bluuebunny/crossref_metadata_2025 huggingface dataset:
A new anthracnose disease of pyrethrum caused byColletotrichum tanacetisp. nov
Authors: Barimani M. , Pethybridge S. J. , Vaghefi N. , Hay F. S. , Taylor P. W. J.
Published: March 2013

A new pathogen of pyrethrum (Tanacetum cinerariifolium) causing anthracnose was described asColletotrichum tanacetibased on morphological characteristics and a four‐gene phylogeny consisting ofrDNA‐ITS, β‐tubulin (TUB2), glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and actin (ACT) gene sequences. The fungus produced perithecia in culture, requiring an opposite mating type isolate in a heterothallic manner. The initial infection strategy on pyrethrum leaves involved the formation of appressoria followed by production of multilobed infection vesicles in the epidermal cells. Infection and colonization then proceeded through thinner secondary hyphae, which resulted in the initial production of water‐soaked lesions followed by black necrotic lesions. The infection process was suggestive of a hemibiotrophic infection strategy. Moreover, phylogenetic analysis clearly showed thatC. destructivum,C. higginsianumandC. panacicolawere separate species that also had similar intracellular hemibiotrophic infection strategies asC. tanaceti, which all clustered in theC. destructivumcomplex.Colletotrichumspp. were detected at 1% incidence in seed of 1 of 19 seed lines, indicating the potential for seed as a source of inoculum into crops.Colletotrichum tanacetiwas detected in leaf lesions from 11 of 24 pyrethrum fields surveyed between April and July 2012, at a frequency of 1·3–25·0% of lesions. Anthracnose probably contributes to the complex of foliar diseases reducing green leaf area in pyrethrum fields in Australia.
No evidence for peripheral mechanism attenuating auditory ERPs to self‐induced tones
Authors: Horváth János , Burgyán Annamária
Published: March 2013

The N1 and P2 event‐related potentials (ERPs) are attenuated when the eliciting sounds coincide with our own actions. Although this ERP attenuation could be caused by central processes, it may also reflect a peripheral mechanism: the coactivation of the stapedius muscle with the task‐relevant effector, which reduces signal transmission efficiency in the middle ear, reducing the effective intensity of concurrently presented tones, which, in turn, elicit lower amplitude auditory ERPs. Because stapedius muscle contraction attenuates frequencies below 2 kHz, no attenuation should occur at frequencies above 2 kHz. A self‐induced tone paradigm was administered with 0.5, 2.0, and 8.0 kHz pure tones. Self‐induced tones elicited attenuated N1 and P2 ERPs, but the magnitude of attenuation was not affected by tone frequency. This result does not support the hypothesis that ERP attenuation to self‐induced tones are caused by stapedius muscle contractions.
Estimation of left ventricular stroke volume by impedance cardiography: its relation to the aortic reservoir
Authors: Wang Jiun‐Jr , de Vries Gwyneth , Tyberg John V.
Published: March 2013

New Findings

What is the central question of this study?

Thoracic impedance has been used to calculate left ventricular stroke volume for decades, while its theoretical basis remains controversial and the parameters generated have not been related satisfactorily to the haemodynamic events.

What is the main finding and what is its importance?

We provide mechanistic explanations for the following: (i) why the upstroke of the change in thoracic impedance (ΔZ) waveform is constantly delayed with respect to that of the central aortic pressure; (ii) why the contour of the ΔZ waveform is ‘blunted’ compared with that of the central aortic pressure; (iii) what mechanism is related to the ‘second bump’ of the ΔZ waveform in early diastole (the ‘O‐wave’); and (iv) the mechanism that is likely to be associated with the decreasing ΔZ waveform in later diastole.

Impedance cardiography is a non‐invasive technique used to estimate left ventricular (LV) stroke volume (SV) using the change in thoracic impedance (ΔZ). It remains controversial, partly because impedance cardiographic parameters have not been successfully related to haemodynamic events. We hypothesized that the change in ΔZ may be proportional to the variation in thoracic (primarily aortic) blood volumes. Nine anaesthetized and ventilated dogs were divided into the following two groups: the ‘aortic volume group’ (n= 5), in which aortic and IVC (inferior vena caval) dimensions were measured ultrasonically; and the ‘reservoir volume group’, in which aortic and IVC reservoir volumes were calculated using the reservoir–wave model. Measurements were made in control conditions, in the presence of nitroprusside and methoxamine and after volume loading. In both the aortic volume group and the reservoir volume group, the maximal rate of increase in ΔZ[(dZ/dt)max] strongly correlated with the maximal rate of change in aortic/reservoir blood volume (R2= 0.85 and 0.95, respectively), which in turn was proportional to the LV SV. The LV and IVC contributions to ΔZ were small in control conditions (∼5 and 1%, respectively), but the LV contribution increased slightly (to 7%) with administration of methoxamine and after volume loading (to 10%). It is concluded that the change in thoracic impedance (ΔZ) during the cardiac cycle is proportional to the change in aortic reservoir (i.e. Windkessel) volume, which provides a mechanistic explanation for previously demonstrated good correlations with standard measures of cardiac output.
Cyclo‐oxygenase‐1 or ‐2‐mediated metabolism of arachidonic acid in endothelium‐dependent contraction of mouse arteries
Authors: Zhou Yingbi , Luo Wenhong , Zhang Yingzhan , Li Hui , Huang Dongyang , Liu Bin
Published: March 2013

New findings

What is the central question of this study?

