The University of Akron Human Powered Vehicle Team

The University of Akron Human Powered Vehicle Team’s 2016 vehicle, Klokan, was designed, manufactured and tested with safety, reliability, performance and ease of use in mind. The vehicle is a fully faired tadpole trike with a lightweight aluminum frame constructed from 6061-T6 tubing having a total weight of 8.9 lbs. To complement the lightweight frame, the fairing is constructed from polycarbonate, PETG and carbon fiber strips which combine into a lightweight, easy to manufacture weather barrier and aerodynamic structure. Klokan was designed to be a safe and efficient mode of everyday transportation which ensures that riders are sufficiently protected by a rollover protection system (RPS) which was designed to meet the ASME HPVC requirements with a minimum safety factor of two. The project scope includes all aspects of design and fabrication to create a vehicle that is easy to manufacture, easy to use, safe, and low cost to facilitate its usability in everyday situations. The team completed research on how to improve the manufacturability, reliability, and performance through analysis of designs, computer based modeling, and physical testing to validate that the bike meets team goals as well as exceeding the requirements set by the ASME Human Powered Vehicle Competition. The frame was designed in a manner that reduces welding through the use of bends and allows for precision fixturing to be manufactured and used to construct multiple frames quickly and efficiently. The fairing’s modular construction reduces the need for specialized tooling while minimizing weight and construction time. The team designed and successfully implemented an innovative rollover warning system which actively monitors the percentage of vehicle load on each tire and warns the driver through audible tone and visual warning light prior to a dangerous rollover becoming imminent

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The diversity outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression, and as such are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), and DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represented a distinct combination of the four histone modifications. We found that the epigenetic landscape was highly variable across the DO founders and was associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice

An Essential Role for the Proximal but Not the Distal Cytoplasmic Tail of Glycoprotein M in Murid Herpesvirus 4 Infection

Murid herpesvirus-4 (MuHV-4) provides a tractable model with which to define common, conserved features of gamma-herpesvirus biology. The multi-membrane spanning glycoprotein M (gM) is one of only 4 glycoproteins that are essential for MuHV-4 lytic replication. gM binds to gN and is thought to function mainly secondary envelopment and virion egress, for which several predicted trafficking motifs in its C-terminal cytoplasmic tail could be important. We tested the contribution of the gM cytoplasmic tail to MuHV-4 lytic replication by making recombinant viruses with varying C-terminal deletions. Removing an acidic cluster and a distal YXXΦ motif altered the capsid distribution somewhat in infected cells but had little effect on virus replication, either in vitro or in vivo. In contrast, removing a proximal YXXΦ motif as well completely prevented productive replication. gM was still expressed, but unlike its longer forms showed only limited colocalization with co-transfected gN, and in the context of whole virus appeared to support gN expression less well. We conclude that some elements of the gM cytoplasmic tail are dispensible for MuHV-4 replication, but the tail as a whole is not

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease

Electrically controlled nuclear polarization of individual atoms

Nuclear spins serve as sensitive probes in chemistry1 and materials science2 and are promising candidates for quantum information processing3,4,5,6. NMR, the resonant control of nuclear spins, is a powerful tool for probing local magnetic environments in condensed matter systems, which range from magnetic ordering in high-temperature superconductors7,8 and spin liquids9 to quantum magnetism in nanomagnets10,11. Increasing the sensitivity of NMR to the single-atom scale is challenging as it requires a strong polarization of nuclear spins, well in excess of the low polarizations obtained at thermal equilibrium, as well as driving and detecting them individually4,5,12. Strong nuclear spin polarization, known as hyperpolarization, can be achieved through hyperfine coupling with electron spins2. The fundamental mechanism is the conservation of angular momentum: an electron spin flips and a nuclear spin flops. The nuclear hyperpolarization enables applications such as in vivo magnetic resonance imaging using nanoparticles13, and is harnessed for spin-based quantum information processing in quantum dots14 and doped silicon15,16,17. Here we polarize the nuclear spins of individual copper atoms on a surface using a spin-polarized current in a scanning tunnelling microscope. By employing the electron–nuclear flip-flop hyperfine interaction, the spin angular momentum is transferred from tunnelling electrons to the nucleus of individual Cu atoms. The direction and magnitude of the nuclear polarization is controlled by the direction and amplitude of the current. The nuclear polarization permits the detection of the NMR of individual Cu atoms, which is used to sense the local magnetic environment of the Cu electron spin.P.W., Y.B. and A.J.H. acknowledge support from Institute for Basic Science under IBS-R027-D1. P.W. acknowledges support from the Alexander von Humboldt Foundation. A.F. acknowledges CONICET (PIP11220150100327 and PUE-22920170100089CO). J.L.L. thanks the ETH Fellowship program for financial support. J.F.-R. thanks FCT, under the project PTDC/FIS-NAN/4662/2014

Integrative Multi-OMICs Identifies Therapeutic Response Biomarkers and Confirms Fidelity of Clinically Annotated, Serially Passaged Patient-Derived Xenografts Established from Primary and Metastatic Pediatric and AYA Solid Tumors

Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug–gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy

Integrative Multi-OMICs Identifies Therapeutic Response Biomarkers and Confirms Fidelity of Clinically Annotated, Serially Passaged Patient-Derived Xenografts Established from Primary and Metastatic Pediatric and AYA Solid Tumors

Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-na&iuml;ve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug&ndash;gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p &lt; 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy