bluuebunny/crossref_metadata_2025 huggingface dataset:
An Efficient Synthesis of a (−)‐Physostigmine's Library for Identifying Potential Anti‐Alzheimer's Agents
Authors: Wu Yi , Wang Fusheng , Song Hao , Qin Yong
Published: August 2011

An efficient route for the synthesis of (−)‐physostigmine analogs 1a–1g and 2a–2k is described. Analogs 1a–1g were synthesized via copper(I)‐catalyzed cycloaddition between the optically pure azide 10 and a variety of alkynes. Similarly, analogs 2a–2k were prepared through ‘three‐component Huisgen cycloaddition’ using various amines, propargyl bromine, and 10 in H2O. Facile preparation of 10 via MacMillan's organocatalysis has made it possible to generate a great diversity of natural product‐like compounds that can be screened for anti‐Alzheimer's effects.
Gestational age at birth and risk of testicular cancer
Authors: Crump Casey , Sundquist Kristina , Winkleby Marilyn A. , Sieh Weiva , Sundquist Jan
Published: August 2011

Most testicular germ cell tumors originate from carcinoma in situ cells in fetal life, possibly related to sex hormone imbalances in early pregnancy. Previous studies of association between gestational age at birth and testicular cancer have yielded discrepant results and have not examined extreme preterm birth. Our objective was to determine whether low gestational age at birth is independently associated with testicular cancer in later life. We conducted a national cohort study of 354,860 men born in Sweden in 1973–1979, including 19,214 born preterm (gestational age < 37 weeks) of whom 1,279 were born extremely preterm (22–29 weeks), followed for testicular cancer incidence through 2008. A total of 767 testicular cancers (296 seminomas and 471 nonseminomatous germ cell tumors) were identified in 11.2 million person‐years of follow‐up. Extreme preterm birth was associated with an increased risk of testicular cancer (hazard ratio = 3.95; 95% confidence interval = 1.67–9.34) after adjusting for other perinatal factors, family history of testicular cancer and cryptorchidism. Only five cases (three seminomas and two nonseminomas) occurred among men born extremely preterm, limiting the precision of risk estimates. No association was found between later preterm birth, post‐term birth or low or high fetal growth and testicular cancer. These findings suggest that extreme but not later preterm birth may be independently associated with testicular cancer in later life. They are based on a small number of cases and will need confirmation in other large cohorts. Elucidation of the key prenatal etiologic factors may potentially lead to preventive interventions in early life.
An MRI study of the differences in the rate of thrombolysis between red blood cell‐rich and platelet‐rich components of venous thrombi ex vivo
Authors: Vidmar Jernej , Blinc Aleš , Kralj Eduard , Balažic Jože , Bajd Franci , Serša Igor
Published: August 2011

Purpose:

To test whether T1‐weighted MRI can detect the differences in the rate of thrombolysis induced by recombinant tissue plasminogen activator (rt‐PA) between platelet‐rich regions and red blood cell (RBC)‐rich regions of venous thrombi ex vivo.

Materials and Methods:

Each of 21 venous thrombi ex vivo (8 pulmonary emboli and 13 in situ thrombi) was dissected along the longitudinal axis. Half of it was analyzed for the presence of platelet, fibrin, and RBC components by immunohistochemistry and the other half was imaged serially by high‐resolution T1‐weighted three‐dimensional MRI to assess the progression of thrombolysis. The MR images were analyzed for proportions of the remaining platelet‐rich and RBC‐rich regions.

Results:

Laminated platelet‐rich regions, corresponding to Zahn lines, were confirmed immunohistochemically and by MRI in 18/21 venous thrombi. In T1‐weighted MR images (TE/TR = 10/105 ms) the mean signal intensity of platelet‐rich regions was on average 2.3 higher than that of RBC‐rich regions. The rate of thrombolysis in platelet‐rich regions was on average 30% lower than in RBC‐rich regions. After 120 min of thrombolysis the proportion of lysed platelet‐rich regions was 0.27 ± 0.04 versus 0.40 ± 0.08 in RBC regions, which resulted in 1.4% decrease of lysed thrombus volume per 1% increase of platelet‐rich content.

Conclusion:

Venous thrombi are most often composed of interspersed platelet‐rich and RBC‐rich regions. T1‐weighted MRI is capable of noninvasive discrimination between those two components of venous thrombi ex vivo which have a different susceptibility to thrombolysis by rt‐PA. J. Magn. Reson. Imaging 2011;. © 2011 Wiley Periodicals, Inc.
Cage effect and inverse temperature dependence of the kinetic isotope effect in the c‐C6H12/c‐C6D12 reaction with OH radicals in fenton and HOONOH2O systems
Authors: Rudakov Elisey S. , Lobachev Vladimir L. , Volkova Larisa K.
Published: August 2011

