bluuebunny/crossref_metadata_2025 huggingface dataset:
Combinatorial Compounds and Drug Discovery
Authors: Bigelow James C.
Published: December 2011

In this chapter, the termdrugwill be narrowed from the broad definition provided by the U.S. Food and Drug Administration to one that is more appropriate to the disciplines of pharmacology, pharmacy, and medicine. In this context, we will define a “drug” as a specific chemical species able to cause specific changes in the functioning of living things. More specifically, we will further narrow the definition to relatively small (<1500 Da) organic and occasionally inorganic compounds. By doing so, we can examine the great differences between macromolecules and the smaller, discrete organic or inorganic molecules that make up the combinatorial chemistry arena.
Aerosol Drug Delivery to the Lungs
Authors: Martin Andrew R. , Finlay Warren H.
Published: December 2011

This chapter will begin with a very brief introduction to aerosol mechanics as related to the transport and deposition of inhaled drug particles throughout the respiratory tract. This familiarization then will serve as requisite background for the discussion of aerosol particle sizing instruments in use for research and development, regulatory, and quality assurance purposes, as well as for descriptions of the different types of aerosol delivery systems currently available and in development.
Anti‐Inflammatory/Analgesics: An In‐Depth Look atp38MAPKinases
Authors: Brown Kelly L.
Published: December 2011

Inflammation is a complex process controlled by numerous positive and negative regulators. The p38 MAP kinase pathway is integral to the production of mediators that drive inflammation and pain and the cellular responses to these mediators. If not properly controlled, it can cause dire effects in the inflammatory, immune, and nervous systems that manifest in the development of chronic pain and inflammatory disease. As this chapter will discuss, newer versions of these molecular inhibitors must be designed in a manner that is more mindful of the complexity of p38 and the inflammatory response to reach their potential as an effective anti‐inflammatory and analgesic therapy.
Cardiology—In‐Depth Look: Advances in Antiplatelet Therapy
Authors: Mauer Karin , Saucedo Jorge F.
Published: December 2011

Aspirin, ticlopidine, clopidogrel, and IIb/IIIa inhibitors have been widely used in acute coronary syndromes (ACS) and following bare metal and drug‐eluting stent placement. Clopidogrel is superior to aspirin in reducing ischemic vascular events in high‐risk patients and has improved gastrointestinal tolerance but is associated with rash, diarrhea, and adverse hematologic outcomes. Combination antiplatelet therapy with aspirin and a thienopyridine is the optimal currently available combination following percutaneous coronary intervention (PCI) and in patients with an ACS. As this chapter will discuss, current advances in the development of new antiplatelet agents will provide a wider selection of therapeutic options for the management of cardiovascular patients.
Pharmacology of Vasopressin and the Renin–Angiotensin–Aldosterone System
Authors: Brant Elizabeth J. , Lam Albert Q. , Seifter Julian L.
Published: December 2011

Pharmacological agents targeted toward renal pathophysiology have had a profound effect in medicine, serving to advance the understanding of both renal disease and normal physiology, and significantly improve disease outcomes in many circumstances. A review of the mechanisms of action of several of these agents will be reviewed here. In addition, new agents active in major hormonal pathways, including antidiuretic hormone (ADH) and the rennin–angiotensin system will be introduced.
In‐Depth Look: Anti‐TNF‐α Therapies
Authors: Chatterjee Satadal , Gaddameedhi Shobhan
Published: December 2011

Today, anti ‐tumor necrosis factor‐α (TNF‐α) drugs are being successfully used in the treatment of various inflammatory diseases such as rheumatoid arthritis (RA) and Crohn's disease. In later years, research showed that TNF‐α is involved in the progression of cancer in many other ways besides causing cancer‐associated cachexia. Anti‐TNF‐α therapy aiming to block TNF‐α, directly or indirectly, is now being investigated for treatment as well as for supportive care in cancer patients. Currently, it appears to be one of the promising approaches in resistant and nonresistant tumors as well as for cancer‐associated cachexia. This chapter will review some of the approaches being exploited to block TNF‐α and the anti‐TNF‐α drugs that have made it to clinical trials or have been approved by U.S. Food and Drug Administration (FDA) for anticancer therapy.
Thermo‐ and pH‐Responsive Polymersomes of Poly(α,β‐N‐substituted‐DL‐aspartamide)s
Authors: Hsu Shih‐Pin , Chu I‐Ming , Yang Jean‐Dean
Published: December 2011

