cancer cell.

Conclusions

CD44+CD24−/lowand ALDH1+phenotypes seem to identify CSC with distinct levels of differentiation. It seems that the paramount method and biomarkers that identify breast CSC within the distinct molecular subtypes need to be better explored, because it is pivotal to translate the CSC concept to clinical practice. In the future, the recognition of reliable markers to distinguish the CSC pool in each molecular subtype will be decisive for the development of specific target therapies.
A CHARACTERIZATION OF THE MAASS SPACE ON O(2, m + 2) BY SYMMETRIES
Authors: HEIM BERNHARD , MURASE ATSUSHI
Published: June 2011

In this paper, we define certain symmetries for automorphic forms on O(2, m + 2) and show that the space of automorphic forms satisfying these symmetries coincides with the Maass space, the image of a theta lifting studied by Oda and Rallis–Schiffmann.
RATE OF CONVERGENCE OF FLUID APPROXIMATION FOR RE-ENTRANT LINES UNDER FBFS DISCIPLINE
Authors: GUO YONGJIANG
Published: June 2011

The re-entrant line networks under a first-buffer-first-served (FBFS) service discipline are considered in this paper. Under uniform topology, if the scaled arrival process and the scaled service process converge to the corresponding fluid limit processes with an exponential rate, we prove that the scaled processes characterizing the re-entrant line converge to the corresponding fluid limit processes with the exponential rate. Here the scaled processes include the queue length process, workload process, busy time process and idle time process.
SINGLE MACHINE SCHEDULING WITH LINEAR DETERIORATING JOBS UNDER PREDICTIVE DISRUPTION
Authors: ZHAO CHUAN-LI , TANG HENG-YONG
Published: June 2011

This paper considers single machine scheduling problems with linear deteriorating jobs under predictive disruption. In this model, the actual processing time of a job is a increasing linear function of its starting time; and machine is subject to an availability constraint. We assume that an optimal schedule can be obtained by using some algorithms if machine is available at all time. Because of the machine disruption, the original schedule may become infeasible or too far from optimal. We want to create the new schedule that takes into account both the original objective function and a measure of deviation from the original schedule. We consider two versions of the problem. In the first one, the objective is weighted sum of total completion time and total tardiness while in the second one, the objective is weighted sum of total completion time and total earliness. We first prove some properties of the optimal schedule then dynamic programming algorithms are proposed, respectively.
NUCLEAR ISOMERS90m, gZr,89m, gZr,89m, gYAND85m, gSrFORMED BY BOMBARDMENT OF89YWITH PROTONS OF ENERGIES FROM 4 TO 40MeV
Authors: SATHEESH B. , MUSTHAFA M. M. , SINGH B. P. , PRASAD R.
Published: June 2011

Excitation functions for the reactions89Y (p, n)89gZr and89Y (p, n)89mZr have been measured over the energy ranges from threshold to 15 MeV using stacked foil activation technique. The isomeric cross-section ratio σm/(σm+σg) for the formation of89m, gZr was determined. The excitation functions and isomeric cross-section ratios were calculated for the reactions89Y (p, γ)90m, gZr ,89Y (p, n)89m, gZr ,89Y (p, p)89m, gY and89Y (p, αn)85m, gSr also for energy range 4–40 MeV . The PE emission fraction is found to depend strongly on the energy of the incident particle. The isomeric cross-section ratio is found to depend strongly on the relative spins of the isomeric and ground state and some dependence on energy difference between the levels.
COMPLEX ACTION SUPPORT FROM COINCIDENCES OF COUPLINGS
Authors: NIELSEN H. B.
Published: June 2011

Our model (Refs. 1–7) with a complex action in a functional integral formulation with path integrals extending over all times, both past and future, is reviewed. Several numerical relations between coupling constants are presented as supporting evidence. The new evidence is that several more hitherto unexplained coincidences are explained by our model:

(1) The "scale problem" is solved because the Higgs field expectation value is predicted to be very small compared to say some fundamental scale, that might be the Planck scale.

(2) The Higgs VEV need not be just zero, but rather is predicted to be so that the running top-quark Yukawa coupling just is about to be unity at this scale; in this way the (weak) scale easily becomes "exponentially small." Instead of the top-Yukawa we should rather say the highest flavor Yukawa coupling here.

These predictions are only achieved by allowing the principle of minimization of the imaginary part of the action SI(history) to a certain extent adjust some coupling constants in addition to the initial conditions.