Recently, we have discovered the unusual inverse temperature dependence of the kinetic isotope effect (KIE) for the OH + c‐C6H12/c‐C6D12 reaction in water. Temperature increase causes a KIE increase; this is valid for both the Fenton system (I) and the HOONOH2O system (II) (a new source of OH radicals in alkane reactions), whereas in the gas phase KIE decreases with increasing temperature. Results of these studies are considered. The KIE temperature dependences for both reactions in solution, (kH/kD)w = (2.65 ± 0.15) exp[(−2.0 ± 0.1)/RT], ED−EH in kJ mol−1, and gas‐phase reactions, (kH/kD)g = (1.2 ± 0.1) exp[(+2.0 ± 0.1)/RT], differ significantly. The anomalous temperature behavior of KIE in water is described by a cage effect model at the step of the reactant encounter, which was proposed earlier by Rudakov. The model can be represented in a concise form: RH + OH \documentclass{article}\usepackage{amssymb}\begin{document}\pagestyle{empty}$\begin{array}{c}{\scriptstyle 1}\\ \rightleftarrows \\ {\scriptstyle -1}\end{array}$\end{document} 〈RH··OH〉* \documentclass{article}\usepackage{amssymb}\begin{document}\pagestyle{empty}$\begin{array}{c}{\scriptstyle 2}\\ \rightarrow\end{array}$\end{document} R• + H2O, where 〈RH··OH〉*is the oriented encounter complex in the water cage. It is suggested that elementary acts of H‐abstraction (step 2) are identical for both gas phase and solution. It allows calculation of the competition parameter between steps 2 and –1 (the alkane leaves the cage via diffusion), (k−1/k2H) = [(kH/kD)g− 1]/[(kH/kD)g− (kH/kD)w], by using the experimental KIEs. A temperature‐dependence average for systems I and II was found as (k−1/k2H) = (245 ± 35) exp[(18.5 ± 0.5)/RT]. The hypothetical dependence of (kH/kD)w on T was calculated within the overall temperature range (by extrapolations outside the experimental area, 278–328 K), and its connection with that of (kH/kD)g on T is considered. © 2011 Wiley Periodicals, Inc. Int J Chem Kinet 43: 557–562, 2011
Lipid rafts function in Ca2+ signaling responsible for activation of sperm motility and chemotaxis in the ascidian Ciona intestinalis
Authors: Zhu Lihong , Inaba Kazuo
Published: August 2011

Lipid rafts are specialized membrane microdomains that function as signaling platforms across plasma membranes of many animal and plant cells. Although there are several studies implicating the role of lipid rafts in capacitation of mammalian sperm, the function of these structures in sperm motility activation and chemotaxis remains unknown. In the ascidian Ciona intestinalis, egg‐derived sperm activating‐ and attracting‐factor (SAAF) induces both activation of sperm motility and sperm chemotaxis to the egg. Here we found that a lipid raft disrupter, methyl‐β‐cyclodextrin (MCD), inhibited both SAAF‐induced sperm motility activation and chemotaxis. MCD inhibited both SAAF‐promoted synthesis of intracellular cyclic AMP and sperm motility induced by ionophore‐mediated Ca2+ entry, but not that induced by valinomycin‐mediated hyperpolarization. Ca2+‐imaging revealed that lipid raft disruption inhibited Ca2+ influx upon activation of sperm motility. The Ca2+‐activated adenylyl cyclase was clearly inhibited by MCD in isolated lipid rafts. The results suggest that sperm lipid rafts function in signaling upstream of cAMP synthesis, most likely in SAAF‐induced Ca2+ influx, and are required for Ca2+‐dependent pathways underlying activation and chemotaxis in Ciona sperm. Mol. Reprod. Dev. 78:920–929, 2011. © 2011 Wiley Periodicals, Inc.
Accelerated diffusion spectrum imaging in the human brain using compressed sensing
Authors: Menzel Marion I. , Tan Ek T. , Khare Kedar , Sperl Jonathan I. , King Kevin F. , Tao Xiaodong , Hardy Christopher J. , Marinelli Luca
Published: August 2011

We developed a novel method to accelerate diffusion spectrum imaging using compressed sensing. The method can be applied to either reduce acquisition time of diffusion spectrum imaging acquisition without losing critical information or to improve the resolution in diffusion space without increasing scan time. Unlike parallel imaging, compressed sensing can be applied to reconstruct a sub‐Nyquist sampled dataset in domains other than the spatial one. Simulations of fiber crossings in 2D and 3D were performed to systematically evaluate the effect of compressed sensing reconstruction with different types of undersampling patterns (random, gaussian, Poisson disk) and different acceleration factors on radial and axial diffusion information. Experiments in brains of healthy volunteers were performed, where diffusion space was undersampled with different sampling patterns and reconstructed using compressed sensing. Essential information on diffusion properties, such as orientation distribution function, diffusion coefficient, and kurtosis is preserved up to an acceleration factor of R = 4. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.
Quantitative pancreatic β cell MRI using manganese‐enhanced Look‐Locker imaging and two‐site water exchange analysis
Authors: Antkowiak Patrick F. , Vandsburger Moriel H. , Epstein Frederick H.
Published: August 2011

Pancreatic β‐cell imaging would be useful in monitoring the progression of and therapies for diabetes. The purpose of this study was to develop and evaluate quantitative β‐cell MRI using manganese (Mn2+) labeling of β cells, T1 mapping, and a two‐site water exchange model. Normal, pharmacologically‐treated, and severely diabetic mice underwent injection of MnCl2. Pancreatic water proton T1 relaxation was measured using Look‐Locker MRI, and two‐site water exchange analysis was used to estimate model parameters including the intracellular water proton relaxation rate constant (R1ic) and the intracellular fraction as indicators of β‐cell function and mass, respectively. Logarithmic plots of T1 relaxation revealed two distinct proton pools relaxing with different T1s, and the two‐site water exchange model fit the measured T1 relaxation data better than a monoexponential model. The intracellular R1ic time course revealed the kinetics of β‐cell Mn2+ labeling. Pharmacological treatments with nifedipine, tolbutamide, and diazoxide altered R1ic, indicating that beta cell function was a determinant of Mn2+ uptake. Intracellular fraction was significantly higher in mice with normal β cell mass than in diabetic mice (14.9% vs. 14.4%, P < 0.05). Two‐site water exchange analysis of T1 relaxation of the Mn2+‐enhanced pancreas is a promising method for quantifying β cell volume fraction and function. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.
T2 measurement of J‐coupled metabolites in the human brain at 3T
Authors: Ganji Sandeep K. , Banerjee Abhishek , Patel Aditya M. , Zhao Yan D. , Dimitrov Ivan E. , Browning Jeffrey D. , Sherwood Brown E. , Maher Elizabeth A. , Choi Changho
Published: August 2011