Materials that can respond to multiple stimuli, such as temperature and pH changes, are of considerable interest for applications in drug delivery systems. Notably, α,β‐[poly(2‐hydroxyethyl)‐DL‐aspartamide] is a potentially useful material for such applications. This study investigated the temperature and pH responsiveness of polymers structurally similar to α,β‐[poly(2‐hydroxyethyl)‐DL‐aspartamide], namely, poly(α,β‐N‐substituted‐DL‐aspartamide)s, in aqueous media. These polymers were derived from polysuccinimide (PSI), which was first synthesized via acid‐catalyzed bulk polycondensation of L‐aspartic acid (L‐ASP) in the presence of 85% o‐phosphoric acid under N2. Two primary amino alcohols, 4‐aminobutanol (4AB) and 6‐aminohexanol (6AH), were then respectively utilized to modify PSI to form poly (α,β‐N‐substituted‐DL‐aspartamide)s via aminolysis. Different ratios of these two amino alcohols were used to modify the polymer to produce a series of copolymers with lower critical solution temperatures ranging from 53–28°C when dispersed in aqueous media. Moreover, the properties of the poly(α,β‐N‐ substituted‐DL‐aspartamide)s in aqueous solution were affected by pH changes. The morphology of the particles formed by these amphiphilic polymers was observed using scanning electronic microscopy and transmission electronic microscopy, and the particles were found to be polymersomes with shell and hollow core structures and diameters of 0.5–1 μm. Other properties of this series of self‐assembly copolymers were also characterized. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Biomimetic micropatterned multi‐channel nerve guides by templated electrospinning
Authors: Jeffries Eric M. , Wang Yadong
Published: December 2011

This report describes a new approach for fabricating microchannels within three‐dimensional electrospun constructs. These key features serve to mimic the fascicular architecture and fibrous extracellular matrix found in native nerve. Both electrospun fibers and multi‐channeled structure nerve guides have become areas of increasing interest for their beneficial roles in nerve repair. However, to the best of our knowledge, this is the first report of a guide that incorporates both. Multiple parallel channels provide a greater number of defined paths and increased surface area compared to cylindrical guides. Additionally, the fibrous nature of electrospun fibers permits better mass transport than solid‐walled constructs. The flexible fabrication scheme allows tailoring of nerve guide parameters such as channel diameters ranging from 33 to 176 µm and various wall thicknesses. Channel and fiber structures were assessed by optical and electron microscope images. Geometric calculations estimated a porosity of over 85% for these guides with 16% or less from the channels. In vitro culture with Schwann cells demonstrated cellular infiltration into channels with restricted migration between fibers. Finally, cell proliferation and survival throughout the guide indicates that this design warrants future in vivo examination. Biotechnol. Bioeng. 2012; 109:1571–1582. © 2011 Wiley Periodicals, Inc.
Simplifying and streamlining Escherichia coli‐based cell‐free protein synthesis
Authors: Yang William C. , Patel Kedar G. , Wong H. Edward , Swartz James R.
Published: December 2011

Escherichia coli cell‐free protein synthesis (CFPS) uses E. coli extracts to make active proteins in vitro. The basic CFPS reaction mixture is comprised of four main reagent components: (1) energy source and CFPS chemicals, (2) DNA encoding the protein of interest, (3) T7 RNA Polymerase (RNAP) for transcription, and (4) cell extract for translation. In this work, we have simplified and shortened the protocols for preparing the CFPS chemical mixture, cell extract, and T7 RNAP. First, we streamlined the workflow for preparing the CFPS chemical solutions by combining all the chemicals into a single reagent mixture, which we call Premix. We showed that productive cell extracts could be made from cells grown in simple shake flasks, and we also truncated the preparation protocol. Finally, we discovered that T7 RNAP purification was not necessary for CFPS. Crude lysate from cells over‐expressing T7 RNAP could be used without deleteriously affecting protein production. Using chloramphenicol acetyltransferase (CAT) as a model protein, we showed that these streamlined protocols still support high‐yielding CFPS. These simplified procedures save time and offer greater accessibility to our laboratory's CFPS technology. © 2012 American Institute of Chemical Engineers Biotechnol. Prog., 2012
Chromophores in Conjugated Polymers—All Straight?
Authors: Lupton John M.
Published: December 2011

What is the physical shape of the π‐electron system in a large macromolecule such as a conjugated polymer? Although intuitively one may argue that any departure from rigidity by bending or twisting should disrupt conjugation, leading to the formation of discrete chromophores, single‐molecule and ensemble time‐resolved studies support the notion that the π‐bond is remarkably persistent in space: even individual chromophores can be bent and twisted, so that caution is warranted when interpreting a wide range of polarisation‐based spectroscopies.
Evolution of phenols and pigments in extra virgin olive oil from irrigated super‐intensive orchard
Authors: Benito Marta , Lasa José Manuel , Gracia Pilar , Oria Rosa , Abenoza María , Sánchez‐Gimeno Ana Cristina
Published: December 2011

Phenolic compounds have a high importance in olive oil because of their effect on shelf life and sensory properties. This study reports on the HPLC profiles of the phenolic compounds of virgin olive oils obtained from Arbequina olives from the harvesting in a super‐intensive orchard under a linear irrigation system. In addition, phenolic content, carotenoid and chlorophyllic pigments, and oxidative stability were analyzed. Total phenol content and 3,4‐DHPEA‐EDA increased up to a maximum throughout the ripening process. The simple phenols tyrosol and hydroxytyrosol acetate increased throughout the ripening process, however, there was not found a clear trend in hydroxytyrosol content. Minor constituents such as vanillic acid and p‐coumaric acid increased up to a maximum and then decreased, since vanillin decreased progressively throughout the time of harvest. 3,4‐DHPEA‐EDA and lignans were present in considerable amounts in the studied samples, while oleuropein aglycone was present in a low amount. Total phenol content and oil stability followed the same trend throughout the study, so a very good correlation was established between them. Total secoiridoids and, specifically, 3,4‐DHPEA‐EDA seemed to be responsible for oil stability. The pigment content decreased during ripening, and not a positive correlation was found between pigments and oil stability.