If supersymmetric partners are not found at LHC it would strengthen the need for a "solution" to the hierarchy problem in our direction of an explanation via a fine-tuning scheme inside the Standard Model, from say minimizing "the imaginary part of the action" in our complex action model.
Role of inhibitory κB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes
Authors: Jiang Shaoning , Messina Joseph L.
Published: June 2011

Hyperglycemia and insulin resistance induced by acute injuries or critical illness are associated with increased mortality and morbidity, as well as later development of type 2 diabetes. The molecular mechanisms underlying the acute onset of insulin resistance following critical illness remain poorly understood. In the present studies, the roles of serine kinases, inhibitory κB kinase (IKK) and c-Jun NH2-terminal kinase (JNK), in the acute development of hepatic insulin resistance were investigated. In our animal model of critical illness diabetes, activation of hepatic IKK and JNK was observed as early as 15 min, concomitant with the rapid impairment of hepatic insulin signaling and increased serine phosphorylation of insulin receptor substrate 1. Inhibition of IKKα or IKKβ, or both, by adenovirus vector-mediated expression of dominant-negative IKKα or IKKβ in liver partially restored insulin signaling. Similarly, inhibition of JNK1 kinase by expression of dominant-negative JNK1 also resulted in improved hepatic insulin signaling, indicating that IKK and JNK1 kinases contribute to critical illness-induced insulin resistance in liver.
Coffee Consumption and Cystatin-C-Based Estimated Glomerular Filtration Rates in Healthy Young Adults: Results of a Clinical Trial
Authors: Saito Masafumi , Nemoto Tohru , Tobimatsu Satoshi , Ebata Midori , Le Yulan , Nakajima Kei
Published: June 2011

Recently it has been reported that the estimated glomerular filtration rate (eGFR) is higher in habitual coffee consumers than in noncoffee consumers. However, the causality remains unclear. Therefore, we conducted a clinical trial to investigate the effects of coffee consumption on kidney function. Nineteen asymptomatic nonsmokers aged 21–27 years old participated in this study. They consumed coffee (18 g coffee beans/450 mL per day) or green tea as a comparator for 2 weeks in a crossover design. Although creatinine-based eGFR was not affected after consuming either beverage, all cystatin-C-based eGFRs determined using five different equations were significantly increased after coffee consumption (means: 5.0–7.7%), but not after green tea consumption (means: 0.1–1.6%). Serum adiponectin and magnesium levels increased significantly after coffee consumption (means: 13.6% and 4.3%, resp.), but not after green tea consumption. These findings suggest that even a short period of coffee consumption may increase cystatin-C-based eGFR, along with favorable changes in serum adiponectin, in healthy young adults.
The Mechanosensory Role of Primary Cilia in Vascular Hypertension
Authors: Nauli Surya M. , Jin Xingjian , Hierck Beerend P.
Published: June 2011

Local regulation of vascular tone plays an important role in cardiovascular control of blood pressure. Aside from chemical or hormonal regulations, this local homeostasis is highly regulated by fluid-shear stress. It was previously unclear how vascular endothelial cells were able to sense fluid-shear stress. The cellular functions of mechanosensory cilia within vascular system have emerged recently. In particular, hypertension is insidious and remains a continuous problem that evolves during the course of polycystic kidney disease (PKD). The basic and clinical perspectives on primary cilia are discussed with regard to the pathogenesis of hypertension in PKD.
The Role of mTOR Inhibitors for the Treatment of B-Cell Lymphomas
Authors: Argyriou Pinelopi , Economopoulou Panagiota , Papageorgiou Sotirios
Published: June 2011

Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR) is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus) represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short.
Myeloid-Derived Suppressor Cell Inhibition of the IFN Response in Tumor-Bearing Mice
Authors: Mundy-Bosse Bethany L. , Lesinski Gregory B. , Jaime-Ramirez Alena C. , Benninger Kristen , Khan Mahmood , Kuppusamy Periannan , Guenterberg Kristan , Kondadasula Sri Vidya , Chaudhury Abhik Ray , La Perle Krista M. , Kreiner Melanie , Young Gregory , Guttridge Denis C. , Carson William E.
Published: June 2011

