Hermes CX-7: Air transport system design simulation

The Hermes CX-7 has been designed to service the overnight parcel package delivery needs of the cities of Aeroworld as determined in the G-Dome Enterprises market survey. The design optimization centers on the prime goal of servicing the needs of these cities as efficiently and profitably as possible. The greatest factors which affect the design of an aircraft for the mission outlined in the Request for Proposal are cost, construction feasibility and effectiveness of the design. Other influencing factors are given by the constraints of the market, including a maximum takeoff and landing distance of 60 feet, storage capability in a container of size 5 ft. x 3 ft. x 2 ft., cargo packages of 2 inch and 4 inch cubes, and ability to turn with a radius no larger than 60 feet. Safety considerations such as flying at or below Mach one (30 ft/s) and controllability and maintainability of the aircraft must also be designed into the aircraft. Another influential factor is the efficiency of the aircraft which involves optimizations and tradeoffs of such factors as weight, lifting surface sizing, structural redundancy, and material costs

Dickkopf-3 is upregulated in osteoarthritis and has a chondroprotective role

Objective Dickkopf-3 (Dkk3) is a non-canonical member of the Dkk family of Wnt antagonists and its upregulation has been reported in microarray analysis of cartilage from mouse models of osteoarthritis (OA). In this study we assessed Dkk3 expression in human OA cartilage to ascertain its potential role in chondrocyte signaling and cartilage maintenance. Methods Dkk3 expression was analysed in human adult OA cartilage and synovial tissues and during chondrogenesis of ATDC5 and human mesenchymal stem cells. The role of Dkk3 in cartilage maintenance was analysed by incubation of bovine and human cartilage explants with interleukin-1 (IL1) and oncostatin-M (OSM). Dkk3 expression was measured in cartilage following murine hip avulsion. Whether Dkk3 influenced Wnt, TGF and activin cell signaling was assessed in primary human chondrocytes and SW1353 chondrosarcoma cells using RT-qPCR and luminescence assays. Results Increased gene and protein levels of Dkk3 were detected in human OA cartilage, synovial tissue and synovial fluid. DKK3 expression was decreased during chondrogenesis of both ATDC5 cells and humans MSCs. Dkk3 inhibited IL1 and OSM-mediated proteoglycan loss from human and bovine cartilage explants and collagen loss from bovine cartilage explans. Cartilage DKK3 expression was decreased following hip avulsion injury. TGF signaling was enhanced by Dkk3 and Wnt3a and activin signaling were inhibited. Conclusions We provide evidence that Dkk3 is upregulated in OA and may have a protective effect on cartilage integrity by preventing proteoglycan loss and helping to restore OA-relevant signaling pathway activity. Targeting Dkk3 may be a novel approach in the treatment of OA

The relationship of circulating fibroblast growth factor 21 levels with pericardial fat: The Multi-Ethnic Study of Atherosclerosis.

Previous small studies have reported an association between circulating fibroblast growth factor 21 (FGF21) levels and pericardial fat volume in post-menopausal women and high cardiovascular disease (CVD) risk patients. In this study, we investigated the relationship of FGF21 levels with pericardial fat volume in participants free of clinical CVD at baseline. We analysed data from 5765 men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) with both pericardial fat volume and plasma FGF21 levels measured at baseline. 4746 participants had pericardial fat volume measured in at least one follow-up exam. After adjusting for confounding factors, ln-transformed FGF21 levels were positively associated with pericardial fat volume at baseline (β = 0.055, p < 0.001). When assessing change in pericardial fat volume over a mean duration of 3.0 years using a linear mixed-effects model, higher baseline FGF21 levels were associated with higher pericardial fat volume at baseline (2.381 cm3 larger in pericardial fat volume per one SD increase in ln-transformed FGF21 levels), but less pericardial fat accumulation over time (0.191 cm3/year lower per one SD increase in ln-transformed FGF21 levels). Cross-sectionally, higher plasma FGF21 levels were significantly associated with higher pericardial fat volume, independent of traditional CVD risk factors and inflammatory markers. However, higher FGF21 levels tended to be associated with less pericardial fat accumulation over time. Nevertheless, such change in pericardial fat volume is very modest and could be due to measurement error. Further studies are needed to elucidate the longitudinal relationship of baseline FGF21 levels with pericardial fat accumulation

