Network theory approach for data evaluation in the dynamic force spectroscopy of biomolecular interactions

Investigations of molecular bonds between single molecules and molecular complexes by the dynamic force spectroscopy are subject to large fluctuations at nanoscale and possible other aspecific binding, which mask the experimental output. Big efforts are devoted to develop methods for effective selection of the relevant experimental data, before taking the quantitative analysis of bond parameters. Here we present a methodology which is based on the application of graph theory. The force-distance curves corresponding to repeated pulling events are mapped onto their correlation network (mathematical graph). On these graphs the groups of similar curves appear as topological modules, which are identified using the spectral analysis of graphs. We demonstrate the approach by analyzing a large ensemble of the force-distance curves measured on: ssDNA-ssDNA, peptide-RNA (system from HIV1), and peptide-Au surface. Within our data sets the methodology systematically separates subgroups of curves which are related to different intermolecular interactions and to spatial arrangements in which the molecules are brought together and/or pulling speeds. This demonstrates the sensitivity of the method to the spatial degrees of freedom, suggesting potential applications in the case of large molecular complexes and situations with multiple binding sites

Management of preterm labor: atosiban or nifedipine?

Preterm birth is strongly associated with neonatal death and long-term neurological morbidity. The purpose of tocolytic drug administration is to postpone threatening preterm delivery for 48 hours to allow maximal effect of antenatal corticosteroids and maternal transportation to a center with specialized neonatal care facilities. There is uncertainty about the value of atosiban (oxytocin receptor antagonist) and nifedipine (calcium channel blocker) as first-line tocolytic drugs in the management of preterm labor. For nifedipine, concerns have been raised about unproven safety, lack of placebo-controlled trials, and its off-label use. The tocolytic efficacy of atosiban has also been questioned because of a lack of reduction in neonatal morbidity. This review discusses the available evidence, the pros and cons of either drug and aims to provide information to support a balanced choice of first-line tocolytic drug: atosiban or nifedipine

Pulmonary involvement in primary Sjogren's syndrome, as measured by the ESSDAI

Objective: Systemic features influence disease prognosis and choice of treatment in primary Sjogren's syndrome (pSS). Our aim was to investigate the prevalence of pulmonary involvement in pSS patients and to classify patients according to the pulmonary domain of the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI). Methods: This retrospective cohort study included consecutive pSS patients, fulfilling American-European Consensus Group/American College of Rheumatology classification criteria, who visited the Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, in 2015. Data on pulmonary complaints and pulmonary tests were obtained from electronic patient records. Pulmonary involvement was recorded if therapy was needed or follow-up was recommended, and when it was possibly or assumed to be related to pSS instead of coincidental factors. Results: Of the 262 included pSS patients, 88 (34%) had pulmonary complaints, mostly cough or dyspnoea on exertion. Pulmonary diagnostics were performed in 225 patients (86%). Pulmonary involvement was present and assumed to be related to pSS in 25 patients (10%) and possibly related to pSS in 14 (5%). Interstitial lung disease (ILD, n = 15), especially non-specific interstitial pneumonia (n = 7), was present most commonly. In total, 16 patients (6%) were scored as low (n = 4), moderate (n = 11), or high activity (n = 1) on the ESSDAI pulmonary domain. Conclusion: In this cross-sectional study in daily clinical practice, pulmonary involvement was present in 10-15% of pSS patients, of which ILD was most common. Of all pSS patients, 6% were scored as active on the pulmonary domain of the ESSDAI

Observational Validation of The Compensating Mass Flux Through The Shell Around Cumulus Clouds

The existence of a subsiding shell around cumulus clouds has been observed before in several aircraft measurement campaigns. Recent results from large-eddy simulations (LES) showed that the downward mass flux through the shell compensates for a significant fraction of the upward mass flux through the cloud. In this study, aeroplane measurements from the Rain In Cumulus over the Ocean (RICO) field campaign are used to verify the existence of this compensating mass flux. Just as in the LES results, the in-shell downward mass flux is found to be significant. However, a few differences were found in comparison with the LES results; most of them were explained by taking into account the difference between the two-dimensional slabs in LES and the one-dimensional lines from aeroplane observations

A Statistical Approach to The Life Cycle Analysis of Cumulus Clouds Selected in A Virtual Reality Environment