Practical applications: The results can be used to determine the best time for harvesting in order to obtain olive oils with different phenols and pigment contents. This is important for sensory characteristics of the olive oils and also for olive oil stability.
Metal‐Free Intermolecular Cfur–Nsucc Bond Coupling of Highly Substituted 3‐Furancarbaldehydes and Their Use in meso‐Substituted BODIPY Synthesis
Authors: Singh Atul P. , Lee Kang Mun , Kim Kibong , Jun Taehong , Churchill David G.
Published: December 2011

Two novel highly substituted 3‐furancarbaldehydes have been synthesized by the reaction of 3‐furancarbaldehyde and NBS in chloroform and N,N‐dimethylformamide. Importantly, NBS serves as a succinimide donor under mild metal‐free conditions whereas NCS does not. Also, NBS does not undergo the same reaction with 3‐thiophenecarbaldehyde. We show how solvent plays a crucial role in C–Br and C–N bond formation, including through the use of DFT calculations, which demonstrated that a bromonium‐mediated transformation is energetically allowable. Other 3‐furan derivatives gave no evidence of analogous C–N bond‐forming reactions, underscoring the potential uniqueness of the 3‐furancarbaldehyde moiety. A variety of meso‐aryl‐ and ‐hydrogen‐substituted BODIPY species were then prepared from pyrrole and 2,4‐dimethylpyrrole and characterized by NMR spectroscopy and crystallography.
Active screen plasma surface modification of polycaprolactone to improve cell attachment
Authors: Fu Xin , Sammons Rachel L. , Bertóti Imre , Jenkins Mike J. , Dong Hanshan
Published: December 2011

To tailor polycaprolactone (PCL) surface properties for biomedical applications, film samples of PCL were surface modified by the active screen plasma nitriding (ASPN) technique. The chemical composition and structure were characterized by Fourier transform infrared spectroscopy and X‐ray photoelectron spectroscopy. The wettability of the surface modified polymers was investigated by contact angle and surface energy methods. Biocompatibility of the prepared PCL samples was evaluated in vitro using MC3T3‐E1 osteoblast‐like cells. The degradability was assessed by determining the self‐degradation rate (catalyzed by lipase). The results show that ASPN surface modification can effectively improve osteoblast cell adhesion and spreading on the surface of PCL. The main change in chemical composition is the exchange of some carboxyl groups on the surface for hydroxyl groups. The active‐screen plasma nitriding technique has been found to be an effective and practical method to effectively improve osteoblast cell adhesion and spreading on the PCL surface. Such changes have been attributed to the increase in wettablity and generation of new hydroxyl groups by plasma treatment. After active‐screen plasma treatment, the PCL film is still degradable, but the enzymatic degradation rate is slower compared with untreated PCL film. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 100B: 314–320, 2012.
Hadamard‐encoding combined with two‐dimensional‐selective radiofrequency excitations for flexible and efficient acquisitions of multiple voxels in MR spectroscopy
Authors: Busch Martin G. , Finsterbusch Jürgen
Published: December 2011

Purpose:

To improve the efficiency and flexibility of acquisitions of multiple voxels in MR spectroscopy by combining two‐dimensional‐selective radiofrequency (2DRF) excitations and Hadamard encoding.

Materials and Methods:

With 2DRF excitations (PROPELLER trajectory, 16 half‐Fourier segments, each with five lines) two voxels are defined. By combining the individual 2DRF pulses with Hadamard‐like encoded phases, the voxels are acquired simultaneously but the individual contributions can be isolated from the obtained spectra. This is demonstrated on a 3 Tesla whole‐body MR system in phantoms and in the human brain in vivo.

Results:

Compared with sequential single‐voxel acquisitions the signal efficiency increases with the number of voxels covered. Furthermore, in comparison to conventional single‐voxel MRS based on cross‐sectional RF excitations, 2DRF excitations offer a higher flexibility because they allow for arbitrary voxel sizes, orientations, in‐plane positions, and shapes.

Conclusion:

The presented approach improves the flexibility and efficiency of acquisitions of multiple voxels, i.e., can shorten acquisition times accordingly, and can help to reduce partial volume effects. J. Magn. Reson. Imaging 2012;35:976–983. © 2011 Wiley Periodicals, Inc.
MRI reconstruction from 2D truncated k‐space
Authors: Luo Jianhua , Zhu Yuemin , Li Wanqing , Croisille Pierre , Magnin Isabelle E.
Published: December 2011

Purpose:

To shorten acquisition time by means of both partial scanning and partial echo acquisition and to reconstruct images from such 2D partial k‐space acquisitions.

Materials and Methods:

We propose an approach to reconstructing magnetic resonance images from 2D truncated k‐space in which the k‐space is truncated in both phase‐ and frequency‐encoding directions. Unlike conventional reconstruction techniques, the proposed approach is based on a newly developed 2D singularity function analysis (SFA) model and a sparse representation of an image whose parameters can be estimated from the 2D partial k‐space data. Such a sparse representation leads to an accurate recovery of the missing k‐space data and, hence, an accurate reconstruction of the image.

