Jacobian Ensembles Improve Robustness Trade-offs to Adversarial Attacks

Deep neural networks have become an integral part of our software infrastructure and are being deployed in many widely-used and safety-critical applications. However, their integration into many systems also brings with it the vulnerability to test time attacks in the form of Universal Adversarial Perturbations (UAPs). UAPs are a class of perturbations that when applied to any input causes model misclassification. Although there is an ongoing effort to defend models against these adversarial attacks, it is often difficult to reconcile the trade-offs in model accuracy and robustness to adversarial attacks. Jacobian regularization has been shown to improve the robustness of models against UAPs, whilst model ensembles have been widely adopted to improve both predictive performance and model robustness. In this work, we propose a novel approach, Jacobian Ensembles-a combination of Jacobian regularization and model ensembles to significantly increase the robustness against UAPs whilst maintaining or improving model accuracy. Our results show that Jacobian Ensembles achieves previously unseen levels of accuracy and robustness, greatly improving over previous methods that tend to skew towards only either accuracy or robustness

Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management.

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed

Combined systems approaches reveal highly plastic responses to antimicrobial peptide challenge in Escherichia coli

Obtaining an in-depth understanding of the arms races between peptides comprising the innate immune response and bacterial pathogens is of fundamental interest and will inform the development of new antibacterial therapeutics. We investigated whether a whole organism view of antimicrobial peptide (AMP) challenge on Escherichia coli would provide a suitably sophisticated bacterial perspective on AMP mechanism of action. Selecting structurally and physically related AMPs but with expected differences in bactericidal strategy, we monitored changes in bacterial metabolomes, morphological features and gene expression following AMP challenge at sub-lethal concentrations. For each technique, the vast majority of changes were specific to each AMP, with such a plastic response indicating E. coli is highly capable of discriminating between specific antibiotic challenges. Analysis of the ontological profiles generated from the transcriptomic analyses suggests this approach can accurately predict the antibacterial mode of action, providing a fresh, novel perspective for previous functional and biophysical studies

The funding and use of high-cost medicines in Australia: the example of anti-rheumatic biological medicines

BACKGROUND: Subsidised access to high-cost medicines in Australia is restricted under national programs (the Pharmaceutical Benefits Scheme, PBS, and the Repatriation Pharmaceutical Benefits Scheme, RPBS) with a view to achieving cost-effective use. The aim of this study was to examine the use and associated government cost of biological agents for treating rheumatoid arthritis over the first two years of subsidy, and to compare these data to the predicted outcomes. METHODS: National prescription and expenditure data for the biologicals, etanercept, infliximab, adalimumab, and anakinra were collected and analysed for the period August 2003 to July 2005. Dispensing data on biologicals sorted by the metropolitan, rural and remote zones and by prescriber major specialty were also examined. RESULTS: A total of 27,970 prescriptions for biologicals was reimbursed. The government expenditure was A$53.1 million, representing only 19$52 million) and the remainder by the RPBS. Approximately 62% of the prescriptions were for concessional patients (A$32.9 million). There was considerable variability in the use of biologicals across Australian states and territories, usage roughly correlating with the per capita adjusted number of rheumatologists. The total number of prescriptions continued to increase over the study period. Etanercept was the most highly prescribed agent (74% by number of prescriptions), although its use was beginning to plateau. Use of adalimumab increased steadily. Use of infliximab and anakinra was considerably lower. The resultant health outcomes for individual patients are unknown. Prescribers from capital cities and other metropolitan centres provided a majority of prescriptions of biologicals (89%). CONCLUSION: The overall uptake of biologicals for treating rheumatoid arthritis over the first two years of PBS subsidy was considerably lower than expected. Long-term safety concerns and the expanded clinical uses of these drugs emphasise the need for evaluation. It is essential that there is comprehensive, ongoing analysis of utilisation data, associated expenditure and, importantly, patient outcomes in order to enhance accountability, efficiency and equity of policies that allocate substantial resources to subsidising national access to high-cost medicines

Dietary phenethylisothiocyanate attenuates bowel inflammation in mice

<p>Abstract</p> <p>Background</p> <p>Phenethylisothiocyanate (PEITC) is produced by Brassica food plants. PEO is a <b>P</b>EITC <b>E</b>ssential <b>O</b>il containing >95% natural PEITC. PEITC is known to produce various health benefits but its effect in alleviation of ulcerative colitis signs is unknown.</p> <p>Results</p> <p>In two efficacy studies (acute and chronic) oral administration of PEO was effective at remitting acute and chronic signs of ulcerative colitis (UC) in mice. Disease activity, histology and biochemical characteristics were measured in the treated animals and were compared with appropriate controls. PEO treatment significantly improved body weights and stool consistency as well as decreased intestinal bleeding. PEO treatment also reduced mucosal inflammation, depletion of goblet cells and infiltration of inflammatory cells. Attenuation of proinflammatory interleukin1β production was observed in the colons of PEO-treated animals. Expression analyses were also carried out for immune function related genes, transcription factors and cytokines in lipopolysaccharide-activated mouse macrophage cells. PEO likely affects an intricate network of immune signaling genes including a novel concentration dependent reduction of total cellular Signal Transducer and Activator of Transcription 1 (STAT1) as well as nuclear phosphorylated-STAT1 (activated form of STAT1). A PEO-concentration dependent decrease of mRNA of C-X-C motif ligand 10 (a STAT1 responsive chemokine) and Interleukin 6 were also observed.</p> <p>Conclusions</p> <p>PEO might be a promising candidate to develop as a treatment for ulcerative colitis patients. The disease attenuation by PEO is likely associated with suppression of activation of STAT1 transcription and inhibition of pro-inflammatory cytokines.</p

