Dynamic damage in carbon-fibre composites.

The Taylor test is used to determine damage evolution in carbon-fibre composites across a range of strain rates. The hierarchy of damage across the scales is key in determining the suite of operating mechanisms and high-speed diagnostics are used to determine states during dynamic loading. Experiments record the test response as a function of the orientation of the cylinder cut from the engineered multi-ply composite with high-speed photography and post-mortem target examination. The ensuing damage occurs during the shock compression phase but three other tensile loading modes operate during the test and these are explored. Experiment has shown that ply orientations respond to two components of release; longitudinal and radial as well as the hoop stresses generated in inelastic flow at the impact surface. The test is a discriminant not only of damage thresholds but of local failure modes and their kinetics. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'.

Preliminary study of video imaging of blood vessels in tissues lining the gingival sulcus in periodontally healthy individuals.

BACKGROUND AND OBJECTIVE: The aim of this study was to obtain in vivo images of the microcirculation in tissues lining the gingival crevice in periodontally healthy volunteers and to assess the repeatability of the parameters measured. MATERIAL AND METHODS: Video microscopy images of the microcirculation of tissues lining the gingival crevice were obtained from 20 periodontally healthy volunteers. Images were obtained with a single 1 mm diameter 1 pitch gradient index lens with a high numerical aperture and with a plain glass lens and illumination with a green 525 nm light-emitting diode and recorded using a video microscope. RESULTS: The morphological features of the vessels (including vessel diameter, vessel density, loops, branches, dilated vessels) were similar to those described previously in other mammals. The Kappa values for the assessment of morphology of the vessels using the gradient index lens range from 0.83 for branching to 0.91 for dilated and using the glass lens 0.47 for branching and 0.38 for dilated. CONCLUSIONS: This novel system allowed for a consistent and repeatable assessment of the gingival microvasculature. However, there was some evidence of possible pressure artefacts in those cases where the measurements of separation between vessels exceeded 150 µm.

Nutrients and water masses in the Gulf of Maine - Georges Bank region: Variability and importance to blooms of the toxic dinoflagellate Alexandrium fundyense.

We report here the results of ten oceanographic survey cruises carried out in the Gulf of Maine - Georges Bank region of the Northwest Atlantic during the late spring to summer period in 2007, 2008 and 2010, for which we examine and characterize relationships among dissolved inorganic nutrient fields, water mass dynamics and cell densities of the toxic dinoflagellate Alexandrium fundyense. Nutrients are supplied to continental shelf waters of the Gulf of Maine - Georges Bank region by inflows of deep offshore water masses; once in the Gulf they are transported with the residual circulation and mix with surface waters, both in the Gulf and on the Bank. Those fluxes of offshore water masses and their nutrient loads are the major source of nutrients for phytoplankton production in the region, including annual blooms of A. fundyense in the Gulf and on Georges Bank. This much is already known. We suggest here that the locations and magnitude of A. fundyense blooms are controlled in part by variable nutrient fluxes to the interior Gulf of Maine from offshore, and, those interior Gulf of Maine waters are, in turn, the main nutrient source to Georges Bank, which are brought onto the Bank by tidal pumping on the Northern Flank. We present evidence that nitrate is the initial form of nitrogenous nutrient for A. fundyense blooms, but it is quickly depleted to limiting concentrations of less than 0.5 µM, at which time continued growth and maintenance of the population is likely fueled by recycled ammonium. We also show that phosphate may be the limiting nutrient over much of Georges Bank in summer, allowing recycled ammonium concentrations to increase. Our temperature-salinity analyses reveal spatial and temporal (seasonal and interannual) variability in the relative proportions of two deep source waters that enter the Gulf of Maine at depth through the Northeast Channel: Warm Slope Water (WSW) and Labrador Slope Water (LSW). Those two source waters are known to vary in their nutrient loads, with nitrate concentrations about 50% higher in WSW than LSW, for example, and as such the proportions of these two water masses to one another are important determinants of the overall nutrient loads in the interior Gulf. In addition to these deep slope water fluxes, we show evidence here of episodic fluxes of relatively fresh and low-nutrient shelf waters from the Nova Scotian Shelf, which enter the Gulf in pulses at depths between the surface and approximately 150 m, displacing deep slope waters, and consequently they significantly dilute the Gulf's interior waters, reducing nutrient concentrations and, in turn, affect the magnitude of A. fundyense blooms.

Georges Bank: a leaky incubator of Alexandrium fundyense blooms.

