Per la corretta attribuzione del "Romanzo delle donne contemporanee in Italia" (1863)

The use of free energy simulation techniques in the study of protein stability is critically evaluated. Results from two simulations of the thermostability mutation Asn218 to Ser218 in Subtilisin are presented. It is shown that components of the free energy change can be highly sensitive to the computational details of the simulation leading to the conclusion that free energy calculations cannot currently be used to reliably predict protein stability. The different factors that undermine the reliability are discussed

Solution structure of the second bromodomain of Brd2 and its specific interaction with acetylated histone tails

<p>Abstract</p> <p>Background</p> <p>Brd2 is a transcriptional regulator and belongs to BET family, a less characterized novel class of bromodomain-containing proteins. Brd2 contains two tandem bromodomains (BD1 and BD2, 46% sequence identity) in the N-terminus and a conserved motif named ET (extra C-terminal) domain at the C-terminus that is also present in some other bromodomain proteins. The two bromodomains have been shown to bind the acetylated histone H4 and to be responsible for mitotic retention on chromosomes, which is probably a distinctive feature of BET family proteins. Although the crystal structure of Brd2 BD1 is reported, no structure features have been characterized for Brd2 BD2 and its interaction with acetylated histones.</p> <p>Results</p> <p>Here we report the solution structure of human Brd2 BD2 determined by NMR. Although the overall fold resembles the bromodomains from other proteins, significant differences can be found in loop regions, especially in the ZA loop in which a two amino acids insertion is involved in an uncommon <it>π</it>-helix, termed <it>π</it>D. The helix <it>π</it>D forms a portion of the acetyl-lysine binding site, which could be a structural characteristic of Brd2 BD2 and other BET bromodomains. Unlike Brd2 BD1, BD2 is monomeric in solution. With NMR perturbation studies, we have mapped the H4-AcK12 peptide binding interface on Brd2 BD2 and shown that the binding was with low affinity (2.9 mM) and in fast exchange. Using NMR and mutational analysis, we identified several residues important for the Brd2 BD2-H4-AcK12 peptide interaction and probed the potential mechanism for the specific recognition of acetylated histone codes by Brd2 BD2.</p> <p>Conclusion</p> <p>Brd2 BD2 is monomeric in solution and dynamically interacts with H4-AcK12. The additional secondary elements in the long ZA loop may be a common characteristic of BET bromodomains. Surrounding the ligand-binding cavity, five aspartate residues form a negatively charged collar that serves as a secondary binding site for H4-AcK12. We suggest that Brd2 BD1 and BD2 may possess distinctive roles and cooperate to regulate Brd2 functions. The structure basis of Brd2 BD2 will help to further characterize the functions of Brd2 and its BET members.</p

Predictive model for diabetic retinopathy under limited medical resources: A multicenter diagnostic study

BackgroundComprehensive eye examinations for diabetic retinopathy is poorly implemented in medically underserved areas. There is a critical need for a widely available and economical tool to aid patient selection for priority retinal screening. We investigated the possibility of a predictive model for retinopathy identification using simple parameters.MethodsClinical data were retrospectively collected from 4, 159 patients with diabetes admitted to five tertiary hospitals. Independent predictors were identified by univariate analysis and least absolute shrinkage and selection operator (LASSO) regression, and a nomogram was developed based on a multivariate logistic regression model. The validity and clinical practicality of this nomogram were assessed using concordance index (C-index), area under the receiver operating characteristic curve (AUROC), calibration curves, decision curve analysis (DCA), and clinical impact curves (CIC).ResultsThe predictive factors in the multivariate model included the duration of diabetes, history of hypertension, and cardiovascular disease. The three-variable model displayed medium prediction ability with an AUROC of 0.722 (95%CI 0.696-0.748) in the training set, 0.715 (95%CI 0.670-0.754) in the internal set, and 0.703 (95%CI 0.552-0.853) in the external dataset. DCA showed that the threshold probability of DR in diabetic patients was 17-55% according to the nomogram, and CIC also showed that the nomogram could be applied clinically if the risk threshold exceeded 30%. An operation interface on a webpage (https://cqmuxss.shinyapps.io/dr_tjj/) was built to improve the clinical utility of the nomogram.ConclusionsThe predictive model developed based on a minimal amount of clinical data available to diabetic patients with restricted medical resources could help primary healthcare practitioners promptly identify potential retinopathy

Use of real-world evidence in pharmacoeconomic analysis: illustrations in The Netherlands and China

The main objective of the thesis is to assess the added value of use of observational data in pharmacoeconomic (PE) evaluations. Five sub-aims were addressed in the thesis: 1) a systematic literature review summarized results evidencing the cost-saving potentials of renin-angiotensin-aldosterone system (RAAS) inhibitors, including angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs), in type 2 diabetes (T2D) patients with nephropathy compared with conventional therapy excluding a RAAS inhibitor; 2) a general framework was developed to illustrate the problems and solutions of data quality assessment and preprocessing, based on the ‘fit-for-use’ concept; 3) a comparative effectiveness study compared the effectiveness of ACE inhibitors vs. ARBs for protecting T2D patients from renal function decline in a real-world setting, the value of observational data in outcomes research studies was assessed; 4) a real-world study described the changes of diabetes cost in Chinese patients using electronic claims data, and the value of observational data in health economics studies was assessed; 5) a cost-effectiveness analysis of RAAS inhibitors (ACE inhibitors and ARBs) vs. other active anti-hypertensive agents and no anti-hypertensive treatment in patients with T2D and nephropathy in China was performed from a healthcare payer perspective, and a budget impact analysis was conducted alongside the PE evaluation to analyze the budget changes of Chinese urban employee basic medical insurance (UEBMI) when different strategies of medication use are applied; the use of observational data in PE evaluations was assessed

