Integrated microcantilever fluid sensor as a blood coagulometer

The work presented concerns the improvement in mechanical to thermal signal of a microcantilever fluid probe for monitoring patient prothrombin time (PT) and international normalized ratio (INR) based on the physical measurement of the clotting cascade. The current device overcomes hydrodynamic damping limitations by providing an internal thermal actuation force and is realised as a disposable sensor using an integrated piezoresistive deflection measurement. Unfortunately, the piezoresistor is sensitive to thermal changes and in the current design the signal is saturated by the thermal actuation. Overcoming this problem is critical for demonstrating a blood coagulometer and in the wider field as a microsensor capable of simultaneously monitoring rheological and thermal measurements of micro-litre samples. Thermal, electrical, and mechanical testing of a new design indicates a significant reduction in the thermal crosstalk and has led to a breakthrough in distinguishing the mechanical signal when operated in moderately viscous fluids (2-3 cP). A clinical evaluation has been conducted at The Royal London Hospital to measure the accuracy and precision of the improved microcantilever fluid probe. The correlation against the standard laboratory analyser INR, from a wide range of patient clotting times(INR 0.9-6.08) is equal to 0.987 (n=87) and precision of the device measured as the percentage coefficient of variation, excluding patient samples tested < 3 times, is equal to 4.00% (n=64). The accuracy and precision is comparable to that of currently available point-of-care PT/INR devices. The response of the fluid probe in glycerol solutions indicates the potential for simultaneous measurement of rheological and thermal properties though further work is required to establish the accuracy and range of the device as a MEMS based viscometer

Construction of a "mutagenesis cartridge" for poliovirus genome-linked viral protein: Isolation and characterization of viable and nonviable mutants

By following a strategy of genetic analysis of poliovirus, we have constructed a synthetic "mutagenesis cartridge" spanning the genome-linked viral protein coding region and flanking cleavage sites in an infectious cDNA clone of the type 1 (Mahoney) genome. The insertion of new restriction sites within the infectious clone has allowed us to replace the wild-type sequences with short complementary pairs of synthetic oligonucleotides containing various mutations. A set of mutations have been made that create methionine codons within the genome-linked viral protein region. The resulting viruses have growth characteristics similar to wild type. Experiments that led to an alteration of the tyrosine residue responsible for the linkage to RNA have resulted in nonviable virus. In one mutant, proteolytic processing assayed in vitro appeared unimpaired by the mutation. We suggest that the position of the tyrosine residue is important for genome-linked viral protein function(s)

Performance Evaluation of a Kinesthetic-Tactual Display

Simulator studies demonstrated the feasibility of using kinesthetic-tactual (KT) displays for providing collective and cyclic command information, and suggested that KT displays may increase pilot workload capability. A dual-axis laboratory tracking task suggested that beyond reduction in visual scanning, there may be additional sensory or cognitive benefits to the use of multiple sensory modalities. Single-axis laboratory tracking tasks revealed performance with a quickened KT display to be equivalent to performance with a quickened visual display for a low frequency sum-of-sinewaves input. In contrast, an unquickened KT display was inferior to an unquickened visual display. Full scale simulator studies and/or inflight testing are recommended to determine the generality of these results

Management Implications of Molt Migration by the Atlantic Flyway Resident Population of Canada Geese, Branta canadensis

We used satellite-tracked transmitters in 2001 and 2003 to document the timing, location, and extent of molt migrations by female Canada Geese (Branta canadensis) affiliated with the Atlantic Flyway Resident Population (AFRP) of Canada Geese that breed in the temperate region of eastern North America. Twenty-seven adult females were captured during the nesting period in late May and fitted with a satellite transmitter mounted either on a plastic neck collar or backpack harness. Nests of 24 birds were destroyed late in incubation to prevent renesting and ensure nest failure; three females did not have nests. Twelve of the 27 birds (44%) made a northward migration to molt in northern Quebec, Canada: seven to the eastern coast of Hudson Bay (58°12'N, 76°60'W), three to lowland areas east of James Bay (53°30'N, 79°02'W), and two to interior locations south of Ungava Bay (55°54'N, 68°24'W). Molt migrants were present in northern Quebec from June to September, a period that coincides with breeding ground aerial surveys and banding operations conducted for Atlantic Population (AP) Canada Geese that breed in this same region of northern Quebec. With &gt;1 million AFRP geese estimated in the Atlantic Flyway, the potential exists for substantial numbers of yearling, sub-adult, and nest-failed or non-breeding adults to molt migrate to northern breeding areas and bias efforts to survey and mark AP geese. Within AFRP breeding areas, many local flocks have reached nuisance levels. We hypothesized that by inducing molt migration in breeding adults, through destruction of nests late in incubation, we would lessen recruitment, reduce numbers of summer resident adults with young, and increase adult mortality from hunting. However, molt migration behavior was not uniform throughout our study area. Molt migrants were from rural areas in New York, Pennsylvania, and Vermont, whereas marked birds that did not make molt migrations were from more coastal regions of the flyway. The 14 birds that did not make a molt migration remained within 60 km of their banding site. A genetic comparison of these two groups revealed no detectable differences. We conclude that failure to undergo a molt migration is likely attributed to the historical origin of captive-reared birds of mixed subspecies that comprise AFRP flocks in the eastern regions of the flyway and the availability of quality local habitat, distinct from brood-rearing areas, for molting

