Dynamically Distinguishing Polynomials

A polynomial with integer coefficients yields a family of dynamical systems indexed by primes as follows: For any prime p, reduce its coefficients mod p and consider its action on the field FpFp. We say a subset of Z[x]Z[x] is dynamically distinguishable mod p if the associated mod pdynamical systems are pairwise non-isomorphic. For any k,M∈Z\u3e1k,M∈Z\u3e1, we prove that there are infinitely many sets of integers MM of size M such that {xk+m∣m∈M}{xk+m∣m∈M} is dynamically distinguishable mod p for most p (in the sense of natural density). Our proof uses the Galois theory of dynatomic polynomials largely developed by Morton, who proved that the Galois groups of these polynomials are often isomorphic to a particular family of wreath products. In the course of proving our result, we generalize Morton’s work and compute statistics of these wreath products

Dynamically Distinguishing Polynomials

A polynomial with integer coefficients yields a family of dynamical systems indexed by primes as follows: For any prime p, reduce its coefficients mod p and consider its action on the field FpFp. We say a subset of Z[x]Z[x] is dynamically distinguishable mod p if the associated mod pdynamical systems are pairwise non-isomorphic. For any k,M∈Z\u3e1k,M∈Z\u3e1, we prove that there are infinitely many sets of integers MM of size M such that {xk+m∣m∈M}{xk+m∣m∈M} is dynamically distinguishable mod p for most p (in the sense of natural density). Our proof uses the Galois theory of dynatomic polynomials largely developed by Morton, who proved that the Galois groups of these polynomials are often isomorphic to a particular family of wreath products. In the course of proving our result, we generalize Morton’s work and compute statistics of these wreath products

Energija i pravednost

The airborne transmission of infection relies on the ability of pathogens to survive aerosol transport as they transit between hosts. Understanding the parameters that determine the survival of airborne microorganisms is critical to mitigating the impact of disease outbreaks. Conventional techniques for investigating bioaerosol longevity in vitro have systemic limitations that prevent the accurate representation of conditions that these particles would experience in the natural environment. Here, we report a new approach that enables the robust study of bioaerosol survival as a function of relevant environmental conditions. The methodology uses droplet-on-demand technology for the generation of bioaerosol droplets (1 to greater than 100 per trial) with tailored chemical and biological composition. These arrays of droplets are captured in an electrodynamic trap and levitated within a controlled environmental chamber. Droplets are then deposited on a substrate after a desired levitation period (less than 5 s to greater than 24 h). The response of bacteria to aerosolization can subsequently be determined by counting colony forming units, 24 h after deposition. In a first study, droplets formed from a suspension of Escherichia coli MRE162 cells (108 ml21 ) with initial radii of 27.8+0.08 mm were created and levitated for extended periods of time at 30% relative humidity. The time-dependence of the survival rate was measured over a time period extending to 1 h. We demonstrate that this approach can enable direct studies at the interface between aerobiology, atmospheric chemistry and aerosol physics to identify the factors that may affect the survival of airborne pathogens with the aim of developing infection control strategies for public health and biodefence applications

Engineering proximal vs. distal heme–NO coordination via dinitrosyl dynamics: implications for NO sensor design

Proximal vs. distal heme–NO coordination is a novel strategy for selective gas response in heme-based NO-sensors. In the case of Alcaligenes xylosoxidans cytochrome c′ (AXCP), formation of a transient distal 6cNO complex is followed by scission of the trans Fe–His bond and conversion to a proximal 5cNO product via a putative dinitrosyl species. Here we show that replacement of the AXCP distal Leu16 residue with smaller or similar sized residues (Ala, Val or Ile) traps the distal 6cNO complex, whereas Leu or Phe residues lead to a proximal 5cNO product with a transient or non-detectable distal 6cNO precursor. Crystallographic, spectroscopic, and kinetic measurements of 6cNO AXCP complexes show that increased distal steric hindrance leads to distortion of the Fe–N–O angle and flipping of the heme 7-propionate. However, it is the kinetic parameters of the distal NO ligand that determine whether 6cNO or proximal 5cNO end products are formed. Our data support a ‘balance of affinities’ mechanism in which proximal 5cNO coordination depends on relatively rapid release of the distal NO from the dinitrosyl precursor. This mechanism, which is applicable to other proteins that form transient dinitrosyls, represents a novel strategy for 5cNO formation that does not rely on an inherently weak Fe–His bond. Our data suggest a general means of engineering selective gas response into biologically-derived gas sensors in synthetic biology

ROCK1 and ROCK2 Are Required for Non-Small Cell Lung Cancer Anchorage-Independent Growth and Invasion