A qualitative study of the practices and experiences of staff in multidisciplinary child sexual exploitation partnerships in three English coastal towns

This article presents findings from a qualitative study of the practices and experiences of people working in multi-disciplinary child sexual exploitation (CSE) partnerships in three coastal towns in England. The study is based on focus groups conducted with 36 practitioners from a range of professional groups, including police, social work, substance misuse, education, specialist youth workers, sexual health, and statutory and non-statutory children's services. The article begins with an overview of the three towns and the structure of their responses to CSE. It goes on to explore a range of factors, which contribute to the local issues around CSE and which affect and direct multiagency working. These include practitioner perspectives on CSE vulnerabil-ity, the discrepancy between young peoples' and practi-tioners' views about “exploitation”, a discussion of how CSE perpetrators initiate and develop contact with young people and the role of incentives—including drugs and alcohol—as part of CSE exploitation. We finish by drawing out some general conclusions

Long non-coding RNA ROCR contributes to SOX9 expression and chondrogenic differentiation of human mesenchymal stem cells

Long non-coding RNAs (lncRNAs) are expressed in a highly tissue-specific manner where they function in various aspects of cell biology, often as key regulators of gene expression. In this study we established a role for lncRNAs in chondrocyte differentiation. Using RNA sequencing we identified a human articular chondrocyte repertoire of lncRNAs from normal hip cartilage donated by neck of femur fracture patients. Of particular interest are lncRNAs upstream of the master chondrocyte transcription factor SOX9 locus. SOX9 is an HMG-box transcription factor which is essential for chondrocyte development by directing the expression of chondrocyte specific genes. Two of these lncRNAs are upregulated during chondrogenic differentiation of MSCs. Depletion of one of these lncRNA, LOC102723505, which we termed ROCR (regulator of chondrogenesis RNA), by RNAi disrupted MSC chondrogenesis, concomitant with reduced cartilage-specific gene expression and incomplete matrix component production, indicating an important role in chondrocyte biology. Specifically, SOX9 induction was significantly ablated in the absence of ROCR, and overexpression of SOX9 rescued the differentiation of MSCs into chondrocytes. Our work sheds further light on chondrocyte specific SOX9 expression and highlights a novel method of chondrocyte gene regulation involving a lncRNA

The function of microRNAs in cartilage and osteoarthritis

MicroRNAs are small double-stranded RNAs, which negatively regulate gene expression and have been shown to have key roles in both chondrocyte development and cartilage homeostasis with age. Deletion of all microRNAs in chondrocytes leads to skeletal growth defects in mice, whilst deletion of specific mi croRNAs, e.g. miR-140, leads to premature articular cartilage degradation and increased susceptibility to posttraumatic osteoarthritis. Studies comparing microRNA expression in normal human articular cartilage compared to osteoarthritic cartilage show differential expression, but varying sample groups make interpretation difficult. MicroRNAs have been proposed as circulating biomarkers of osteoarthritis, but again, this differs amongst patient cohorts. Many micro- RNAs have been shown to have roles in chondrocyte phenotype via signaling pathways, apoptosis, autophagy and senescence. Modulating microRNAs in the joint has been shown to reduce osteoarthritis in animal models and translating this to man as a novel therapeutic strategy will be key

The role of microRNA-3085 in chondrocyte function

MicroRNAs have been shown to play a role in cartilage development, homeostasis and breakdown during osteoarthritis. We previously identified miR-3085 in humans as a chondrocyte-selective microRNA, however it could not be detected by Northern blot. The aim of the current study was to prove that miR-3085 is a microRNA and to investigate the function of miR-3085 in signaling pathways relevant to cartilage homeostasis and osteoarthritis. Here, we confirm that miR-3085 is a microRNA and not another class of small RNA using (1) a pre-miR hairpin maturation assay, (2) expression levels in a Dicer null cell line, and (3) Ago2 pulldown. MicroRNA-3085-3p is expressed more highly in micromass than monolayer cultured chondrocytes. Transfection of miR-3085-3p into chondrocytes decreases expression of COL2A1 and ACAN, both of which are validated as direct targets of miR-3085-3p. Interleukin-1 induces the expression of miR-3085-3p, at least in part via NFκB. In a feed-forward mechanism, miR-3085-3p then potentiates NFκB signaling. However, at early time points after transfection, its action appears to be inhibitory. MyD88 has been shown to be a direct target of miR-3085-3p and may be responsible for the early inhibition of NFκB signaling. However, at later time points, MyD88 knockdown remains inhibitory and so other functions of miR-3085-3p are clearly dominant. TGFβ1 also induces the expression of miR-3085-3p, but in this instance, it exerts a feedback inhibition on signaling with SMAD3 and SMAD4 shown to be direct targets. This in vitro analysis shows that miR-3085-3p functions in chondrocytes to induce IL-1-signaling, reduce TGFβ1 signaling, and inhibit expression of matrix genes. These data suggest that miR-3085-3p has a role in chondrocyte function and could contribute to the process of osteoarthritis