To determine the specific cyclo‐oxygenase (COX) isoform(s) involved in endothelium‐dependent contraction and whether prostaglandin I2, a mediator of endothelium‐derived vasoconstrictor activity, can be generated in medial smooth muscle from prostaglandin H2 that might diffuse from the endothelium.

What is the main finding and its importance?

Our results demonstrate a predominant role for COX‐1 in arachidonic acid metabolism and suggest that in the given mouse arteries, metabolites from either COX isoform cause contraction. Moreover, our results imply that some of the prostaglandin I2 involved in the vasoconstrictor activity of endothelial COX‐mediated metabolism could possibly be generated from prostaglandin H2 in the medial smooth muscle. These findings add to our current understanding of mechanisms for endothelium‐dependent contraction.

This study aimed to determine whether the cyclo‐oxygenase (COX) substrate arachidonic acid (AA) evokes endothelium‐dependent contraction and, if so, the specific COX isoform(s) involved and whether prostacyclin (prostaglandin I2; PGI2), a mediator of endothelium‐derived vasoconstrictor activity, can be generated in medial smooth muscle from the intermediate COX product prostaglandin H2 (PGH2) that might diffuse from the endothelium. Aortae and/or carotid arteries were isolated from C57BL/6 mice or those lacking one of the two COX isoforms (COX‐1−/− or COX‐2−/−) for functional and/or biochemical analyses. Results showed that in vessels from C57BL/6 mice, exogenous AA evoked not only endothelium‐dependent production of the PGI2 metabolite 6‐keto‐PGF1α, but also contractions reduced by thromboxane–prostanoid receptor antagonism or endothelial denudation. The minimal concentration for AA to evoke contraction was 0.3 μm, a level thought to activate only COX‐2. However, neither the contraction nor 6‐keto‐PGF1α production was altered in vessels from COX‐2−/− mice, while both were reduced in COX‐1−/− counterparts. In vessels from COX‐1−/− mice, AA also caused minor contractions that were sensitive to non‐selective COX inhibition. Real‐time PCR showed that like COX‐1, COX‐2 mainly existed in the endothelium, but it was unaltered in COX‐1−/− mice. Also, we noted that in endothelium‐denuded aortae, PGH2 generated PGI2 as in intact vessels. These results demonstrate a predominant role for COX‐1 and suggest that in the given mouse arteries, metabolites from either COX isoform cause contraction. Moreover, our results imply that some of the PGI2 involved in vasoconstrictor activity of endothelial COX‐mediated metabolism could possibly be generated from PGH2 in medial smooth muscle.
Vibration Analysis of Doubly Curved Shallow Shells With Elastic Edge Restraints
Authors: Jiang Shiliang , Yang Tiejun , Li W. L. , Du Jingtao
Published: March 2013

An analytical method is derived for the vibration analysis of doubly curved shallow shells with arbitrary elastic supports alone its edges, a class of problems which are rarely attempted in the literature. Under this framework, all the classical homogeneous boundary conditions for both in-plane and out-of-plane displacements can be universally treated as the special cases when the stiffness for each of restraining springs is equal to either zero or infinity. Regardless of the boundary conditions, the displacement functions are invariably expanded as an improved trigonometric series which converges uniformly and polynomially over the entire solution domain. All the unknown expansion coefficients are treated as the generalized coordinates and solved using the Rayleigh–Ritz technique. Unlike most of the existing solution techniques, the current method offers a unified solution to a wide spectrum of shell problems involving, such as different boundary conditions, varying material and geometric properties with no need of modifying or adapting the solution schemes and implementing procedures. A numerical example is presented to demonstrate the accuracy and reliability of the current method.
Effect of Roughness Orientation on the Elastohydrodynamic Lubrication Film Thickness
Authors: Zhu Dong , Jane Wang Q.
Published: March 2013

Effect of roughness orientation on lubricant film thickness has been an important issue of surface design, attracting much attention since the 1970 s. A systematical study, however, is still needed for various contact types in an extended range of operating conditions, especially in mixed lubrication cases with film thickness to roughness ratio (λ ratio) smaller than 0.5. The present study employs a deterministic mixed elastohydrodynamic lubrication (EHL) model to investigate the performance of lubricating films in different types of contact geometry, including the line contact, circular contact, and elliptical contacts of various ellipticity ratios. The speed range for analyzed cases covers 11 orders of magnitude so that the entire transition from full-film and mixed EHL down to dry contact (corresponding λ ratio from about 3.5 down to 0.001 or so) is simulated. Three types of machined surfaces are used, representing transverse, longitudinal, and isotropic roughness, respectively. The line contact results are compared with those from the stochastic models by Patir and Cheng (“Effect of Surface Roughness Orientation on the Central Film Thickness in EHD Contacts,” Proc. 5th Leeds-Lyon Symp. on Tribol., 1978, pp. 15–21) and the influence of roughness orientation predicted by the deterministic model is found to be less significant than that by the stochastic models, although the basic trends are about the same when λ > 0.5. The orientation effect for circular or elliptical contact problems appears to be more complicated than that for line contacts due to the existence of significant lateral flows. In circular contacts, or elliptical contacts with the ellipticity ratio smaller than one, the longitudinal roughness may become more favorable than the isotropic and transverse. Overall, the orientation effect is significant in the mixed EHL regime where theλratio is roughly in the range from 0.05 to 1.0. It is relatively insignificant for both the full-film EHL (λ > 1.2 or so) and the boundary lubrication/dry contact (λ < 0.025 ∼ 0.05).
Electromagnetically-Induced Vibration in Particulate-Functionalized Materials
Authors: Zohdi T. I.
Published: March 2013