Proton T2 relaxation times of metabolites in the human brain were measured using point resolved spectroscopy at 3T in vivo. Four echo times (54, 112, 246 and 374 ms) were selected from numerical and phantom analyses for effective detection of the glutamate multiplet at ~ 2.35 ppm. In vivo data were obtained from medial and left occipital cortices of five healthy volunteers. The cortices contained predominantly gray and white matter, respectively. Spectra were analyzed with LCModel software using volume‐localized calculated spectra of brain metabolites. The estimate of the signal strength vs. TE was fitted to a monoexponential function for estimation of apparent T2 (T2†). T2† was estimated to be similar between the brain regions for creatine, choline, glutamate and myo‐inositol, but significantly different for N‐acetylaspartate singlet and multiplet. T2†s of glutamate and myo‐inositol were measured as 181 ± 16 and 197 ± 14 ms (mean ± SD, N = 5) for medial occipital cortices, and 180 ± 12 and 196 ± 17 ms for left occipital cortices, respectively. Copyright © 2011 John Wiley & Sons, Ltd.
A Comparison of Climate Change Mitigation and Adaptation Strategies for the Construction Industries of Three Coastal Territories
Authors: Gunawansa Asanga , Kua Harn Wei
Published: August 2011

The success of climate change strategies depends on how well mitigation and adaptation measures are implemented. It is especially important to implement effective mitigation and adaptation measures in coastal territories because they will be more directly affected by some of the possible effects of climate change. This study assessed and compared how Singapore, Miami‐Dade and San Francisco – three coastal territories – implement climate change strategies in their construction industries. Case study method – in which primary and secondary information was collected and analyzed – was used. It was found that these three territories have a few similarities; for example, Singapore and San Francisco mandate green building requirements, whereas Singapore and Miami‐Dade do not explicitly consider adaptation measures in their building codes. It was also noted that although mitigation has entered mainstream policy‐making, adaptation still lags behind. Consequently, this study has proposed a few lessons; for example, policy‐makers in Singapore and Miami‐Dade should complement existing measures with platforms to engage the public on disaster management. Copyright © 2011 John Wiley & Sons, Ltd and ERP Environment.
SYN flooding attack detection by TCP handshake anomalies
Authors: Bellaïche Martine , Grégoire Jean‐Charles
Published: August 2011

We present an original approach to identify synchronize (SYN) flooding attacks from the victim's side, on the basis of a classification of the different forms that TCP handshakes can take during a connection set‐up between a client and a server (e.g. for Web traffic). We first identify the unusual handshake sequences that result from an attack and show how such observations can be used for SYN flooding attack detection. We then introduce a data structure to monitor, in real time, the state of the TCP handshake and study its performance. In addition, we explain the management of the data structure for operations such as initialization, adding and removing flows. Finally, we analyse the effectiveness of our TCP handshake monitoring to identify the presence of SYN flooding attacks by applying it to real traffic traces. To allow quick protection and help guarantee a proper defence, the detection is done in real time. Our detection system uses a non‐parametric cumulative sum algorithm (CUSUM), which has the benefit of not requiring a detailed model of the normal and attack traffic while achieving excellent detection levels. Copyright © 2011 John Wiley & Sons, Ltd.
The chemistry and thermal stability of HfTaO/Si interface by x‐ray photoelectron spectroscopy
Authors: Yu T. , Jin C. G. , Yang X. M. , Wu X. M. , Zhuge L. J. , Ge S. B.
Published: August 2011

The chemistry and thermal stability of HfTaO/Si interface as a function of annealing temperature have been investigated by x‐ray photoelectron spectroscopy. For the as‐deposited sample, the formation of Hf‐silicate bond is observed on Hf 4f core‐level spectra, which contributes to bulk HfO2 and SiO2. Besides, the suboxide of tantalum (Ta+1) is formed at the interface at room temperature because of oxygen‐deficient conditions. HfSi2, HfxSiyO4, and HfO2 coexists in interfacial region at 850 °C, meanwhile, an evidence for transforming from the Ta1+ to tantalum oxide (Ta5+) is verified. The peaks of Hf–O–Si and Hf–O have disappeared, only one peak of Hf silicide remained after the annealing at 950 °C. A stable SiO2 phase in HfTaO/Si is formed under different annealing conditions. Copyright © 2011 John Wiley & Sons, Ltd.
Ion‐beam synthesis of 3C‐SiC surface layers on silicon
Authors: Hopf T. , Schuette F. , Leveneur J. , Kennedy J. , Markwitz A.
Published: August 2011