A series of oceanographic surveys on Georges Bank document variability of populations of the toxic dinoflagellate Alexandrium fundyense on time scales ranging from synoptic to seasonal to interannual. Blooms of A. fundyense on Georges Bank can reach concentrations on the order of 104 cells l-1, and are generally bank-wide in extent. Georges Bank populations of A. fundyense appear to be quasi-independent of those in the adjacent coastal Gulf of Maine, insofar as they occupy a hydrographic niche that is colder and saltier than their coastal counterparts. In contrast to coastal populations that rely on abundant resting cysts for bloom initiation, very few cysts are present in the sediments on Georges Bank. Bloom dynamics must therefore be largely controlled by the balance between growth and mortality processes, which are at present largely unknown for this population. Based on correlations between cell abundance and nutrient distributions, ammonium appears to be an important source of nitrogen for A. fundyense blooms on Georges Bank.

A red tide of Alexandrium fundyense in the Gulf of Maine.

In early July 2009, an unusually high concentration of the toxic dinoflagellate Alexandrium fundyense occurred in the western Gulf of Maine, causing surface waters to appear reddish brown to the human eye. The discolored water appeared to be the southern terminus of a large-scale event that caused shellfish toxicity along the entire coast of Maine to the Canadian border. Rapid-response shipboard sampling efforts together with satellite data suggest the water discoloration in the western Gulf of Maine was a highly ephemeral feature of less than two weeks in duration. Flow cytometric analysis of surface samples from the red water indicated the population was undergoing sexual reproduction. Cyst fluxes downstream of the discolored water were the highest ever measured in the Gulf of Maine, and a large deposit of new cysts was observed that fall. Although the mechanisms causing this event remain unknown, its timing coincided with an anomalous period of downwelling-favorable winds that could have played a role in aggregating upward-swimming cells. Regardless of the underlying causes, this event highlights the importance of short-term episodic phenomena on regional population dynamics of A. fundyense.

Synergism of small molecules targeting VDAC with sorafenib, regorafenib or lenvatinib on hepatocarcinoma cell proliferation and survival.

Voltage dependent anion channels (VDAC) in the outer mitochondrial membrane regulate the influx of metabolites that sustain mitochondrial metabolism and the efflux of ATP to the cytosol. Free tubulin and NADH close VDAC. The VDAC-binding small molecules X1 and SC18 modulate mitochondrial metabolism. X1 antagonizes the inhibitory effect of tubulin on VDAC. SC18 occupies an NADH-binding pocket in the inner wall of all VDAC isoforms. Here, we hypothesized that X1 and SC18 have a synergistic effect with sorafenib, regorafenib or lenvatinib to arrest proliferation and induce death in hepatocarcinoma cells. We used colony formation assays to determine cell proliferation, and a combination of calcein/propidium iodide, and trypan blue exclusion to assess cell death in the well differentiated Huh7 and the poorly differentiated SNU-449 cells. Synergism was assessed using the Chou-Talalay method. The inhibitory effect of X1, SC18, sorafenib, regorafenib and lenvatinib was concentration and time dependent. IC50s calculated from the inhibition of clonogenic capacity were lower than those determined from cell survival. At IC50s that inhibited cell proliferation, SC18 arrested cells in G0/G1. SC18 at 0.25-2 IC50s had a synergistic effect with sorafenib on clonogenic inhibition in Huh7 and SNU-449 cells, and with regorafenib or lenvatinib in SNU-449 cells. X1 or SC18 also had synergistic effects with sorafenib on promoting cell death at 0.5-2 IC50s for SC18 in Huh7 and SNU-449 cells. These results suggest that small molecules targeting VDAC represent a potential new class of drugs to treat liver cancer.

Static compressive tracking.

This paper presents the Static Computational Optical Undersampled Tracker (SCOUT), an architecture for compressive motion tracking systems. The architecture uses compressive sensing techniques to track moving targets at significantly higher resolution than the detector array, allowing for low cost, low weight design and a significant reduction in data storage and bandwidth requirements. Using two amplitude masks and a standard focal plane array, the system captures many projections simultaneously, avoiding the need for time-sequential measurements of a single scene. Scenes with few moving targets on static backgrounds have frame differences that can be reconstructed using sparse signal reconstruction techniques in order to track moving targets. Simulations demonstrate theoretical performance and help to inform the choice of design parameters. We use the coherence parameter of the system matrix as an efficient predictor of reconstruction error to avoid performing computationally intensive reconstructions over the entire design space. An experimental SCOUT system demonstrates excellent reconstruction performance with 16X compression tracking movers on scenes with zero and nonzero backgrounds.

Negative-frequency resonant radiation.

Optical solitons or solitonlike states shed light to blueshifted frequencies through a resonant emission process. We predict a mechanism by which a second propagating mode is generated. This mode, called negative resonant radiation, originates from the coupling of the soliton mode to the negative-frequency branch of the dispersion relation. Measurements in both bulk media and photonic-crystal fibers confirm our predictions.

Suppression of the 2010 Alexandrium fundyense bloom by changes in physical, biological, and chemical properties of the Gulf of Maine.

For the period 2005-2009, the abundance of resting cysts in bottom sediments from the preceding fall was a first-order predictor of the overall severity of spring-summer blooms of Alexandrium fundyense in the western Gulf of Maine and southern New England. Cyst abundance off mid-coast Maine was significantly higher in fall 2009 than it was preceding a major regional bloom in 2005. A seasonal ensemble forecast was computed using a range of forcing conditions for the period 2004-2009, suggesting that a large bloom was likely in the western Gulf of Maine in 2010. This did not materialize, perhaps because environmental conditions in spring-summer 2010 were not favorable for growth of A.fundyense. Water mass anomalies indicate a regional-scale change in circulation with direct influence on A. fundyense's niche. Specifically, near-surface waters were warmer, fresher, more stratified, and had lower nutrients than during the period of observations used to construct the ensemble forecast. Moreover, a weaker-than-normal coastal current lessened A. fundyense transport into the western Gulf of Maine and Massachusetts Bay. Satellite ocean color observations indicate the 2010 spring phytoplankton bloom was more intense than usual. Early-season nutrient depletion may have caused a temporal mismatch with A. fundyense's endogenous clock that regulates the timing of cyst germination. These findings highlight the difficulties of ecological forecasting in a changing oceanographic environment, and underscore the need for a sustained observational network to drive such forecasts.

Thermal desorption effects on fragment ion production from multi-photon ionized uridine and selected analogues.

Experiments on neutral gas-phase nucleosides are often complicated by thermal lability. Previous mass spectrometry studies of nucleosides have identified enhanced relative production of nucleobase ions (e.g. uracil+ from uridine) as a function of desorption temperature to be the critical indicator of thermal decomposition. On this basis, the present multi-photon ionization (MPI) experiments demonstrate that laser-based thermal desorption is effective for producing uridine, 5-methyluridine, and 2'-deoxyuridine targets without thermal decomposition. Our experiments also revealed one notable thermal dependence: the relative production of the sugar ion C5H9O4 + from intact uridine increased substantially with the desorption laser power and this only occurred at MPI wavelengths below 250 nm (full range studied 222-265 nm). We argue that this effect can only be rationalized plausibly in terms of changing populations of different isomers, tautomers, or conformers in the target as a function of the thermal desorption conditions. Furthermore, the wavelength threshold behavior of this thermally-sensitive MPI channel indicates a critical dependence on neutral excited state dynamics between the absorption of the first and second photons. The experimental results are complemented by density functional theory (DFT) optimizations of the lowest-energy structure of uridine and two further conformers distinguished by different orientations of the hydroxymethyl group on the sugar part of the molecule. The energies of the transitions states between these three conformers are low compared with the energy required for decomposition.

Retrograde signaling by a mtDNA-encoded non-coding RNA preserves mitochondrial bioenergetics.

Alveolar epithelial type II (AETII) cells are important for lung epithelium maintenance and function. We demonstrate that AETII cells from mouse lungs exposed to cigarette smoke (CS) increase the levels of the mitochondria-encoded non-coding RNA, mito-RNA-805, generated by the control region of the mitochondrial genome. The protective effects of mito-ncR-805 are associated with positive regulation of mitochondrial energy metabolism, and respiration. Levels of mito-ncR-805 do not relate to steady-state transcription or replication of the mitochondrial genome. Instead, CS-exposure causes the redistribution of mito-ncR-805 from mitochondria to the nucleus, which correlated with the increased expression of nuclear-encoded genes involved in mitochondrial function. These studies reveal an unrecognized mitochondria stress associated retrograde signaling, and put forward the idea that mito-ncRNA-805 represents a subtype of small non coding RNAs that are regulated in a tissue- or cell-type specific manner to protect cells under physiological stress.

Demography of genotypes: failure of the limited life-span paradigm in Drosophila melanogaster.