Pathogen transmission from vaccinated hosts can cause dose-dependent reduction in virulence

Many livestock and human vaccines are leaky because they block symptoms but do not prevent infection or onward transmission. This leakiness is concerning because it increases vaccination coverage required to prevent disease spread and can promote evolution of increased pathogen virulence. Despite leakiness, vaccination may reduce pathogen load, affecting disease transmission dynamics. However, the impacts on post-transmission disease development and infectiousness in contact individuals are unknown. Here, we use transmission experiments involving Marek disease virus (MDV) in chickens to show that vaccination with a leaky vaccine substantially reduces viral load in both vaccinated individuals and unvaccinated contact individuals they infect. Consequently, contact birds are less likely to develop disease symptoms or die, show less severe symptoms, and shed less infectious virus themselves, when infected by vaccinated birds. These results highlight that even partial vaccination with a leaky vaccine can have unforeseen positive consequences in controlling the spread and symptoms of disease

Regional Action Plan for the Conservation of the Cross River Gorilla (Gorilla gorilla diehli)

From Executive Summary: This document represents the consensus of experts who met at a workshop in April 2006 in Calabar, Cross River State, Nigeria, to formulate a set of priority actions that would increase the survival prospects for the Cross River gorilla (Gorilla gorilla diehli). The Cross River gorilla is recognized by IUCN as Critically Endangered, and is the most threatened taxon of ape in Africa. It is the most westerly and northerly form of gorilla, and occurs only in a limited area around the mountainous headwaters of the Cross River, straddling the border between Cameroon and Nigeria. Participants at the 2006 workshop, which built upon the outcomes of previous meetings in Calabar in 2001 and Limbe, Cameroon, in 2003, included representatives of forestry and wildlife conservation agencies from the two range countries, of local and international nongovernmental conservation and development organizations, and of university-based researchers

Promoter keyholes enable specific and persistent multi-gene expression programs in primary T cells without genome modification

Non-invasive epigenome editing is a promising strategy for engineering gene expression programs, yet potency, specificity, and persistence remain challenging. Here we show that effective epigenome editing is gated at single-base precision via 'keyhole' sites in endogenous regulatory DNA. Synthetic repressors targeting promoter keyholes can ablate gene expression in up to 99% of primary cells with single-gene specificity and can seamlessly repress multiple genes in combination. Transient exposure of primary T cells to keyhole repressors confers mitotically heritable silencing that persists to the limit of primary cultures in vitro and for at least 4 weeks in vivo, enabling manufacturing of cell products with enhanced therapeutic efficacy. DNA recognition and effector domains can be encoded as separate proteins that reassemble at keyhole sites and function with the same efficiency as single chain effectors, enabling gated control and rapid screening for novel functional domains that modulate endogenous gene expression patterns. Our results provide a powerful and exponentially flexible system for programming gene expression and therapeutic cell products

The Infrared Imaging Spectrograph (IRIS) for TMT: Instrument Overview

We present an overview of the design of IRIS, an infrared (0.84 - 2.4 micron) integral field spectrograph and imaging camera for the Thirty Meter Telescope (TMT). With extremely low wavefront error (<30 nm) and on-board wavefront sensors, IRIS will take advantage of the high angular resolution of the narrow field infrared adaptive optics system (NFIRAOS) to dissect the sky at the diffraction limit of the 30-meter aperture. With a primary spectral resolution of 4000 and spatial sampling starting at 4 milliarcseconds, the instrument will create an unparalleled ability to explore high redshift galaxies, the Galactic center, star forming regions and virtually any astrophysical object. This paper summarizes the entire design and basic capabilities. Among the design innovations is the combination of lenslet and slicer integral field units, new 4Kx4k detectors, extremely precise atmospheric dispersion correction, infrared wavefront sensors, and a very large vacuum cryogenic system.Comment: Proceedings of the SPIE, 9147-76 (2014