Repetitive N-WASP–Binding Elements of the Enterohemorrhagic Escherichia coli Effector EspFU Synergistically Activate Actin Assembly

Enterohemorrhagic Escherichia coli (EHEC) generate F-actin–rich adhesion pedestals by delivering effector proteins into mammalian cells. These effectors include the translocated receptor Tir, along with EspFU, a protein that associates indirectly with Tir and contains multiple peptide repeats that stimulate actin polymerization. In vitro, the EspFU repeat region is capable of binding and activating recombinant derivatives of N-WASP, a host actin nucleation-promoting factor. In spite of the identification of these important bacterial and host factors, the underlying mechanisms of how EHEC so potently exploits the native actin assembly machinery have not been clearly defined. Here we show that Tir and EspFU are sufficient for actin pedestal formation in cultured cells. Experimental clustering of Tir-EspFU fusion proteins indicates that the central role of the cytoplasmic portion of Tir is to promote clustering of the repeat region of EspFU. Whereas clustering of a single EspFU repeat is sufficient to bind N-WASP and generate pedestals on cultured cells, multi-repeat EspFU derivatives promote actin assembly more efficiently. Moreover, the EspFU repeats activate a protein complex containing N-WASP and the actin-binding protein WIP in a synergistic fashion in vitro, further suggesting that the repeats cooperate to stimulate actin polymerization in vivo. One explanation for repeat synergy is that simultaneous engagement of multiple N-WASP molecules can enhance its ability to interact with the actin nucleating Arp2/3 complex. These findings define the minimal set of bacterial effectors required for pedestal formation and the elements within those effectors that contribute to actin assembly via N-WASP-Arp2/3–mediated signaling pathways

Dynamics of mechanical waves in periodic grapheme nanoribbon assemblies

We simulate the natural frequencies and the acoustic wave propagation characteristics of graphene nanoribbons (GNRs) of the type (8,0) and (0,8) using an equivalent atomistic-continuum FE model previously developed by some of the authors, where the C-C bonds thickness and average equilibrium lengths during the dynamic loading are identified through the minimisation of the system Hamiltonian. A molecular mechanics model based on the UFF potential is used to benchmark the hybrid FE models developed. The acoustic wave dispersion characteristics of the GNRs are simulated using a Floquet-based wave technique used to predict the pass-stop bands of periodic mechanical structures. We show that the thickness and equilibrium lengths do depend on the specific vibration and dispersion mode considered, and that they are in general different from the classical constant values used in open literature (0.34 nm for thickness and 0.142 nm for equilibrium length). We also show the dependence of the wave dispersion characteristics versus the aspect ratio and edge configurations of the nanoribbons, with widening band-gaps that depend on the chirality of the configurations. The thickness, average equilibrium length and edge type have to be taken into account when nanoribbons are used to design nano-oscillators and novel types of mass sensors based on periodic arrangements of nanostructures

Improving Salmonella vector with rec mutation to stabilize the DNA cargoes

<p>Abstract</p> <p>Background</p> <p><it>Salmonella </it>has been employed to deliver therapeutic molecules against cancer and infectious diseases. As the carrier for target gene(s), the cargo plasmid should be stable in the bacterial vector. Plasmid recombination has been reduced in <it>E. coli </it>by mutating several genes including the <it>recA</it>, <it>recE</it>, <it>recF </it>and <it>recJ</it>. However, to our knowledge, there have been no published studies of the effect of these or any other genes that play a role in plasmid recombination in <it>Salmonella enterica</it>.</p> <p>Results</p> <p>The effect of <it>recA</it>, <it>recF </it>and <it>recJ </it>deletions on DNA recombination was examined in three serotypes of <it>Salmonella enterica</it>. We found that (1) intraplasmid recombination between direct duplications was RecF-independent in Typhimurium and Paratyphi A, but could be significantly reduced in Typhi by a Δ<it>recA </it>or Δ<it>recF </it>mutation; (2) in all three <it>Salmonella </it>serotypes, both Δ<it>recA </it>and Δ<it>recF </it>mutations reduced intraplasmid recombination when a 1041 bp intervening sequence was present between the duplications; (3) Δ<it>recA </it>and Δ<it>recF </it>mutations resulted in lower frequencies of interplasmid recombination in Typhimurium and Paratyphi A, but not in Typhi; (4) in some cases, a Δ<it>recJ </it>mutation could reduce plasmid recombination but was less effective than Δ<it>recA </it>and Δ<it>recF </it>mutations. We also examined chromosome-related recombination. The frequencies of intrachromosomal recombination and plasmid integration into the chromosome were 2 and 3 logs lower than plasmid recombination frequencies in Rec⁺strains. A Δ<it>recA </it>mutation reduced both intrachromosomal recombination and plasmid integration frequencies.</p> <p>Conclusions</p> <p>The Δ<it>recA </it>and Δ<it>recF </it>mutations can reduce plasmid recombination frequencies in <it>Salmonella enterica</it>, but the effect can vary between serovars. This information will be useful for developing <it>Salmonella </it>delivery vectors able to stably maintain plasmid cargoes for vaccine development and gene therapy.</p