Objective: Arterial remodeling is associated with vascular function alteration and with hypertension development. This remodeling is due to cells reorganization within the vascular wall and in some ...cases to smooth muscle cells proliferation. PDGF (Platelet-derived Growth Factor) is a major regulator of arterial remodeling and some studies suggest that PDGFRα, one of its receptors, could be activated during hypertension. Our aim is to determine the role of PDGFRα and of PDGFRα-expressing progenitor cells in vascular remodeling. Design and method: We used a tamoxifen-inducible genetic mouse model of PDGFRα constitutive activation. Blood pressure was measured by the tail-cuff method and by carotid catheter. Small mesenteric arteries reactivity was studied using ex vivo arteriography. Vascular remodeling was analyzed by immunofluorescence. Results: PDGFRα constitutive activation for 6 weeks led to a 25% increase in blood pressure (p<0.05) and a 25% decrease in cardiac output in male mice (p<0.05), without changes in other cardiac parameters. In these mice, small mesenteric arteries showed no alteration in contractility or endothelium-dependent and independent relaxation but an increase of media thickness, whereas larger vessels did not show structure or function alteration. Echo-doppler analyses showed an increased resistivity index of the renal artery (+13% p<0.05) but not of the aorta suggesting an increased resistance of small renal arteries. The remodeling of small mesenteric arteries was characterized by an early proliferation of perivascular cells at 4 days but not of medial cells followed by the production of new smooth muscle cells after 2 weeks. Female mice did not show blood pressure increase following induction of PDGFRα constitutive activation for 6 weeks. Small mesenteric arteries showed a reduced contractility with alteration of endothelium-dependent and independent relaxation. Conclusions: These results suggest that PDGFRα activation could participate in arterial hypertension development by leading to increased media thickness and stiffness in small arteries in males. Our results suggest that in females the increased resistance of small vessels is compensated by a decreased contractility.
The term clustering designates a comprehensive family of unsupervised learning methods allowing to group similar elements into sets called clusters. Geometrical clustering of molecular dynamics (MD) ...trajectories is a well-established analysis to gain insights into the conformational behavior of simulated systems. However, popular variants collapse when processing relatively long trajectories because of their quadratic memory or time complexity. From the arsenal of clustering algorithms, HDBSCAN stands out as a hierarchical density-based alternative that provides robust differentiation of intimately related elements from noise data. Although a very efficient implementation of this algorithm is available for programming-skilled users (HDBSCAN*), it cannot treat long trajectories under the de facto molecular similarity metric RMSD.
Here, we propose MDSCAN, an HDBSCAN-inspired software specifically conceived for non-programmers users to perform memory-efficient RMSD-based clustering of long MD trajectories. Methodological improvements over the original version include the encoding of trajectories as a particular class of vantage-point tree (decreasing time complexity), and a dual-heap approach to construct a quasi-minimum spanning tree (reducing memory complexity). MDSCAN was able to process a trajectory of 1 million frames using the RMSD metric in about 21 h with <8 GB of RAM, a task that would have taken a similar time but more than 32 TB of RAM with the accelerated HDBSCAN* implementation generally used.
The source code and documentation of MDSCAN are free and publicly available on GitHub (https://github.com/LQCT/MDScan.git) and as a PyPI package (https://pypi.org/project/mdscan/).
Supplementary data are available at Bioinformatics online.
Large studies on severe imported malaria in non-endemic industrialized countries are lacking. We sought to describe the clinical spectrum of severe imported malaria in French adults and to identify ...risk factors for mortality at admission to the intensive care unit.
Retrospective review of severe Plasmodium falciparum malaria episodes according to the 2000 World Health Organization definition and requiring admission to the intensive care unit. Data were collected from medical charts using standardised case-report forms, in 45 French intensive care units in 2000-2006. Risk factors for in-hospital mortality were identified by univariate and multivariate analyses. Data from 400 adults admitted to the intensive care unit were analysed, representing the largest series of severe imported malaria to date. Median age was 45 years; 60% of patients were white, 96% acquired the disease in sub-Saharan Africa, and 65% had not taken antimalarial chemoprophylaxis. Curative quinine treatment was used in 97% of patients. Intensive care unit mortality was 10.5% (42 deaths). By multivariate analysis, three variables at intensive care unit admission were independently associated with hospital death: older age (per 10-year increment, odds ratio OR, 1.72; 95% confidence interval 95%CI, 1.28-2.32; P = 0.0004), Glasgow Coma Scale score (per 1-point decrease, OR, 1.32; 95%CI, 1.20-1.45; P<0.0001), and higher parasitemia (per 5% increment, OR, 1.41; 95%CI, 1.22-1.62; P<0.0001).
