Two Years Later: Journals Are Not Yet Enforcing the ARRIVE Guidelines on Reporting Standards for Pre-Clinical Animal Studies

There is growing concern that poor experimental design and lack of transparent reporting contribute to the frequent failure of pre-clinical animal studies to translate into treatments for human disease. In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were introduced to help improve reporting standards. They were published in PLOS Biology and endorsed by funding agencies and publishers and their journals, including PLOS, Nature research journals, and other top-tier journals. Yet our analysis of papers published in PLOS and Nature journals indicates that there has been very little improvement in reporting standards since then. This suggests that authors, referees, and editors generally are ignoring guidelines, and the editorial endorsement is yet to be effectively implemented

The Index-Based Subgraph Matching Algorithm (ISMA): Fast Subgraph Enumeration in Large Networks Using Optimized Search Trees

Subgraph matching algorithms are designed to find all instances of predefined subgraphs in a large graph or network and play an important role in the discovery and analysis of so-called network motifs, subgraph patterns which occur more often than expected by chance. We present the index-based subgraph matching algorithm (ISMA), a novel tree-based algorithm. ISMA realizes a speedup compared to existing algorithms by carefully selecting the order in which the nodes of a query subgraph are investigated. In order to achieve this, we developed a number of data structures and maximally exploited symmetry characteristics of the subgraph. We compared ISMA to a naive recursive tree-based algorithm and to a number of well-known subgraph matching algorithms. Our algorithm outperforms the other algorithms, especially on large networks and with large query subgraphs. An implementation of ISMA in Java is freely available at http://sourceforge.net/projects/isma

Negotiating Value: Comparing Human and Animal Fracture Care in Industrial Societies

At the beginning of the twentieth-century, human and veterinary surgeons faced the challenge of a medical marketplace transformed by technology. The socio-economic value ascribed to their patients – people and domestic animals – was changing, reflecting the increasing mechanisation of industry and the decreasing dependence of society upon non-human animals for labour. In human medicine, concern for the economic consequences of fractures “pathologised” any significant level of post-therapeutic disability, a productivist perspective contrary to the traditional corpus of medical values. In contrast, veterinarians adapted to the mechanisation of horse-power by shifting their primary professional interest to companion animals; a type of veterinary patient generally valued for the unique emotional attachment of the owner, and not the productive capacity of the animal. The economic rationalisation of human fracture care and the “sentimental” transformation of veterinary orthopaedic expertise indicates how these specialists utilised increasingly convergent rhetorical arguments to justify the application of innovative fracture care technologies to their humans and animal patients. Keywords: Fracture care, Industrialisation, Veterinary History, Human/animal relation

Synthetic Double-Stranded RNAs Are Adjuvants for the Induction of T Helper 1 and Humoral Immune Responses to Human Papillomavirus in Rhesus Macaques

Toll-like receptor (TLR) ligands are being considered as adjuvants for the induction of antigen-specific immune responses, as in the design of vaccines. Polyriboinosinic-polyribocytoidylic acid (poly I:C), a synthetic double-stranded RNA (dsRNA), is recognized by TLR3 and other intracellular receptors. Poly ICLC is a poly I:C analogue, which has been stabilized against the serum nucleases that are present in the plasma of primates. Poly I:C12U, another analogue, is less toxic but also less stable in vivo than poly I:C, and TLR3 is essential for its recognition. To study the effects of these compounds on the induction of protein-specific immune responses in an animal model relevant to humans, rhesus macaques were immunized subcutaneously (s.c.) with keyhole limpet hemocyanin (KLH) or human papillomavirus (HPV)16 capsomeres with or without dsRNA or a control adjuvant, the TLR9 ligand CpG-C. All dsRNA compounds served as adjuvants for KLH-specific cellular immune responses, with the highest proliferative responses being observed with 2 mg/animal poly ICLC (p = 0.002) or 6 mg/animal poly I:C12U (p = 0.001) when compared with immunization with KLH alone. Notably, poly ICLC—but not CpG-C given at the same dose—also helped to induce HPV16-specific Th1 immune responses while both adjuvants supported the induction of strong anti-HPV16 L1 antibody responses as determined by ELISA and neutralization assay. In contrast, control animals injected with HPV16 capsomeres alone did not develop substantial HPV16-specific immune responses. Injection of dsRNA led to increased numbers of cells producing the T cell–activating chemokines CXCL9 and CXCL10 as detected by in situ hybridization in draining lymph nodes 18 hours after injections, and to increased serum levels of CXCL10 (p = 0.01). This was paralleled by the reduced production of the homeostatic T cell–attracting chemokine CCL21. Thus, synthetic dsRNAs induce an innate chemokine response and act as adjuvants for virus-specific Th1 and humoral immune responses in nonhuman primates

Megabase deletions of gene deserts result in viable mice

The functional importance of the approximately 98 percent of mammalian genomes not corresponding to protein coding sequences remain largely un-scrutinized 1. To test experimentally whether some extensive regions of non-coding DNA, referred to as gene deserts 2-4, contain critical functions essential for the viability of the organism, we deleted two large non-coding intervals, 1,511 kb and 845 kb in length, from the mouse genome. Viable mice homozygous for the deletions were generated and were indistinguishable from wild-type littermates with regards to morphology, reproductive fitness, growth, longevity and a variety of parameters assaying general homeostasis. Further in-depth analysis of the expression of genes bracketing the deletions revealed similar expression characteristics in homozygous deletion and wild-type mice. Together, the two deleted segments harbour 1,243 non-coding sequences conserved between humans and rodents (>100bp, 70 percent identity). These studies demonstrate that some large-scale deletions of non-coding DNA can be well tolerated by an organism, bringing into question the role of many human-mouse conserved sequences 5,6, and further supports the existence of potentially "disposable DNAi" in the genomes of mammals