Experimental systems that are amenable to genetic manipulation can be used to address fundamental questions about genetic and nongenetic determinants of longevity. Analysis of large cohorts of ten genotypes of Drosophila melanogaster raised under conditions that favored extended survival has revealed variation between genotypes in both the slope and location of age-specific mortality curves. More detailed examination of a single genotype showed that the mortality trajectory was best fit by a two-stage Gompertz model, with no age-specific increase in mortality rates beyond 30 days after emergence. These results are contrary to the limited life-span paradigm, which postulates well-defined, genotype-specific limits on life-span and brief periods of intense and rapidly accelerating mortality rates at the oldest age.

Internal fertilization in an oviparous frog.

Eleutherodactylus coqui, an oviparous frog, undergoes internal fertilization. If this mode of fertilization occurs in other species of anurans, interpretations of anuran reproductive strategies based on the assumption of external fertilization must be reviewed.

Multimodality imaging of structure and function.

Historically, medical devices to image either anatomical structure or functional processes have developed along somewhat independent paths. The recognition that combining images from different modalities can nevertheless offer significant diagnostic advantages gave rise to sophisticated software techniques to coregister structure and function. Recently, alternatives to retrospective software-based fusion have become available through instrumentation that combines two imaging modalities within a single device, an approach that has since been termed hardware fusion. As a result, following their recent introduction into the clinic, combined PET/CT and SPECT/CT devices are now playing an increasingly important role in the diagnosis and staging of human disease. Recently, although limited to the brain, the first clinical MR scanner with a PET insert, a technically-challenging design, has been undergoing evaluation. This review will follow the development of multimodality instrumentation for clinical use from conception to present-day technology and assess the status and future potential for such devices.

Glutathione S-transferase polymorphisms: cancer incidence and therapy.

The super family of glutathione S-transferases (GSTs) is composed of multiple isozymes with significant evidence of functional polymorphic variation. Over the last three decades, data from cancer studies have linked aberrant expression of GST isozymes with the development and expression of resistance to a variety of chemicals, including cancer drugs. This review addresses how differences in the human GST isozyme expression patterns influence cancer susceptibility, prognosis and treatment. In addition to the well-characterized catalytic activity, recent evidence has shown that certain GST isozymes can regulate mitogen-activated protein kinases or can facilitate the addition of glutathione to cysteine residues in target proteins (S-glutathionylation). These multiple functionalities have contributed to the recent efforts to target GSTs with novel small molecule therapeutics. Presently, at least two drugs are in late-stage clinical testing. The evolving functions of GST and their divergent expression patterns in individuals make them an attractive target for drug discovery.

Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism.

Several types of autosomal recessive oculocutaneous albinism (OCA) are associated with abnormal tyrosinase function and a generalized reduction in or absence of cutaneous and eye melanin. Each is thought to result from a different mutant allele at the tyrosinase locus, with the mutation producing an enzyme with little or no activity in all involved tissues. In this paper, we report a new type of OCA that results from a tyrosinase allele producing a temperature-sensitive enzyme. The proband had white hair in the warmer areas (scalp and axilla) and progressively darker hair in the cooler areas (extremities) of her body. Melanocyte and melanosome architecture were normal. Quantitative hairbulb tyrosinase (dopa oxidase) assay demonstrated a loss of activity above 35-37 degrees C. Plasma pheomelanin and urine eumelanin intermediates were reduced and correlated with hair melanin content. This is the first temperature-sensitive tyrosinase mutation to be reported in humans and is analogous to the Siamese mutation in the cat and the Himalayan mutation in the mouse.

A new technique for probing chirality via photoelectron circular dichroism.

We present a proof-of-principle approach for discriminating chiral enantiomers based on the phenomenon of multiphoton photoelectron circular dichroism. A novel stereo detection setup was used to measure the number of photoelectrons emitted from chiral molecules in directions parallel or anti-parallel to the propagation of the ionising femtosecond laser pulses. In this study, we show how these asymmetries in the ketones camphor and fenchone depend upon the ellipticity of the laser pulses and the enantiomeric excess of the sample. By using a high repetition rate femtosecond laser, enantiomer excesses with uncertainties at the few-percent level could be measured in close to real-time. As the instrument is compact, and commercial turnkey femtosecond lasers are readily available, the development of a stand-alone chiral analysis instrument for a range of applications is now possible.

The ATP-binding cassette transporter ABCA2 as a mediator of intracellular trafficking.

