Efficient Design and Analysis of Lightweight Reinforced Core Sandwich and PRSEUS Structures

Design, analysis, and sizing methods for two novel structural panel concepts have been developed and incorporated into the HyperSizer Structural Sizing Software. Reinforced Core Sandwich (RCS) panels consist of a foam core with reinforcing composite webs connecting composite facesheets. Boeing s Pultruded Rod Stitched Efficient Unitized Structure (PRSEUS) panels use a pultruded unidirectional composite rod to provide axial stiffness along with integrated transverse frames and stitching. Both of these structural concepts are ovencured and have shown great promise applications in lightweight structures, but have suffered from the lack of efficient sizing capabilities similar to those that exist for honeycomb sandwich, foam sandwich, hat stiffened, and other, more traditional concepts. Now, with accurate design methods for RCS and PRSEUS panels available in HyperSizer, these concepts can be traded and used in designs as is done with the more traditional structural concepts. The methods developed to enable sizing of RCS and PRSEUS are outlined, as are results showing the validity and utility of the methods. Applications include several large NASA heavy lift launch vehicle structures

The RNA Binding Protein Quaking Regulates Formation of circRNAs

SummaryCircular RNAs (circRNAs), formed by non-sequential back-splicing of pre-mRNA transcripts, are a widespread form of non-coding RNA in animal cells. However, it is unclear whether the majority of circRNAs represent splicing by-products without function or are produced in a regulated manner to carry out specific cellular functions. We show that hundreds of circRNAs are regulated during human epithelial-mesenchymal transition (EMT) and find that the production of over one-third of abundant circRNAs is dynamically regulated by the alternative splicing factor, Quaking (QKI), which itself is regulated during EMT. Furthermore, by modulating QKI levels, we show the effect on circRNA abundance is dependent on intronic QKI binding motifs. Critically, the addition of QKI motifs is sufficient to induce de novo circRNA formation from transcripts that are normally linearly spliced. These findings demonstrate circRNAs are both purposefully synthesized and regulated by cell-type specific mechanisms, suggesting they play specific biological roles in EMT

Making use of transcription factor enrichment to identify functional microRNA-regulons

microRNAs (miRNAs) are important modulators of messenger RNA stability and translation, controlling wide gene networks. Albeit generally modest on individual targets, the regulatory effect of miRNAs translates into meaningful pathway modulation through concurrent targeting of regulons with functional convergence. Identification of miRNA-regulons is therefore essential to understand the function of miRNAs and to help realise their therapeutic potential, but it remains challenging due to the large number of false positive target sites predicted per miRNA. In the current work, we investigated whether genes regulated by a given miRNA were under the transcriptional control of a predominant transcription factor (TF). Strikingly we found that for ~50% of the miRNAs analysed, their targets were significantly enriched in at least one common TF. We leveraged such miRNA-TF co-regulatory networks to identify pathways under miRNA control, and demonstrated that filtering predicted miRNA-target interactions (MTIs) relying on such pathways significantly enriched the proportion of predicted true MTIs. To our knowledge, this is the first description of an in- silico pipeline facilitating the identification of miRNA-regulons, to help understand miRNA function.Pacôme B. Prompsy, John Toubia, Linden J. Gearing, Randle L. Knight, Samuel C. Forster, Cameron P. Bracken, Michael P. Gantie

Assessing the gene regulatory properties of Argonaute-bound small RNAs of diverse genomic origin

High-throughput sequencing reveals an abundance of microRNA-sized fragments derived from larger non-coding RNAs. Roles for these small RNAs in gene silencing are suggested by their co-precipitation with Argonaute, the microRNA effector protein, though the extent to which they suppress gene expression endogenously remains unclear. To address this, we used luciferase reporters to determine the endogenous functionality of small RNAs from a diverse range of sources. We demonstrate small RNAs derived from snoRNAs have the capacity to act in a microRNA-like manner, though we note the vast majority of these are bound to Argonaute at levels below that required for detectable silencing activity. We show Argonaute exhibits a high degree of selectivity for the small RNAs with which it interacts and note that measuring Argonaute-associated levels is a better indicator of function than measuring total expression. Although binding to Argonaute at sufficient levels is necessary for demonstrating microRNA functionality in our reporter assay, this alone is not enough as some small RNAs derived from other non-coding RNAs (tRNAs, rRNAs, Y-RNAs) are associated with Argonaute at very high levels yet do not serve microRNA-like roles.Daniel W. Thomson, Katherine A. Pillman, Matthew L. Anderson, David M. Lawrence, John Toubia, Gregory J. Goodall and Cameron P. Bracke

Spontaneous splenic rupture in an active duty Marine upon return from Iraq: a case report