In this study, a new method is developed to investigate the entire life cycle of shallow cumuli in large eddy simulations. Although trained observers have no problem in distinguishing the different life stages of a cloud, this process proves difficult to automate, because cloud-splitting and cloud-merging events complicate the distinction between a single system divided in several cloudy parts and two independent systems that collided. Because the human perception is well equipped to capture and to make sense of these time-dependent three-dimensional features, a combination of automated constraints and human inspection in a three-dimensional virtual reality environment is used to select clouds that are exemplary in their behavior throughout their entire life span. Three specific cases (ARM, BOMEX, and BOMEX without large-scale forcings) are analyzed in this way, and the considerable number of selected clouds warrants reliable statistics of cloud properties conditioned on the phase in their life cycle. The most dominant feature in this statistical life cycle analysis is the pulsating growth that is present throughout the entire lifetime of the cloud, independent of the case and of the large-scale forcings. The pulses are a self-sustained phenomenon, driven by a balance between buoyancy and horizontal convergence of dry air. The convective inhibition just above the cloud base plays a crucial role as a barrier for the cloud to overcome in its infancy stage, and as a buffer region later on, ensuring a steady supply of buoyancy into the cloud

Improving Breast Cancer Treatment Specificity Using Aptamers Obtained by 3D Cell-SELEX

Three-dimensional spheroids of non-malignant MCF10A and malignant SKBR3 breast cells were used for subsequent 3D Cell-SELEX to generate aptamers for specific binding and treatment of breast cancer cells. Using 3D Cell-SELEX combined with Next-Generation Sequencing and bioinformatics, ten abundant aptamer families with specific structures were identified that selectively bind to SKBR3, and not to MCF10A cells. Multivalent aptamer polymers were synthesized by co-polymerization and analyzed for binding performance as well as therapeutic efficacy. Binding performance was determined by confocal fluorescence imaging and revealed specific binding and efficient internalization of aptamer polymers into SKBR3 spheroids. For therapeutic purposes, DNA sequences that intercalate the cytotoxic drug doxorubicin were co-polymerized into the aptamer polymers. Viability tests show that the drug-loaded polymers are specific and effective in killing SKBR3 breast cancer cells. Thus, the 3D-selected aptamers enhanced the specificity of doxorubicin against malignant over non-malignant breast cells. The innovative modular DNA aptamer platform based on 3D Cell SELEX and polymer multivalency holds great promise for diagnostics and treatment of breast cancer

The methodological quality of 176,620 randomized controlled trials published between 1966 and 2018 reveals a positive trend but also an urgent need for improvement

Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. There is increasing attention for responsible research practices and implementation of reporting guidelines, but whether these efforts have improved the methodological quality of RCTs (e.g., lower risk of bias) is unknown. We, therefore, mapped risk-of-bias trends over time in RCT publications in relation to journal and author characteristics. Meta-information of 176,620 RCTs published between 1966 and 2018 was extracted. The risk-of-bias probability (random sequence generation, allocation concealment, blinding of patients/personnel, and blinding of outcome assessment) was assessed using a risk-of-bias machine learning tool. This tool was simultaneously validated using 63,327 human risk-of-bias assessments obtained from 17,394 RCTs evaluated in the Cochrane Database of Systematic Reviews (CDSR). Moreover, RCT registration and CONSORT Statement reporting were assessed using automated searches. Publication characteristics included the number of authors, journal impact factor (JIF), and medical discipline. The annual number of published RCTs substantially increased over 4 decades, accompanied by increases in authors (5.2 to 7.8) and institutions (2.9 to 4.8). The risk of bias remained present in most RCTs but decreased over time for allocation concealment (63% to 51%), random sequence generation (57% to 36%), and blinding of outcome assessment (58% to 52%). Trial registration (37% to 47%) and the use of the CONSORT Statement (1% to 20%) also rapidly increased. In journals with a higher impact factor (>10), the risk of bias was consistently lower with higher levels of RCT registration and the use of the CONSORT Statement. Automated risk-of-bias predictions had accuracies above 70% for allocation concealment (70.7%), random sequence generation (72.1%), and blinding of patients/personnel (79.8%), but not for blinding of outcome assessment (62.7%). In conclusion, the likelihood of bias in RCTs has generally decreased over the last decades. This optimistic trend may be driven by increased knowledge augmented by mandatory trial registration and more stringent reporting guidelines and journal requirements. Nevertheless, relatively high probabilities of bias remain, particularly in journals with lower impact factors. This emphasizes that further improvement of RCT registration, conduct, and reporting is still urgently needed

Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study

Objective To evaluate the incidence of serious maternal complications after the use of various tocolytic drugs for the treatment of preterm labour in routine clinical situations