Our group and others have determined that immune effector cells from patients with advanced cancers exhibit reduced activation of IFN signaling pathways. We hypothesized that increases in immune regulatory cells termed myeloid-derived suppressor cells (MDSC) could interfere with the host immune response to tumors by inhibiting immune cell responsiveness to IFNs. The C26 murine adenocarcinoma model was employed to study immune function in advanced malignancy. C26-bearing mice had significantly elevated levels of GR1+CD11b+ MDSC as compared with control mice, and splenocytes from tumor-bearing mice exhibited reduced phosphorylation of STAT1 (P-STAT1) on Tyr701 in response to IFN-α or IFN-γ. This inhibition was seen in splenic CD4+ and CD8+ T cells as well as natural killer cells. In vitro coculture experiments revealed that MDSC inhibited the IFN responsiveness of splenocytes from normal mice. Treatment of C26-bearing mice with gemcitabine or an anti-GR1 antibody led to depletion of MDSC and restored splenocyte IFN responsiveness. Spleens from C26-bearing animals displayed elevated levels of iNOS protein and nitric oxide. In vitro treatment of splenocytes with a nitric oxide donor led to a decreased STAT1 IFN response. The elevation in nitric oxide in C26-bearing mice was associated with increased levels of nitration on STAT1. Finally, splenocytes from iNOS knockout mice bearing C26 tumors exhibited a significantly elevated IFN response as compared with control C26 tumor-bearing mice. These data suggest that nitric oxide produced by MDSC can lead to reduced IFN responsiveness in immune cells. Cancer Res; 71(15); 5101–10. ©2011 AACR.
Overcoming Chemotherapy Resistance in Prostate Cancer
Authors: Madan Ravi A. , Pal Sumanta Kumar , Sartor Oliver , Dahut William L.
Published: June 2011

Although treatment for prostate cancer has improved over the past several years, taxanes remain the only form of chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). In addition to the promising therapeutic cancer vaccines and newly developed agents targeting androgen receptor signaling, chemotherapy-based treatments will likely continue to play a significant role in patients with mCRPC. Recently published data that showed that a second taxane (cabazitaxel) extends survival after progression on docetaxel was a significant step forward, but also highlighted the need to overcome taxane resistance in prostate cancer. Preliminary evidence suggests that several treatment strategies may improve the activity of taxanes in prostate cancer and perhaps enhance clinical outcomes. Clin Cancer Res; 17(12); 3892–902. ©2011 AACR.
KIT Pathway Alterations in Mucosal Melanomas of the Vulva and Other Sites
Authors: Omholt Katarina , Grafström Eva , Kanter-Lewensohn Lena , Hansson Johan , Ragnarsson-Olding Boel K.
Published: June 2011

Purpose: A significant proportion of mucosal melanomas contain alterations in KIT. The aim of this study was to characterize the pattern of KIT, NRAS, and BRAF mutations in mucosal melanomas at specific sites and to assess activation of the KIT downstream RAF/MEK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in mucosal melanoma specimens.

Experimental Design: Seventy-one primary mucosal melanomas from various sites were studied. Mutation analysis was done by DNA sequencing. Expression of KIT, phosphorylated (p)-ERK, and p-AKT was evaluated by immunohistochemistry.

Results: KIT mutations were detected in 35% (8 of 23) of vulvar, 9% (2 of 22) of anorectal, 7% (1 of 14) of nasal cavity, and 20% (1 of 5) of penile melanomas. No KIT mutations were found in 7 vaginal melanomas. The difference in KIT mutation frequency between vulvar and nonvulvar cases was statistically significant (P = 0.014). The overall frequencies of NRAS and BRAF mutations were 10% and 6%, respectively. Notably, vaginal melanomas showed a NRAS mutation rate of 43%. KIT gene amplification (≥4 copies), as assessed by quantitative real-time PCR, was observed in 19% of cases. KIT expression was associated with KIT mutation status (P < 0.001) and was more common in vulvar than nonvulvar tumors (P = 0.016). Expression of p-ERK and p-AKT was observed in 42% and 59% of tumors, respectively, and occurred irrespective of KIT/NRAS/BRAF mutation status. NRAS mutation was associated with worse overall survival in univariate analysis.