In a large population of adults treated in a non-endemic industrialized country, severe malaria still carried a high mortality rate. Our data, including predictors of death, can probably be generalized to other non-endemic countries where high-quality healthcare is available.
Pharmacokinetic analyses of clopidogrel are hampered by the existence of multiple active metabolite isomers (H1 to H4) and their instability in blood. We sought to retest the pharmacodynamic ...activities of the four individual active metabolite isomers in vitro, with the ultimate aim of determining the isomers responsible for clopidogrel activity in vivo. In vitro activity was evaluated by measuring binding of 33P-2-methylthio-ADP on P2Y12-expressing Chinese hamster ovary (CHO) cells and human platelets in platelet-rich plasma (PRP). A stereoselective method that used reverse-phase ultra high-performance liquid chromatography (UHPLC) and tandem mass spectrometry (MS) was developed to measure individual concentrations of the stable 3’-methoxyacetophenone (MP) derivatives of H1–H4. The new method was used to analyze plasma samples from clopidogrel-treated subjects enrolled in a phase I clinical trial. In vitro binding assays confirmed the previously observed biological activity of H4 (IC50: CHO-P2Y12: 0.12μM; PRP: 0.97μM) and inactivity of H3, and demonstrated that H1 was also inactive. Furthermore, H2 demonstrated approximately half of the biological activity in vitro compared with H4. Optimisation of UHPLC conditions and MS collision parameters allowed the resolution and detection of the four derivatised active metabolite isomers (MP-H1 to MP-H4). The stereoselective assay was extensively validated, and was accurate and precise over the concentration range 0.5–250 ng/ml. Only MP-H3 and MP-H4 were quantifiable in incurred clinical samples. Based on in vitro pharmacodynamic data and found concentrations, the active metabolite isomer H4 is the only diastereoisomer of clinical relevance for documenting the pharmacokinetic profile of the active metabolite of clopidogrel.
Hard magnetic films with precisely tuned switching fields are of great interest for advanced magnetic microsystems. Here, we report on the specific evolution of semi-hard magnetic properties of ...Formula Omitted-FePt films integrating a graded concentration of soft cobalt nanomagnets. These nanocomposites are prepared by the combination of mass selected cluster beam deposition (MS-LECBD) and e-beam evaporation techniques where 8 nm Co nanoparticles (Co-NPs) are embedded with various Formula Omitted atomic concentration up to 50%, into Fe/Pt multilayers. Subsequent annealing allows us to reach the alloy chemical order for the FePt matrix by conserving Co-rich nanometer-sized inclusions. The focus is put on the interplay between the local microstructure and the coercive magnetic field through a combinatorial approach that involves local determinations of composition, magnetization reversal from scanning magneto-optical Kerr effect (MOKE), and element-specific spin and orbital magnetic moments from X-ray magnetic circular dichroism (XMCD) performed at the Co and Fe L-edges of absorption. We show how the nanostructuration changes the magnetic coercivity, and how both Co and Fe effective magnetic spin moments evolve with the composition of the nanocomposite film.
Anticipating the time to renal replacement therapy (RRT) in chronic kidney disease (CKD) patients is an important but challenging issue. Natriuretic peptides are biomarkers of ventricular dysfunction ...related to poor outcome in CKD. We comparatively investigated the value of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) as prognostic markers for the risk of RRT in stage 4 and 5 CKD patients, and in foretelling all-cause mortality and major cardiovascular events within a 5-year follow-up period.
Baseline plasma BNP (Triage, Biosite) and NT-proBNP (Elecsys, Roche) were measured at inclusion. Forty-three patients were followed-up during 5 years. Kaplan-Meier analysis, with log-rank testing and hazard ratios (HR), were calculated to evaluate survival without RRT, cardiovascular events or mortality. The independent prognostic value of the biomarkers was estimated in separate Cox multivariate analysis, including estimated glomerular filtration rate (eGFR), creatininemia and comorbidities.