In many small-scale devices, the materials employed are functionalized (doped) with microscale and/or nanoscale particles, in order to deliver desired overall dielectric properties. In this work, we develop a reduced-order lumped-mass model to characterize the dynamic response of a material possessing a microstructure that is comprised of an electromagnetically-neutral binder with embedded electromagnetically-sensitive (charged) particles. In certain industrial applications, such materials may encounter external electrical loading that can be highly oscillatory. Therefore, it is possible for the forcing frequencies to activate the inherent resonant frequencies of these micro- and nanostructures. In order to extract qualitative information, this paper first analytically investigates the mechanical and electromagnetic (cyclotronic) contributions to the dynamic response for a single particle, and then quantitatively investigates the response of a model problem consisting of a coupled multiparticle periodic array, via numerical simulation, using an implicit temporally-adaptive trapezoidal time-stepping scheme. For the model problem, numerical studies are conducted to observe the cyclotronically-dominated resonant frequency and associated beat phenomena, which arises due to the presence of mechanical and electromagnetic harmonics in the material system.
A Local Adaptive Multigrid Control Volume Method for the Air Bearing Problem in Hard Disk Drives
Authors: Li Liping , Bogy David B.
Published: March 2013

A new, local-adaptive, grid-generating algorithm is developed and integrated with the multigrid control volume method to simulate the steady flying state of the air bearing sliders in hard disk drives (HDDs) accurately and efficiently. Local finer meshes (mesh dimension decreases to half) are created on the nodes of the current finest grids that have pressure gradients or geometry gradients larger than a predefined tolerance after the pressure distribution has been obtained on the initial uniform mesh. In this way, the pressure- or geometry-sensitive regions have higher resolution, leading to more accurate results without inefficiently larger meshes. Two sliders are used to demonstrate the applicability of this method. It is found that this new, local-adaptive, grid-generating method improves the stability and efficiency of the simulation scheme.
Steering Cancer Genomics Into the Fast Lane
Authors: Pennisi Elizabeth
Published: March 2013

With her passion for DNA sequencing technology, Elaine Mardis now hopes to help cancer patients.
Illness and injury in athletes during the competition period at the London 2012 Paralympic Games: development and implementation of a web-based surveillance system (WEB-IISS) for team medical staff
Authors: Derman Wayne , Schwellnus Martin , Jordaan Esme , Blauwet Cheri A , Emery Carolyn , Pit-Grosheide Pia , Marques Norma-Angelica Patino , Martinez-Ferrer Oriol , Stomphorst Jaap , Van de Vliet Peter , Webborn Nick , Willick Stuart E
Published: March 2013

Background

In this study we describe (1) the implementation of a novel web-based injury and illness surveillance system (WEB-IISS) for use by a team of physicians at multisport events and (2) the incidence and characteristics of injuries and illness in athletes during the London 2012 Paralympic Games.

Methods

Overall, 3565 athletes from 160 of the 164 participating countries were followed daily over a 14-day period, consisting of a precompetition period (3 days), and a competition period (11 days) (49 910 athlete-days). Daily injury and illness data were obtained from teams with their own medical support (78 teams, 3329 athletes) via the WEB-IISS, and without their own medical support through the London Organising Committee of the Olympic Games and Paralympic Games database (82 teams and 236 athletes).

Results

There were no differences between incidence rates (IR) of injury and illness, or between the precompetition and competition periods. The IR of injury during the competition period was 12.1/1000 athlete-days, with an incidence proportion (IP) of 11.6% (95% CI 11.0% to 13.3%). Upper limb injuries (35%), particularly of the shoulder (17%) were most common. The IR of illness during the competition period was 12.8/1000 athlete-days (95% CI 12.18 to 1421), with an IP of 10.2%. The IP was highest in the respiratory system (27.4%), skin (18.3%) and the gastrointestinal (14.5%) systems.

Conclusions

During the competition period, the IR and IP of illness and injury at the Games were similar and comparable to the observed rates in other elite competitions. In Paralympic athletes, the IP of upper limb injuries is higher than that of lower limb injuries and non-respiratory illnesses are more common.
Ductal carcinoma in situ associated with triple negative invasive breast cancer: evidence for a precursor–product relationship
Authors: Thike Aye Aye , Iqbal Jabed , Cheok Poh Yian , Tse Gary Man-Kit , Tan Puay Hoon
Published: March 2013

Aim

We evaluated pathological features of the ductal carcinoma in situ component of 241 triple negative invasive breast cancers.