Conclusions: Results show that KIT mutations are more common in vulvar melanomas than other types of mucosal melanomas and that both the RAF/MEK/ERK and PI3K/AKT pathways are activated in mucosal melanoma specimens. Clin Cancer Res; 17(12); 3933–42. ©2011 AACR.
Translating Scientific Advancement into Clinical Benefit for Castration-Resistant Prostate Cancer Patients
Authors: Attard Gerhardt , de Bono Johann S.
Published: June 2011

In the past 12 months, three novel therapeutics—sipuleucel-T, cabazitaxel, and abiraterone acetate—were granted Food and Drug Administration regulatory approval for the treatment of metastatic castration-resistant prostate cancer (CRPC) patients based on phase III studies that showed a survival advantage. Other agents, including the novel antiandrogen MDV3100, are at an advanced stage of clinical phase III evaluation. The treatment paradigm for CRPC has now changed significantly, and this has introduced new challenges for physicians, including selecting patients for specific therapies, developing the best sequencing and combination regimens for the several new effective agents that have recently been approved or are in development, and dissecting mechanisms of resistance that will inform the development of a new generation of therapeutics. This Focus issue reviews the results obtained with immunotherapies, taxane cytotoxics, and androgen receptor targeting therapeutics for CRPC, as well as the postulated mechanisms of resistance to these protocols and proposed strategies for improvement. The use of biomarkers for patient selection, monitoring of treatment activity, and acceleration of drug approval will be critical for achieving further improvements in the treatment for CRPC, and is also discussed in detail. Clin Cancer Res; 17(12); 3867–75. ©2011 AACR.
Estrogen Receptor-Alpha Gene Polymorphisms and Body Composition in Children and Adolescents
Authors: Voorhoeve Paul G. , van Mechelen Willem , Uitterlinden André G. , Delemarre-van de Waal Henriette A. , Lamberts Steven W.J.
Published: June 2011

Background/Aims: Gender differences in body composition are largely explained by differences in sex hormones, such as estrogens. Associations between 2 polymorphisms in the estrogen receptor-α gene (ESR1) and body composition in children and adolescents were investigated. Methods: Two comparable Dutch cohorts with a generational difference of about 20 years were investigated. The first consisted of 350 subjects (184 girls) and the second of 316 subjects (155 girls). Associations between height, weight, BMI, fat mass (FM) and fat-free mass and two polymorphisms in the ESR1 gene were investigated. Results: In girls in the recent cohort, the PvuII-XbaI haplotype 2 polymorphism in the ESR1 gene was associated with a lower body weight, BMI, and FM. These associations were not observed in the older cohort. The younger cohort had a significantly higher total FM, body weight and BMI compared to the older cohort. Conclusion: Because the associations between the PvuII-XbaI haplotype 2 polymorphism and body FM in girls were only found in the recent cohort, but not in a comparable, generally leaner cohort from an older generation, it is suggested that non-carriers of this polymorphism are likely to be more vulnerable to fat accumulation in today’s obesity promoting environment, than carriers.
Levels and interrelationships of serum and lipoprotein cholesterol and triglycerides. Association with adiposity and the consumption of ethanol, tobacco, and beverages containing caffeine.
Authors: Phillips N R , Havel R J , Kane J P
Published: June 2011

We have carried out a cross-sectional multivariate analysis of serum and lipoprotein lipid levels in white persons from an industrial population. Very low density lipoprotein triglyceride level was independent of ethanol consumption but increased with adiposity and cigarette smoking and decreased with coffee-tea drinking. Concomitant age variation in indices of adiposity accounted for only a small part of the sex-specific age trends in triglyceride level. Very low density lipoprotein cholesterol level was independent of all variables considered when controlled for very low density lipoprotein triglyceride. Low density lipoprotein cholesterol covaried with very low density lipoprotein triglyceride among normotriglyceridemic persons. Small increases in low density lipoprotein cholesterol level with adiposity and cigarette smoking appeared to reflect associated increases in very low density lipoprotein triglyceride. Increased low density lipoprotein cholesterol level with age, however, was largely independent of concomitant age variation in very low density lipoprotein triglyceride. High density lipoprotein cholesterol level increased with ethanol consumption and decreased with adiposity and cigarette smoking even after adjustment for its inverse relationship with very low density lipoprotein triglyceride.
Effects of moderate hypercholesterolemia on rabbit endothelium.
Authors: Stemerman M B
Published: June 2011

