Copy number variation and transposable elements feature in recent, ongoing adaptation at the Cyp6g1 locus

The increased transcription of the Cyp6g1 gene of Drosophila melanogaster, and consequent resistance to insecticides such as DDT, is a widely cited example of adaptation mediated by cis-regulatory change. A fragment of an Accord transposable element inserted upstream of the Cyp6g1 gene is causally associated with resistance and has spread to high frequencies in populations around the world since the 1940s. Here we report the existence of a natural allelic series at this locus of D. melanogaster, involving copy number variation of Cyp6g1, and two additional transposable element insertions (a P and an HMS-Beagle). We provide evidence that this genetic variation underpins phenotypic variation, as the more derived the allele, the greater the level of DDT resistance. Tracking the spatial and temporal patterns of allele frequency changes indicates that the multiple steps of the allelic series are adaptive. Further, a DDT association study shows that the most resistant allele, Cyp6g1-[BP], is greatly enriched in the top 5% of the phenotypic distribution and accounts for ~16% of the underlying phenotypic variation in resistance to DDT. In contrast, copy number variation for another candidate resistance gene, Cyp12d1, is not associated with resistance. Thus the Cyp6g1 locus is a major contributor to DDT resistance in field populations, and evolution at this locus features multiple adaptive steps occurring in rapid succession.

Maternal overnutrition programs changes in the expression of skeletal muscle genes that are associated with insulin resistance and defects of oxidative phosphorylation in adult male rat offspring.

Children of obese mothers have increased risk of metabolic syndrome as adults. Here we report the effects of a high-fat diet in the absence of maternal obesity at conception on skeletal muscle metabolic and transcriptional profiles of adult male offspring. Female Sprague Dawley rats were fed a diet rich in saturated fat and sucrose [high-fat diet (HFD): 23.5% total fat, 9.83% saturated fat, 20% sucrose wt:wt] or a normal control diet [(CD) 7% total fat, 0.5% saturated fat, 10% sucrose wt:wt] for the 3 wk prior to mating and throughout pregnancy and lactation. Maternal weights were not different at conception; however, HFD-fed dams were 22% heavier than controls during pregnancy. On a normal diet, the male offspring of HFD-fed dams were not heavier than controls but demonstrated features of insulin resistance, including elevated plasma insulin concentration [40.1 ± 2.5 (CD) vs 56.2 ± 6.1 (HFD) mU/L; P = 0.023]. Next-generation mRNA sequencing was used to identify differentially expressed genes in the offspring soleus muscle, and gene set enrichment analysis (GSEA) was used to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 upregulated pathways, including cytokine signaling (P < 0.005), starch and sucrose metabolism (P < 0.017), inflammatory response (P < 0.024), and cytokine-cytokine receptor interaction (P < 0.037). A further 8 pathways were downregulated, including oxidative phosphorylation (P < 0.004), mitochondrial matrix (P < 0.006), and electron transport/uncoupling (P < 0.022). Phosphorylation of the insulin signaling protein kinase B was reduced [2.86 ± 0.63 (CD) vs 1.02 ± 0.27 (HFD); P = 0.027] and mitochondrial complexes I, II, and V protein were downregulated by 50-68% (P < 0.005). On a normal diet, the male offspring of HFD-fed dams did not become obese adults but developed insulin resistance, with transcriptional evidence of muscle cytokine activation, inflammation, and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of prepregnancy obesity, can promote metabolic dysregulation and predispose offspring to type 2 diabetes.

