Molecular epidemiological characterisation of carried Neisseria meningitidis isolates in Scotland, 1974 - 2004 and a comparison with an invasive meningococcal disease strain collection

Neisseria meningitidis is an important cause of meningitis and septicaemia worldwide. Invasive meningococcal disease (IMD) is cyclical and varies by age group, being more common in children, especially those under 5 years. However, IMD is a rare outcome relative to asymptomatic carriage of the organism by the host and disease-causing isolates represent the tip of the iceberg in terms of the overall meningococcal population biology. The emphasis of previous research into N. meningitidis has rested firmly on the study of IMD isolates. In more recent times, however, there has been a more conscious effort to re-dress this balance to aid in our understanding of the relationship between carriage and disease. The Scottish Haemophilus, Legionella, Meningococcus and Pneumococcus Reference Laboratory (SHLMPRL) have accrued an extensive isolate archive dating back to the 1960s. Only recently with the expansion of molecular techniques has the SHLMPRL begun to investigate this valuable resource. For around a decade or more the SHLMPRL have routinely used genotyping techniques to characterise all IMD isolates it receives. However, these methods have hitherto not been employed to investigate isolates of the archive not obtained from cases of IMD. This study sought to characterise a collection of carried meningococci assembled from the isolate archive of the SHLMPRL that was obtained during the 31-year period, 1974 – 2004. Multi-locus sequence typing (MLST), porA Variable Region (VR) subtyping and a panel of genogrouping PCRs was used to characterise 791 carriage isolates. Temporal analyses of the data revealed how the presence of individual serogroups, clonal complexes, Sequence Types (STs), PorA subtypes and individual strain types in carried meningococci had changed in Scotland. Furthermore, these data were used in a comparison with a previously characterised collection of IMD isolates obtained during the same 31-year period to investigate the association of individual serogroups, clonal complexes, STs, PorA subtypes and individual strain types either with a carriage phenotype or with invasive disease. Nongroupable isolates [Odds Ratio: OR 17.66; 95% Confidence Interval: CI (12.71 to 24.54)] and those of serogroups W135 [OR 2.49; 95% CI (1.72 to 3.60)], Y [OR 6.26; 95% CI (4.18 to 9.39)], X [OR 3.13; 95% CI (1.20 to 8.14)], Z [OR 131.89; 95% CI (18.00 to 960.76)] and 29E [OR 21.30; 95% CI (4.76 to 95.36)] were significantly associated with a carriage phenotype. In contrast, serogroups A [OR 3.64; 95% CI (1.96 to 6.76)], B [OR 2.65; 95% CI (2.25 to 3.12)] and C [OR 1.92; 95% CI (1.58 to 2.33)] were significantly associated with invasive disease. The carriage strain collection reported herein was also observed to be highly diverse with the majority of STs identified only once. This diversity observed within the carriage strain collection [0.981; 95% CI (0.955, 1.006)] was significantly greater than the diversity within an IMD strain collection [0.938; 95%CI (0.934, 0.942)] from the same period. Temporal changes in the most prevalent clonal complexes (ccs) were observed throughout the 31-year period with increases in cc22, cc41/44 and cc269 and decreases in cc1, cc5, cc8, cc11, cc32, cc35, cc37, cc254, cc334 and cc364. Furthermore, for several ccs a significant association with a carriage phenotype (cc22, cc23, cc35, cc92, cc167, cc174, cc212, cc213, cc254, cc461, cc750, cc1157 and meningococci unassigned to a clonal complex) or with invasive disease (cc1, cc8, cc11, cc32, cc41-44 and cc269) was observed. Four lineages were identified amongst capsule null locus-containing meningococci, two of which, cc53 and cc1117, contained a unique allele (cnl-8) that was distinct from isolates of these lineages reported elsewhere. Despite significant associations at the level of cc, distinct differences in those associations were apparent for individual STs within a given clonal complex; most notably the significant association of ST41 and both ST43 and ST44 with invasive disease and a carriage phenotype, respectively. A feature of the carriage strain collection was the concentration of cc8 isolates during the period 1984 – 1986 and the high proportion of isolates obtained from individuals resident in Lanarkshire at a time when an episode of increased disease was experienced within that region. In this study, cc8 was found to be significantly associated with invasive disease. Furthermore, whilst ST8 was also significantly associated with invasive disease the most common strain type within cc8, C:8:8:5,2,36-2, [OR 1.68; 95% CI (1.25, 2.27)] was however, significantly associated with a carriage phenotype. The strain types B:213:22,14,36 [OR 2.38 (95% CI 1.40, 4.07)] and B:43:19,15-1,36 [OR 2.88 (95% CI 1.42, 5.88)] were also significantly associated with a carriage phenotype. Due to the heterogeneity of PorA subtypes in meningococci in Scotland the potential coverage by experimental or licensed PorA-based OMV vaccines would be limited. Therefore the introduction of monovalent or multivalent PorA-based vaccines in Scotland may be of little benefit. Improved strain coverage as a whole, not just against those of serogroup B, may require the addition of other vaccine antigens. Several other vaccine targets, including factor H-binding protein, are currently under investigation to improve coverage. Surveillance of these antigens and of the different lineages and serogroups in carriage and IMD isolates is essential to accurately monitor the effects that future vaccines will have on the meningococcus. We must remain vigilant despite a downward trend in cases of meningococcal disease in more industrialised countries