The microRNA-29 family in cartilage homeostasis and osteoarthritis

MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family were also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways

A school intervention for 13- to 15-year-olds to prevent dating and relationship violence: the Project Respect pilot cluster RCT

Background ‘Dating and relationship violence’ is intimate partner violence during adolescence. Among dating adolescents in England, 66–75% of girls and 32–50% of boys report victimisation. Multicomponent school-based interventions might reduce dating and relationship violence. We optimised and piloted Project Respect, a new intervention in secondary schools in England, and study methods, to assess the value of a Phase III randomised controlled trial. Objectives To optimise Project Respect and to then conduct a pilot randomised controlled trial in southern England, addressing whether or not progression to a Phase III trial is justified in terms of prespecified criteria. To assess which of two dating and relationship violence scales is optimal, to assess response rates and to consider any necessary refinements. Design Optimisation activities aimed at intervention development and a pilot randomised controlled trial. Setting Optimisation in four secondary schools across southern England, varying by region and local deprivation. A pilot cluster randomised controlled trial in six other such schools (four intervention schools and two control schools), varying by region, attainment and local deprivation. Participants School students in years 8–10 at baseline and staff. Interventions Schools were randomised to the intervention or control arm in a 2 : 1 ratio; intervention comprised staff training, mapping ‘hotspots’ in school for dating and relationship violence, modifying staff patrols, school policy review, informing parents and carers, an application supporting student help-seeking, and a classroom curriculum for students in years 9 and 10 (including student-led campaigns). Main outcome measures Prespecified criteria for progression to Phase III of the trial, concerning acceptability, feasibility, fidelity and response rates. Primary health outcomes were assessed using the Safe Dates and short Conflicts in Adolescent Dating Relationships Inventory measures collected and analysed by individuals who were masked to allocation. Feasibility of economic analysis was assessed. Data sources Baseline and follow-up student and staff surveys, interviews, observations and logbooks. Results The intervention was optimised and approved by the Study Steering Committee. The student response rates in intervention and control groups were 1057 (84.8%) and 369 (76.6%) at baseline, and 1177 (76.8%) and 352 (83.4%) at follow-up, respectively. Safe Dates and the short Conflicts in Adolescent Dating Relationships Inventory had high levels of completion and reliability. At follow-up, prevalence of past-year dating and relationship violence victimisation was around 35% (Safe Dates scale and short Conflicts in Adolescent Dating Relationships Inventory). Staff response rates were very low. Training occurred in all four schools, with suboptimal fidelity. The curriculum was delivered with optimal fidelity in three schools. Other components were delivered inconsistently. Dating and relationship violence was addressed in control schools via violence prevention and responses, but not systematically. Intervention acceptability among students and staff was mixed. An economic evaluation would be feasible. Limitations One school did not undertake baseline surveys. Staff survey response rates were low and completion of the logbook was patchy. Conclusions Our findings suggest that progression to a Phase III trial of this intervention is not indicated because of limited fidelity and acceptability. Future work High prevalence of dating and relationship violence highlights the ongoing need for effective intervention. Potential intervention refinements would include more external support for schools and enhanced curriculum materials. Any future randomised controlled trials could consider having a longer lead-in from randomisation to intervention commencement, using the short Conflicts in Adolescent Dating Relationships Inventory as the primary outcome and not relying on staff surveys. Trial registration Current Controlled Trials ISRCTN65324176. Funding This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 8, No. 5. See the NIHR Journals Library website for further project information