During the first 12-month follow-up period, 16 patients started RRT. NT-proBNP concentration was higher in patients who reached endpoint (3221 ng/L vs 777 ng/L, p = 0.02). NT-proBNP concentration > 1345 ng/L proved significant predictive value on survival analysis for cardiovascular events (p = 0.04) and dialysis within 60 months follow-up (p = 0.008). BNP concentration > 140 ng/L was an independent predictor of RRT after 12 months follow-up (p<0.005), and of significant predictive value for initiation of dialysis within 60 months follow-up.
Our results indicate a prognostic value for BNP and NT-proBNP in predicting RRT in stage 4 and 5 CKD patients, regarding both short- and long-term periods. NT-proBNP also proved a value in predicting cardiovascular events. Natriuretic peptides could be useful predictive biomarkers for therapeutic guidance in CKD.
Computational fragment-based approaches are widely used in drug design and discovery. One of their limitations is the lack of performance of docking methods, mainly the scoring functions. With the ...emergence of fragment-based approaches for single-stranded RNA ligands, we analyze the performance in docking and screening powers of an MCSS-based approach. The performance is evaluated on a benchmark of protein-nucleotide complexes where the four RNA residues are used as fragments. The screening power can be considered the major limiting factor for the fragment-based modeling or design of sequence-selective oligonucleotides. We show that the MCSS sampling is efficient even for such large and flexible fragments. Hybrid solvent models based on some partial explicit representation improve both the docking and screening powers. Clustering of the {\it n} best-ranked poses can also contribute to a lesser extent to better performance. A detailed analysis of molecular features suggests various ways to optimize the performance further.
Abstract
Motivation
Classical Molecular Dynamics (MD) is a standard computational approach to model time-dependent processes at the atomic level. The inherent sparsity of increasingly huge generated ...trajectories demands clustering algorithms to reduce other post-simulation analysis complexity. The Quality Threshold (QT) variant is an appealing one from the vast number of available clustering methods. It guarantees that all members of a particular cluster will maintain a collective similarity established by a user-defined threshold. Unfortunately, its high computational cost for processing big data limits its application in the molecular simulation field.
Results
In this work, we propose a methodological parallel between QT clustering and another well-known algorithm in the field of Graph Theory, the Maximum Clique Problem. Molecular trajectories are represented as graphs whose nodes designate conformations, while unweighted edges indicate mutual similarity between nodes. The use of a binary-encoded RMSD matrix coupled to the exploitation of bitwise operations to extract clusters significantly contributes to reaching a very affordable algorithm compared to the few implementations of QT for MD available in the literature. Our alternative provides results in good agreement with the exact one while strictly preserving the collective similarity of clusters.
Availability and implementation
The source code and documentation of BitQT are free and publicly available on GitHub (https://github.com/LQCT/BitQT.git) and ReadTheDocs (https://bitqt.readthedocs.io/en/latest/), respectively.
Supplementary information
Supplementary data are available at Bioinformatics online.
Current guidelines for patients presenting to the emergency department (ED) with chest pain without ST-segment elevation myocardial infarction (STEMI) on ECG are based on serial troponin ...measurements. A clinical tool able to identify very low-risk patients who could forgo a troponin test and low-risk patients requiring only one troponin measurement would be of great interest. To do so, the HEAR and HEART score, standing for history, ECG, age, risk factors±troponin were prospectively assessed, but not combined and implemented in clinical practice. The objective of the eCARE study is to assess the impact of implementing a diagnostic strategy based on a HEAR score <2 or a HEART score <4 (HEAR-T strategy) to rule out non-STEMI without or with a single troponin measurement in patients presenting to the ED with chest pain without obvious diagnosis after physical examination and an ECG.
Stepped-wedge cluster-randomised control trial in 10 EDs. Patients with non-traumatic chest pain and no formal diagnosis were included and followed for 30 days. In the interventional phase, the doctor will be asked not to perform a troponin test to look for an acute coronary if the HEAR score is <2 and not to perform an additional troponin test if the HEAR score is ≥2 and HEART score is <4. The main endpoint is the non-inferiority of the rates of major adverse cardiac events occurring between a patient's discharge and the 30-day follow-up against current recommended guidelines.
The study was approved by an institutional review board for all participating centres. If successful, the eCARE study will cover a gap in the evidence, proving that it is safe and efficient to rule out the hypothesis of an acute myocardial infarction in some selected very low-risk patients or based on a single troponin measurement in some low-risk patients.
NCT04157790.
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