Powers in a class of A-strict standard episturmian words

This paper concerns a specific class of strict standard episturmian words whose directive words resemble those of characteristic Sturmian words. In particular, we explicitly determine all integer powers occurring in such infinite words, extending recent results of Damanik and Lenz (2003), who studied powers in Sturmian words. The key tools in our analysis are canonical decompositions and a generalization of singular words, which were originally defined for the ubiquitous Fibonacci word. Our main results are demonstrated via some examples, including the $k$-bonacci word: a generalization of the Fibonacci word to a $k$-letter alphabet ($k\geq2$).Comment: 26 pages; extended version of a paper presented at the 5th International Conference on Words, Montreal, Canada, September 13-17, 200

Quasiperiodic and Lyndon episturmian words

Recently the second two authors characterized quasiperiodic Sturmian words, proving that a Sturmian word is non-quasiperiodic if and only if it is an infinite Lyndon word. Here we extend this study to episturmian words (a natural generalization of Sturmian words) by describing all the quasiperiods of an episturmian word, which yields a characterization of quasiperiodic episturmian words in terms of their "directive words". Even further, we establish a complete characterization of all episturmian words that are Lyndon words. Our main results show that, unlike the Sturmian case, there is a much wider class of episturmian words that are non-quasiperiodic, besides those that are infinite Lyndon words. Our key tools are morphisms and directive words, in particular "normalized" directive words, which we introduced in an earlier paper. Also of importance is the use of "return words" to characterize quasiperiodic episturmian words, since such a method could be useful in other contexts.Comment: 33 pages; minor change

Episturmian words: a survey

In this paper, we survey the rich theory of infinite episturmian words which generalize to any finite alphabet, in a rather resembling way, the well-known family of Sturmian words on two letters. After recalling definitions and basic properties, we consider episturmian morphisms that allow for a deeper study of these words. Some properties of factors are described, including factor complexity, palindromes, fractional powers, frequencies, and return words. We also consider lexicographical properties of episturmian words, as well as their connection to the balance property, and related notions such as finite episturmian words, Arnoux-Rauzy sequences, and "episkew words" that generalize the skew words of Morse and Hedlund.Comment: 36 pages; major revision: improvements + new material + more reference

Do guidelines influence breathlessness management in advanced lung diseases? A multinational survey of respiratory medicine and palliative care physicians

Background: Respiratory medicine (RM) and palliative care (PC) physicians’ management of chronic breathlessness in advanced chronic obstructive pulmonary disease (COPD), fibrotic interstitial lung disease (fILD) and lung cancer (LC), and the influence of practice guidelines was explored via an online survey. Methods: A voluntary, online survey was distributed to RM and PC physicians via society newsletter mailing lists. Results: 450 evaluable questionnaires (348 (77%) RM and 102 (23%) PC) were analysed. Significantly more PC physicians indicated routine use (often/always) of opioids across conditions (COPD: 92% vs. 39%, fILD: 83% vs. 36%, LC: 95% vs. 76%; all p < 0.001) and significantly more PC physicians indicated routine use of benzodiazepines for COPD (33% vs. 10%) and fILD (25% vs. 12%) (both p < 0.001). Significantly more RM physicians reported routine use of a breathlessness score (62% vs. 13%, p < 0.001) and prioritised exercise training/rehabilitation for COPD (49% vs. 7%) and fILD (30% vs. 18%) (both p < 0.001). Overall, 40% of all respondents reported reading non-cancer palliative care guidelines (either carefully or looked at them briefly). Respondents who reported reading these guidelines were more likely to: routinely use a breathlessness score (χ2 = 13.8; p < 0.001), use opioids (χ2 = 12.58, p < 0.001) and refer to pulmonary rehabilitation (χ2 = 6.41, p = 0.011) in COPD; use antidepressants (χ2 = 6.25; p = 0.044) and refer to PC (χ2 = 5.83; p = 0.016) in fILD; and use a handheld fan in COPD (χ2 = 8.75, p = 0.003), fILD (χ2 = 4.85, p = 0.028) and LC (χ2 = 5.63; p = 0.018). Conclusions: These findings suggest a need for improved dissemination and uptake of jointly developed breathlessness management guidelines in order to encourage appropriate use of existing, evidence-based therapies. The lack of opioid use by RM, and continued benzodiazepine use in PC, suggest that a wider range of acceptable therapies need to be developed and trialled

A study of alterations in DNA epigenetic modifications (5mC and 5hmC) and gene expression influenced by simulated microgravity in human lymphoblastoid cells

Cells alter their gene expression in response to exposure to various environmental changes. Epigenetic mechanisms such as DNA methylation are believed to regulate the alterations in gene expression patterns. In vitro and in vivo studies have documented changes in cellular proliferation, cytoskeletal remodeling, signal transduction, bone mineralization and immune deficiency under the influence of microgravity conditions experienced in space. However microgravity induced changes in the epigenome have not been well characterized. In this study we have used Next-generation Sequencing (NGS) to profile ground-based “simulated” microgravity induced changes on DNA methylation (5-methylcytosine or 5mC), hydroxymethylation (5-hydroxymethylcytosine or 5hmC), and simultaneous gene expression in cultured human lymphoblastoid cells. Our results indicate that simulated microgravity induced alterations in the methylome (~60% of the differentially methylated regions or DMRs are hypomethylated and ~92% of the differentially hydroxymethylated regions or DHMRs are hyperhydroxymethylated). Simulated microgravity also induced differential expression in 370 transcripts that were associated with crucial biological processes such as oxidative stress response, carbohydrate metabolism and regulation of transcription. While we were not able to obtain any global trend correlating the changes of methylation/ hydroxylation with gene expression, we have been able to profile the simulated microgravity induced changes of 5mC over some of the differentially expressed genes that includes five genes undergoing differential methylation over their promoters and twenty five genes undergoing differential methylation over their gene-bodies. To the best of our knowledge, this is the first NGS-based study to profile epigenomic patterns induced by short time exposure of simulated microgravity and we believe that our findings can be a valuable resource for future explorations

