System Reliability: Exact Bayesian Intervals Compared With Fiducial Intervals

This paper compares numerically two different, widely used lower limit estimates for the reliability of a series system: Bayesian limits and fiducial limits. The fiducial limits are obtained by Monte Carlo simulation because of its simplicity and ease of computer programming. Subsystem failures are s-independent and exponentially distributed; life test data are available for estimating the failure rate of each system. Copyright © 1975 by The Institute of Electrical and Electronics Engineers, Inc

Quantitative LSPR Imaging for Biosensing with Single Nanostructure Resolution

AbstractLocalized surface plasmon resonance (LSPR) imaging has the potential to map complex spatio-temporal variations in analyte concentration, such as those produced by protein secretions from live cells. A fundamental roadblock to the realization of such applications is the challenge of calibrating a nanoscale sensor for quantitative analysis. Here, we introduce a new, to our knowledge, LSPR imaging and analysis technique that enables the calibration of hundreds of individual gold nanostructures in parallel. The calibration allowed us to map the fractional occupancy of surface-bound receptors at individual nanostructures with nanomolar sensitivity and a temporal resolution of 225 ms. As a demonstration of the technique’s applicability to molecular and cell biology, the calibrated array was used for the quantitative LSPR imaging of anti-c-myc antibodies harvested from a cultured 9E10 hybridoma cell line without the need for further purification or processing

Anti-Insulin Receptor Autoantibodies Are Not Required for Type 2 Diabetes Pathogenesis in NZL/Lt Mice, a New Zealand Obese (NZO)-Derived Mouse Strain

The New Zealand obese (NZO) mouse strain shares with the related New Zealand black (NZB) strain a number of immunophenotypic traits. Among these is a high proportion of B-1 B lymphocytes, a subset associated with autoantibody production. Approximately 50% of NZO/HlLt males develop a chronic insulin-resistant type 2 diabetes syndrome associated with 2 unusual features: the presence of B lymphocyte–enriched peri-insular infiltrates and the development of anti-insulin receptor autoantibodies (AIRAs). To establish the potential pathogenic contributions ofBlymphocytes and AIRAs in this model, a disrupted immunoglobulin heavy chain gene (Igh-6) congenic on the NZB/BlJ background was backcrossed 4 generations into the NZO/HlLt background and was then intercrossed to produce mice that initially segregated for wild-type versus the mutant Igh-6 allele and thus permitted comparison of syndrome development. A new flow cytometric assay (AIRA binding to transfected Chinese hamster ovary cells stably expressing mouse insulin receptor) showed IgM and IgG subclass AIRAs in serum from Igh-6 intact males, but not in Igh6null male serum. However, the absence of B lymphocytes and antibodies distinguishing mutant from wild-type males failed to significantly affect diabetes-free survival. The Igh6nullmales gained weight less rapidly than wild-type males, probably accounting for a retardation, but not prevention, of hyperglycemia. Thus, AIRA and the Blymphocyte component of the peri-insulitis in chronic diabetics were not essential either to development of insulin resistance or to eventual pancreatic beta cell failure and loss. A new substrain, designated NZL, was generated by inbreeding Igh-6 wild-type segregants. Currently at the F10 generation, NZL mice exhibit the same juvenile-onset obesity as NZO/HlLt males, but develop type 2 diabetes at a higher frequency (> 80%). Also, unlike NZO/HlLt mice that are difficult to breed, the NZL/Lt strain breeds well and thus offers clear advantages to obesity/diabetes researchers

The macroecology of infectious diseases: a new perspective on global-scale drivers of pathogen distributions and impacts

© 2016 John Wiley & Sons Ltd/CNRS. Identifying drivers of infectious disease patterns and impacts at the broadest scales of organisation is one of the most crucial challenges for modern science, yet answers to many fundamental questions remain elusive. These include what factors commonly facilitate transmission of pathogens to novel host species, what drives variation in immune investment among host species, and more generally what drives global patterns of parasite diversity and distribution? Here we consider how the perspectives and tools of macroecology, a field that investigates patterns and processes at broad spatial, temporal and taxonomic scales, are expanding scientific understanding of global infectious disease ecology. In particular, emerging approaches are providing new insights about scaling properties across all living taxa, and new strategies for mapping pathogen biodiversity and infection risk. Ultimately, macroecology is establishing a framework to more accurately predict global patterns of infectious disease distribution and emergence

A Pearson-Dirichlet random walk

A constrained diffusive random walk of n steps and a random flight in Rd, which can be expressed in the same terms, were investigated independently in recent papers. The n steps of the walk are identically and independently distributed random vectors of exponential length and uniform orientation. Conditioned on the sum of their lengths being equal to a given value l, closed-form expressions for the distribution of the endpoint of the walk were obtained altogether for any n for d=1, 2, 4 . Uniform distributions of the endpoint inside a ball of radius l were evidenced for a walk of three steps in 2D and of two steps in 4D. The previous walk is generalized by considering step lengths which are distributed over the unit (n-1) simplex according to a Dirichlet distribution whose parameters are all equal to q, a given positive value. The walk and the flight above correspond to q=1. For any d >= 3, there exist, for integer and half-integer values of q, two families of Pearson-Dirichlet walks which share a common property. For any n, the d components of the endpoint are jointly distributed as are the d components of a vector uniformly distributed over the surface of a hypersphere of radius l in a space Rk whose dimension k is an affine function of n for a given d. Five additional walks, with a uniform distribution of the endpoint in the inside of a ball, are found from known finite integrals of products of powers and Bessel functions of the first kind. They include four different walks in R3 and two walks in R4. Pearson-Liouville random walks, obtained by distributing the total lengths of the previous Pearson-Dirichlet walks, are finally discussed.Comment: 33 pages 1 figure, the paper includes the content of a recently submitted work together with additional results and an extended section on Pearson-Liouville random walk

Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants’ pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine

Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome.

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine

Specific niche requirements underpin multidecadal range edge stability, but may introduce barriers for climate change adaptation

Aim: To investigate some of the environmental variables underpinning the past and present distribution of an ecosystem engineer near its poleward range edge. Location: >500 locations spanning >7,400 km around Ireland. Methods: We collated past and present distribution records on a known climate change indicator, the reef-forming worm Sabellaria alveolata (Linnaeus, 1767) in a biogeographic boundary region over 182 years (1836–2018). This included repeat sampling of 60 locations in the cooler 1950s and again in the warmer 2000s and 2010s. Using species distribution modelling, we identified some of the environmental drivers that likely underpin S. alveolata distribution towards the leading edge of its biogeographical range in Ireland. Results: Through plotting 981 records of presence and absence, we revealed a discontinuous distribution with discretely bounded sub-populations, and edges that coincide with the locations of tidal fronts. Repeat surveys of 60 locations across three time periods showed evidence of population increases, declines, local extirpation and recolonization events within the range, but no evidence of extensions beyond the previously identified distribution limits, despite decades of warming. At a regional scale, populations were relatively stable through time, but local populations in the cold Irish Sea appear highly dynamic and vulnerable to local extirpation risk. Contemporary distribution data (2013–2018) computed with modelled environmental data identified specific niche requirements which can explain the many distribution gaps, namely wave height, tidal amplitude, stratification index, then substrate type. Main conclusions: In the face of climate warming, such specific niche requirements can create environmental barriers that may prevent species from extending beyond their leading edges. These boundaries may limit a species’ capacity to redistribute in response to global environmental change