Results

We found that 151 (62.6%) in situ lesions were of high nuclear grade, and 236 (97.9%) were triple negative (oestrogen receptor, progesterone receptor, cerbB2 negative). Immunohistochemistry for cytokeratin (CK)5/6, CK14, CK17, epidermal growth factor receptor (EGFR), CD117, 34βE12, p63 and smooth muscle actin (SMA) revealed positive staining in 5 (2.1%), 60 (24.9%), 69 (28.6%), 37 (15.4%), 69 (28.6%), 137 (56.8%), 3 (1.2%) and 22 (9.1%) in situ ductal components respectively, with fair to substantial agreement of staining results (positive versus negative) between in situ and corresponding invasive elements for CK5/6, CK14, CK17, EGFR, CD117 and 34βE12; but none to fair agreement for p63 and SMA respectively. When the tri-panel of CK14, EGFR and 34βE12 was used to define the basal phenotype, 68% revealed basal-like expression of both in situ and invasive components of the same case.

Conclusions

Our data support the notion that triple negative ductal carcinoma in situ is the precursor of the corresponding invasive counterpart, and that basal-like expression is maintained in the majority of invasive cancers associated with basal-like in situ disease. Future studies that prospectively evaluate morphological and biological characteristics of invasive cancers that develop from triple negative and basal-like ductal carcinoma in situ lesions will assist in validating these findings.
The role of diagnostic CT imaging in the acute assessment of battlefield external genital injuries
Authors: Rushambuza Roger P M
Published: March 2013

Introduction

The external genitalia are routinely included in the‘CT-Traumagram’ at the Role 3 hospital in Afghanistan. Although the radiologist may have the opportunity to diagnose clinically undetected genital injury, little emphasis has been placed on the CT appearances of the external genitalia after Improvised Explosive Device related injury.

Methods

A prospective observational study was carried out on casualties admitted during 1 month in 2011. Genital findings on CT were correlated with clinical operative findings.

Results

One hundred and twenty-eight casualties were admitted of which 12 (9%) had genital injury. 17 testes were exposed to blast injury—5/17 (29%) were unharmed, one was dislocated, two were lost, one had a testicular haematoma and 8/17 (47%) were disrupted and underwent salvage. The CT findings—loss of the definition of the tunica albuginea and intra-testicular contrast blushing correlated with testicular disruption in all cases. The single dislocated testis and the two cases where there were no testes remaining after injury were all evident on CT.

Discussion

The CT appearance of the external genitalia following trauma are unfamiliar. However, despite the small numbers and clear limitations, the results suggest that CT has an important role to play in the diagnosis of significant genital trauma. Ultrasound assessment should be considered if there is persisting uncertainty.

Conclusions

‘CT-Traumagram’provides rapid, whole body information in casualties exposed to blast injury and this should be exploited in its entirety by the trauma team. Abnormal genital findings on contrast CT should alert radiologists and surgeons to the possibility of significant genital trauma.
Pelvic fracture-related urethral and bladder injury
Authors: Durrant Jordan J , Ramasamy A , Salmon M S , Watkin N , Sargeant I
Published: March 2013

Major pelvic ring fracture (PRF) due to blunt trauma results in lower urinary tract injury (LUTI) in up to 10% of cases. Significant comorbidity may result and this is particularly the case for unrecognised injury. The increase in military injuries due to improvised explosive devices in recent conflicts has revealed a complex injury cohort. The incidence of pelvic fracture related LUTI in these casualties is up to three times higher than that seen in civilian patients with pelvic fracture. A complete understanding of LUTI following pelvic fracture is still lacking. Complex fractures of the anterior pelvic arch are associated with LUTI and initial management is largely conservative. In battlefield injuries, the combination of the blast wave, penetrating fragment and bodily displacement results in open pelvic fracture combined with gross perineal and pelvic soft-tissue destruction and traumatic femoral amputations. These are some of the most challenging injuries that any surgical team will manage and life saving measures are the priority. There are established pathways for the management of LUTI following blunt trauma related pelvic fracture. Military injuries are more complex and require a significantly different approach. This paper outlines the developments in the understanding and management of pelvic fracture-related LUTI, focussing primarily on injury mechanisms and early management. Recent military surgical experience is discussed, highlighting the significant differences to civilian practice.
The management of genitourinary war injuries: a multidisciplinary consensus
Authors: Sharma Davendra M ,   on behalf of the Genitourinary Working Group (Trauma)
Published: March 2013

Genitourinary injuries as a result of current warfare may be severe and result in significant long term morbidity. There is no high quality evidence to guide management and the logistics involved require the development of bespoke management strategies. The multidisciplinary Genitourinary Working Group (Trauma) has the remit of leading this service, primarily addressing the management of casualties in the medical evacuation chain of the Defence Medical Services of the UK. The recommendations made are based mainly upon expert opinion and are intended to provide guidance to the deploying surgeon and the teams that manage these casualties thereafter.
The physical basis of explosion and blast injury processes
Authors: Proud WG
Published: March 2013

Energetic materials are widely used in civilian and military applications, such as quarrying and mining, flares, and in munitions. Recent conflicts have involved the widespread use of improvised explosive devices to attack military, civilians and infrastructure. This article gives a basic overview of explosive technology and the underlying physical processes that produce the injuries encountered. In particular aspects relevant to primary and secondary injuries are discussed.
Factors determining the in vitro emergence of sexual stages of Hepatozoon clamatae from erythrocytes of the Green Frog (Rana clamitans)
Authors: Trites M.J. , Ferguson L.V. , Ogbuah C.T. , Dickson C.M. , Smith T.G.
Published: March 2013