Evidence is emerging that the closely related ROCK1 and ROCK2 serine/threonine kinases support the invasive and metastatic growth of a spectrum of human cancer types. Therefore, inhibitors of ROCK are under preclinical development. However, a key step in their development involves the identification of genetic biomarkers that will predict ROCK inhibitor anti-tumor activity. One identified mechanism for ROCK activation in cancer involves the loss of function of the DLC1 tumor suppressor gene, which encodes a GTPase activating protein (RhoGAP) for the RhoA and RhoC small GTPases. DLC-1 loss may lead to hyperactivation of RhoA/C and its downstream effectors, the ROCK kinases. We therefore determined whether loss of DLC-1 protein expression identifies non-small cell lung carcinoma (NSCLC) cell lines whose growth and invasion phenotypes are sensitive to ROCK inhibition. We identified and characterized a novel small molecule pharmacologic inhibitor of ROCK and additionally applied genetic approaches to impair ROCK1 and/or ROCK2 activity, and we determined that although NSCLC anchorage-dependent growth was ROCK-independent, both anchorage-independent growth and Matrigel invasion were ROCK-dependent. However, loss of DLC-1 expression did not correlate with ROCK activation or with OXA-06 sensitivity. Unexpectedly, suppression of ROCK1 or ROCK2 expression alone was sufficient to impair anchorage-independent growth, supporting their non-overlapping roles in oncogenesis. Mechanistically, the block in anchorage-independent growth was associated with accumulation of cells in the G0/G1 phase of the cell cycle, but not increased anoikis. We conclude that ROCK may be a useful therapeutic target for NSCLC

Rapid intraoperative histology of unprocessed surgical specimens via fibre-laser-based stimulated Raman scattering microscopy

Conventional methods for intraoperative histopathologic diagnosis are labor- and time-intensive and may delay decision-making during brain tumor surgery. Stimulated Raman scattering (SRS) microscopy, a label-free optical process, has been shown to rapidly detect brain tumor infiltration in fresh, unprocessed human tissues. Previously, the execution of SRS microscopy in a clinical setting has not been possible. We report the first demonstration of SRS microscopy in an operating room using a portable fiber-laser-based microscope in unprocessed specimens from 101 neurosurgical patients. Additionally, we introduce an image-processing method, stimulated Raman histology (SRH), which leverages SRS images to create virtual hematoxylin and eosin- stained slides, revealing essential diagnostic features. In a simulation of intraoperative pathologic consultation in 30 patients, the concordance of SRH and conventional histology for predicting diagnosis was nearly perfect (κ>0.89) and accuracy exceeded 92%. We also built and validated a multilayer perceptron based on quantified SRH image attributes that predicts brain tumor subtype with 90% accuracy. This study provides insight into how SRH can now be used to improve the surgical care of brain tumor patients.Chemistry and Chemical Biolog

Soda and Tobacco Industry Corporate Social Responsibility Campaigns: How Do They Compare?

In an article that forms part of the PLoS Medicine series on Big Food, Andrew Cheyne and colleagues compare soda companies' corporate social responsibility (CSR) campaigns - which are designed to bolster the image and popularity of their products and to prevent regulation - with the tobacco industry's CSR campaigning

One fold, two functions: cytochrome P460 and cytochrome c′-β from the methanotroph Methylococcus capsulatus (Bath)

Nature is adept at utilising highly similar protein folds to carry out very different functions, yet the mechanisms by which this functional divergence occurs remain poorly characterised. In certain methanotrophic bacteria, two homologous pentacoordinate c-type heme proteins have been identified: a cytochrome P460 (cyt P460) and a cytochrome c′-β (cyt cp-β). Cytochromes P460 are able to convert hydroxylamine to nitrous oxide (N2O), a potent greenhouse gas. This reactivity is similar to that of hydroxylamine oxidoreductase (HAO), which is a key enzyme in nitrifying and methanotrophic bacteria. Cyt P460 and HAO both have unusual protein-heme cross-links, formed by a Tyr residue in HAO and a Lys in cyt P460. In contrast, cyts cp-β (the only known cytochromes c′ with a β-sheet fold) lack this crosslink and appears to be optimized for binding non-polar molecules (including NO and CO) without enzymatic conversion. Our bioinformatics analysis supports the proposal that cyt cp-β may have evolved from cyt P460 via a gene duplication event. Using high-resolution X-ray crystallography, UV-visible absorption, electron paramagnetic resonance (EPR) and resonance Raman spectroscopy, we have characterized the overall protein folding and active site structures of cyt cp-β and cyt P460 from the obligate methanotroph, Methylococcus capsulatus (Bath). These proteins display a similar β-sheet protein fold, together with a pattern of changes to the heme pocket regions and localised tertiary structure that have converted a hydroxylamine oxidizing enzyme into a gas-binding protein. Structural comparisons provide insights relevant to enzyme redesign for synthetic enzymology and engineering of gas sensor proteins. We also show the widespread occurrence of cyts cp-β and characterise their phylogeny

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology