Effectiveness of biomaterial-based combination strategies for spinal cord repair – a systematic review and meta-analysis of preclinical literature

Funding This work was supported by the Institute of Medical Sciences of the University of Aberdeen, International Spinal Research Trust, Scottish Rugby Union, RS McDonald Charitable Trust and The European Union’s Horizon 2020 research and innovation programme (Marie Skłodowska-Curie grant agreement no. 702213).Peer reviewedPublisher PD

Ethical and Scientific Considerations Regarding Animal Testing and Research

In 1959, William Russell and Rex Burch published the seminal book, The Principles of Humane Experimental Technique, which emphasized reduction, refinement, and replacement of animal use, principles which have since been referred to as the ‘‘3 Rs’’. These principles encouraged researchers to work to reduce the number of animals used in experiments to the minimum considered necessary, refine or limit the pain and distress to which animals are exposed, and replace the use of animals with non-animal alternatives when possible. Despite the attention brought to this issue by Russell and Burch and since, the number of animals used in research and testing has continued to increase, raising serious ethical and scientific issues. Further, while the ‘‘3 Rs’’ capture crucially important concepts, they do not adequately reflect the substantial developments in our new knowledge about the cognitive and emotional capabilities of animals, the individual interests of animals, or an updated understanding of potential harms associated with animal research. This Overview provides a brief summary of the ethical and scientific considerations regarding the use of animals in research and testing, and accompanies a Collection entitled Animals, Research, and Alternatives: Measuring Progress 50 Years Later, which aims to spur ethical and scientific advancement

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Technology selection —the impact of economic risk on decision making

Developing an understanding of economic variance (risk) is critical when evaluating alternative aquaculture production technologies. This article assesses the efficacy of employing a quantitative stochastic analysis technique to support technology selection decision making by undertaking a case study investment assessment of three alternative production expansion strategies (offshore sea-pens, land-based RAS growout and larger post-smolt) for the Tasmanian salmon industry. Results demonstrate that salmon aquaculture is undertaken with considerable underlying levels of economic risk, expansion offshore probably represents the lowest initial capital investment and greatest economic return, and that levels of financial uncertainty increase with land-based RAS production. The study highlights stochastic modeling provides significant “added-value” over single-point deterministic analysis and that developing an appreciation of the input variability is a key component in critically evaluating alternative production technologies

Influence of small-scale patchiness on resilience of nutrient cycling to extended hypoxia in estuarine sediments

Although much work has been done to predict the effects of hypoxia (dissolved oxygen \u3c 2 mg l−1) at regional scales, individual estuaries consist of a patchwork of micro-environments that can have different responses. We followed the effects of extended dissolved oxygen (DO) depletion on benthic fluxes of CO2, O2, NO3−, NH4+, N2, PO43− and Fe from estuarine sediments from 3 shallow sites with different macrofauna communities and levels of organic enrichment. DO depletion was achieved by a prolonged (40 d) dark incubation of sealed sediment cores. There were no discernible differences in NO3− and N2 fluxes between sites, but the effects of hypoxia on sediment metabolism, and on bioavailable nutrient release, NH4+ and PO43−, were modified by the initial macrofauna communities. The DO in cores containing sediments from a site dominated by small epifauna declined significantly faster than in cores containing a greater portion of burrowing infauna; burrows may provide an oxic reservoir within the sediments. Macrofauna mortality led to a more rapid efflux of mineralization products (CO2, NH4+ and PO43−) in the epifauna-dominated sites, as the small surface-dwelling animals decomposed more quickly. However, the cores were sealed, preventing migration of mobile epifauna away from the hypoxic conditions. The site with the lowest abundance of macrofauna also contained a large amount of refractory organic matter. Decomposition of this material was slow, with little release of nutrients. The study highlights the fact that environmental patchiness can modify the effects of hypoxia and stresses the importance of deeper burrowing fauna as a buffer against declining DO conditions

Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption

In multiple myeloma, inflammatory and anti-viral pathways promote disease progression and cancer stem cell generation. Using diverse pre-clinical models, we investigated the role of interferon regulatory factor 4 (IRF4) in myeloma progenitor regeneration. In a patient-derived xenograft model that recapitulates IRF4 pathway activation in human myeloma, we test the effects of IRF4 antisense oligonucleotides (ASOs) and identify a lead agent for clinical development (ION251). IRF4 overexpression expands myeloma progenitors, while IRF4 ASOs impair myeloma cell survival and reduce IRF4 and c-MYC expression. IRF4 ASO monotherapy impedes tumor formation and myeloma dissemination in xenograft models, improving animal survival. Moreover, IRF4 ASOs eradicate myeloma progenitors and malignant plasma cells while sparing normal human hematopoietic stem cell development. Mechanistically, IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion transcript expression, and promotes sensitivity to myeloma drugs. These findings will enable rapid clinical development of selective IRF4 inhibitors to prevent myeloma progenitor-driven relapse