Sexual reproduction of apicomplexan parasites in haematophagous arthropods requires that intracellular sexual stages of these protozoa escape vertebrate erythrocytes in the blood meal. Although cues that signal sexual stages of the human malaria parasite (Plasmodium falciparum Welch, 1897) to emerge from erythrocytes are well documented, such signals are poorly known for other blood-dwelling Apicomplexa. The objective of this comparative study was to investigate conditions required to induce in vitro emergence of sexual stages of Hepatozoon clamatae (Stebbins, 1905) from frog erythrocytes. Blood was drawn from Green Frogs (Rana clamitans Latreille in Sonnini de Manoncourt and Latreille, 1801 = Lithobates clamitans clamitans (Latreille in Sonnini de Manoncourt and Latreille, 1801)) infected with H. clamatae and treated with solutions of various concentrations of saline, pH, and xanthurenic acid at different temperatures. Hypertonic saline solutions of 200 and 222 mmol/L at pH 7.4 and 7.7 elicited emergence of nearly 100% of gamonts from frog erythrocytes, but at pH 8.0 resulted in decreased emergence. Solutions containing 1, 10, and 100 μmol/L xanthurenic acid increased gamont emergence at saline concentrations of 156, 178, and 244 mmol/L, but decreased emergence at 200 and 222 mmol/L. Gamont emergence increased as incubation temperatures increased from 18 to 26 °C. These results suggest that conditions necessary for emergence of sexual stages of bloodstream Apicomplexa from erythrocytes vary among genera.
Metabolic Engineering: Past and Future
Authors: Woolston Benjamin M. , Edgar Steven , Stephanopoulos Gregory
Published: March 2013

We present here a broad overview of the field of metabolic engineering, describing in the first section the key fundamental principles that define and distinguish it, as well as the technological and intellectual developments over the past approximately 20 years that have led to the current state of the art. Discussion of concepts such as metabolic flux analysis, metabolic control analysis, and rational and combinatorial methods is facilitated by illustrative examples of their application drawn from the extensive metabolic engineering literature. In the second section, we present some of the rapidly emerging technologies that we think will play pivotal roles in the continued growth of the field, from improving production metrics to expanding the range of attainable compounds.
Biodegradable Polyesters from Renewable Resources
Authors: Tsui Amy , Wright Zachary C. , Frank Curtis W.
Published: March 2013

Environmental concerns have led to the development of biorenewable polymers with the ambition to utilize them at an industrial scale. Poly(lactic acid) and poly(hydroxyalkanoates) are semicrystalline, biorenewable polymers that have been identified as the most promising alternatives to conventional plastics. However, both are inherently susceptible to brittleness and degradation during thermal processing; we discuss several approaches to overcome these problems to create a balance between durability and biodegradability. For example, copolymers and blends can increase ductility and the thermal-processing window. Furthermore, chain modifications (e.g., branching/crosslinking), processing techniques (fiber drawing/annealing), or additives (plasticizers/nucleating agents) can improve mechanical properties and prevent thermal degradation during processing. Finally, we examine the impacts of morphology on end-of-life degradation to complete the picture for the most common renewable polymers.
Rheology of Slurries and Environmental Impacts in the Mining Industry
Authors: Boger David V.
Published: March 2013

The world's resource industries are the largest producers of waste. Much of this waste is produced as a fine particle slurry, which is pumped to a storage area, generally at a low concentration, where it behaves like a Newtonian fluid. Simply removing, reusing, and recycling water from the slurry represents a step toward a more sustainable practice in this industry. As the concentration of such a slurry is increased as a result of dewatering, the materials exhibit non-Newtonian behavior, which is characterized by shear thinning, a yield stress, and in some instances thixotropic behavior. Such high-concentration, nonideal (dirty) suspensions in the resource industries have meant that new rheological methods and techniques have been needed to measure and interpret the basic flow properties. Also, some older empirical techniques have needed to be modified and interpreted in a more fundamental way so that the results could be used in design. This article reviews these techniques and illustrates how the industry itself has motivated their development. Understanding and exploiting this rheology has resulted in dramatic improvement in the waste-disposal strategy for some industries, but many have failed to embrace the available technology. The reasons for this are discussed. The article concludes that a greater positive change in waste-management practice will occur in the future, motivated by several factors, including public perception, tighter regulation, and perhaps even commonsense life cycle accounting.
Mixed Semiconductor Alloys for Optical Devices
Authors: Kuech Thomas F. , Mawst Luke J. , Brown April S.
Published: March 2013

There is an increasing technological need for a wider array of semiconducting materials that will allow greater control over the physical and electronic structure within multilayer heterostructures. This need has led to an expansion in the range of semiconducting alloys explored and used in new applications. These alloy semiconductors are often complicated by a limited range of miscibility. The current research has focused on the properties, stability, and detailed chemistry required to realize these materials. The use of synthetic conditions that permit the growth of these alloys to be dominated by kinetic rather than mass-transport considerations has allowed many of these nominally unstable materials to be grown and used in device structures. These materials have found important applications within optical communications as emitters and detectors and in solid-state lighting.
Earth's Background Free Oscillations
Authors: Nishida Kiwamu
Published: March 2013