The attempt to grow 3C‐SiC thin films on silicon substrates has become an area of significant scientific interest, largely as a consequence of the impressive electrical properties that this polytype displays. In this paper, we have utilized low‐energy (20 keV) high‐fluence carbon implantation and a subsequent annealing step to form layers of 3C‐SiC directly on a silicon surface, and have investigated the effect of implantation fluence on the resultant materials properties. The quality of the Si/SiC interface is shown to be highly fluence‐dependent, with the formation of voids decreasing significantly with increased fluence. The conversion of carbon into 3C‐SiC is found to be most efficient at near‐stoichiometric concentrations, while at higher implantation fluences clusters of excess carbon are discovered to form within the silicon and to diffuse to the surface of the grown 3C‐SiC layer upon annealing. Copyright © 2011 John Wiley & Sons, Ltd.
Design and analysis of a glass roof structure
Authors: Cai Jianguo , Xu Yixiang , Feng Jian , Zhang Jin
Published: August 2011

The hybrid grid shell, made of quadrangular meshes diagonally stiffened by pre‐tensioned thin cables, is an attractive structural form in the design and construction of long‐span transparent glass roof structures. These hybrid structures are very slender and lightweight, and it is desirable to understand their detailed structural behavior. The mechanical characteristic of the hybrid structure was investigated based on a quadrangle of slats with cross cables. The construction of the design model for the glass roof was firstly described. Then, the static behavior and stability capacity of the hybrid grid dome and the corresponding single‐layer lattice dome were studied based on a finite element model. Moreover, the modal analyses of the two domes were carried out. The natural frequencies and the vibration modes of the domes were given to investigate the dynamic behavior of the hybrid grid dome. Finally, the effects of the asymmetric loads and rise‐to‐span ratios on the structural behavior were studied in detail. Copyright © 2011 John Wiley & Sons, Ltd.
Efficient data dissemination in cooperative vehicular networks
Authors: Cherif Mohamed Oussama , Senouci Sidi‐Mohammed , Ducourthial Bertrand
Published: August 2011

Vehicular networks are drawing the attention of both research community and automotive industry because they provide intelligent transportation systems as well as drivers and passengers’ assistant services. However, the industrialization of such networks faces a number of challenges, in particular, the high cost of the infrastructure to deploy. To overcome this problem, an effective solution is to rely on cooperative vehicle‐to‐vehicle communication to minimize the deployed infrastructure. Because a large number of cooperative vehicle‐to‐vehicle applications are broadcasting by nature, we proposed an efficient dissemination protocol: Road‐Oriented Dissemination (ROD). ROD consists in two modules: (i) Optimized Distance Defer Transfer Module and (ii) Store‐and‐Forward Module. We compare our protocol with other dissemination protocols and analyze its performance by simulations, on‐road tests and analytically. Performance study shows interesting results of ROD compared with the other existing solutions. ROD is able to provide a low end‐to‐end delay, high delivery ratios, and a minimum bandwidth usage because only a limited number of vehicles are involved in the broadcast scheme. Copyright © 2011 John Wiley & Sons, Ltd.
Milk fatty acid profile related to energy balance in dairy cows
Authors: Gross Josef , van Dorland Hendrika A , Bruckmaier Rupert M , Schwarz Frieder J
Published: August 2011

Milk fatty acid (FA) profile is a dynamic pattern influenced by lactational stage, energy balance and dietary composition. In the first part of this study, effects of the energy balance during the proceeding lactation [weeks 1–21 post partum (pp)] on milk FA profile of 30 dairy cows were evaluated under a constant feeding regimen. In the second part, effects of a negative energy balance (NEB) induced by feed restriction on milk FA profile were studied in 40 multiparous dairy cows (20 feed-restricted and 20 control). Feed restriction (energy balance of −63 MJ NEL/d, restriction of 49 % of energy requirements) lasted 3 weeks starting at around 100 days in milk. Milk FA profile changed markedly from week 1 pp up to week 12 pp and remained unchanged thereafter. The proportion of saturated FA (predominantly 10:0, 12:0, 14:0 and 16:0) increased from week 1 pp up to week 12 pp, whereas monounsaturated FA, predominantly the proportion of 18:1,9c decreased as NEB in early lactation became less severe. During the induced NEB, milk FA profile showed a similarly directed pattern as during the NEB in early lactation, although changes were less marked for most FA. Milk FA composition changed rapidly within one week after initiation of feed restriction and tended to adjust to the initial composition despite maintenance of a high NEB. C18:1,9c was increased significantly during the induced NEB indicating mobilization of a considerable amount of adipose tissue. Besides 18:1,9c, changes in saturated FA, monounsaturated FA, de-novo synthesized and preformed FA (sum of FA >C16) reflected energy status in dairy cows and indicated the NEB in early lactation as well as the induced NEB by feed restriction.
Ovarian activity in Fleckvieh, Brown Swiss and two strains of Holstein-Friesian cows in pasture-based, seasonal calving dairy systems
Authors: Piccand Valérie , Meier Susanne , Cutullic Erwan , Weilenmann Sara , Thomet Peter , Schori Fredy , Burke Chris R , Weiss Daniel , Roche John R , Kunz Peter L
Published: August 2011

