Statistical Inference for Multi-Pathogen Systems

There is growing interest in understanding the nature and consequences of interactions among infectious agents. Pathogen interactions can be operational at different scales, either within a co-infected host or in host populations where they co-circulate, and can be either cooperative or competitive. The detection of interactions among pathogens has typically involved the study of synchrony in the oscillations of the protagonists, but as we show here, phase association provides an unreliable dynamical fingerprint for this task. We assess the capacity of a likelihood-based inference framework to accurately detect and quantify the presence and nature of pathogen interactions on the basis of realistic amounts and kinds of simulated data. We show that when epidemiological and demographic processes are well understood, noisy time series data can contain sufficient information to allow correct inference of interactions in multi-pathogen systems. The inference power is dependent on the strength and time-course of the underlying mechanism: stronger and longer-lasting interactions are more easily and more precisely quantified. We examine the limitations of our approach to stochastic temporal variation, under-reporting, and over-aggregation of data. We propose that likelihood shows promise as a basis for detection and quantification of the effects of pathogen interactions and the determination of their (competitive or cooperative) nature on the basis of population-level time-series data

Phylogenetic Distinctiveness of Middle Eastern and Southeast Asian Village Dog Y Chromosomes Illuminates Dog Origins

Modern genetic samples are commonly used to trace dog origins, which entails untested assumptions that village dogs reflect indigenous ancestry or that breed origins can be reliably traced to particular regions. We used high-resolution Y chromosome markers (SNP and STR) and mitochondrial DNA to analyze 495 village dogs/dingoes from the Middle East and Southeast Asia, along with 138 dogs from >35 modern breeds to 1) assess genetic divergence between Middle Eastern and Southeast Asian village dogs and their phylogenetic affinities to Australian dingoes and gray wolves (Canis lupus) and 2) compare the genetic affinities of modern breeds to regional indigenous village dog populations. The Y chromosome markers indicated that village dogs in the two regions corresponded to reciprocally monophyletic clades, reflecting several to many thousand years divergence, predating the Neolithic ages, and indicating long-indigenous roots to those regions. As expected, breeds of the Middle East and East Asia clustered within the respective regional village dog clade. Australian dingoes also clustered in the Southeast Asian clade. However, the European and American breeds clustered almost entirely within the Southeast Asian clade, even sharing many haplotypes, suggesting a substantial and recent influence of East Asian dogs in the creation of European breeds. Comparison to 818 published breed dog Y STR haplotypes confirmed this conclusion and indicated that some African breeds reflect another distinct patrilineal origin. The lower-resolution mtDNA marker consistently supported Y-chromosome results. Both marker types confirmed previous findings of higher genetic diversity in dogs from Southeast Asia than the Middle East. Our findings demonstrate the importance of village dogs as windows into the past and provide a reference against which ancient DNA can be used to further elucidate origins and spread of the domestic dog

Convergence versus Divergence: Testing Varieties of Capitalism Perspective on the Globalization of Business Practices

This paper analyses links between intra-organizational adaptation and institutional variation across countries. Using the varieties of capitalism viewpoint, we examine strategic options open to multinational firms operating simultaneously in liberal market economies and coordinated market economies. A holistic perspective is achieved by implementing an original ‘index of institutional impact.’ Data are drawn from a survey of the subsidiaries of German firms in the UK in 2007. The results suggest that pressure towards accepting local practices for multinational firms varies across the dimensions in which firms resolve coordination problems, inciting speedy convergence in some, but allowing for maintaining distinctive practices in other

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Do Bat Gantries and Underpasses Help Bats Cross Roads Safely?

Major roads can reduce bat abundance and diversity over considerable distances. To mitigate against these effects and comply with environmental law, many European countries install bridges, gantries or underpasses to make roads permeable and safer to cross. However, through lack of appropriate monitoring, there is little evidence to support their effectiveness. Three underpasses and four bat gantries were investigated in northern England. Echolocation call recordings and observations were used to determine the number of bats using underpasses in preference to crossing the road above, and the height at which bats crossed. At gantries, proximity to the gantry and height of crossing bats were measured. Data were compared to those from adjacent, severed commuting routes that had no crossing structure. At one underpass 96% of bats flew through it in preference to crossing the road. This underpass was located on a pre-construction commuting route that allowed bats to pass without changing flight height or direction. At two underpasses attempts to divert bats from their original commuting routes were unsuccessful and bats crossed the road at the height of passing vehicles. Underpasses have the potential to allow bats to cross roads safely if built on pre-construction commuting routes. Bat gantries were ineffective and used by a very small proportion of bats, even up to nine years after construction. Most bats near gantries crossed roads along severed, pre-construction commuting routes at heights that put them in the path of vehicles. Crossing height was strongly correlated with verge height, suggesting that elevated verges may have some value in mitigation, but increased flight height may be at the cost of reduced permeability. Green bridges should be explored as an alternative form of mitigation. Robust monitoring is essential to assess objectively the case for mitigation and to ensure effective mitigation