Earth's background free oscillations, known as Earth's hum, were discovered in 1998. Excited modes of the oscillations are almost exclusively fundamental spheroidal and toroidal modes from 2 to 20 mHz. Seasonal variations in the source distribution suggest that the dominant sources are ocean infragravity waves in the shallow and deep oceans. A probable excitation mechanism is random shear traction acting on the sea bottom owing to linear topographic coupling of the infragravity waves. Excitation by pressure sources on Earth's surface is also significant for a frequency below 5 mHz. A possible pressure source is atmospheric turbulence, which can cause observed resonant oscillations between the solid modes and atmospheric acoustic modes.
Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis
Authors: Ziogas Dimitrios C. , Gras-Miralles Beatriz , Mustafa Sarah , Geiger Brenda M. , Najarian Robert M. , Nagel Jutta M. , Flier Sarah N. , Popov Yury , Tseng Yu-Hua , Kokkotou Efi
Published: March 2013

Fibrosis represents a major complication of several chronic diseases, including inflammatory bowel disease (IBD). Treatment of IBD remains a clinical challenge despite several recent therapeutic advances. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide shown to regulate appetite and energy balance. However, accumulating evidence suggests that MCH has additional biological effects, including modulation of inflammation. In the present study, we examined the efficacy of an MCH-blocking antibody in treating established, dextran sodium sulfate-induced experimental colitis. Histological and molecular analysis of mouse tissues revealed that mice receiving anti-MCH had accelerated mucosal restitution and lower colonic expression of several proinflammatory cytokines, as well as fibrogenic genes, including COL1A1. In parallel, they spared collagen deposits seen in the untreated mice, suggesting attenuated fibrosis. These findings raised the possibility of perhaps direct effects of MCH on myofibroblasts. Indeed, in biopsies from patients with IBD, we demonstrate expression of the MCH receptor MCHR1 in α-smooth muscle actin(+) subepithelial cells. CCD-18Co cells, a primary human colonic myofibroblast cell line, were also positive for MCHR1. In these cells, MCH acted as a profibrotic modulator by potentiating the effects of IGF-1 and TGF-β on proliferation and collagen production. Thus, by virtue of combined anti-inflammatory and anti-fibrotic effects, blocking MCH might represent a compelling approach for treating IBD.
Arcuate nucleus injection of an anti-insulin affibody prevents the sympathetic response to insulin
Authors: Luckett Brittany S. , Frielle Jennifer L. , Wolfgang Lawrence , Stocker Sean D.
Published: March 2013

Accumulating evidence suggests that insulin acts within the hypothalamus to alter sympathetic nerve activity (SNA) and baroreflex function. Although insulin receptors are widely expressed across the hypothalamus, recent evidence suggests that neurons of the arcuate nucleus (ARC) play an important role in the sympathoexcitatory response to insulin. The purpose of the present study was to determine whether circulating insulin acts directly in the ARC to elevate SNA. In anesthetized male Sprague-Dawley rats (275–425 g), the action of insulin was neutralized by microinjection of an anti-insulin affibody (1 ng/40 nl). To verify the efficacy of the affibody, ARC pretreatment with injection of the anti-insulin affibody completely prevented the increase in lumbar SNA produced by ARC injection of insulin. Next, ARC pretreatment with the anti-insulin affibody attenuated the lumbar sympathoexcitatory response to intracerebroventricular injection of insulin. Third, a hyperinsulinemic-euglycemic clamp increased lumbar, but not renal, SNA in animals that received ARC injection of a control affibody. However, this sympathoexcitatory response was absent in animals pretreated with the anti-insulin affibody in the ARC. Injection of the anti-insulin affibody in the adjacent ventromedial hypothalamus did not alter the sympathoexcitatory response to insulin. The ability of the anti-insulin affibody to prevent the sympathetic effects of insulin cannot be attributed to a general inactivation or nonspecific effect on ARC neurons as the affibody did not alter the sympathoexcitatory response to ARC disinhibition by gabazine. Collectively, these findings suggest that circulating insulin acts within the ARC to increase SNA.
DiBAC4(3) hits a “sweet spot” for the activation of arterial large-conductance Ca2+-activated potassium channels independently of the β1-subunit
Authors: Scornik Fabiana S. , Bucciero Ronald S. , Wu Yuesheng , Selga Elisabet , Bosch Calero Cristina , Brugada Ramon , Pérez Guillermo J.
Published: March 2013

The voltage-sensitive dye bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC4(3)] has been reported as a novel large-conductance Ca2+-activated K+ (BK) channel activator with selectivity for its β1- or β4-subunits. In arterial smooth muscle, BK channels are formed by a pore-forming α-subunit and a smooth muscle-abundant regulatory β1-subunit. This tissue specificity has driven extensive pharmacological research aimed at regulating arterial tone. Using animals with a disruption of the gene for the β1-subunit, we explored the effects of DiBAC4(3) in native channels from arterial smooth muscle. We tested the hypothesis that, in native BK channels, activation by DiBAC4(3) relies mostly on its α-subunit. We studied BK channels from wild-type and transgenic β1-knockout mice in excised patches. BK channels from brain arteries, with or without the β1-subunit, were similarly activated by DiBAC4(3). In addition, we found that saturating concentrations of DiBAC4(3) (∼30 μM) promote an unprecedented persistent activation of the channel that negatively shifts its voltage dependence by as much as −300 mV. This “sweet spot” for persistent activation is independent of Ca2+ and/or the β1–4-subunits and is fully achieved when DiBAC4(3) is applied to the intracellular side of the channel. Arterial BK channel response to DiBAC4(3) varies across species and/or vascular beds. DiBAC4(3) unique effects can reveal details of BK channel gating mechanisms and help in the rational design of BK channel activators.
Anti-inflammatory interventions and skeletal muscle injury: benefit or detriment?
Authors: Urso Maria L.
Published: March 2013