RiboSys, a high-resolution, quantitative approach to measure the in vivo kinetics of pre-mRNA splicing and 3'-end processing in Saccharomyces cerevisiae

We describe methods for obtaining a quantitative description of RNA processing at high resolution in budding yeast. As a model gene expression system, we constructed tetON (for induction studies) and tetOFF (for repression, derepression, and RNA degradation studies) yeast strains with a series of reporter genes integrated in the genome under the control of a tetO7 promoter. Reverse transcription and quantitative real-time-PCR (RT-qPCR) methods were adapted to allow the determination of mRNA abundance as the average number of copies per cell in a population. Fluorescence in situ hybridization (FISH) measurements of transcript numbers in individual cells validated the RT-qPCR approach for the average copy-number determination despite the broad distribution of transcript levels within a population of cells. In addition, RT-qPCR was used to distinguish the products of the different steps in splicing of the reporter transcripts, and methods were developed to map and quantify 3′-end cleavage and polyadenylation. This system permits pre-mRNA production, splicing, 3′-end maturation and degradation to be quantitatively monitored with unprecedented kinetic detail, suitable for mathematical modeling. Using this approach, we demonstrate that reporter transcripts are spliced prior to their 3′-end cleavage and polyadenylation, that is, cotranscriptionally.

New insights into the role of MHC diversity in devil facial tumour disease

Devil facial tumour disease (DFTD) is a fatal contagious cancer that has decimated Tasmanian devil populations. The tumour has spread without invoking immune responses, possibly due to low levels of Major Histocompatibility Complex (MHC) diversity in Tasmanian devils. Animals from a region in north-western Tasmania have lower infection rates than those in the east of the state. This area is a genetic transition zone between sub-populations, with individuals from north-western Tasmania displaying greater diversity than eastern devils at MHC genes, primarily through MHC class I gene copy number variation. Here we test the hypothesis that animals that remain healthy and tumour free show predictable differences at MHC loci compared to animals that develop the disease.

Selection on mitochondrial variants occurs between and within individuals in an expanding invasion

Mitochondria are critical for life, yet their underlying evolutionary biology is poorly understood. In particular, little is known about interaction between two levels of evolution: between individuals and within individuals (competition between cells, mitochondria or mitochondrial DNA molecules). Rapid evolution is suspected to occur frequently in mitochondrial DNA, whose maternal inheritance predisposes advantageous mutations to sweep rapidly though populations. Rapid evolution is also predicted in response to changed selection regimes after species invasion or removal of pathogens or competitors. Here, using empirical and simulated data from a model invasive bird species, we provide the first demonstration of rapid selection on the mitochondrial genome within individuals in the wild. Further, we show differences in mitochondrial DNA copy number associated with competing genetic variants, which may provide a mechanism for selection. We provide evidence for three rarely documented phenomena: selection associated with mitochondrial DNA abundance, selection on the mitochondrial control region, and contemporary selection during invasion.

Variations in vascular access flows in haemodialysis can depend on needle orientation

Introduction: While using the Transonic Qc[TM] machine to assess access flow in arteriovenous fistulae (AVF), we observed that when compared to antegrade arterial needle insertion, retrograde arterial needle insertion could regularly produce lower access flow measurements. This study sought to explore this phenomenon.

Method: 23 patients entered and 20 finished the study. Patient selection criteria included: functioning AVF and an adequate AVF length for either retrograde or antegrade arterial needle insertion. After ensuring stable and similar blood pressures, 3 flow measurements were taken during the first 2 hours on the same dialysis day of 3 consecutive weeks using antegrade needle insertion then were repeated on 3 further consecutive weeks using retrograde insertion.

Results: Overall, access flows measured with retrograde insertion were significantly lower by a mean difference of 107.15 ml/min (57-484 ml/min) than the flows measured with antegrade needle placement. In 5/20, 3 recorded minimal difference and 2 had a higher access flows during retrograde insertion. No recirculation was observed during either antegrade or retrograde needle insertion. The paired t-test showed that there was significant difference between the antegrade versus retrograde mean measurements (p = 0.005).

Conclusion: Although the sample size is small and the number of measurements limited, we conclude that access flows may be greater with an antegrade arterial orientation compared to flows recorded with a retrograde orientation. The phenomenon behind this conclusion is yet to be investigated. We suggest that when using the Transonic Qc[TM] access measurement device the arterial needle should always be in the same direction for each measurement for each individual patient.

Traceback of DDoS attacks using entropy variations

Distributed Denial-of-Service (DDoS) attacks are a critical threat to the Internet. However, the memoryless feature of the Internet routing mechanisms makes it extremely hard to trace back to the source of these attacks. As a result, there is no effective and efficient method to deal with this issue so far. In this paper, we propose a novel traceback method for DDoS attacks that is based on entropy variations between normal and DDoS attack traffic, which is fundamentally different from commonly used packet marking techniques. In comparison to the existing DDoS traceback methods, the proposed strategy possesses a number of advantagesit is memory nonintensive, efficiently scalable, robust against packet pollution, and independent of attack traffic patterns. The results of extensive experimental and simulation studies are presented to demonstrate the effectiveness and efficiency of the proposed method. Our experiments show that accurate traceback is possible within 20 seconds (approximately) in a large-scale attack network with thousands of zombies.

Oxidative stress : emerging mitochondrial and cellular themes and variations in neuronal injury

Oxidative stress plays a central role in neuronal injury and cell death in acute and chronic pathological conditions. The cellular responses to oxidative stress embrace changes in mitochondria and other organelles, notably endoplasmic reticulum, and can lead to a number of cell death paradigms, which cover a spectrum from apoptosis to necrosis and include autophagy. In Alzheimer's disease, and other pathologies including Parkinson's disease, protein aggregation provides further cellular stresses that can initiate or feed into the pathways to cell death engendered by oxidative stress. Specific attention is paid here to mitochondrial dysfunction and programmed cell death, and the diverse modes of cell death mediated by mitochondria under oxidative stress. Novel insights into cellular responses to neuronal oxidative stress from a range of different stressors can be gained by detailed transcriptomics analyses. Such studies at the cellular level provide the key for understanding the molecular and cellular pathways whereby neurons respond to oxidative stress and undergo injury and death. These considerations underpin the development of detailed knowledge in more complex integrated systems, up to the intact human bearing the neuropathology, facilitating therapeutic advances.

Dematerialised data and human desire : the Internet and copy culture

Since Licklider in the 1960s [27] influential proponents of networked computing have envisioned electronic information in terms of a relatively small (even singular) number of 'sources', distributed through technologies such as the Internet. Most recently, Levy writes, in Becoming Virtual, that "in cyberspace, since any point is directly accessible from any other point, there is an increasing tendency to replace copies of documents with hypertext links. Ultimately, there will only need to be a single physical exemplar of the text" [13 p.61]. Hypertext implies, in theory, the end of 'the copy', and the multiplication of access points to the original. But, in practice, the Internet abounds with copying, both large and small scale, both as conscious human practice, and also as autonomous computer function. Effective and cheap data storage that encourages computer users to keep anything of use they have downloaded, lest the links they have found, 'break'; while browsers don't 'browse' the Internet - they download copies of everything to client machines. Not surprisingly, there is significant regulation against 'copying' - regulation that constrains our understanding of 'copying' to maintain a legal fiction of the 'original' for the purposes of intellectual property protection. In this paper, I will firstly demonstrate, by a series of examples, how 'copying' is more than just copyright infringement of music and software, but is a defining, multi-faceted feature of Internet behaviour. I will then argue that the Internet produces an interaction between dematerialised, digital data and human subjectivity and desire that fundamentally challenges notions of originality and copy. Walter Benjamin noted about photography: "one can make any number of prints [from a negative]; to ask for the 'authentic' print makes no sense" [4 p.224]. In cyberspace, I conclude, it makes no sense to ask which one is the copy.