The objectives of the study were to compare the ovarian activity of Holstein-Friesian (CH HF), Fleckvieh (CH FV) and Brown Swiss (CH BS) dairy cows of Swiss origin with that of Holstein-Friesian (NZ HF) dairy cows of New Zealand origin, the latter being used as a reference for reproductive performance in pasture-based seasonal calving systems. Fifty, second-lactation NZ HF cows were each paired with a second-lactation Swiss cow (17, 15 and 18 CH HF, CH FV and CH BS respectively) in 13 pasture-based, seasonal-calving commercial dairy farms in Switzerland. Ovarian activity was monitored by progesterone profiling from calving to first breeding service. CH BS cows produced less energy-corrected milk (mean 22·8 kg/d) than the other breeds (26·0–26·5 kg/d) during the first 100 d of lactation. CH HF cows had the lowest body condition score (BCS) at calving and the greatest BCS loss from calving to 30 d post partum. Commencement of luteal activity (CLA) was later for NZ HF than for CH FV (51·5 v. 29·2 d; P <0·01), with CH HF and CH BS intermediate (43 d). On average, NZ HF and CH HF cows had one oestrous cycle before the onset of the seasonal breeding period; this was less (P<0·01) than either CH FV (1·7) or CH BS (1·6). There was a low prevalence of luteal persistency (3%) among the studied cows. First and second oestrous cycle inter-ovulatory intervals did not differ between breeds (20·5–22·6 d). The luteal phase length of CH BS during the second cycle was shorter (10·6 d) than that of the other breeds (13·8–16·0 d), but the inter-luteal interval was longer (9·8 d v. 7·0–8·0 d). The results suggest that the Swiss breeds investigated have a shorter interval from calving to CLA than NZ HF cows.
Guideline concordant monitoring of metabolic risk in people treated with antipsychotic medication: systematic review and meta-analysis of screening practices
Authors: Mitchell A. J. , Delaffon V. , Vancampfort D. , Correll C. U. , De Hert M.
Published: August 2011

Background

Despite increased cardiometabolic risk in individuals with mental illness taking antipsychotic medication, metabolic screening practices are often incomplete or inconsistent.

Method

We undertook a systematic search and a PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) meta-analysis of studies examining routine metabolic screening practices in those taking antipsychotics both for patients in psychiatric care before and following implementation of monitoring guidelines.

Results

We identified 48 studies (n=290 534) conducted between 2000 and 2011 in five countries; 25 studies examined predominantly schizophrenia-spectrum disorder populations; 39 studies (n=218 940) examined routine monitoring prior to explicit guidelines; and nine studies (n=71 594) reported post-guideline monitoring. Across 39 studies, routine baseline screening was generally low and above 50% only for blood pressure [69.8%, 95% confidence interval (CI) 50.9–85.8] and triglycerides (59.9%, 95% CI 36.6–81.1). Cholesterol was measured in 41.5% (95% CI 18.0–67.3), glucose in 44.3% (95% CI 36.3–52.4) and weight in 47.9% (95% CI 32.4–63.7). Lipids and glycosylated haemoglobin (HbA1c) were monitored in less than 25%. Rates were similar for schizophrenia patients, in US and UK studies, for in-patients and out-patients. Monitoring was non-significantly higher in case-recordversusdatabase studies and in fasting samples. Following local/national guideline implementation, monitoring improved for weight (75.9%, CI 37.3–98.7), blood pressure (75.2%, 95% CI 45.6–95.5), glucose (56.1%, 95% CI 43.4–68.3) and lipids (28.9%, 95% CI 20.3–38.4). Direct head-to-head pre–post-guideline comparison showed a modest but significant (15.4%) increase in glucose testing (p=0.0045).

Conclusions

In routine clinical practice, metabolic monitoring is concerningly low in people prescribed antipsychotic medication. Although guidelines can increase monitoring, most patients still do not receive adequate testing.
Guest Editorial: A Call for Contextualized Bioethics: Health, Biomedical Research, and Security
Authors: SUTROP MARGIT , SIMM KADRI
Published: August 2011

A decade has passed since the mapping of the human genome—an event that paved the way for many new developments in biomedicine and related fields. In ethics, this milestone was accompanied by calls for changes in ruling ethical frameworks.
The Concepts of Common Good and Public Interest: From Plato to Biobanking
Authors: SIMM KADRI
Published: August 2011

The expression “common good” usually conjures up benevolent associations: it is something to be desired, a worthy goal, and it would be a brave person who declared he or she was against the common good. Yet modern times have taught us to be critical and even suspicious of such grand rhetoric, leading us to query what lies behind this ambitious notion, who formulates what it stands for, and how such formulations have been reached.
Tackling Epistemological Naivety: Large-Scale Information Systems and the Complexities of the Common Good
Authors: ROMMETVEIT KJETIL
Published: August 2011

We have arrived at a situation in which policymakers and ethicists are considering abandoning informed consent in the governance of certain new technologies, many of which are related to large-scale information systems. A paradigm case is the problem with using individuals’ informed consent to regulate biobanks. As sometimes suggested, there is a need for “new ethical frameworks.”
Skin depth at microwave frequencies of sea foam layers with vertical profile of void fraction
Authors: Anguelova Magdalena D. , Gaiser Peter W.
Published: August 2011