Results:

The proposed approach can reconstruct an image from as little as 20%–30% of the k‐space data and the quality of the reconstructed image is comparable to the reference image that is reconstructed from the complete k‐space data.

Conclusion:

Despite the high asymmetry of a 2D truncated k‐space, the proposed approach allows for accurate reconstruction without the need of phase correction and, thus, overcomes the assumption of slow phase variations that is usually required by the existing reconstruction methods. It provides a new way of fast imaging for applications that require a significant reduction of the acquisition time. J. Magn. Reson. Imaging 2012;35:1196‐1206. © 2011 Wiley Periodicals, Inc.
Potential dietary sources of ellagic acid and other antioxidants among fruits consumed in Brazil: Jabuticaba (Myrciaria jaboticaba (Vell.) Berg)
Authors: Abe Lucile T , Lajolo Franco M , Genovese Maria Inés
Published: December 2011

BACKGROUND: The objectives of this study were (1) to evaluate the content of ellagic acid in fruits consumed by the Brazilian population, including native ones; (2) to further characterize rich sources in relation to ascorbic acid, phenolics contents and in vitro antioxidant capacity; and (3) to study the distribution and effect of ripening stage on ellagitannins content of jabuticaba (Myrciaria jaboticaba). The content of free ellagic acid and ellagic acid derivatives such as ellagitannins was analyzed using high‐performance liquid chromatography (HPLC).

RESULTS: Ellagic acid was detected in 10 out of a total of 35 fruits analyzed. The content of free ellagic acid in fruits varied from 0.0028 to 0.085 g kg−1 (FW) and total ellagic acid varied from 0.215 to 3.11 g kg−1 (FW). All the seven fruits belonging to the Myrtaceae family evaluated in this study presented high contents of ellagitannins in their composition, with jabuticaba, grumixama and cambuci (all native from Brazil) showing the highest total ellagic acid contents. Jabuticaba, the most consumed in Brazil among those and already adapted to commercial plantations, contained concentrated phenolics compounds, including ellagitannins, in the peel. Anthocyanins (cyanidin derivatives) increased significantly through ripening of jabuticaba and were not present in the pulp or seeds. Samples collected from three different locations during summer, winter and spring had total ellagic contents varying from 1.88 to 3.31 g kg−1 (FW). The decrease in ellagic acid content with ripening was more accentuated for pulp (eight times) compared to seeds (2.3 times) and peel (2.0 times).

CONCLUSION: These results showed the potential of jabuticaba as dietary source of ellagic acid and reinforced consumption of the whole fruit by the population. Copyright © 2011 Society of Chemical Industry
Tolerance, fermentation, and cytokine expression in healthy aged male C57BL/6J mice fed resistant starch
Authors: Zhou June , Keenan Michael J. , Keller Jeffrey , Fernandez‐Kim Sun O. , Pistell Paul J. , Tulley Richard T. , Raggio Anne M. , Shen Li , Zhang Hanjie , Martin Roy J. , Blackman Marc R.
Published: December 2011

Health benefits of resistant starch (RS), a dietary fermentable fiber, have been well documented in young, but not in old populations. As the essential step of more comprehensive evaluations of RS on healthy aging, we examined the effects of dietary RS on tolerance, colonic fermentation, and cytokine expression in aged mice. Healthy older (18‐20 months) C57BL/6J male mice were fed control, 18% RS, or 36% RS diets for 10 weeks. Body weight gain, body composition, and fat pad weights did not differ among the three groups after 10 weeks, indicating good tolerance of the RS diet. Fermentation indicators (cecum weights, and cecal proglucagon and PYY mRNA expression) were enhanced in an RS dose‐dependent manner (p<0.01). Serum concentrations of soluble cytokine receptors (sTNF‐Rb, sIL‐4R, sIL‐2Rα, sVEGFR1, and sRAGE) and TNFα expression (gene and protein) in visceral fat did not differ significantly among groups. Adiponectin protein concentrations, but not gene expression, were greater in epididymal fat of the 36% RS versus control groups (p<0.05). As a conclusion in aged mice, dietary RS is well tolerated, fermented in the colon, and stimulates colonic expression of proglucagon and PYY mRNA, and adiponectin protein in visceral fat.
Influence of caffeine on the survival of leaf‐cutting ants Atta sexdens rubropilosa and in vitro growth of their mutualistic fungus
Authors: Miyashira Carlos H , Tanigushi Daniel G , Gugliotta Adriana M , Santos Déborah YAC
Published: December 2011

BACKGROUND: Leaf‐cutting ants collect plant fresh material for the cultivation of their mutualistic fungus. Atta sexdens rubropilosa Forel (Hymenoptera: Formicidae) cause great economic losses through their foraging activity, mainly in agriculture. The main control method is the application of granulated toxic baits incorporated with an active ingredient (AI). The present goal is to evaluate the effect of caffeine on in vitro growth of the mutualistic fungus and on the survival of the leaf‐cutting ants, aiming to verify the potential toxicity of this secondary metabolite over these organisms.

RESULTS: Three distinct patterns of fungal growth correlated with caffeine concentration were observed: (1) no effect (0.01% caffeine); (2) intermediate growth reduction (0.05% caffeine); (3) drastic growth reduction (0.10 and 0.50% caffeine). The highest caffeine concentration causes fungus death in the first week. As for insect survival, caffeine does not seem to exert any effect. The treatments with diet containing caffeine showed similar values of M50, irrespective of caffeine concentration.