Online Multikernel Learning Based on a Triple-Norm Regularizer for Semantic Image Classification

Currently image classifiers based on multikernel learning (MKL) mostly use batch approach, which is slow and difficult to scale up for large datasets. In the meantime, standard MKL model neglects the correlations among examples associated with a specific kernel, which makes it infeasible to adjust the kernel combination coefficients. To address these issues, a new and efficient multikernel multiclass algorithm called TripleReg-MKL is proposed in this work. Taking the principle of strong convex optimization into consideration, we propose a new triple-norm regularizer (TripleReg) to constrain the empirical loss objective function, which exploits the correlations among examples to tune the kernel weights. It highlights the application of multivariate hinge loss and a conservative updating strategy to filter noisy samples, thereby reducing the model complexity. This novel MKL formulation is then solved in an online mode using a primal-dual framework. A theoretical analysis of the complexity and convergence of TripleReg-MKL is presented. It shows that the new algorithm has a complexity of OCMT and achieves a fast convergence rate of OlogT/T. Extensive experiments on four benchmark datasets demonstrate the effectiveness and robustness of this new approach

An analysis on rational use and affordability of medicine after the implementation of National Essential Medicines Policy and Zero Mark-up Policy in Hangzhou, China.

BackgroundThe National Essential Medicine Policy and the Zero Mark-up Policy was introduced to improve the rational use and affordability of medicine. This study analyzed the changes of medicine use at different Health Care Institutions in Hangzhou city after the implementation of National Essential Medicine Policy and the Zero Mark-up Policy.MethodsFacility based survey was conducted in 17 Health Care Institutions and 16406 outpatient prescriptions in 2011 and 2013 were collected. Average number of medicines, average number of antibiotics and average expenditure per prescription were analyzed. Comparisons between 2011 and 2013, among different levels of Health Care Institutions and age groups were conducted.ResultsThe average number of medicines per prescription, use of antibiotics, intramuscular (IM) injections and intravenous (IV) injections decreased while the use of hormones increased. No significant change of the average medicine expenditure per prescription was observed. Disparities among different levels of Health Care Institutions and different age groups existed.ConclusionThe problems of poly-pharmacy, overuse of antibiotics, intramuscular (IM) injections and intravenous (IV) injections and hormones still existed, however mitigated after the implementation of The National Essential Medicine Policy and the Zero Mark-up Policy

Using primary care electronic health record data for comparative effectiveness research: experience of data quality assessment and preprocessing in The Netherlands

Aim: Details of data quality and how quality issues were solved have not been reported in published comparative effectiveness studies using electronic health record data. Methods: We developed a conceptual framework of data quality assessment and preprocessing and apply it to a study comparing angiotensin-converting enzyme inhibitors with angiotensin receptor blockerss on renal function decline in diabetes patients. Results: The framework establishes a line of thought to identify and act on data issues. The core concept is to evaluate whether data are fit-for-use for research tasks. Possible quality problems are listed through specific signal detections, and verified whether they are true problems. Optimal solutions are selected for the identified problems. Conclusion: This framework can be used in observational studies to improve validity of results

Comparing the effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on renal function decline in diabetes

Aim: To compare effectiveness of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) for protecting Type 2 diabetes mellitus (DM2) patients from renal function decline in a real-world setting. Methods: Retrospective cohort study of new ACEi/ARB users in 2007-2012 in an unselected primary care DM2 population. Outcome is decline in renal function stage (combining estimated glomerular filtration rate and albuminuria). Patients were matched on a propensity score. Extended Cox models with time-varying covariates were used to estimate hazard ratios of outcome. Results: The time to renal function decline for ARB users was slightly, but not significantly longer than for ACEi users (hazard ratio: 0.80; 95% CI: 0.58-1.10; p = 0.166). Conclusion: This study did not show significant differences between the classes in preventing renal function decline in DM2 patients in primary care

Comparison of anther and microspore culture in androgenic embryogenesis and regeneration of broccoli (Brassica oleracea L. var. italica P.)

The aim of this study was to compare the efficiency of broccoli anther and microspore culture methods for doubled haploid (DH) lines production. We evaluated the main influencing factors and optimized the culture methods to improve embryo induction and plant regeneration for efficient doubled haploid production in broccoli breeding. Six broccoli hybrids were used in this study. Our results show that generally, the efficiency of androgenic embryogenesis and regeneration in microspore culture is higher than that in the anther culture. Moreover, the microspore culture eliminated the possibility of plantlets coming from diploid tissue. In this study, the four-day cold pre-treatment yielded the highest number of embryos in both anther and microspore culture methods; the embryo yield at 32.5°C for 24 h was the highest in anther and microspore culture. Optimal plating densities were 30 anthers per dish in anther culture and 4×105 microspores per ml in microspore culture. In androgenic embryo production, the PG-96 medium proved to be more effective than NLN medium. Sucrose concentration at 10% for anther culture and 13% (w/v) for microspore culture was recommended. A total of 70 regenerants were obtained from three genotypes including doubled haploids, haploids and aneuploids.Keywords: Anther, broccoli, doubled haploid, microspore, plant regeneratio