Exercise, eccentric contractions, acute trauma, and disease are all causal mechanisms of skeletal muscle injury. After skeletal muscle is injured, it undergoes sequential phases of degeneration, inflammation, regeneration, and fibrosis. Events that occur in response to inflammation trigger regenerative processes. However, since inflammation causes pain, decreases skeletal muscle function, has a negative effect on performance, and contributes to fibrosis, which is one of the leading causes of delayed regeneration, the general practice has been to reduce inflammation. The problem with this approach is that preventing inflammation may hinder recovery. Current treatment options for inflammation are not necessarily effective and, in some cases, they may be unsafe. This review focuses on the question of whether the most beneficial course of treatment should be to block inflammation or if it is sensible to allow inflammatory processes to progress naturally. If blocking inflammation is perceived as a beneficial approach, it is not yet known at what time point during the inflammatory response it is most sensible to interfere. To address these issues, this review evaluates the effects of various anti-inflammatory agents on recovery processes in response to exercise-induced, traumatic, and disease-associated models of skeletal muscle injury. A collective analysis such as this should lay the foundation for future work that systematically manipulates the inflammatory response to most effectively promote regeneration and functional recovery in injured skeletal muscle, while reducing the negative effects of inflammatory processes such as pain and fibrosis.
Genomic Aberrations Occurring in Subsets of Serrated Colorectal Lesions but not Conventional Adenomas
Authors: Burnett-Hartman Andrea N. , Newcomb Polly A. , Potter John D. , Passarelli Michael N. , Phipps Amanda I. , Wurscher Michelle A. , Grady William M. , Zhu Lee-Ching , Upton Melissa P. , Makar Karen W.
Published: March 2013

A subset of aggressive colorectal cancers exhibit BRAF mutation, MLH1 methylation, and a CpG island methylator phenotype (CIMP), but precursors are poorly established. In this study, we determined the status of these markers in colorectal polyps and evaluated associated risk factors. The study included 771 polyp cases and 1,027 controls who were ages 24 to 80 years, part of a group health program, received a colonoscopy from 1998 to 2007, and completed a structured questionnaire assessing risk factors. Following standard pathology review, polyps were assayed for BRAF mutation (V600E) and tested for MLH1 and CIMP methylation, the latter including the genes, CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Polytomous logistic regression was used to estimate ORs and 95% confidence intervals for the association between molecularly defined subsets of polyps and potential risk factors. There were 580 conventional adenomas and 419 serrated lesions successfully assayed. For adenomas, the prevalence of each marker was ≤1%. In contrast, 55% of serrated lesions harbored mutant BRAF, 26% were CIMP-high, and 5% had methylated MLH1. In these lesions, the highest prevalence of markers was in sessile-serrated polyps (SSP) of ≥10 mm that were in the right-side/cecal regions of the colon. Risk factors for CIMP-high–serrated lesions included Caucasian race, current smoking status, and a history of polyps, whereas for serrated lesions with mutant BRAF, the significant risk factors were male sex, current smoking status, obesity, and a history of polyps. Our results suggest that SSPs and other large, right-sided serrated lesions have a unique molecular profile that is similar to CIMP-high, BRAF-mutated colorectal cancers. Cancer Res; 73(9); 2863–72. ©2013 AACR.
Androgen Receptor-Independent Function of FoxA1 in Prostate Cancer Metastasis
Authors: Jin Hong-Jian , Zhao Jonathan C. , Ogden Irene , Bergan Raymond C. , Yu Jindan
Published: March 2013

FoxA1 (FOXA1) is a pioneering transcription factor of the androgen receptor (AR) that is indispensible for the lineage-specific gene expression of the prostate. To date, there have been conflicting reports on the role of FoxA1 in prostate cancer progression and prognosis. With recent discoveries of recurrent FoxA1 mutations in human prostate tumors, comprehensive understanding of FoxA1 function has become very important. Here, through genomic analysis, we reveal that FoxA1 regulates two distinct oncogenic processes via disparate mechanisms. FoxA1 induces cell growth requiring the AR pathway. On the other hand, FoxA1 inhibits cell motility and epithelial-to-mesenchymal transition (EMT) through AR-independent mechanism directly opposing the action of AR signaling. Using orthotopic mouse models, we further show that FoxA1 inhibits prostate tumor metastasis in vivo. Concordant with these contradictory effects on tumor progression, FoxA1 expression is slightly upregulated in localized prostate cancer wherein cell proliferation is the main feature, but is remarkably downregulated when the disease progresses to metastatic stage for which cell motility and EMT are essential. Importantly, recently identified FoxA1 mutants have drastically attenuated ability in suppressing cell motility. Taken together, our findings illustrate an AR-independent function of FoxA1 as a metastasis inhibitor and provide a mechanism by which recurrent FoxA1 mutations contribute to prostate cancer progression. Cancer Res; 73(12); 3725–36. ©2013 AACR.
Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN
Authors: Bjerke Lynn , Mackay Alan , Nandhabalan Meera , Burford Anna , Jury Alexa , Popov Sergey , Bax Dorine A. , Carvalho Diana , Taylor Kathryn R. , Vinci Maria , Bajrami Ilirjana , McGonnell Imelda M. , Lord Christopher J. , Reis Rui M. , Hargrave Darren , Ashworth Alan , Workman Paul , Jones Chris
Published: March 2013

