Design diversity: an update from research on reliability modelling

Diversity between redundant subsystems is, in various forms, a common design approach for improving system dependability. Its value in the case of software-based systems is still controversial. This paper gives an overview of reliability modelling work we carried out in recent projects on design diversity, presented in the context of previous knowledge and practice. These results provide additional insight for decisions in applying diversity and in assessing diverseredundant systems. A general observation is that, just as diversity is a very general design approach, the models of diversity can help conceptual understanding of a range of different situations. We summarise results in the general modelling of common-mode failure, in inference from observed failure data, and in decision-making for diversity in development.

Synthesis and <em>In Vitro</em> Evaluation of a HER2-Specific ImmunoSCIFI Probe

Secondary Cerenkov-induced fluorescence imaging (SCIFI) is an emerging biomedical optical imaging modality that leverages Cerenkov luminescence, primarily generated by β-emitting radioisotopes, to excite fluorophores that offer near-infrared emissions with optimal tissue penetrance. Dual-functionalized immunoconjugates composed of an antibody, a near-infrared fluorophore, and a β-emitting radioisotope have potential utility as novel SCIFI constructs with high specificity for molecular biomarkers of disease. Here, we report the synthesis and characterization of [89Zr]Zr-DFO-trastuzumab-BOD665, a self-excitatory HER2-specific “immunoSCIFI” probe capable of yielding near-infrared fluorescence in situ without external excitation. The penetration depth of the SCIFI signal was measured in hemoglobin-infused optical tissue phantoms that indicated a 2.05-fold increase compared to 89Zr-generated Cerenkov luminescence. Additionally, the binding specificity of the immunoSCIFI probe for HER2 was evaluated in a cellular assay that showed significantly higher binding to SKBR3 (high HER2 expression) relative to MDA-MB-468 (low HER2) breast cancer cells based on measurements of total flux in the near-infrared region with external excitation blocked. Taken together, the results of this study indicate the potential utility of immunoSCIFI constructs for interrogation of molecular biomarkers of disease

An Integrated Approach to Defining Genetic and Environmental Determinants for Major Clinical Outcomes Involving Vitamin D

There is substantial genetic and epidemiological evidence implicating vitamin D in the pathogenesis of many common diseases. A number of studies have sought to define an association for disease with sequence variation in the VDR gene, encoding the ligand-activated nuclear hormone receptor for vitamin D. The results of such studies have been difficult to replicate and are likely to need to account for specific environmental exposures. Here, we review recent work that has begun to study the interactions between VDR gene polymorphisms, vitamin D blood levels, and complex disease susceptibility, notably in the context of major clinical outcomes. We highlight the challenges moving forward in this area and its importance for effective clinical translation of current research

Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders.

Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways

Posit and Floating-Point Based Izhikevich Neuron: A Comparison of Arithmetic

Preprint submitted to Elsevier. It has not been certified by peer review.Reduced precision number formats are gaining popularity in many areas of computational science, due to their potential to improve energy efficiency, silicon use, and speed. However, this is often at the expense of introducing arithmetic errors which affect the accuracy of a system. The optimal balance must be struck, judiciously choosing a number format using as few bits as possible, while minimising accuracy loss. In this study, we examine one such format, posit arithmetic as a replacement for floating-point when conducting spiking neuron simulations, specifically using the Izhikevich neuron model. This model is capable of simulating complex neural firing behaviours, 20 of which were originally identified by Izhikevich and are used in this study. We compare the accuracy, spike count, and spike timing of the two arithmetic systems at different bit-depths against a 64-bit floating-point gold-standard. Additionally, we test a rescaled set of Izhikevich equations to mitigate against arithmetic errors by taking advantage of posit arithmetic’s tapered accuracy.Our findings indicate that there is no difference in performance between 32-bit posit, 32-bit floating-point, and our reference standard for 95% of the tested firing types. However, at 16-bit, both arithmetic systems diverge from the 64-bit reference, albeit non-uniformly. For instance, the posit implementation demonstrates an accumulated spike timing error of 0.5ms over a 1000ms simulation compared to 9ms for floating-point – an 18x improvement using posit arithmetic for regular (tonic) spiking. This finding holds particular importance given the prevalence of this particular firing type in specific regions of the brain. Furthermore, when we rescale the neuron equations, this error is eliminated altogether. Hence, our results demonstrate that posit arithmetic is not only a viable replacement for 64-bit floating-point in these simulations, it can do so while using 4× fewer bits. As a Posit Arithmetic Unit has similar area to a Floating Point Unit with the same bit width, this constitutes a significant saving of hardware resources while maintaining full accuracy compared to 64-bit floating-point.TFH was part funded by Sundance Multiprocesssor Ltd., UK and an EPSRC Doctoral Training Partnerships (DTP) grant. JK was funded by the EPSRC (grant EP/V052241/1)