<p>Abstract</p> <p>Introduction</p> <p>Atraumatic splenic rupture is a rare event that has been associated with several infectious disease processes. In the active duty military population, potential exposure to these pathogens is significant. Here we discuss the case of an active duty Marine with spontaneous splenic rupture upon return from a six-month deployment in Iraq.</p> <p>Case presentation</p> <p>A previously healthy 30-year-old Caucasian male active duty Marine presented with abdominal pain, fever and diarrhea after deployment to Iraq in support of Operation Iraqi Freedom. Based on clinical and radiographic evidence, a diagnosis of spontaneous splenic rupture was ultimately suspected. After exploratory laparotomy with confirmation of rupture, splenectomy was performed, and the patient made a full, uneventful recovery. Histopathologic examination revealed mild splenomegaly with a ruptured capsule of undetermined cause.</p> <p>Conclusion</p> <p>Spontaneous splenic rupture is a rare event that may lead to life-threatening hemorrhage if not diagnosed and treated quickly. Although the cause of this patient's case was unknown, atraumatic splenic rupture has been associated with a variety of infectious diseases and demonstrates some risks the active duty military population may face while on deployment. Having an awareness of these pathogens and their role in splenic rupture, clinicians caring for military personnel must be prepared to recognize and treat this potentially fatal complication.</p

Naturally existing isoforms of miR-222 have distinct functions

Deep-sequencing reveals extensive variation in the sequence of endogenously expressed microRNAs (termed 'isomiRs') in human cell lines and tissues, especially in relation to the 3' end. From the immunoprecipitation of the microRNA-binding protein Argonaute and the sequencing of associated small RNAs, we observe extensive 3'-isomiR variation, including for miR-222 where the majority of endogenously expressed miR-222 is extended by 1-5 nt compared to the canonical sequence. We demonstrate this 3' heterogeneity has dramatic implications for the phenotype of miR-222 transfected cells, with longer isoforms promoting apoptosis in a size (but not 3' sequence)-dependent manner. The transfection of longer miR-222 isomiRs did not induce an interferon response, but did downregulate the expression of many components of the pro-survival PI3K-AKT pathway including PIK3R3, a regulatory subunit whose knockdown phenocopied the expression of longer 222 isoforms in terms of apoptosis and the inhibition of other PI3K-AKT genes. As this work demonstrates the capacity for 3' isomiRs to mediate differential functions, we contend more attention needs to be given to 3' variance given the prevalence of this class of isomiR.Feng Yu, Katherine A. Pillman, Corine T. Neilsen, John Toubia, David M. Lawrence, Anna Tsykin, Michael P. Gantier, David F. Callen, Gregory J. Goodall and Cameron P. Bracke

Characterising Distinct Migratory Profiles of Infiltrating T-Cell Subsets in Human Glioblastoma

Glioblastoma is the most common and aggressive form of primary brain cancer, with no improvements in the 5-year survival rate of 4.6% over the past three decades. T-cellbased immunotherapies such as immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapy have prolonged the survival of patients with other cancers and have undergone early-phase clinical evaluation in glioblastoma patients. However, a major challenge for T-cell-based immunotherapy of glioblastoma and other solid cancers is Tcell infiltration into tumours. This process is mediated by chemokine-chemokine receptor and integrin-adhesion molecule interactions, yet the specific nature of the molecules that may facilitate T-cell homing into glioblastoma are unknown. Here, we have characterised chemokine receptor and integrin expression profiles of endogenous glioblastomainfiltrating T cells, and the chemokine expression profile of glioblastoma-associated cells, by single-cell RNA-sequencing. Subsequently, chemokine receptors and integrins were validated at the protein level to reveal enrichment of receptors CCR2, CCR5, CXCR3, CXCR4, CXCR6, CD49a, and CD49d in glioblastoma-infiltrating T-cell populations relative to T cells in matched patient peripheral blood. Complementary chemokine ligand expression was then validated in glioblastoma biopsies and glioblastoma-derived primary cell cultures. Together, enriched expression of homing receptor-ligand pairs identified in this study implicate a potential role in mediating T-cell infiltration into glioblastoma. Importantly, our data characterising the migratory receptors on endogenous tumour-infiltrating T cells could be exploited to enhance the tumour-homing properties of future T-cell immunotherapies for glioblastoma.Paris M. Kollis, Lisa M. Ebert, John Toubia, Cameron R. Bastow, Rebecca J. Ormsby, Santosh I. Poonnoose, Sakthi Lenin, Melinda N. Tea, Stuart M. Pitson, Guillermo A. Gomez, Michael P. Brown, and Tessa Garget

Harnessing the Creative Potential of Consumers: Money, Participation and Creativity in Idea Crowdsourcing

Given the growing importance of innovation and consumer engagement, many firms are strongly interested in finding ways to encourage their consumers to generate creative new product ideas for them in their crowdsourcing initiatives. To that end, managers often use monetary rewards – one of the most commonly used managerial tools to stimulate desired behaviors. A critical question in this respect is whether the use of monetary rewards is effective in stimulating creativity and, if so, how large those rewards should be. This study aims to answer these questions. The results of an experiment suggest that introducing monetary rewards does not contribute to the number of new product ideas generated by a single consumer or the novelty of his/her ideas, and when the reward is relatively small it can even be harmful. Monetary rewards, however, are effective in encouraging widespread participation in crowdsourcing initiatives and improving the appropriateness of the new product ideas. As a whole, these findings take us a step further toward better understanding the motivational mechanisms of consumer creativity in new product ideation