CONCLUSION: As caffeine was shown to reduce growth of the mutualistic fungus of Atta sexdens rubropilosa, but with no conclusive effect on insect survival, a hypothetical explanation for the selection of different Coffea species by this leaf‐cutting ant species might be associated with caffeine toxicity to the fungus. Copyright © 2011 Society of Chemical Industry
ECOLOGICAL FUNCTIONS OF FISH BYPASS CHANNELS IN STREAMS: MIGRATION CORRIDOR AND HABITAT FOR RHEOPHILIC SPECIES
Authors: Pander J. , Mueller M. , Geist J.
Published: December 2011

The introduction of weirs into stream ecosystems resulted in modifications of serial continuity and in the decline of riverine fish species. Successful river restoration requires information on the ecological functionality of fish bypass channels that are considered an ecological improvement according to the European Water Framework Directive. In this study, we compared the functionality of three nature‐oriented fish passes as compensatory habitats and migration corridors for fishes. Fish passes differed significantly from upstream and downstream reaches of the weirs, revealing higher current speed, lower water depth, smaller channel width and greater habitat variability. Following these structural differences, they provided key habitats for juvenile, small and rheophilic fishes that are typically underrepresented in highly modified water bodies. All fish passes were used as migration corridors, with increased fish movements during high discharge and at spawning periods. Because river stretches with high variability of current speed and water depth are scarce in highly modified water bodies, fish passes can play an important role as compensatory habitats and should thus be considered more intensively in habitat assessments and river restoration. Ideally, fish bypasses should mirror the natural discharge dynamics and consider all occurring fish species and sizes. Copyright © 2011 John Wiley & Sons, Ltd.
Underground cabling and marking of power lines: conservation measures rapidly reduced mortality of West-Pannonian Great Bustards Otis tarda
Authors: RAAB RAINER , SCHÜTZ CLAUDIA , SPAKOVSZKY PÉTER , JULIUS EIKE , SCHULZE CHRISTIAN H.
Published: December 2011

Collisions with power lines represent an important mortality factor for Great Bustards Otis tarda throughout the distribution range of the species. This study evaluates the success of two conservation measures implemented in the West-Pannonian distribution range to reduce the number of power line collision casualties: (1) extensive underground cabling of 43.1 km power lines, and (2) marking of 89.7 km power lines starting in 2005 and 2006, respectively. The mortality rate of Great Bustards in our study area (covering 686.5 km2) decreased significantly between 2002 and 2011, predominantly caused by reduced mortality due to power line collisions. Univariate tests indicate that underground cabling and power line marking significantly decreased power line collision casualties. Generalised linear models (GLMs) highlighted the prominent effect of underground cabling. Our results indicate that five years after underground cabling and marking of power lines within core areas of the West-Pannonian distribution range of the Great Bustard, the population already benefited through a significantly decreased mortality rate. Both conservation measures most likely contributed strongly to the rapid recovery of the West-Pannonian Great Bustard population observed within the last decade.
Synergism between altered cortical polarity and the PI3K/TOR pathway in the suppression of tumour growth
Authors: Rossi Fabrizio , Gonzalez Cayetano
Published: December 2011

Loss of function of pins (partner of inscuteable) partially disrupts neuroblast (NB) polarity and asymmetric division, results in fewer and smaller NBs and inhibits Drosophila larval brain growth. Food deprivation also inhibits growth. However, we find that the combination of loss of function of pins and dietary restriction results in loss of NB asymmetry, overproliferation of Miranda‐expressing cells, brain overgrowth and increased frequency of tumour growth on allograft transplantation. The same effects are observed in well‐fed pins larvae that are mutant for pi3k (phosphatidylinositol 3‐kinase) or exposed to the TOR inhibitor rapamycin. Thus, pathways that are sensitive to food deprivation and dependent on PI3K and TOR are essential to suppress tumour growth in Drosophila larval brains with compromised pins function. These results highlight an unexpected crosstalk whereby the normally growth‐promoting, nutrient‐sensing PI3K/TOR pathway suppresses tumour formation in neural stem cells with compromised cell polarity.
Effect of pulse direct current signals on electrotactic movement of nematodes Caenorhabditis elegans and Caenorhabditis briggsae
Authors: Rezai Pouya , Salam Sangeena , Selvaganapathy Ponnambalam Ravi , Gupta Bhagwati P.
Published: December 2011

The nematodes (worms) Caenorhabditis elegans and Caenorhabditis briggsae are well-known model organisms to study the basis of animal development and behaviour. Their sinusoidal pattern of movement is highly stereotypic and serves as a tool to monitor defects in neurons and muscles that control movement. Until recently, a simple yet robust method to initiate movement response on-demand did not exist. We have found that the electrical stimulation in a microfluidic channel, using constant DC electric field, induces movement (termed electrotaxis) that is instantaneous, precise, sensitive, and fully penetrant. We have further characterized this behaviour and, in this paper, demonstrate that electrotaxis can also be induced using a pulse DC electric signal. Worms responded to pulse DC signals with as low as 30% duty cycle by moving towards the negative electrode at the same speed as constant DC fields (average speed of C. elegans = 296 ± 43 μm/s and C. briggsae = 356 ± 20 μm/s, for both constant and pulse DC electric fields with various frequencies). C. briggsae was found to be more sensitive to electric signals compared to C. elegans. We also investigated the turning response of worms to a change in the direction of constant and pulse DC signals. The response for constant DC signal was found to be instantaneous and similar for most worms. However, in the case of pulse DC signal, alterations in duty cycle affected the turning response time as well as the number of responding worms. Our findings show that pulse DC method allows quantitative measurement of response behaviour of worms and suggest that it could be used as a tool to study the neuronal basis of such a behaviour that is not observed under constant DC conditions.
Torsional bridge setup for the characterization of integrated circuits and microsensors under mechanical shear stress
Authors: Herrmann M. , Gieschke P. , Ruther P. , Paul O.
Published: December 2011

We present a torsional bridge setup for the electro-mechanical characterization of devices integrated in the surface of silicon beams under mechanical in-plane shear stress. It is based on the application of a torsional moment to the longitudinal axis of the silicon beams, which results in a homogeneous in-plane shear stress in the beam surface. The safely applicable shear stresses span the range of ±50 MPa. Thanks to a specially designed clamping mechanism, the unintended normal stress typically stays below 2.5% of the applied shear stress. An analytical model is presented to compute the induced shear stress. Numerical computations verify the analytical results and show that the homogeneity of the shear stress is very high on the beam surface in the region of interest. Measurements with piezoresistive microsensors fabricated using a complementary metal–oxide–semiconductor process show an excellent agreement with both the computational results and comparative measurements performed on a four-point bending bridge. The electrical connection to the silicon beam is performed with standard bond wires. This ensures that minimal forces are applied to the beam by the electrical interconnection to the external instrumentation and that devices with arbitrary bond pad layout can be inserted into the setup.
An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copper
II
Authors: Donnelly Paul S. , Liddell Jeffrey R. , Lim SinChun , Paterson Brett M. , Cater Michael A. , Savva Maria S. , Mot Alexandra I. , James Janine L. , Trounce Ian A. , White Anthony R. , Crouch Peter J.
Published: December 2011

Radiolabeled diacetylbis(4-methylthiosemicarbazonato)copper
II
[Cu
II
(atsm)] is an effective positron-emission tomography imaging agent for myocardial ischemia, hypoxic tumors, and brain disorders with regionalized oxidative stress, such as mitochondrial myopathy, encephalopathy, and lactic acidosis with stroke-like episodes (MELAS) and Parkinson’s disease. An excessively elevated reductive state is common to these conditions and has been proposed as an important mechanism affecting cellular retention of Cu from Cu
II
(atsm). However, data from whole-cell models to demonstrate this mechanism have not yet been provided. The present study used a unique cell culture model, mitochondrial xenocybrids, to provide whole-cell mechanistic data on cellular retention of Cu from Cu
II
(atsm). Genetic incompatibility between nuclear and mitochondrial encoded subunits of the mitochondrial electron transport chain (ETC) in xenocybrid cells compromises normal function of the ETC. As a consequence of this impairment to the ETC we show xenocybrid cells upregulate glycolytic ATP production and accumulate NADH. Compared to control cells the xenocybrid cells retained more Cu after being treated with Cu
II
(atsm). By transfecting the cells with a metal-responsive element reporter construct the increase in Cu retention was shown to involve a Cu
II
(atsm)-induced increase in intracellular bioavailable Cu specifically within the xenocybrid cells. Parallel experiments using cells grown under hypoxic conditions confirmed that a compromised ETC and elevated NADH levels contribute to increased cellular retention of Cu from Cu
II
(atsm). Using these cell culture models our data demonstrate that compromised ETC function, due to the absence of O
2
as the terminal electron acceptor or dysfunction of individual components of the ETC, is an important determinant in driving the intracellular dissociation of Cu
II
(atsm) that increases cellular retention of the Cu.
Low-driving-voltage and colour-stable white organic light-emitting diodes with a cross-patterned multi-emissive layer
Authors: Hyun Woo Jin , Park Jae Kyun , Park O Ok , Chin Byung Doo
Published: December 2011

We have applied a simple cross-patterning technique for the fabrication of phosphorescent white organic light-emitting diodes (WOLEDs) with red, green and blue (RGB) emitters; the resulting device has relatively low driving voltage and high colour stability. The selectively cross-patterned multicolour emitting layer (EML) was easily prepared using a metal mask without an alignment process. Not only was the characteristic of low driving voltage obtained but also of improved colour stability, which can be ascribed to the simplified stack of the EML and the corresponding suppression of the biased shift in the recombination zone. The spatial distribution and variation of the stacked EML structure could explain the origin of the robust white emission. Compared with the conventional WOLED with a RGB simple stack, the cross-patterned multi-EML device showed a slight change in colour coordinates in the luminance range 100–8000 cd m−2, with a decrease in the driving voltage of 0.5–2.0 V, while the luminous efficiency was maintained.
Molecular dynamics study of grain boundary diffusion of hydrogen in tungsten
Authors: von Toussaint U , Gori S , Manhard A , Höschen T , Höschen C
Published: December 2011