To develop a foam emissivity model, we started a systematic investigation of sea foam properties at microwave frequencies from 1 to 37 GHz. We first examined various permittivity formulae to find the most suitable one for obtaining the dielectric constant of sea foam. This paper presents an investigation of the skin depth of vertically structured foam layers for the first time. Various void fraction profiles representing variations of foam properties within the foam thickness are examined. The skin depth of foam layer thicknesses from 0.2 cm to 10 cm is obtained. The dependence of foam skin depth on frequency and foam layer thickness is investigated and compared to seawater skin depth. It was found that for exponential void fraction profile ranging from 99% at the air‐foam interface to 1% at the foam‐seawater boundary, the foam skin depth varies from 0.17 cm to no more than 7 cm. Possible variations of the foam skin depth due to permittivity formula choice, seawater temperature and salinity, and shape of void fraction profile, as well as its upper and lower limits, are presented. Analyses of the results help explain the sensitivity of microwave frequencies to foam layer thicknesses, infer the formation of the emissivity signal and its variations from foam‐covered surfaces, infer implications for the passive remote sensing of whitecaps, discuss modeling approaches for vertically structured foam layers, and infer qualitatively the relative contributions of different foam structures to the absorption and emission of electromagnetic radiation. These findings give conceptual understanding of foam emissivity.
Return of inactivated whole‐virus vaccine for superior efficacy
Authors: Furuya Yoichi
Published: August 2011

The swine, influenza, H1N1 outbreak in 2009 highlighted the inadequacy of the currently used antibody‐based vaccine strategies as a preventive measure for combating influenza pandemics. The ultimate goal for successful control of newly arising influenza outbreaks is to design a single‐shot vaccine that will provide long‐lasting immunity against all strains of influenza A virus. A large amount of data from animal studies has indicated that the cross‐reactive cytotoxic T (Tc) cell response against conserved influenza virus epitopes may be the key immune response needed for a universal influenza vaccine. However, decades of research have shown that the development of safe T‐cell‐based vaccines for influenza is not an easy task. Here, I discuss the overlooked but potentially highly advantageous inactivation method, namely, γ‐ray irradiation, as a mean to reach the Holy Grail of influenza vaccinology.
Dispersion and attenuation on the Brillouin sound waves of a lubricant: Di(2-ethylhexyl) sebacate under high pressures
Authors: Fujita Yoshitaka , Kobayashi Hiroshi
Published: August 2011

The Brillouin spectra of di(2-ethylhexyl) sebacate, which is a liquid lubricant known as DOS, were measured at up to 5 GPa at 25 °C and up to 2.5 GPa at 80 °C. At 25 °C, the Brillouin frequency linewidth (acoustic attenuation) has a large maximum at 0.1 MPa, and at 80 °C, it has a large broad maximum at 0.8 GPa. The Brillouin frequency shift (sound velocity) and linewidth obtained indicate that the large dispersion of the sound velocities of DOS occurs from 0.1 MPa at 25 °C and from 0.8 GPa at 80 °C. The origins of this attenuation and dispersion are discussed on the basis of the theory for a viscoelastic liquid. It is proposed that the large acoustic attenuation and dispersion of DOS are due to the production of higher-rank structures with nano-order domains in a polymeric liquid by pressurization. The results show that DOS is strongly viscoelastic above 0.8 GPa at 80 °C, but it is not viscous below 0.8 GPa at 80 °C, with the disappearance of the frequency dispersion. The result obtained is used to explain a limiting shear stress observed in a traction oil. Above a given sliding speed, the oil reaches the region of temperature and pressure in which its viscosity decreases with increasing shear rate and conveys a constant torque above some high shear rate. Then, the oil flows as a plastic solid at a limiting shear stress. These findings regarding the dynamical properties of DOS under high pressures are very useful for the production and analysis of lubricants and traction oils.
Two synaptobrevin molecules are sufficient for vesicle fusion in central nervous system synapses
Authors: Sinha Raunak , Ahmed Saheeb , Jahn Reinhard , Klingauf Jurgen
Published: August 2011

Exocytosis of synaptic vesicles (SVs) during fast synaptic transmission is mediated by soluble
N
-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly formed by the coil-coiling of three members of this protein family: vesicle SNARE protein, synaptobrevin 2 (syb2), and the presynaptic membrane SNAREs syntaxin-1A and SNAP-25. However, it is controversially debated how many SNARE complexes are minimally needed for SV priming and fusion. To quantify this effective number, we measured the fluorescence responses from single fusing vesicles expressing pHluorin (pHl), a pH-sensitive variant of GFP, fused to the luminal domain of the vesicular SNARE syb2 (spH) in cultured hippocampal neurons lacking endogenous syb2. Fluorescence responses were quantal, with the unitary signals precisely corresponding to single pHluorin molecules. Using this approach we found that two copies of spH per SV fully rescued evoked fusion whereas SVs expressing only one spH were unable to rapidly fuse upon stimulation. Thus, two syb2 molecules and likely two SNARE complexes are necessary and sufficient for SV fusion during fast synaptic transmission.
Free radical functionalization of surfaces to prevent adverse responses to biomedical devices
Authors: Bilek Marcela M. M. , Bax Daniel V. , Kondyurin Alexey , Yin Yongbai , Nosworthy Neil J. , Fisher Keith , Waterhouse Anna , Weiss Anthony S. , dos Remedios Cristobal G. , McKenzie David R.
Published: August 2011

Immobilizing a protein, that is fully compatible with the patient, on the surface of a biomedical device should make it possible to avoid adverse responses such as inflammation, rejection, or excessive fibrosis. A surface that strongly binds and does not denature the compatible protein is required. Hydrophilic surfaces do not induce denaturation of immobilized protein but exhibit a low binding affinity for protein. Here, we describe an energetic ion-assisted plasma process that can make any surface hydrophilic and at the same time enable it to covalently immobilize functional biological molecules. We show that the modification creates free radicals that migrate to the surface from a reservoir beneath. When they reach the surface, the radicals form covalent bonds with biomolecules. The kinetics and number densities of protein molecules in solution and free radicals in the reservoir control the time required to form a full protein monolayer that is covalently bound. The shelf life of the covalent binding capability is governed by the initial density of free radicals and the depth of the reservoir. We show that the high reactivity of the radicals renders the binding universal across all biological macromolecules. Because the free radical reservoir can be created on any solid material, this approach can be used in medical applications ranging from cardiovascular stents to heart-lung machines.
S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide
Authors: Qu Jing , Nakamura Tomohiro , Cao Gang , Holland Emily A. , McKercher Scott R. , Lipton Stuart A.
Published: August 2011

