Genetic Variation in Spatio-Temporal Confined USA300 Community-Associated MRSA Isolates: A Shift from Clonal Dispersion to Genetic Evolution?

NTRODUCTION: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are increasingly isolated, with USA300-0114 being the predominant clone in the USA. Comparative whole genome sequencing of USA300 isolates collected in 2002, 2003 and 2005 showed a limited number of single nucleotide polymorphisms and regions of difference. This suggests that USA300 has undergone rapid clonal expansion without great genomic diversification. However, whole genome comparison of CA-MRSA has been limited to isolates belonging to USA300. The aim of this study was to compare the genetic repertoire of different CA-MRSA clones with that of HA-MRSA from the USA and Europe through comparative genomic hybridization (CGH) to identify genetic clues that may explain the successful and rapid emergence of CA-MRSA. MATERIALS AND METHODS: Hierarchical clustering based on CGH of 48 MRSA isolates from the community and nosocomial infections from Europe and the USA revealed dispersed clustering of the 19 CA-MRSA isolates. This means that these 19 CA-MRSA isolates do not share a unique genetic make-up. Only the PVL genes were commonly present in all CA-MRSA isolates. However, 10 genes were variably present among 14 USA300 isolates. Most of these genes were present on mobile elements. CONCLUSION: The genetic variation present among the 14 USA300 isolates is remarkable considering the fact that the isolates were recovered within one month and originated from a confined geographic area, suggesting continuous evolution of this clone

Detecting Incorrect Build Rules

Automated build systems are routinely used by software engineers to minimize the number of objects that need to be recompiled after incremental changes to the source files of a project. In order to achieve efficient and correct builds, developers must provide the build tools with dependency information between the files and modules of a project, usually expressed in a macro language specific to each build tool. Most build systems offer good support for well-known languages and compilers, but as projects grow larger, engineers tend to include source files generated using custom tools. In order to guarantee correctness, the authors of these tools are responsible for enumerating all the files whose contents an output depends on. Unfortunately, this is a tedious process and not all dependencies are captured in practice, which leads to incorrect builds. We automatically uncover such missing dependencies through a novel method that we call build fuzzing. The correctness of build definitions is verified by modifying files in a project, triggering incremental builds and comparing the set of changed files to the set of expected changes. These sets are determined using a dependency graph inferred by tracing the system calls executed during a clean build. We evaluate our method by exhaustively testing build rules of open-source projects, uncovering issues leading to race conditions and faulty builds in 31 of them. We provide a discussion of the bugs we detect, identifying anti-patterns in the use of the macro languages. We fix some of the issues in projects where the features of build systems allow a clean solution

Verifying Spatial Properties of Array Computations

Arrays computations are at the core of numerical modelling and computational science applications. However, low-level manipulation of array indices is a source of program error. Many practitioners are aware of the need to ensure program correctness, yet very few of the techniques from the programming research community are applied by scientists. We aim to change that by providing targetted lightweight veriication techniques for scientiic code. We focus on the all too common mistake of array ofset errors as a generalisation of of-by-one errors. Firstly, we report on a code analysis study on eleven real-world computational science code base, identifying common idioms of array usage and their spatial properties. This provides much needed data on array programming idioms common in scientiic code. From this data, we designed a lightweight declarative speciication language capturing the majority of array access patterns via a small set of combinators. We detail a semantic model, and the design and implementation of a veriication tool for our speciication language, which both checks and infers speciications. We evaluate our tool on our corpus of scientiic code. Using the inference mode, we found roughly 87,000 targets for speciication across roughly 1.1 million lines of code, showing that the vast majority of array computations read from arrays in a pattern with a simple, regular, static shape. We also studied the commit logs of one of our corpus packages, inding past bug ixes for which our speciication system distinguishes the change and thus could have been applied to detect such bugs.This work was supported by the EPSRC [grant number EP/M026124/1]