Understanding the influence of the microstructure of tungsten on hydrogen transport is crucial for the use of tungsten as first-wall material in fusion reactors. Here, we report the results of molecular dynamics and transition state studies on the influence of grain boundaries in tungsten on the transport of hydrogen. An exhaustive mapping of possible minimum activation energy migration trajectories for hydrogen as the trace impurity reveals a strongly modified activation energy distribution in the neighborhood of grain boundaries together with an altered connectivity matrix. The results indicate that grain boundaries in polycrystalline tungsten may provide an important transport channel, especially for neutron-damaged tungsten.
Passive protection of the ITER diagnostic mirrors
Authors: Kotov V , Reiter D , Litnovsky A , Krimmer A , Kirschner A , Krasikov Yu
Published: December 2011

A conservative engineering model of the impurity deposition on the diagnostic mirrors is proposed. The model is applied to analyze numerically the effect of protecting structures (ducts) with and without baffles in the conditions of the ITER main chamber. It was found that the gross deposition rate in the ducts with baffles, if they are long enough, can be made by an order of magnitude smaller than that in the ducts of an equivalent length without baffles. This model prediction can be tested experimentally. The calculated efficiency of the impurity flux attenuation depends strongly on the model assumption: the variation between the ‘best’ and ‘worst’ cases reaches two orders of magnitude. A case study with the real 3D geometry of one specific diagnostic, core-CXRS, is conducted. For this particular geometry, the effect of baffles is nearly marginal; that is, this is not a universal solution.
Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract
Authors: Fijneman Remond J. A. , Anderson Rebecca A. , Richards Ethan , Liu Jieming , Tijssen Marianne , Meijer Gerrit A. , Anderson Janae , Rod Annette , O’Sullivan Michael G. , Scott Patricia M. , Cormier Robert T.
Published: December 2011

The Runx1 transcription factor plays an important role in tissue homeostasis through its effects on stem/progenitor cell populations and differentiation. The effect of Runx1 on epithelial differentiation of the secretory cell lineage of the colon was recently demonstrated. This study aimed to examine the role of Runx1 in tumor development in epithelial cells of the gastrointestinal tract. Conditional knockout mice that lacked Runx1 expression in epithelial cells of the GI tract were generated. These mice were crossed onto the ApcMin background, killed and their intestinal tumor phenotypes were compared with ApcMinRunx1 wild‐type control mice. Apc‐wild‐type Runx1‐mutant mice were also examined for tumor development. Colons from Runx1 knockout and wild‐type mice were used for genome‐wide mRNA expression analyses followed by gene‐specific quantitative RT‐PCR of whole colon and colon epithelium to identify Runx1 target genes. Runx1 deficiency in intestinal epithelial cells significantly enhanced tumorigenesis in ApcMin mice. Notably, epithelial Runx1 deficiency in Apc‐wild‐type mice was sufficient to cause tumor development. Absence of Runx1 was associated with global changes in the expression of genes involved in inflammation and intestinal metabolism, and with gene sets indicative of a metastatic phenotype and poor prognosis. Gene‐specific analysis of Runx1‐deficient colon epithelium revealed increased expression of genes linked to an expansion of the stem/progenitor cell population. These results identify Runx1 as a novel tumor suppressor gene for gastrointestinal tumors and support a role for Runx1 in maintaining the balance between the intestinal stem/progenitor cell population and epithelial differentiation of the GI tract. (Cancer Sci 2012; 103: 593–599)
Cardiovascular risk tables: opinion and degree of use of Primary Care doctors from Madrid, Spain
Authors: Elustondo Sofía Garrido , Aguado Pedro Nogales , de La Rasilla Cooper Cristina García , Manzanet Juanma Pinar , Sendín Domingo Sánchez
Published: December 2011

Aims and objectives  To determine the opinion of primary care doctors regarding the cardiovascular risk tables, their degree of use in clinical practice and the specific difficulties encountered when using them.

Method  Transversal descriptive study.

Location  Primary Care, Madrid, Spain.

Participants  Primary care doctors from four of Madrid's sanitary areas.

Principal measurements  Anonymous self‐administered questionnaire that studies age, gender, professional data, variables related with the opinion on cardiovascular risk tables, with their application in daily clinical practice, and main barriers for their use. A total of 34 closed questions and one open question were performed.

Results  Four hundred and sixty‐two questionnaires were received (46% replied). Ninety‐three per cent agrees that prevention based on a global evaluation of cardiovascular risk is more convenient than the one based on an independent assessment of each factor. When a new diagnosis of hypertension or elevated cholesterol is performed, 45 and 52% respectively estimate the cardiovascular risk systematically. Twenty per cent uses this information to start a treatment for hypertension and 32% for raised cholesterol. Seventy‐three per cent is aware of the tool available in the computer program to estimate the cardiovascular risk and 35% uses it. Eighty‐seven per cent gives their patients information about cardiovascular risk. Main identified barriers: lack of time, lack of consensus and absence of computer support.