The Cryptosporidium parvum Kinome

<p>Abstract</p> <p>Background</p> <p>Hundreds of millions of people are infected with cryptosporidiosis annually, with immunocompromised individuals suffering debilitating symptoms and children in socioeconomically challenged regions at risk of repeated infections. There is currently no effective drug available. In order to facilitate the pursuit of anti-cryptosporidiosis targets and compounds, our study spans the classification of the <it>Cryptosporidium parvum </it>kinome and the structural and biochemical characterization of representatives from the CDPK family and a MAP kinase.</p> <p>Results</p> <p>The <it>C</it>. <it>parvum </it>kinome comprises over 70 members, some of which may be promising drug targets. These <it>C. parvum </it>protein kinases include members in the AGC, Atypical, CaMK, CK1, CMGC, and TKL groups; however, almost 35% could only be classified as OPK (other protein kinases). In addition, about 25% of the kinases identified did not have any known orthologues outside of <it>Cryptosporidium spp</it>. Comparison of specific kinases with their <it>Plasmodium falciparum </it>and <it>Toxoplasma gondii </it>orthologues revealed some distinct characteristics within the <it>C. parvum </it>kinome, including potential targets and opportunities for drug design. Structural and biochemical analysis of 4 representatives of the CaMK group and a MAP kinase confirms features that may be exploited in inhibitor design. Indeed, screening <it>Cp</it>CDPK1 against a library of kinase inhibitors yielded a set of the pyrazolopyrimidine derivatives (PP1-derivatives) with IC₅₀values of < 10 nM. The binding of a PP1-derivative is further described by an inhibitor-bound crystal structure of <it>Cp</it>CDPK1. In addition, structural analysis of <it>Cp</it>CDPK4 identified an unprecedented Zn-finger within the CDPK kinase domain that may have implications for its regulation.</p> <p>Conclusions</p> <p>Identification and comparison of the <it>C. parvum </it>protein kinases against other parasitic kinases shows how orthologue- and family-based research can be used to facilitate characterization of promising drug targets and the search for new drugs.</p

Improving Identification Of Strangulation Injuries In Domestic Violence: Pilot Data From A Researcher–Practitioner Collaboration

Efforts to partner researchers and practitioners have the potential to significantly improve both research and response to non-fatal strangulation within the context of domestic violence. Non-fatal strangulation is far more common than most formal data suggest and is a highly gendered form of domestic assault often used to control or intimidate a partner; however, depending on how the assault takes place, it can leave little obvious physical evidence to an untrained investigator. The present study estimates the occurrence of strangulation cases and possible strangulation cases that may not be explicitly classified as such in official police reports due to inadequacies in law enforcement training. We offer a description of these types of cases as they compare with domestic violence police reports from non-strangulation cases. Results highlight the gendered nature of strangulation as well as the importance of practitioners and researchers critically reflecting on issues within the criminal justice system in an effort to redress inadequacies, hold offenders accountable, and save lives

Microfluidic Biopsy Trapping Device for the Real-Time Monitoring of Tumor Microenvironment

<div><p>The tumor microenvironment is composed of cellular and stromal components such as tumor cells, mesenchymal cells, immune cells, cancer associated fibroblasts and the supporting extracellular matrix. The tumor microenvironment provides crucial support for growth and progression of tumor cells and affects tumor response to therapeutic interventions. To better understand tumor biology and to develop effective cancer therapeutic agents it is important to develop preclinical platforms that can faithfully recapitulate the tumor microenvironment and the complex interaction between the tumor and its surrounding stromal elements. Drug studies performed in vitro with conventional two-dimensional cancer cell line models do not optimally represent clinical drug response as they lack true tumor heterogeneity and are often performed in static culture conditions lacking stromal tumor components that significantly influence the metabolic activity and proliferation of cells. Recent microfluidic approaches aim to overcome such obstacles with the use of cell lines derived in artificial three-dimensional supportive gels or micro-chambers. However, absence of a true tumor microenvironment and full interstitial flow, leads to less than optimal evaluation of tumor response to drug treatment. Here we report a continuous perfusion microfluidic device coupled with microscopy and image analysis for the assessment of drug effects on intact fresh tumor tissue. We have demonstrated that fine needle aspirate biopsies obtained from patient-derived xenograft models of adenocarcinoma of the lung can successfully be analyzed for their response to ex vivo drug treatment within this biopsy trapping microfluidic device, wherein a protein kinase C inhibitor, staurosporine, was used to assess tumor cell death as a proof of principle. This approach has the potential to study tumor tissue within its intact microenvironment to better understand tumor response to drug treatments and eventually to choose the most effective drug and drug combination for individual patients in a cost effective and timely manner.</p></div