The chemistry of protoplanetary fragments formed via gravitational instabilities

In this paper, we model the chemical evolution of a 0.25 M$_{\odot}$ protoplanetary disc surrounding a 1 M$_{\odot}$ star that undergoes fragmentation due to self-gravity. We use Smoothed Particle Hydrodynamics including a radiative transfer scheme, along with time-dependent chemical evolution code to follow the composition of the disc and resulting fragments over approximately 4000 yrs. Initially, four quasi-stable fragments are formed, of which two are eventually disrupted by tidal torques in the disc. From the results of our chemical modelling, we identify species that are abundant in the fragments (e.g. H$_{\rm 2}$O, H$_{\rm 2}$S, HNO, N$_{\rm 2}$, NH$_{\rm 3}$, OCS, SO), species that are abundant in the spiral shocks within the disc (e.g. CO, CH$_{\rm 4}$, CN, CS, H$_{\rm 2}$CO), and species which are abundant in the circumfragmentary material (e.g. HCO$^{\rm +}$). Our models suggest that in some fragments it is plausible for grains to sediment to the core before releasing their volatiles into the planetary envelope, leading to changes in, e.g., the C/O ratio of the gas and ice components. We would therefore predict that the atmospheric composition of planets generated by gravitational instability should not necessarily follow the bulk chemical composition of the local disc material

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration

Chronic non-freezing cold injury results in neuropathic pain due to a sensory neuropathy

Non-freezing cold injury develops after sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. This can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. Both vascular and neurological aetiologies of this pain have been suggested but remain unproven. We prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between 12 February 2014 and 30 November 2016. Of 47 patients approached, 42 consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intraepidermal nerve fibre assessment. Of the 42 study participants, all had experienced non-freezing cold injury while serving in the UK armed services and the majority were of African descent (76.2%) and male (95.2%). Many participants reported multiple exposures to cold. The median time between initial injury and referral was 3.72 years. Pain was principally localized to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. Clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. In all cases, large fibre nerve conduction studies were normal. The intraepidermal nerve fibre density was markedly reduced with 90.5% of participants having a count at or below the 0.05 centile of published normative controls. Using the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain grading for neuropathic pain, 100% had probable and 95.2% definite neuropathic pain. Chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known, but individuals of African descent appear vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients

Modeling Slope Instability as Shear Rupture Propagation in a Saturated Porous Medium

When a region of intense shear in a slope is much thinner than other relevant geometric lengths, this shear failure may be approximated as localized slip, as in faulting, with strength determined by frictional properties of the sediment and effective stress normal to the failure surface. Peak and residual frictional strengths of submarine sediments indicate critical slope angles well above those of most submarine slopes—in contradiction to abundant failures. Because deformation of sediments is governed by effective stress, processes affecting pore pressures are a means of strength reduction. However, common methods of exami ning slope stability neglect dynamically variable pore pressure during failure. We examine elastic-plastic models of the capped Drucker-Prager type and derive approximate equations governing pore pressure about a slip surface when the adjacent material may deform plastically. In the process we identify an elastic-plastic hydraulic diffusivity with an evolving permeability and plastic storage term analogous to the elastic term of traditional poroelasticity. We also examine their application to a dynamically propagating subsurface rupture and find indications of downslope directivity.Earth and Planetary SciencesEngineering and Applied Science

Need-based resource allocation: different need indicators, different results?

<p>Abstract</p> <p>Background</p> <p>A key policy objective in most publicly financed health care systems is to allocate resources according to need. Many jurisdictions implement this policy objective through need-based allocation models. To date, no gold standard exists for selecting need indicators. In the absence of a gold standard, sensitivity of the choice of need indicators is of concern. The primary objective of this study was to assess the consistency and plausibility of estimates of per capita relative need for health services across Canadian provinces based on different need indicators.</p> <p>Methods</p> <p>Using the 2000/2001 Canadian Community Health Survey, we estimated relative per capita need for general practitioner, specialist, and hospital services by province using two approaches that incorporated a different set of need indicators: (1) demographics (age and sex), and (2) demographics, socioeconomic status, and health status. For both approaches, we first fitted regression models to estimate standard utilization of each of three types of health services by indicators of need. We defined the standard as average levels of utilization by needs indicators in the national sample. Subsequently, we estimated expected per capita utilization of each type of health services in each province. We compared these estimates of per capita relative need with premature mortality in each province to check their face validity.</p> <p>Results</p> <p>Both approaches suggested that expected relative per capita need for three services vary across provinces. Different approaches, however, yielded different and inconsistent results. Moreover, provincial per capita relative need for the three health services did not always indicate the same direction of need suggested by premature mortality in each province. In particular, the two approaches suggested Newfoundland had less need than the Canadian average for all three services, but it had the highest premature mortality in Canada.</p> <p>Conclusion</p> <p>Substantial differences in need for health care may exist across Canadian provinces, but the direction and magnitude of differences depend on the need indicators used. Allocations from models using survey data lacked face validity for some provinces. These results call for the need to better understand the biases that may result from the use of survey data for resource allocation.</p