A genome-wide association analysis for body weight at 35 days measured on 137,343 broiler chickens

Background: Body weight (BW) is an economically important trait in the broiler (meat-type chickens) industry. Under the assumption of polygenicity, a "large" number of genes with "small" effects is expected to control BW. To detect such effects, a large sample size is required in genome-wide association studies (GWAS). Our objective was to conduct a GWAS for BW measured at 35 days of age with a large sample size.Methods: The GWAS included 137,343 broilers spanning 15 pedigree generations and 392,295 imputed single nucleotide polymorphisms (SNPs). A false discovery rate of 1% was adopted to account for multiple testing when declaring significant SNPs. A Bayesian ridge regression model was implemented, using AlphaBayes, to estimate the contribution to the total genetic variance of each region harbouring significant SNPs (1 Mb up/downstream) and the combined regions harbouring non-significant SNPs.Results: GWAS revealed 25 genomic regions harbouring 96 significant SNPs on 13 Gallus gallus autosomes (GGA1 to 4, 8, 10 to 15, 19 and 27), with the strongest associations on GGA4 at 65.67-66.31 Mb (Galgal4 assembly). The association of these regions points to several strong candidate genes including: (i) growth factors (GGA1, 4, 8, 13 and 14); (ii) leptin receptor overlapping transcript (LEPROT)/leptin receptor (LEPR) locus (GGA8), and the STAT3/STAT5B locus (GGA27), in connection with the JAK/STAT signalling pathway; (iii) T-box gene (TBX3/TBX5) on GGA15 and CHST11 (GGA1), which are both related to heart/skeleton development); and (iv) PLAG1 (GGA2). Combined together, these 25 genomic regions explained similar to 30% of the total genetic variance. The region harbouring significant SNPs that explained the largest portion of the total genetic variance (4.37%) was on GGA4 (similar to 65.67-66.31 Mb).Conclusions: To the best of our knowledge, this is the largest GWAS that has been conducted for BW in chicken to date. In spite of the identified regions, which showed a strong association with BW, the high proportion of genetic variance attributed to regions harbouring non-significant SNPs supports the hypothesis that the genetic architecture of BW35 is polygenic and complex. Our results also suggest that a large sample size will be required for future GWAS of BW35

High incidence of Hepatitis C infection observed in the PROUD study of HIV pre-exposure prophylaxis

HIV negative men who have sex with men (MSM) who access pre-exposure prophylaxis (PrEP) report sexual behaviours that could place them at high risk of hepatitis C virus infection (HCV). We report HCV prevalence and incidence from the PROUD trial of PrEP.PROUD was an open-label, wait-list design randomised trial of HIV PrEP for MSM.Participants were recruited between November 2012 and April 2014, and follow-up continued to October 2016. Initial HCV testing followed national guidelines, with screening "on indication", but was replaced by routine quarterly screening in the latter part of the study.We estimated HCV seroprevalence at enrolment and incidence overall and according to calendar year.544 participants were recruited to PROUD. 133 (24.4%) were screened for HCV at enrolment, and 490 (90.1%) were tested at least once during follow-up. Seroprevalence at enrolment was 2.1% (11/530; 95% CI: 1.0-3.7%). Median follow-up time was 2.6 (IQR: 2.1-3.0) years and total follow-up of 1188.8 person years (PY). Twenty-five participants had a new HCV infection during the trial, yielding an incidence rate of 2.1 per 100 PY (25/1188.8; 95% CI: 1.4-3.1), of which three were re-infections. There was some evidence that HCV incidence increased over calendar time (P-value for trend=0.09), reaching an estimated 4.0 per 100 PY (95% CI: 2.0-8.1)in 2016. In conclusion, participants in PROUD had a high, and possibly increasing, incidence of HCV infection. This high incidence of HCV supports the 2018 BHIVA/BASHH recommendation for quarterly HCV testing among HIV-negative MSM using PrEP in the UK