The activity of Cdk5 and its regulatory subunit p35 is thought to be important in both normal brain function and neurodegenerative disease pathogenesis. Increased Cdk5 activity, via proteolytic cleavage of p35 to a p25 fragment by the calcium-activated protease calpain or by phosphorylation at Cdk5(Tyr15), can contribute to neurotoxicity. Nonetheless, our knowledge of regulation of Cdk5 activity in disease states is still emerging. Here we demonstrate that Cdk5 is activated by S-nitrosylation or reaction of nitric oxide (NO)-related species with the thiol groups of cysteine residues 83 and 157, to form SNO-Cdk5. We then show that S-nitrosylation of Cdk5 contributes to amyloid-β (Aβ) peptide-induced dendritic spine loss. Furthermore, we observed significant levels of SNO-Cdk5 in postmortem Alzheimer’s disease (AD) but not in normal human brains. These findings suggest that S-nitrosylation of Cdk5 is an aberrant regulatory mechanism of enzyme activity that may contribute to the pathogenesis of AD.
Normal hearing is not enough to guarantee robust encoding of suprathreshold features important in everyday communication
Authors: Ruggles Dorea , Bharadwaj Hari , Shinn-Cunningham Barbara G.
Published: August 2011

“Normal hearing” is typically defined by threshold audibility, even though everyday communication relies on extracting key features of easily audible sound, not on sound detection. Anecdotally, many normal-hearing listeners report difficulty communicating in settings where there are competing sound sources, but the reasons for such difficulties are debated: Do these difficulties originate from deficits in cognitive processing, or differences in peripheral, sensory encoding? Here we show that listeners with clinically normal thresholds exhibit very large individual differences on a task requiring them to focus spatial selective auditory attention to understand one speech stream when there are similar, competing speech streams coming from other directions. These individual differences in selective auditory attention ability are unrelated to age, reading span (a measure of cognitive function), and minor differences in absolute hearing threshold; however, selective attention ability correlates with the ability to detect simple frequency modulation in a clearly audible tone. Importantly, we also find that selective attention performance correlates with physiological measures of how well the periodic, temporal structure of sounds above the threshold of audibility are encoded in early, subcortical portions of the auditory pathway. These results suggest that the fidelity of early sensory encoding of the temporal structure in suprathreshold sounds influences the ability to communicate in challenging settings. Tests like these may help tease apart how peripheral and central deficits contribute to communication impairments, ultimately leading to new approaches to combat the social isolation that often ensues.
Combination therapy utilizing shRNA knockdown and an optimized resistant transgene for rescue of diseases caused by misfolded proteins
Authors: Li Chengwen , Xiao Pingjie , Gray Steven James , Weinberg Marc Scott , Samulski R. Jude
Published: August 2011

Molecular knockdown of disease proteins and restoration of wild-type activity represent a promising but challenging strategy for the treatment of diseases that result from the accumulation of misfolded proteins (i.e., Huntington disease, amyotrophic lateral sclerosis, and α-1 antitrypsin deficiency). In this study we used alpha-1 antitrypsin (AAT) deficiency with the piZZ mutant phenotype as a model system to evaluate the efficiency of gene-delivery approaches that both silence the piZZ transcript (e.g., shRNA) and restore circulating wild-type AAT expression from resistant codon-optimized AAT (AAT-opt) transgene cassette using adeno-associated virus (AAV) vector delivery. After systemic injection of a self-complimentary AAV serotype 8 (scAAV8) vector encoding shRNA in piZZ transgenic mice, both mutant AAT mRNA in the liver and defected serum protein level were inhibited by 95%, whereas liver pathology, as monitored by dPAS and fibrosis staining, reversed. To restore blood AAT levels in AAV8/shRNA-treated mice, several strategies to restore functional AAT levels were tested, including using AAV AAT-opt transgene cassettes targeted to muscle and liver, or combination vectors carrying piZZ shRNA and AAT-opt transgenes separately, or a single bicistronic AAV vector. With these molecular approaches, we observed over 90% knockdown of mutant AAT with a 13- to 30-fold increase of circulating wild-type AAT protein from the shRNA-resistant AAT-opt cassette. The molecular approaches applied in this study can simultaneously prevent liver pathology and restore blood AAT concentration in AAT deficiencies. Based on these observations, similar gene-therapy strategies could be considered for any diseases caused by accumulation of misfolded proteins.
Multifaceted cytoprotection by synthetic polyacetylenes inspired by the ginseng-derived natural product, panaxytriol
Authors: Chou Ting-Chao , Dong Huajin , Zhang Xiuguo , Lei Xiaoguang , Hartung John , Zhang Yandong , Lee Jun Hee , Wilson Rebecca M. , Danishefsky Samuel J.
Published: August 2011