We investigated the effects of moderate hypercholesterolemia and endothelial regrowth on the function of vascular endothelium. Groups of rabbits were fed either a high or low cholesterol diet and subjected to removal of the aortic endothelium or sham-operated. Endothelial removal caused diffuse thickening of the myointima. The high cholesterol diet did not affect the extent of endothelial regeneration. To test endothelial function, 1 minute before sacrifice each animal was infused with horseradish peroxidase, which will penetrate the intima in areas of increased permeability. After sacrifice, the aorta was removed en bloc and exposed to diaminobenzidine and H2O2, which produce a brown stain on reaction with horseradish peroxidase. The luminal surface of the aorta was examined, and brown-stained areas, indicating increased permeability, were quantitated by stereology. Rabbits fed the cholesterol-rich diet had a greater percentage of brown-stained areas than did rabbits fed the low cholesterol diet; this was true for both intact and regenerated endothelium. The differences were significant at the p less than 0.01 level. Scanning electron microscopy of brown areas showed that, although the surface characteristics of the endothelium were altered, endothelial sloughing did not occur. Therefore, it appears that hypercholesterolemia can be associated with a functional endothelial defect in the absence of endothelial loss.
Blood glucose and risk of coronary heart disease.
Authors: Ostrander L D , Lamphiear D E , Carman W J , Williams G W
Published: June 2011

Health status of 1877 Tecumseh Study subjects aged 35-64 years was ascertained in 1977. They represented 77% of the persons in this age range who were apparently healthy and had participated in comprehensive examinations of nearly the entire population of the community in 1959-1960 and 1962-1965. Subjects who developed coronary heart disease had a significantly higher mean blood glucose concentration than other members of the cohort, even after exclusion of diabetics. Similarly, when examined as single variables, age, sex, serum cholesterol, systolic blood pressure, number of cigarettes smoked per day, and relative weight were significantly related to incidence of coronary events. In the multiple logistic function, however, age, cigarette smoking, blood pressure, and blood glucose were the only significant variables. In a two-way interaction model, glucose and cholesterol were a highly predictive pair. After exclusion of diagnosed diabetics, glucose by itself or in interaction with other variables was not significant in the multiple logistic functions.
Lipoproteins in familial hyperalphalipoproteinemia.
Authors: Patsch W , Kuisk I , Glueck C , Schonfeld G
Published: June 2011

Familial hyperalphalipoproteinemia is determined by a major gene and is characterized by high levels of high density lipoprotein cholesterol and longevity. To describe the plasma lipoproteins in this condition more completely, a kindred consisting of the proband, her affected father, add her two affected brothers was studied. Fasting plasmas were analyzed for lipoprotein lipids by combined preparative ultracentrifugal and precipitation methods. Levels of apolipoprotein A-1 and apolipoprotein A-11, the major apoproteins of high density lipoproteins, were assayed by radioimmunoassay. The flotation properties of very low density, low density and high density lipoprotein were determined by zonal ultracentrifugation, and the isolated high density lipoprotein subfractions were characterized according to their lipid and apoprotein compositions. Total cholesterol of all subjects was normal, but triglycerides were elevated (above the 90th percentile) in the two brothers. High density lipoprotein cholesterol ranged from 150 to 165 mg/dl in the proband and from 72 to 89 mg/dl in her relatives. Apolipoprotein A-1 was 318 mg/dl in the proband and 156 to 169 mg/dl in the siblings; respective apolipoprotein A-11 values were 67 and 82 to 83 mg/dl. The high density lipoprotein cholesterol and apolipoprotein A-1 and A-11 values for the relatives are above the 95th percentile for sex and age, while the levels of the proband are the highest recorded in our laboratories. On zonal ultracentrifugation, very low density lipoprotein and low density lipoprotein had normal flotation properties. High density lipoprotein was divisible into three populations, HDL2, HDL3L, and HDL3D (Sf(1,21,26 degrees C), 59, 2.9, and 1.7 respectively), each of which floated in its usual position. But HDL2 was grossly elevated, accounting for most of the rise in the high density lipoprotein fraction. The compositions of the high density lipoprotein fractions with respect to the major lipid and apoprotein classes did not differ from normal. Thus, in this kindred, high density lipoprotein was quantitatively rather than qualitatively unusual. It is of interest that hypertriglyceridemia and hyperalphalipoproteinemia coexisted in the siblings. These concurrent elevations differ from the expected reciprocal relationship between high density lipoprotein and very low density lipoprotein levels in plasma, and suggests that in some subject the two abnormalities may be independently transmitted.