Spontaneous Stratification in Granular Mixtures

Granular materials size segregate when exposed to external periodic perturbations such as vibrations. Moreover, mixtures of grains of different sizes spontaneously segregate in the absence of external perturbations: when a mixture is simply poured onto a pile, the large grains are more likely to be found near the base, while the small grains are more likely to be near the top. Here, we report a spontaneous phenomenon arising when we pour a mixture between two vertical plates: the mixture spontaneously stratifies into alternating layers of small and large grains whenever the large grains are rougher than the small grains. In contrast, we find only spontaneous segregation when the large grains are more rounded than the small grains. The stratification is related to the occurrence of avalanches; during each avalanche the grains comprising the avalanche spontaneously stratify into a pair of layers through a "kink" mechanism, with the small grains forming a sublayer underneath the layer of large grains.Comment: 4 pages, 6 figures, http://polymer.bu.edu/~hmakse/Home.htm

Adaptive multiphoton endomicroscopy through a dynamically deformed multicore optical fiber using proximal detection

This paper demonstrates multiphoton excited fluorescence imaging through a polarisation maintaining multicore fiber (PM-MCF) while the fiber is dynamically deformed using all-proximal detection. Single-shot proximal measurement of the relative optical path lengths of all the cores of the PM-MCF in double pass is achieved using a Mach-Zehnder interferometer read out by a scientific CMOS camera operating at 416 Hz. A non-linear least squares fitting procedure is then employed to determine the deformation-induced lateral shift of the excitation spot at the distal tip of the PM-MCF. An experimental validation of this approach is presented that compares the proximally measured deformation-induced lateral shift in focal spot position to an independent distally measured ground truth. The proximal measurement of deformation-induced shift in focal spot position is applied to correct for deformation-induced shifts in focal spot position during raster-scanning multiphoton excited fluorescence imaging

Whole genome sequencing identifies putative associations between genomic polymorphisms and clinical response to the antiepileptic drug levetiracetam

In the context of pharmacogenomics, whole genome sequencing provides a powerful approach for identifying correlations between response variability to specific drugs and genomic polymorphisms in a population, in an unbiased manner. In this study, we employed whole genome sequencing of DNA samples from patients showing extreme response (n=72) and non-response (n=27) to the antiepileptic drug levetiracetam, in order to identify genomic variants that underlie response to the drug. Although no common SNP (MAF>5%) crossed the conventional genome-wide significance threshold of 5e-8, we found common polymorphisms in genes SPNS3, HDC, MDGA2, NSG1 and RASGEF1C, which collectively predict clinical response to levetiracetam in our cohort with ~91% predictive accuracy. Among these genes, HDC, NSG1, MDGA2 and RASGEF1C are potentially implicated in synaptic neurotransmission, while SPNS3 is an atypical solute carrier transporter homologous to SV2A, the known molecular target of levetiracetam. Furthermore, we performed gene- and pathway-based statistical analysis on sets of rare and low-frequency variants (MAF<5%) and we identified associations between the following genes or pathways and response to levetiracetam: a) genes PRKCB and DLG2, which are involved in glutamatergic neurotransmission, a known target of anticonvulsants, including levetiracetam; b) genes FILIP1 and SEMA6D, which are involved in axon guidance and modelling of neural connections; and c) pathways with a role in synaptic neurotransmission, such as WNT5A-dependent internalization of FZD4 and disinhibition of SNARE formation. In summary, our approach to utilise whole genome sequencing on subjects with extreme response phenotypes is a feasible route to generate plausible hypotheses for investigating the genetic factors underlying drug response variability in cases of pharmaco-resistant epilepsy