We describe herein the discovery of a series of panaxytriol (PXT)-derived polyacetylene small molecules with promising cytoprotective activity. In mouse xenograft models, we have demonstrated the capacity of our synthetic analogs to mitigate a range of cancer therapeutic agent-induced toxicities, including body weight loss, lethality, neurotoxicity, and hematotoxicity. Our PXT analogs have also been found to reduce radiation-induced body weight loss and lethality in mouse models. Moreover, several PXT analogs appear to exhibit moderate in vivo antiinflammatory activity as well as in vitro immunoenhancing capabilities. These compounds appear to derive their activity through induction of cancer preventive phase 2 enzymes. The studies described herein suggest that coadministration of a PXT-derived agent with cancer chemotherapeutics or radiation therapy may serve to mitigate a range of therapy-associated toxicities.
The DExD/H box ATPase Dhh1 functions in translational repression, mRNA decay, and processing body dynamics
Authors: Carroll Johanna S. , Munchel Sarah E. , Weis Karsten
Published: August 2011

Translation, storage, and degradation of messenger ribonucleic acids (mRNAs) are key steps in the posttranscriptional control of gene expression, but how mRNAs transit between these processes remains poorly understood. In this paper, we functionally characterized the DExD/H box adenosine triphosphatase (ATPase) Dhh1, a critical regulator of the cytoplasmic fate of mRNAs. Using mRNA tethering experiments in yeast, we showed that Dhh1 was sufficient to move an mRNA from an active state to translational repression. In actively dividing cells, translational repression was followed by mRNA decay; however, deleting components of the 5′–3′ decay pathway uncoupled these processes. Whereas Dhh1’s ATPase activity was not required to induce translational inhibition and mRNA decay when directly tethered to an mRNA, ATP hydrolysis regulated processing body dynamics and the release of Dhh1 from these RNA–protein granules. Our results place Dhh1 at the interface of translation and decay controlling whether an mRNA is translated, stored, or decayed.
Targeting glioma stem cells: A novel framework for brain tumors
Authors: Binello Emanuela , Germano Isabelle M.
Published: August 2011

The past decade has seen a dramatic increase in stem cell research that focuses on glioma stem cells (GSC) and their mechanisms of action, revealing multiple potential targets for primary malignant brain tumors. Herein, we present a novel framework for considering GSC targets based on direct and indirect strategies. Direct strategies target GSC molecular pathways to overcome their resistance to radiation and chemotherapy, block their function or induce their differentiation. Indirect strategies target the microenvironment of the GSC, namely the perivascular, hypoxic and immune niches. Progress made on GSC targets is reviewed in detail and specific pathways are identified in context of the proposed framework. The potential barriers for translation to the clinical setting are also discussed. Overall, targeting GSC provides an unprecedented opportunity for revolutionary approaches to treat high‐grade gliomas that continue to have a poor patient prognosis. (Cancer Sci 2011; 102: 1958–1966)
Tapered oral dexamethasone for the acute chest syndrome of sickle cell disease
Authors: Quinn Charles T. , Stuart Marie J. , Kesler Karen , Ataga Kenneth I. , Wang Winfred C. , Styles Lori , Smith‐Whitley Kim , Wun Ted , Raj Ashok , Hsu Lewis L. , Krishnan Suba , Kuypers Frans A. , Setty Yamaja , Rhee Seungshin , Key Nigel S. , Buchanan George R. ,   on behalf of the Investigators of the Comprehensive Sickle Cell Centers
Published: August 2011

Tapered oral dexamethasone for acute chest syndrome (ACS) in sickle cell anaemia was studied using a novel ACS assessment tool and investigational biomarkers. Twelve participants were randomized (mean age 17·3 years) before early study termination. Dexamethasone decreased duration of hospitalization for ACS by 20·8 h compared to placebo (P = 0·024). Rebound pain occurred in both groups (3 dexamethasone versus 1 placebo). Overall, dexamethasone decreased the leucocyte activation biomarker, sL‐selectin; however, participants with rebound pain had higher sL‐selectin within 24 h of treatment (dexamethasone or placebo). This ACS assessment tool was feasibly applied, and sL‐selectin is a promising biomarker of ACS therapy.
‘Providing more scaffolding’: parenting a child with developmental co‐ordination disorder, a hidden disability
Authors: Novak C. , Lingam R. , Coad J. , Emond A.
Published: August 2011

Background  Few studies exist reporting the experiences of parents of children with developmental co‐ordination disorder (DCD) a common disorder with a prevalence of 1.8–6%. DCD is characterized by poor motor co‐ordination, not caused by a general medical condition, but significantly affecting daily living. This study explores the experiences of parents living with a child with DCD in obtaining a diagnosis; the impact of the diagnosis on parenting and the effect on parents as individuals.

Methods  Semi‐structured interviews with a purposive sample of 15 parents of children with DCD data were recorded and then transcribed. Data were analysed using a coding framework and themes identified similar to Attride‐Stirling (2001, Qualitative Research, 1, 385–405).

Findings  DCD was an all‐encompassing condition that dominated all aspects of family life and was a ‘hidden disability’. Parents were frustrated by the poor knowledge and expertise of health and education professionals working with children with DCD and the lack of good quality accessible information and support services. Parents became by default the ‘expert’ on DCD for schools and other services; they were advocates for DCD and their own children. They provided additional support for longer to their child with DCD and had concerns for their future. Parenting a child with DCD was frustrating, exhausting, guilt‐ridden as well as rewarding. There was little available time to provide for the needs of other family members.

Conclusion  A better‐trained, knowledgeable workforce would redress the balance for families with DCD by providing better information, support and advocacy freeing parents to parent their families.