Hoarding of pulsed resources : temporal variations in egg-caching by arctic fox

Resource pulses are common in various ecosystems and often have large impacts on ecosystem functioning. Many animals hoard food during resource pulses, yet how this behaviour affects pulse diffusion through trophic levels is poorly known because of a lack of individual-based studies. Our objective was to examine how the hoarding behaviour of arctic foxes (Alopex lagopus) preying on a seasonal pulsed resource (goose eggs) was affected by annual and seasonal changes in resource availability. We monitored foraging behaviour of foxes in a greater snow goose (Chen caerulescens atlanticus) colony during 8 nesting seasons that covered 2 lemming cycles. The number of goose eggs taken and cached per hour by foxes declined 6-fold from laying to hatching, while the proportion of eggs cached remained constant. In contrast, the proportion of eggs cached by foxes fluctuated in response to the annual lemming cycle independently of the seasonal pulse of goose eggs. Foxes cached the majority of eggs taken (> 90%) when lemming abundance was high or moderate but only 40% during the low phase of the cycle. This likely occurred because foxes consumed a greater proportion of goose eggs to fulfill their energy requirement at low lemming abundance. Our study clearly illustrates a behavioural mechanism that extends the energetic benefits of a resource pulse. The hoarding behaviour of the main predator enhances the allochthonous nutrients input brought by migrating birds from the south into the arctic terrestrial ecosystem. This could increase average predator density and promote indirect interactions among prey.

Stabilized sparse ordinal regression for medical risk stratification

The recent wide adoption of electronic medical records (EMRs) presents great opportunities and challenges for data mining. The EMR data are largely temporal, often noisy, irregular and high dimensional. This paper constructs a novel ordinal regression framework for predicting medical risk stratification from EMR. First, a conceptual view of EMR as a temporal image is constructed to extract a diverse set of features. Second, ordinal modeling is applied for predicting cumulative or progressive risk. The challenges are building a transparent predictive model that works with a large number of weakly predictive features, and at the same time, is stable against resampling variations. Our solution employs sparsity methods that are stabilized through domain-specific feature interaction networks. We introduces two indices that measure the model stability against data resampling. Feature networks are used to generate two multivariate Gaussian priors with sparse precision matrices (the Laplacian and Random Walk). We apply the framework on a large short-term suicide risk prediction problem and demonstrate that our methods outperform clinicians to a large margin, discover suicide risk factors that conform with mental health knowledge, and produce models with enhanced stability. © 2014 Springer-Verlag London.

Behavioural effects of tourism on oceanic common dolphins, Delphinus sp., in New Zealand: the effects of Markov analysis variations and current tour operator compliance with regulations

Common dolphins, Delphinus sp., are one of the marine mammal species tourism operations in New Zealand focus on. While effects of cetacean-watching activities have previously been examined in coastal regions in New Zealand, this study is the first to investigate effects of commercial tourism and recreational vessels on common dolphins in an open oceanic habitat. Observations from both an independent research vessel and aboard commercial tour vessels operating off the central and east coast Bay of Plenty, North Island, New Zealand were used to assess dolphin behaviour and record the level of compliance by permitted commercial tour operators and private recreational vessels with New Zealand regulations. Dolphin behaviour was assessed using two different approaches to Markov chain analysis in order to examine variation of responses of dolphins to vessels. Results showed that, regardless of the variance in Markov methods, dolphin foraging behaviour was significantly altered by boat interactions. Dolphins spent less time foraging during interactions and took significantly longer to return to foraging once disrupted by vessel presence. This research raises concerns about the potential disruption to feeding, a biologically critical behaviour. This may be particularly important in an open oceanic habitat, where prey resources are typically widely dispersed and unpredictable in abundance. Furthermore, because tourism in this region focuses on common dolphins transiting between adjacent coastal locations, the potential for cumulative effects could exacerbate the local effects demonstrated in this study. While the overall level of compliance by commercial operators was relatively high, non-compliance to the regulations was observed with time restriction, number or speed of vessels interacting with dolphins not being respected. Additionally, prohibited swimming with calves did occur. The effects shown in this study should be carefully considered within conservation management plans, in order to reduce the risk of detrimental effects on common dolphins within the region.