Conclusions  Primary care doctors are aware of the need to estimate a global cardiovascular risk, recognize the usefulness of the tables but find problems in their practical application. In order to make their application feasible, tables should be simplified and unified, and their format should be improved.
Exposing the third chromosome of Burkholderia cepacia complex strains as a virulence plasmid
Authors: Agnoli K. , Schwager S. , Uehlinger S. , Vergunst A. , Viteri D. F. , Nguyen D. T. , Sokol P. A. , Carlier A. , Eberl L.
Published: December 2011

The Burkholderia cepacia complex (Bcc) consists of 17 closely related species of opportunistic bacterial pathogens, which are particularly problematic for cystic fibrosis patients and immunocompromised individuals. Bcc genomes consist of multiple replicons, and each strain sequenced to date has three chromosomes. In addition to genes thought to be essential for survival, each chromosome carries at least one rRNA operon. We isolated three mutants during a transposon mutagenesis screen that were non‐pathogenic in a Caenorhabditis elegans infection model. It was demonstrated that these mutants had lost chromosome 3 (c3), and that the observed attenuation of virulence was a consequence of this. We constructed a c3 mini‐replicon and used it to cure c3 from strains of several Bcc species by plasmid incompatibility, resulting in nine c3‐null strains covering seven Bcc species. Phenotypic characterization of c3‐null mutants revealed that they were attenuated in virulence in multiple infection hosts (rat, zebrafish, C. elegans, Galleria mellonella and Drosophila melanogaster), that they exhibited greatly diminished antifungal activity, and that c3 was required for d‐xylose, fatty acid and pyrimidine utilization, as well as for exopolysaccharide production and proteolytic activity in some strains. In conclusion, we show that c3 is not an essential chromosomal element, rather a large plasmid that encodes virulence, secondary metabolism and other accessory functions in Bcc bacteria.
Methodology matters: what type of research is suitable for evaluating community treatment supporters for HIV and tuberculosis treatment?
Authors: Maher Dermot , Harries Anthony D. , Nachega Jean B. , Jaffar Shabbar
Published: December 2011

The choice of research method relevant to the evaluation of delivery of a health intervention is not always straightforward. We use the evaluation of HIV and tuberculosis community treatment supporters in promoting adherence to treatment in Africa as a case study to illustrate the pros and cons of operational research and randomised controlled trials. The choice of this intervention for the case study reflects the importance of maximising the benefits of unprecedented efforts to scale‐up treatments of these two epidemics. International policy supporting the role of community treatment supporters in tuberculosis is largely based on the findings of operational research studies. This reflects the advantages that operational research is less costly than randomised controlled trials, provides more rapid answers to policy questions, enables standard evaluation of the intervention in ‘real life’ conditions in several diverse settings and has in‐built potential to influence policy and practice, because the research is conducted within health programmes. Recent evidence on the role of community treatment supporters in HIV is largely based on randomised trials. This reflects the advantages that randomised trials compared to operational research are more rigorous and generate a more convincing result. Operational research and randomised trials may be viewed as providing complementary findings to inform new policies and practice aimed at improving programme performance and patient outcomes. However, in practice, insufficient funds are likely to be made available for randomised trials to answer all the current research questions on delivery of programme interventions. In deciding on the type of research to evaluate a particular health intervention, dialogue is necessary with policy‐makers to weigh up explicitly the trade‐offs between research rigour and other factors such as cost, speed of implementation of research and speed of policy uptake and of change in programme practice.
Stress intensity factors of cracks emanating from a surface square hole in infinite body in tension
Authors: YAN XIANGQIAO , LIU BAOLIANG , YU JIJUN
Published: December 2011

This paper deals with such a kind of surface crack problem with a same depth (called a liked‐plane crack problem for short). Based on the previous investigations on an internal rectangular crack and a surface rectangular crack in an infinite solid in tension and the hybrid displacement discontinuity method, a numerical approach for the liked‐plane crack problem is presented. Numerical examples are given to illustrate the numerical approach is simple, yet accurate for calculating the stress intensity factors (SIFs) of the liked‐plane crack problem. Specifically, SIFs of a pair of cracks emanating from a surface square hole in an infinite body in tension are investigated in detail.
Addressing different biases in analysing drug use on cancer risk in diabetes in non‐clinical trial settings—what, why and how?
Authors: Yang X. L. , Ma R. C. W. , So W.‐Y. , Kong A. P. S. , Xu G. , Chan J. C. N.
Published: December 2011

Motivated by recent reports on associations between diabetes and cancer, many researchers have used administrative databases to examine risk association of cancer with drug use in patients with diabetes. Many of these studies suffered from major biases in study design and data analysis, which can lead to erroneous conclusions if these biases are not adjusted. This article discusses the sources and impacts of these biases and methods for correction of these biases. To avoid erroneous results, this article suggests performing sensitivity and specificity analysis as well as using a drug with a known effect on an outcome to ascertain the validity of the proposed methods. Using the Hong Kong Diabetes Registry, we illustrated the impacts of biases of drug use indication and prevalent user by examining the effects of statins on cardiovascular disease. We further showed that ‘immortal time bias' may have a neutral impact on the estimated drug effect if the hazard is assumed to be constant over time. On the contrary, adjustment for ‘immortal time bias' using time‐dependent models may lead to misleading results biased towards against the treatment. However, artificial inclusion of immortal time in non‐drug users to correct for immortal time bias may bias the result in favour of the therapy. In conclusion, drug use indication bias and prevalent user bias but not immortal time bias are major biases in the design and analysis of drug use effects among patients with diabetes in non‐clinical trial settings.