Children and young adults with glioblastoma (GBM) have a median survival rate of only 12 to 15 months, and these GBMs are clinically and biologically distinct from histologically similar cancers in older adults. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A, occurring either at or close to key residues marked by methylation for regulation of transcription—K27 and G34. Here, we show that the cerebral hemisphere-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem-cell maintenance, cell-fate decisions, and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene that is causative of GBMs when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population through inhibiting kinases responsible for stabilization of the protein.

Significance: We provide the mechanistic explanation for how the first histone gene mutation in human disease biology acts to deliver MYCN, a potent tumorigenic initiator, into a stem-cell compartment of the developing forebrain, selectively giving rise to incurable cerebral hemispheric GBM. Using synthetic lethal approaches to these mutant tumor cells provides a rational way to develop novel and highly selective treatment strategies. Cancer Discov; 3(5); 512–19. ©2013 AACR.

See related commentary by Huang and Weiss, p. 484

This article is highlighted in the In This Issue feature, p. 471
Application of Infrared Laser to the Zebrafish Vascular System
Authors: Kimura Eiji , Deguchi Tomonori , Kamei Yasuhiro , Shoji Wataru , Yuba Shunsuke , Hitomi Jiro
Published: March 2013

Objective—

Infrared laser–evoked gene operator is a new microscopic method optimized to heat cells in living organisms without causing photochemical damage. By combining the promoter system for the heat shock response, infrared laser–evoked gene operator enables laser-mediated gene induction in targeted cells. We applied this method to the vascular system in zebrafish embryos and demonstrated its usability to investigate mechanisms of vascular morphogenesis in vivo.

Approach and Results—

We used double-transgenic zebrafish with
fli1:nEGFP
to identify the endothelial cells, and with
hsp:mCherry
to carry out single-cell labeling. Optimizing the irradiation conditions, we finally succeeded in inducing the expression of the mCherry gene in single targeted endothelial cells, at a maximum efficiency rate of 60%. In addition, we indicated that this system could be used for laser ablation under certain conditions. To evaluate infrared laser–evoked gene operator, we applied this system to the endothelial cells of the first intersegmental arteries, and captured images of the connection between the vascular systems of the brain and spinal cord.

Conclusions—

Our results suggest that the infrared laser–evoked gene operator system will contribute to the elucidation of the mechanisms underlying vascular morphogenesis by controlling spatiotemporal gene activation in single endothelial cells, by labeling or deleting individual vessels in living embryos.
Photodynamic Therapy Using a Protease-Mediated Theranostic Agent Reduces Cathepsin-B Activity in Mouse Atheromata In Vivo
Authors: Shon Soo-Min , Choi Yongdoo , Kim Jeong-Yeon , Lee Dong Kun , Park Jin-Yong , Schellingerhout Dawid , Kim Dong-Eog
Published: March 2013

Objective—

To investigate whether an intravenously injected cathepsin-B activatable theranostic agent (L-SR15) would be cleaved in and release a fluorescent agent (chlorin-e6) in mouse atheromata, allowing both the diagnostic visualization and therapeutic application of these fluorophores as photosensitizers during photodynamic therapy to attenuate plaque-destabilizing cathepsin-B activity by selectively eliminating macrophages.

Approach and Results—

Thirty-week-old apolipoprotein E knock-out mice (n=15) received intravenous injection of L-SR15 theranostic agent, control agent D-SR16, or saline 3× (D0, D7, D14). Twenty-four hours after each injection, the bilateral carotid arteries were exposed, and Cy5.5 near-infrared fluorescent imaging was performed. Fluorescent signal progressively accumulated in the atheromata of the L-SR15 group animals only, indicating that photosensitizers had been released from the theranostic agent and were accumulating in the plaque. After each imaging session, photodynamic therapy was applied with a continuous-wave diode-laser. Additional near-infrared fluorescent imaging at a longer wavelength (Cy7) with a cathepsin-B–sensing activatable molecular imaging agent showed attenuation of cathepsin-B–related signal in the L-SR15 group. Histological studies demonstrated that L-SR15–based photodynamic therapy decreased macrophage infiltration by inducing apoptosis without significantly affecting plaque size or smooth muscle cell numbers. Toxicity studies (n=24) showed that marked erythematous skin lesion was generated in C57/BL6 mice at 24 hours after intravenous injection of free chlorin-e6 and ultraviolet light irradiation; however, L-SR15 or saline did not cause cutaneous phototoxicity beyond that expected of ultraviolet irradiation alone, neither did we observe systemic toxicity or neurobehavioral changes.

Conclusions—

This is the first study showing that macrophage-secreted cathepsin-B activity in atheromata could be attenuated by photodynamic therapy using a protease-mediated theranostic agent.