A Convenient Synthetic Route to Partial-Cone p-Carboxylatocalix[4]arenes.

p-Carboxylatocalix[n]arenes have emerged as useful building blocks for the construction of a diverse range of supramolecular assemblies. A convenient route to a p-carboxylatocalix[4]arene that is locked in a partial-cone conformation is presented. The conformation gives the molecule markedly different topological directionality relative to those previously used in self- and metal-directed assembly studies

On non-normality and classification of amplification mechanisms in stability and resolvent analysis

We seek to quantify non-normality of the most amplified resolvent modes and predict their features based on the characteristics of the base or mean velocity profile. A 2-by-2 model linear Navier-Stokes (LNS) operator illustrates how non-normality from mean shear distributes perturbation energy in different velocity components of the forcing and response modes. The inverse of their inner product, which is unity for a purely normal mechanism, is proposed as a measure to quantify non-normality. In flows where there is downstream spatial dependence of the base/mean, mean flow advection separates the spatial support of forcing and response modes which impacts the inner product. Success of mean stability analysis depends on the normality of amplification. If the amplification is normal, the resolvent operator written in its dyadic representation reveals that the adjoint and forward stability modes are proportional to the forcing and response resolvent modes. If the amplification is non-normal, then resolvent analysis is required to understand the origin of observed flow structures. Eigenspectra and pseudospectra are used to characterize these phenomena. Two test cases are studied: low Reynolds number cylinder flow and turbulent channel flow. The first deals mainly with normal mechanisms and quantification of non-normality using the inverse inner product of the leading forcing and response modes agrees well with the product of the resolvent norm and distance between the imaginary axis and least stable eigenvalue. In turbulent channel flow, structures result from both normal and non-normal mechanisms. Mean shear is exploited most efficiently by stationary disturbances while bounds on the pseudospectra illustrate how non-normality is responsible for the most amplified disturbances at spatial wavenumbers and temporal frequencies corresponding to well-known turbulent structures