Human papillomavirus-mediated carcinogenesis and HPV-associated oral and oropharyngeal squamous cell carcinoma. Part 1: Human papillomavirus-mediated carcinogenesis

High-risk human papillomavirus (HPV) E6 and E7 oncoproteins are essential factors for HPV-induced carcinogenesis, and for the maintenance of the consequent neoplastic growth. Cellular transformation is achieved by complex interaction of these oncogenes with several cellular factors of cell cycle regulation including p53, Rb, cyclin-CDK complexes, p21 and p27. Both persistent infection with high-risk HPV genotypes and immune dysregulation are associated with increased risk of HPV-induced squamous cell carcinoma

Phosphate decreases urine calcium and increases calcium balance: A meta-analysis of the osteoporosis acid-ash diet hypothesis

<p>Abstract</p> <p>Background</p> <p>The acid-ash hypothesis posits that increased excretion of "acidic" ions derived from the diet, such as phosphate, contributes to net acidic ion excretion, urine calcium excretion, demineralization of bone, and osteoporosis. The public is advised by various media to follow an alkaline diet to lower their acidic ion intakes. The objectives of this meta-analysis were to quantify the contribution of phosphate to bone loss in healthy adult subjects; specifically, a) to assess the effect of supplemental dietary phosphate on urine calcium, calcium balance, and markers of bone metabolism; and to assess whether these affects are altered by the b) level of calcium intake, c) the degree of protonation of the phosphate.</p> <p>Methods</p> <p>Literature was identified through computerized searches regarding phosphate with surrogate and/or direct markers of bone health, and was assessed for methodological quality. Multiple linear regression analyses, weighted for sample size, were used to combine the study results. Tests of interaction included stratification by calcium intake and degree of protonation of the phosphate supplement.</p> <p>Results</p> <p>Twelve studies including 30 intervention arms manipulated 269 subjects' phosphate intakes. Three studies reported net acid excretion. All of the meta-analyses demonstrated significant decreases in urine calcium excretion in response to phosphate supplements whether the calcium intake was high or low, regardless of the degree of protonation of the phosphate supplement. None of the meta-analyses revealed lower calcium balance in response to increased phosphate intakes, whether the calcium intake was high or low, or the composition of the phosphate supplement.</p> <p>Conclusion</p> <p>All of the findings from this meta-analysis were contrary to the acid ash hypothesis. Higher phosphate intakes were associated with decreased urine calcium and increased calcium retention. This meta-analysis did not find evidence that phosphate intake contributes to demineralization of bone or to bone calcium excretion in the urine. Dietary advice that dairy products, meats, and grains are detrimental to bone health due to "acidic" phosphate content needs reassessment. There is no evidence that higher phosphate intakes are detrimental to bone health.</p

11β-HSD1 plays a critical role in trabecular bone loss associated with systemic glucocorticoid therapy

Background: Despite their efficacy in the treatment of chronic inflammation, the prolonged application of therapeutic glucocorticoids (GCs) is limited by significant systemic side effects including glucocorticoid-induced osteoporosis (GIOP). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bi-directional enzyme that primarily activates GCs in vivo, regulating tissue-specific exposure to active GC. We aimed to determine the contribution of 11β-HSD1 to GIOP. Methods: Wild type (WT) and 11β-HSD1 knockout (KO) mice were treated with corticosterone (100 μg/ml, 0.66% ethanol) or vehicle (0.66% ethanol) in drinking water over 4 weeks (six animals per group). Bone parameters were assessed by micro-CT, sub-micron absorption tomography and serum markers of bone metabolism. Osteoblast and osteoclast gene expression was assessed by quantitative RT-PCR. Results: Wild type mice receiving corticosterone developed marked trabecular bone loss with reduced bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N). Histomorphometric analysis revealed a dramatic reduction in osteoblast numbers. This was matched by a significant reduction in the serum marker of osteoblast bone formation P1NP and gene expression of the osteoblast markers Alp and Bglap. In contrast, 11β-HSD1 KO mice receiving corticosterone demonstrated almost complete protection from trabecular bone loss, with partial protection from the decrease in osteoblast numbers and markers of bone formation relative to WT counterparts receiving corticosterone. Conclusions: This study demonstrates that 11β-HSD1 plays a critical role in GIOP, mediating GC suppression of anabolic bone formation and reduced bone volume secondary to a decrease in osteoblast numbers. This raises the intriguing possibility that therapeutic inhibitors of 11β-HSD1 may be effective in preventing GIOP in patients receiving therapeutic steroids