Multiplexed identification, quantification and genotyping of infectious agents using a semiconductor biochip

The emergence of pathogens resistant to existing antimicrobial drugs is a growing worldwide health crisis that threatens a return to the pre-antibiotic era. To decrease the overuse of antibiotics, molecular diagnostics systems are needed that can rapidly identify pathogens in a clinical sample and determine the presence of mutations that confer drug resistance at the point of care. We developed a fully integrated, miniaturized semiconductor biochip and closed-tube detection chemistry that performs multiplex nucleic acid amplification and sequence analysis. The approach had a high dynamic range of quantification of microbial load and was able to perform comprehensive mutation analysis on up to 1,000 sequences or strands simultaneously in <2 h. We detected and quantified multiple DNA and RNA respiratory viruses in clinical samples with complete concordance to a commercially available test. We also identified 54 drug-resistance-associated mutations that were present in six genes of Mycobacterium tuberculosis, all of which were confirmed by next-generation sequencing

Treatment with 670 nm light up regulates cytochrome C oxidase expression and reduces inflammation in an age-related macular degeneration model.

Inflammation is an umbrella feature of ageing. It is present in the aged retina and many retinal diseases including age-related macular degeneration (AMD). In ageing and in AMD mitochondrial function declines. In normal ageing this can be manipulated by brief exposure to 670 nm light on the retina, which increases mitochondrial membrane potential and reduces inflammation. Here we ask if 670 nm exposure has the same ability in an aged mouse model of AMD, the complement factor H knockout (CFH(-/-)) where inflammation is a key feature. Further, we ask whether this occurs when 670 nm is delivered briefly in environmental lighting rather than directly focussed on the retina. Mice were exposed to 670 nm for 6 minutes twice a day for 14 days in the form of supplemented environmental light. Exposed animals had significant increase in cytochrome c oxidase (COX), which is a mitochondrial enzyme regulating oxidative phosphorylation.There was a significant reduction in complement component C3, an inflammatory marker in the outer retina. Vimetin and glial fibrillary acidic protein (GFAP) expression, which reflect retinal stress in Muller glia, were also significantly down regulated. There were also significant changes in outer retinal macrophage morphology. However, amyloid beta (Aβ) load, which also increases with age in the outer retina and is pro-inflammatory, did not change. Hence, 670 nm is effective in reducing inflammation probably via COX activation in mice with a genotype similar to that in 50% of AMD patients even when brief exposures are delivered via environmental lighting. Further, inflammation can be reduced independent of Aβ. The efficacy revealed here supports current early stage clinical trials of 670 nm in AMD patients

Modelling particle residence times in agricultural river basins using a sediment budget model and fallout radionuclide tracers

Contemporary patterns in river basin sediment dynamics have been widely investigated but the timescales associated with current sediment delivery processes have received much less attention. Furthermore, no studies have quantified the effect of recent land use change on the residence or travel times of sediment transported through river basins. Such information is crucial for understanding contemporary river basin function and responses to natural and anthropogenic disturbances or management interventions. To address this need, we adopt a process-based modelling approach to quantify changes in spatial patterns and residence times of suspended sediment in response to recent agricultural land cover change. The sediment budget model SedNet was coupled with a mass balance model of particle residence times based on atmospheric and fluvial fluxes of three fallout radionuclide tracers (7Be, excess 210Pb and 137Cs). Mean annual fluxes of suspended sediment were simulated in seven river basins (38-920 km2) in south-west England for three land cover surveys (1990, 2000 and 2007). Suspended sediment flux increased across the basins from 0.5-15 to 1.4-37 kt y-1 in response to increasing arable land area between consecutive surveys. The residence time model divided basins into slow (upper surface soil) and rapid (river channel and connected hillslope sediment source area) transport compartments. Estimated theoretical residence times in the slow compartment decreased from 13-48 to 5.6-14 ky with the increase in basin sediment exports. In contrast, the short residence times for the rapid compartment increased from 185-256 to 260-368 d as the modelled connected source area expanded with increasing sediment supply from more arable land. The increase in sediment residence time was considered to correspond to longer sediment travel distances linked to larger connected source areas. This novel coupled modelling approach provides unique insight into river basin responses to recent environmental change not otherwise available from conventional measurement techniques

Intrinsically Photosensitive Retinal Ganglion Cells

Intrinsically photosensitive retinal ganglion cells (ipRGCs) respond to light in the absence of all rod and cone photoreceptor input. The existence of these ganglion cell photoreceptors, although predicted from observations scattered over many decades, was not established until it was shown that a novel photopigment, melanopsin, was expressed in retinal ganglion cells of rodents and primates. Phototransduction in mammalian ipRGCs more closely resembles that of invertebrate than vertebrate photoreceptors and appears to be mediated by transient receptor potential channels. In the retina, ipRGCs provide excitatory drive to dopaminergic amacrine cells and ipRGCs are coupled to GABAergic amacrine cells via gap junctions. Several subtypes of ipRGC have been identified in rodents based on their morphology, physiology and expression of molecular markers. ipRGCs convey irradiance information centrally via the optic nerve to influence several functions including photoentrainment of the biological clock located in the hypothalamus, the pupillary light reflex, sleep and perhaps some aspects of vision. In addition, ipRGCs may also contribute irradiance signals that interface directly with the autonomic nervous system to regulate rhythmic gene activity in major organs of the body. Here we review the early work that provided the motivation for searching for a new mammalian photoreceptor, the ground-breaking discoveries, current progress that continues to reveal the unusual properties of these neuron photoreceptors, and directions for future investigation

Supercycle in great earthquake recurrence along the Japan Trench over the last 4000 years

Abstract On the landward slope of the Japan Trench, the mid-slope terrace (MST) is located at a depth of 4000–6000 m. Two piston cores from the MST were analyzed to assess the applicability of the MST for turbidite paleoseismology and to find out reliable recurrence record of the great earthquakes along the Japan Trench. The cores have preserved records of ~ 12 seismo-turbidites (event deposits) during the last 4000 years. In the upper parts of the two cores, only the following earthquakes (magnitude M ~ 8 and larger) were clearly recorded: the 2011 Tohoku, the 1896 Sanriku, the 1454 Kyotoku, and the 869 Jogan earthquake. In the lower part of the cores, turbidites were deposited alternately in the northern and southern sites during the periods between concurrent depositional events occurring at intervals of 500–900 years. Considering the characteristics of the coring sites for their sensitivity to earthquake shaking, the concurrent depositional events likely correspond to a supercycle that follows giant (M ~ 9) earthquakes along the Japan Trench. Preliminary estimations of peak ground acceleration for the historical earthquakes recorded as the turbidites imply that each rupture length of the 1454 and 869 earthquakes was over 200 km. The earthquakes related to the supercycle have occurred over at least the last 4000 years, and the cycle seems to have become slightly shorter in recent years. Earthquakes off the Sanriku coast forming the alternative deposition of turbidites in the two cores have released a part of accumulated slip, as indicated by the turbidites deposited in only one core. Decreases in the release of accumulated slip have possibly caused the recent shortening of the supercycle