Vortices as nurseries for planetesimal formation in protoplanetary discs

Turbulent, two-dimensional, hydrodynamic flows are characterized by the emergence of coherent, long-lived vortices without a need to invoke special initial conditions. Vortices have the ability to sequester particles, with typical radii ∼1 mm to ∼10 cm, that are slightly decoupled from the gas. A generic feature of discs with surface density and effective temperature profiles that are decreasing, power-law functions of radial distance is that four vortex zones exist for a fixed particle size. In particular, two of the zones form an annulus at intermediate radial distances within which small particles reside. Particle capture by vortices occurs on a dynamical time-scale near and at the boundaries of this annulus. As the disc ages and the particles grow via coagulation, the size of the annulus shrinks. Older discs prefer to capture smaller particles because the gas surface density decreases with time, a phenomenon we term ‘vortex ageing'. More viscous, more dust-opaque and/or less massive discs can have vortices that age faster and trap a broader range of particle sizes throughout the lifetime of the disc. Thus, how efficiently a disc retains its mass in solids depends on the relative time-scales between coagulation and vortex ageing. If vortices form in protoplanetary discs, they are important in discs with typical masses and for particles that are likely to condense out of the protostellar nebula. Particle capture also occurs at distances relevant to planet formation. Future infrared, submillimetre and centimetre observations of grain opacity as a function of radial distance will test the hypothesis that vortices serve as nurseries for particle growth in protoplanetary disc

Intellectual humility and the difficult knowledge of theology

We seek, in this analytical essay, to complicate the conversation around knowledge production in the academy by proposing “intellectual humility” as a mode for moving toward new avenues of knowledge-making, particularly as an epistemic stance against the kinds of “intellectual arrogance” (Lynch, 2017) that have made certain avenues of knowledge, especially in the social sciences, sparsely traveled in the last half century. Drawing on the conceptual frames of difficult knowledge (Britzman, 1998; Garrett, 2017; Pitt & Britzman, 2003) and weak theology (Caputo, 2006), we turn to our own stories of faith and inquiry as ways in to thinking humility, through which we draw broader conclusions about what humility may offer that’s especially useful in this particular post-truth moment. We might unsettle the dangerous story that theology has no use for educational research, other than as a caution against the backwardness of faith in a patriotic god. If we’re to consider the possibility of evidentiary epistemologies as valuable in the work of combating ignorance and asserting certain values in and around education, then we’d do well to further diversify our sense of the possible in public education to include the difficult knowledge of theology as a rich framework for pursuing new ends

Lifting the veil on the transcriptome

Inhibition of the cellular RNA surveillance system in Arabidopsis reveals a normally hidden transcriptome of small noncoding RNAs

Multimode bolometer development for the PIXIE instrument

The Primordial Inflation Explorer (PIXIE) is an Explorer-class mission concept designed to measure the polarization and absolute intensity of the cosmic microwave background. In the following, we report on the design, fabrication, and performance of the multimode polarization-sensitive bolometers for PIXIE, which are based on silicon thermistors. In particular we focus on several recent advances in the detector design, including the implementation of a scheme to greatly raise the frequencies of the internal vibrational modes of the large-area, low-mass optical absorber structure consisting of a grid of micromachined, ion-implanted silicon wires. With $\sim30$ times the absorbing area of the spider-web bolometers used by Planck, the tensioning scheme enables the PIXIE bolometers to be robust in the vibrational and acoustic environment at launch of the space mission. More generally, it could be used to reduce microphonic sensitivity in other types of low temperature detectors. We also report on the performance of the PIXIE bolometers in a dark cryogenic environment.Comment: 10 pages, 7 figure

Temperature sensitivity of the pyloric neuromuscular system and its modulation by dopamine

We report here the effects of temperature on the p1 neuromuscular system of the stomatogastric system of the lobster (Panulirus interruptus). Muscle force generation, in response to both the spontaneously rhythmic in vitro pyloric network neural activity and direct, controlled motor nerve stimulation, dramatically decreased as temperature increased, sufficiently that stomach movements would very unlikely be maintained at warm temperatures. However, animals fed in warm tanks showed statistically identical food digestion to those in cold tanks. Applying dopamine, a circulating hormone in crustacea, increased muscle force production at all temperatures and abolished neuromuscular system temperature dependence. Modulation may thus exist not only to increase the diversity of produced behaviors, but also to maintain individual behaviors when environmental conditions (such as temperature) vary