ATP-binding cassette (ABC) transporters are a family of proteins that translocate molecules across cellular membranes. Substrates can include lipids, cholesterol and drugs. Mutations in ABC transporter genes can cause human pathologies and drug resistance phenotypes in cancer cells. ABCA2, the second member the A sub-family to be identified, was found at high levels in ovarian carcinoma cells resistant to the anti-cancer agent, estramustine (EM). In vitro models with elevated levels of ABCA2 are resistant to a variety of compounds, including estradiol, mitoxantrone and a free radical initiator, 2,2'-azobis-(2-amidinopropane) (AAPH). ABCA2 is most abundant in the central nervous system (CNS), ovary and macrophages. Enhanced expression of ABCA2 and related proteins, including ABCA1, ABCA4 and ABCA7, is found in human macrophages upon bolus cholesterol treatment. ABCA2 also plays a role in the trafficking of low-density lipoprotein (LDL)-derived free cholesterol and is coordinately expressed with genes involved in cholesterol homeostasis. Additionally, ABCA2 expression has been linked with gene cluster patterns consistent with pathologies including Alzheimer's disease (AD). A single-nucleotide polymorphism (SNP) in exon 14 of the ABCA2 gene was shown to be linked to early onset AD in humans, supporting the observation that ABCA2 expression influences levels of beta-amyloid peptide (Abeta), the primary component of senile plaques. ABCA2 may play a role in cholesterol transport and affect a cellular phenotype conducive to the pathogenesis of a variety of human diseases including AD, atherosclerosis and cancer.

Pathophysiology of fecal incontinence differs between men and women: a case-matched study in 200 patients.

BACKGROUND: Fecal incontinence (FI) is a common and socially disabling condition with obstetric trauma considered the principal etiological factor. This study aimed to systematically evaluate symptom presentation and anorectal function in both females and males with FI. METHODS: One hundred males (M) and 100 age-matched females (F) with FI presenting between 2012 and 2014 were identified from a prospectively collected database. Comparison of clinical (history, symptom profile, and severity using validated questionnaires) and anorectal physiological (manometry, rectal sensory testing, endoanal ultrasonography, and evacuation proctography) data between M and F was performed. KEY RESULTS: Incidence of prior anal surgery (M: 28% vs F: 18%, p = 0.13) and abdominal surgery (M: 25% vs F: 26%, p = 0.90) was similar between sexes, but females had a higher incidence of previous pelvic surgery (M: 4% vs F: 47%, p < 0.001). Eighty-five females were parous and 75% reported history of traumatic vaginal delivery. There was a trend toward higher St Mark's incontinence scores in females (mean ± SD; M: 13 ± 4 vs F: 14 ± 5, p = 0.06). In men, structural sphincter abnormalities were uncommon (M: 37% vs F: 77%, p < 0.001), while impaired rectal sensation (M: 24% vs F: 7%, p = 0.001) and functional disturbances of evacuation (M: 36% vs F: 13%, p = 0.001) were more common than in women. No abnormality on all tests performed was observed in twice as many males (M: 18% vs F: 9%, p = 0.10). CONCLUSIONS & INFERENCES: Pathophysiological mechanisms of FI differ between sexes. Anal sphincter dysfunction was an uncommon finding in males, with impaired rectal sensation and functional disturbances of evacuation much more prominent than in the female cohort. These findings are likely to impact options for symptom management.

The design and implementation of a study to investigate the effectiveness of community vs hospital eye service follow-up for patients with neovascular age-related macular degeneration with quiescent disease.

IntroductionStandard treatment for neovascular age-related macular degeneration (nAMD) is intravitreal injections of anti-VEGF drugs. Following multiple injections, nAMD lesions often become quiescent but there is a high risk of reactivation, and regular review by hospital ophthalmologists is the norm. The present trial examines the feasibility of community optometrists making lesion reactivation decisions.MethodsThe Effectiveness of Community vs Hospital Eye Service (ECHoES) trial is a virtual trial; lesion reactivation decisions were made about vignettes that comprised clinical data, colour fundus photographs, and optical coherence tomograms displayed on a web-based platform. Participants were either hospital ophthalmologists or community optometrists. All participants were provided with webinar training on the disease, its management, and assessment of the retinal imaging outputs. In a balanced design, 96 participants each assessed 42 vignettes; a total of 288 vignettes were assessed seven times by each professional group.The primary outcome is a participant's judgement of lesion reactivation compared with a reference standard. Secondary outcomes are the frequency of sight threatening errors; judgements about specific lesion components; participant-rated confidence in their decisions about the primary outcome; cost effectiveness of follow-up by optometrists rather than ophthalmologists.DiscussionThis trial addresses an important question for the NHS, namely whether, with appropriate training, community optometrists can make retreatment decisions for patients with nAMD to the same standard as hospital ophthalmologists. The trial employed a novel approach as participation was entirely through a web-based application; the trial required very few resources compared with those that would have been needed for a conventional randomised controlled clinical trial.