Rider Assist Technologies: Popular Types, Motivations for Use, and Information Sources Consulted by Users

The ubiquity of advanced in-vehicle technologies for cars highlights the relative scarcity of comparable offerings for motorcycles despite the fact that many can be adapted for this mode of transportation. Aspects of Intelligent Transport Systems (ITS) such as advanced rider assist technologies may increase the safety of motorcyclists. In this study, we surveyed motorcycle riders about the types of advance technologies their current bikes were equipped with, as well as, the primary motivation for purchasing the technology, and how they learned to use the technologies (if applicable). The most frequently reported technologies owned by riders were handle bar controls, engine brake controls, and cruise control. The primary motivation reported for using the technology was increased safety and improved riding capabilities. The riders were more likely to consult online resources (e.g., YouTube) instead of the manufacturer’s materials when learning about the advanced features of their bikes. While the accessibility of the information makes it easy to reference, the lack of standardization and validity of the online content could contribute to the potential misuse of the technology

Wireless aquatic navigator for detection and analysis (WANDA)

The cost of monitoring and detecting pollutants in natural waters is of major concern. Current and forthcoming bodies of legislation will continue to drive demand for spatial and selective monitoring of our environment, as the focus increasingly moves towards effective enforcement of legislation through detection of events, and unambiguous identification of perpetrators. However, these monitoring demands are not being met due to the infrastructure and maintenance costs of conventional sensing models. Advanced autonomous platforms capable of performing complex analytical measurements at remote locations still require individual power, wireless communication, processor and electronic transducer units, along with regular maintenance visits. Hence the cost base for these systems is prohibitively high, and the spatial density and frequency of measurements are insufficient to meet requirements. In this paper we present a more cost effective approach for water quality monitoring using a low cost mobile sensing/communications platform together with very low cost stand-alone ‘satellite’ indicator stations that have an integrated colorimetric sensing material. The mobile platform is equipped with a wireless video camera that is used to interrogate each station to harvest information about the water quality. In simulation experiments, the first cycle of measurements is carried out to identify a ‘normal’ condition followed by a second cycle during which the platform successfully detected and communicated the presence of a chemical contaminant that had been localised at one of the satellite stations

On the causes of the African slave trade

This paper offers an integrated analysis of the forces shaping the emergence of the African slave trade over the early modern period. We focus our attention on two questions. First, why most of the increase in the demand for slaves during this period came exclusively from western Europeans. Second, and of most relevance for present-day development outcomes, why was the overwhelming majority of slaves of African origin. Technological differences in manufacturing technology, the specificities of sugar (and other crops') production, and the cultural fragmentation of the African continent all play a role in the analysis. Supporting evidence for each of our claims is provided from a broad corpus of relevant literature

Structure of acidic pH dengue virus showing the fusogenic glycoprotein trimers

Flaviviruses undergo large conformational changes during their life cycle. Under acidic pH conditions, the mature virus forms transient fusogenic trimers of E glycoproteins that engage the lipid membrane in host cells to initiate viral fusion and nucleocapsid penetration into the cytoplasm. However, the dynamic nature of the fusogenic trimer has made the determination of its structure a challenge. Here we have used Fab fragments of the neutralizing antibody DV2-E104 to stop the conformational change of dengue virus at an intermediate stage of the fusion process. Using cryo-electron microscopy, we show that in this intermediate stage, the E glycoproteins form 60 trimers that are similar to the predicted "open" fusogenic trimer. IMPORTANCE The structure of a dengue virus has been captured during the formation of fusogenic trimers. This was accomplished by binding Fab fragments of the neutralizing antibody DV2-E104 to the virus at neutral pH and then decreasing the pH to 5.5. These trimers had an "open" conformation, which is distinct from the "closed" conformation of postfusion trimers. Only two of the three E proteins within each spike are bound by a Fab molecule at domain III. Steric hindrance around the icosahedral 3-fold axes prevents binding of a Fab to the third domain III of each E protein spike. Binding of the DV2-E104 Fab fragments prevents domain III from rotating by about 130 degrees to the postfusion orientation and thus precludes the stem region from "zipping" together the three E proteins along the domain II boundaries into the "closed" postfusion conformation, thus inhibiting fusion

Validation of the Oncomine™ Focus Panel for Next Generation Sequencing of clinical tumour samples

The clinical utility of next-generation sequencing (NGS) for a diverse range of targets is expanding, increasing the need for multiplexed analysis of both DNA and RNA. However, translation into daily use requires a rigorous and comprehensive validation strategy. The aim of this clinical validation was to assess the performance of the Ion Torrent Personal Genome Machine (IonPGM™) and validate the Oncomine™ Focus DNA and RNA Fusion panels for clinical application in solid tumour testing of formalin-fixed, paraffin-embedded (FFPE) tissue. Using a mixture of routine FFPE and reference material across a variety of tissue and specimen types, we sequenced 86 and 31 samples on the Oncomine™ Focus DNA and RNA Fusion assays, respectively. This validation considered a number of parameters including the clinical robustness of the bioinformatics pipeline for variant detection and interpretation. The Oncomine™ Focus DNA assay had a sample and variant-based sensitivity of 99.1 and 97.1%, respectively, and an assay specificity of 100%. The Oncomine™ Focus Fusion panel had a good sensitivity and specificity based upon the samples assessed, however requires further validation to confirm findings due to limited sample numbers. We observed a good sequencing performance based upon amplicon, gene (hotspot variants within gene) and sample specific analysis with 92% of clinical samples obtaining an average amplicon coverage above 500X. Detection of some indels was challenging for the routine IonReporter™ workflow; however, the addition of NextGENe® software improved indel identification demonstrating the importance of both bench and bioinformatic validation. With an increasing number of clinically actionable targets requiring a variety of methodologies, NGS provides a cost-effective and time-saving methodology to assess multiple targets across different modalities. We suggest the use of multiple analysis software to ensure identification of clinically applicable variants.Publisher PDFPeer reviewe

Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope

We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum from individuals that experienced natural infection or immunization. Herein, we describe the crystal structures of DENV1-E111 bound to a novel CC' loop epitope on domain III (DIII) of the E protein from two different DENV-1 genotypes. Docking of our structure onto the available cryo-electron microscopy models of DENV virions revealed that the DENV1-E111 epitope was inaccessible, suggesting that this antibody recognizes an uncharacterized virus conformation. While the affinity of binding between DENV1-E111 and DIII varied by genotype, we observed limited correlation with inhibitory activity. Instead, our results support the conclusion that potent neutralization depends on genotype-dependent exposure of the CC' loop epitope. These findings establish new structural complexity of the DENV virion, which may be relevant for the choice of DENV strain for induction or analysis of neutralizing antibodies in the context of vaccine development

The Fc region of an antibody impacts the neutralization of West Nile viruses in different maturation states

Flavivirus-infected cells secrete a structurally heterogeneous population of viruses because of an inefficient virion maturation process. Flaviviruses assemble as noninfectious, immature virions composed of trimers of envelope (E) and precursor membrane (prM) protein heterodimers. Cleavage of prM is a required process during virion maturation, although this often remains incomplete for infectious virus particles. Previous work demonstrated that the efficiency of virion maturation could impact antibody neutralization through changes in the accessibility of otherwise cryptic epitopes on the virion. In this study, we show that the neutralization potency of monoclonal antibody (MAb) E33 is sensitive to the maturation state of West Nile virus (WNV), despite its recognition of an accessible epitope, the domain III lateral ridge (DIII-LR). Comprehensive epitope mapping studies with 166 E protein DIII-LR variants revealed that the functional footprint of MAb E33 on the E protein differs subtly from that of the well-characterized DIII-LR MAb E16. Remarkably, aromatic substitutions at E protein residue 306 ablated the maturation state sensitivity of E33 IgG, and the neutralization efficacy of E33 Fab fragments was not affected by changes in the virion maturation state. We propose that E33 IgG binding on mature virions orients the Fc region in a manner that impacts subsequent antibody binding to nearby sites. This Fc-mediated steric constraint is a novel mechanism by which the maturation state of a virion modulates the efficacy of the humoral immune response to flavivirus infection

Functional analysis of antibodies against dengue virus type 4 reveals strain-dependent epitope exposure that impacts neutralization and protection

Although prior studies have characterized the neutralizing activities of monoclonal antibodies (MAbs) against dengue virus (DENV) serotypes 1, 2, and 3 (DENV-1, DENV-2, and DENV-3), few reports have assessed the activity of MAbs against DENV-4. Here, we evaluated the inhibitory activity of 81 new mouse anti-DENV-4 MAbs. We observed strain- and genotype-dependent differences in neutralization of DENV-4 by MAbs mapping to epitopes on domain II (DII) and DIII of the envelope (E) protein. Several anti-DENV-4 MAbs inefficiently inhibited at least one strain and/or genotype, suggesting that the exposure or sequence of neutralizing epitopes varies within isolates of this serotype. Remarkably, flavivirus cross-reactive MAbs, which bound to the highly conserved fusion loop in DII and inhibited infection of DENV-1, DENV-2, and DENV-3, more weakly neutralized five different DENV-4 strains encompassing the genetic diversity of the serotype after preincubation at 37°C. However, increasing the time of preincubation at 37°C or raising the temperature to 40°C enhanced the potency of DII fusion loop-specific MAbs and some DIII-specific MAbs against DENV-4 strains. Prophylaxis studies in two new DENV-4 mouse models showed that neutralization titers of MAbs after preincubation at 37°C correlated with activity in vivo. Our studies establish the complexity of MAb recognition against DENV-4 and suggest that differences in epitope exposure relative to other DENV serotypes affect antibody neutralization and protective activity

INSIG1 influences obesity-related hypertriglyceridemia in humans

In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIGs) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 × 10−3 in 1,560 individuals of the original linkage cohort, P = 8 × 10−4 in 920 unrelated individuals of the replication cohort, combined P = 9.9 × 10−6). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2, the only homolog of INSIG1, enhances the effect of rs2721 (P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans

Potent Dengue virus neutralization by a therapeutic antibody with low monovalent affinity requires bivalent engagement

We recently described our most potently neutralizing monoclonal antibody, E106, which protected against lethal Dengue virus type 1 (DENV-1) infection in mice. To further understand its functional properties, we determined the crystal structure of E106 Fab in complex with domain III (DIII) of DENV-1 envelope (E) protein to 2.45 Å resolution. Analysis of the complex revealed a small antibody-antigen interface with the epitope on DIII composed of nine residues along the lateral ridge and A-strand regions. Despite strong virus neutralizing activity of E106 IgG at picomolar concentrations, E106 Fab exhibited a ∼20,000-fold decrease in virus neutralization and bound isolated DIII, E, or viral particles with only a micromolar monovalent affinity. In comparison, E106 IgG bound DENV-1 virions with nanomolar avidity. The E106 epitope appears readily accessible on virions, as neutralization was largely temperature-independent. Collectively, our data suggest that E106 neutralizes DENV-1 infection through bivalent engagement of adjacent DIII subunits on a single virion. The isolation of anti-flavivirus antibodies that require bivalent binding to inhibit infection efficiently may be a rare event due to the unique icosahedral arrangement of envelope proteins on the virion surface