Glomerular hypertrophy in subjects with low nephron number: contributions of sex, body size and race

Background. We have shown that low nephron number (Nglom) is a strong determinant of individual glomerular volume (IGV) in male Americans. However, whether the same pattern is present in female Americans remains unclear. The contributions of body surface area (BSA) and race to IGV in the context of Nglom also require further evaluation. Methods. Kidneys without overt renal disease were collected at autopsy in Mississippi, USA. The extremes of female Nglom were used to define high and low N glom for both sexes. Nglom and IGV were estimated by design-based stereology. A total of 24 African and Caucasian American females (n = 12 per race; 6 per Nglom extreme) were included. These subjects were subsequently matched to 24 comparable males by age and Nglom and to 18 additional males by age, Nglom and BSA. Results. IGV average and variance were very similar in female African and Caucasian Americans with high and low Nglom. Males with low Nglom from both races showed greater IGV average and variance than comparable females matched by age and Nglom. These differences in IGV between sexes were not observed in Caucasian Americans with low Nglom that were matched by age, Nglom and BSA. In contrast, glomeruli from African Americans were larger than those from Caucasian Americans, especially in subjects with high Nglom. Conclusions. While female Americans with low Nglom did not show glomerular hypertrophy, comparable males with low Nglom showed marked glomerular hypertrophy that was closely associated with high BSA. Glomerular size in African Americans may be confounded by multiple additional factors. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Analysis of texture and R value variations in asymmetric rolling of if steel

Asymmetric rolling (ASR) is a potential process to reach better grain refinement than in conventional rolling, thus, can lead to better mechanical properties. It is not known, however, how the introduction of a shear component will change the ideal orientations of the textures, and consequently, the evolution of plastic anisotropy. To understand the effect of the added shear on texture evolution in ASR, a stability analysis is carried out in orientation space and the variations in the position and strength of the ideal orientations are analysed as a function of the shear component. Then, modelling of R values is presented for various cases. On that basis, it is shown that there is an upper limit for the shear component in asymmetric rolling that still retains the 〈1 1 1〉 ND fibre (ND: direction normal to the sheet) which is good for formability. It is also found that better persistence of the ND fibre can be obtained by cyclically alternating the shear component. The theoretical results are well supported by comparison to experimental evidences. © 2011 Elsevier B.V. All rights reserved.

Few geographic and socioeconomic variations exist in primary total shoulder arthroplasty: a multi-level study of Australian registry data

BACKGROUND:Associations between socioeconomic position (SEP) and the uptake of primary total shoulder arthroplasty (TSA) is not well understood in the Australian population, thus potentially limiting equitable allocation of healthcare resources. We used the Australian Orthopaedic Association National Joint Replacement Registry (AOA NJRR) to examine whether geographic or socioeconomic variations exist in TSA performed for a diagnosis of osteoarthritis 2007-11 for all Australians aged ≥40 years.

METHODS:Primary anatomical and reverse TSA data were extracted from the AOA NJRR which captures >99 % of all TSA nationally. Residential addresses were cross-referenced to Australian Bureau of Statistics 2011 Census data to identify SEP measured at the area-level (categorised into deciles), and geographic location defined as Australian State/Territory of residence. We used a Poisson distribution for the number of TSA over the study period, and modelled the effects of age, SEP and geographic location using multilevel modelling.

RESULTS:During 2007-11, we observed 6,123 TSA (62.2 % female). For both sexes, TSA showed a proportional increase with advancing age. TSA did not vary by SEP or geographic location, with the exception of greater TSA among men in New South Wales.

CONCLUSIONS:Using a national registry approach we provide the first reliable picture of TSA at a national level. The uptake of TSA was equitable across SEP; however, there was some variation between the States/Territories. With an aging population, it is imperative that monitoring of major surgical procedures continues, and be focused toward determining whether TSA uptake correlates with need across different social and area-based groups.