Contrasting patterns of the 5S and 45S rDNA evolutions in the Byblis liniflora complex (Byblidaceae)

To clarify the evolutionary dynamics of ribosomal RNA genes (rDNAs) in the Byblis liniflora complex (Byblidaceae), we investigated the 5S and 45S rDNA genes through (1) chromosomal physical mapping by fluorescence in situ hybridization (FISH) and (2) phylogenetic analyses using the nontranscribed spacer of 5S rDNA (5S-NTS) and the internal transcribed spacer of 45S rDNA (ITS). In addition, we performed phylogenetic analyses based on rbcL and trnK intron. The complex was divided into 2 clades: B. aquatica–B. filifolia and B. guehoi–B. liniflora–B. rorida. Although members of the complex had conservative symmetric karyotypes, they were clearly differentiated on chromosomal rDNA distribution patterns. The sequence data indicated that ITS was almost homogeneous in all taxa in which two or four 45S rDNA arrays were frequently found at distal regions of chromosomes in the somatic karyotype. ITS homogenization could have been prompted by relatively distal 45S rDNA positions. In contrast, 2–12 5S rDNA arrays were mapped onto proximal/interstitial regions of chromosomes, and some paralogous 5S-NTS were found in the genomes harboring 4 or more arrays. 5S-NTS sequence type-specific FISH analysis showed sequence heterogeneity within and between some 5S rDNA arrays. Interlocus homogenization may have been hampered by their proximal location on chromosomes. Chromosomal location may have affected the contrasting evolutionary dynamics of rDNAs in the B. liniflora complex

A physicochemical descriptor-based scoring scheme for effective and rapid filtering of kinase-like chemical space

<p>Abstract</p> <p>Background</p> <p>The current chemical space of known small molecules is estimated to exceed 10⁶⁰structures. Though the largest physical compound repositories contain only a few tens of millions of unique compounds, virtual screening of databases of this size is still difficult. In recent years, the application of physicochemical descriptor-based profiling, such as Lipinski's rule-of-five for drug-likeness and Oprea's criteria of lead-likeness, as early stage filters in drug discovery has gained widespread acceptance. In the current study, we outline a kinase-likeness scoring function based on known kinase inhibitors.</p> <p>Results</p> <p>The method employs a collection of 22,615 known kinase inhibitors from the ChEMBL database. A kinase-likeness score is computed using statistical analysis of nine key physicochemical descriptors for these inhibitors. Based on this score, the kinase-likeness of four publicly and commercially available databases, i.e., National Cancer Institute database (NCI), the Natural Products database (NPD), the National Institute of Health's Molecular Libraries Small Molecule Repository (MLSMR), and the World Drug Index (WDI) database, is analyzed. Three of these databases, i.e., NCI, NPD, and MLSMR are frequently used in the virtual screening of kinase inhibitors, while the fourth WDI database is for comparison since it covers a wide range of known chemical space. Based on the kinase-likeness score, a kinase-focused library is also developed and tested against three different kinase targets selected from three different branches of the human kinome tree.</p> <p>Conclusions</p> <p>Our proposed methodology is one of the first that explores how the narrow chemical space of kinase inhibitors and its relevant physicochemical information can be utilized to build kinase-focused libraries and prioritize pre-existing compound databases for screening. We have shown that focused libraries generated by filtering compounds using the kinase-likeness score have, on average, better docking scores than an equivalent number of randomly selected compounds. Beyond library design, our findings also impact the broader efforts to identify kinase inhibitors by screening pre-existing compound libraries. Currently, the NCI library is the most commonly used database for screening kinase inhibitors. Our research suggests that other libraries, such as MLSMR, are more kinase-like and should be given priority in kinase screenings.</p

Incentivised chronic disease management and the inverse equity hypothesis: findings from a longitudinal analysis of Scottish primary care practice-level data

Background: The inverse equity hypothesis asserts that new health policies initially widen inequality, then attenuate inequalities over time. Since 2004, the UK’s pay-for-performance scheme for chronic disease management (CDM) in primary care general practices (the Quality and Outcomes Framework) has permitted practices to except (exclude) patients from attending annual CDM reviews, without financial penalty. Informed dissent (ID) is one component of exception rates, applied to patients who have not attended due to refusal or non-response to invitations. ‘Population achievement’ describes the proportion receiving care, in relation to those eligible to receive it, including excepted patients. Examination of exception reporting (including ID) and population achievement enables the equity impact of the UK pay-for-performance contract to be assessed. We conducted a longitudinal analysis of practice-level rates and of predictors of ID, overall exceptions and population achievement for CDM to examine whether the inverse equity hypothesis holds true. Methods: We carried out a retrospective, longitudinal study using routine primary care data, analysed by multilevel logistic regression. Data were extracted from 793 practices (83% of Scottish general practices) serving 4.4 million patients across Scotland from 2010/2011 to 2012/2013, for 29 CDM indicators covering 11 incentivised diseases. This provided 68,991 observations, representing a total of 15 million opportunities for exception reporting. Results: Across all observations, the median overall exception reporting rate was 7.0% (7.04% in 2010–2011; 7.02% in 2011–2012 and 6.92% in 2012–2013). The median non-attendance rate due to ID was 0.9% (0.76% in 2010–2011; 0.88% in 2011–2012 and 0.96% in 2012–2013). Median population achievement was 83.5% (83.51% in 2010–2011; 83.41% in 2011–2012 and 83.63% in 2012–2013). The odds of ID reporting in 2012/2013 were 16.0% greater than in 2010/2011 (p &lt; 0.001). Practices in Scotland’s most deprived communities were twice as likely to report non-attendance due to ID (odds ratio 2.10, 95% confidence interval 1.83–2.40, p &lt; 0.001) compared with those in the least deprived; rural practices reported lower levels of non-attendance due to ID. These predictors were also independently associated with overall exceptions. Rates of population achievement did not change over time, with higher levels (higher remuneration) associated with increased rates of overall and ID exception and more affluent practices. Conclusions: Non-attendance for CDM due to ID has risen over time, and higher rates are seen in patients from practices located in disadvantaged areas. This suggests that CDM incentivisation does not conform to the inverse equity hypothesis, because inequalities are widening over time with lower uptake of anticipatory care health checks and CDM reviews noted among those most in need. Incentivised CDM needs to include incentives for engaging with the ‘hard to reach’ if inequalities in healthcare delivery are to be tackled