ThermoScan: Semi-automatic Identification of Protein Stability Data From PubMed

open3noThis work was supported by the PRIN project, “Integrative tools for defining the molecular basis of the diseases: Computational and Experimental methods for Protein Variant Interpretation” of the Ministero Istruzione, Università e Ricerca (201744NR8S).During the last years, the increasing number of DNA sequencing and protein mutagenesis studies has generated a large amount of variation data published in the biomedical literature. The collection of such data has been essential for the development and assessment of tools predicting the impact of protein variants at functional and structural levels. Nevertheless, the collection of manually curated data from literature is a highly time consuming and costly process that requires domain experts. In particular, the development of methods for predicting the effect of amino acid variants on protein stability relies on the thermodynamic data extracted from literature. In the past, such data were deposited in the ProTherm database, which however is no longer maintained since 2013. For facilitating the collection of protein thermodynamic data from literature, we developed the semi-automatic tool ThermoScan. ThermoScan is a text mining approach for the identification of relevant thermodynamic data on protein stability from full-text articles. The method relies on a regular expression searching for groups of words, including the most common conceptual words appearing in experimental studies on protein stability, several thermodynamic variables, and their units of measure. ThermoScan analyzes full-text articles from the PubMed Central Open Access subset and calculates an empiric score that allows the identification of manuscripts reporting thermodynamic data on protein stability. The method was optimized on a set of publications included in the ProTherm database, and tested on a new curated set of articles, manually selected for presence of thermodynamic data. The results show that ThermoScan returns accurate predictions and outperforms recently developed text-mining algorithms based on the analysis of publication abstracts. Availability: The ThermoScan server is freely accessible online at https://folding.biofold.org/thermoscan. The ThermoScan python code and the Google Chrome extension for submitting visualized PMC web pages to the ThermoScan server are available at https://github.com/biofold/ThermoScan.openTurina P.; Fariselli P.; Capriotti E.Turina P.; Fariselli P.; Capriotti E

Myocardial function and structure in aortic valve disease before and after surgery

Left ventricular (LV) micromanometry, cine-angiography and endomyocardial biopsies were performed in 13 patients with aortic valve disease {AVD) before and 12 to 28 months after successful valve replacement. (AVR). Patients with coronary artery disease were excluded. In nine patients (Group I: five AS, four AI) postoperative LV ejection fraction (EF) and total pressure Vmax were normal(EF ≥ 0.61; Vmax ≥ 1.50 ML/s). In four patients (Group II: three AS, one AT) postoperative EF (0.41) and Vmax (1.21 ML/s) were depressed. Pre-operative muscle fiber diameter (MFD; normal < 20 n) was 31 μ in Group I and 38 μ in Group II (P < 0.01). After AVR MFD decreased to 27 μ in Group I (P < 0.005) and to 28 μ in Group II (P < 0.02). Prior to surgery EF and Vmax showed no significant correlation with the LV fibrous content (FC in g/m2; FC = interstitial fibrosis in percent × LV angiographic muscle mass/100) in the 13 patients with AVD. After AVR, however, FC was related inversely to EF (P < 0.01, r = −0.69) and to Vmax (P < 0.025, r = −0.63). It is concluded that: (1) in AVD massive pre-operative fiber hypertrophy heralds impaired postoperative LV function; (2) fiber hypertrophy regresses following AVR regardless of the-LV functional state, and (3) the content of fibrous tissue appears to be a determinant of postoperative LV functio

Spontaneous course of aortic valve disease

The fate of patients with aortic valve disease of varying degrees of severity and the relationship between symptoms and haemodynamic status have been studied in 190 adults undergoing cardiac catheterization during the last two decades. During the follow-up period, 41 patients died and 86 underwent aortic valve replacement; these two events were the endpointsfor the calculation of ‘event-free' cumulative survival. First-year survival in haemodynamically severe disease was 60% in aortic stenosis and 96% in aortic regurgitation; in moderate and mild disease (in the absence of coronary artery disease) first-year survival was 100% in both groups. After 10 years, 9% of those with haemodynamically severe aortic stenosis and 17% of those with severe regurgitation were event-free, in contrast to 35% and 22%, respectively, of those with moderate changes and 85% and 75%, respectively, of those with mild abnormalities. In the presence of haemodynamically severe disease, 66% of the patients with stenosis and 14% of those with regurgitation were severely symptomatic (history of hear (failure, syncope or New York Heart Association class HI and IV); 23% of patients with moderate stenosis and 14% with moderate regurgitation were also severely symptomatic. Only 40% of those with disease that was severe both haemodynamically and symptomatically with either stenosis or regurgitation survived the first two years; only 12% in the stenosis group and none in the regurgitation group were event-free at 5 years. Patients with haemodynamically severe aortic stenosis who had few or no symptoms had a 100% survival at 2 years; the comparable figure for the aortic regurgitation group was 94%; 75% of the patients in the stenosis group and 65% in the regurgitation group were event-free at 5 years. In the moderate or mild stenosis and regurgitation groups there was no mortality within the first 2 years in the absence of coronary artery disease, regardless of symptomatic status. Haemodynamically and symptomatically severe aortic stenosis and regurgitation have a very poor prognosis and require immediate valve surgery. Asymptomatic and mildly symptomatic patients with haemodynamically severe aortic stenosis are at low risk and surgical treatment can be postponed until marked symptoms appear without a significant risk of sudden death. In severe aortic regurgitation, the decision for surgery should depend not only on symptoms but should be considered in patients with few or no symptoms because of risk of sudden death. In the absence of coronary artery disease, moderate aortic valve disease does not require valve operation for prognostic reason

Physiologic or pathologic hypertrophy

Physiologic hypertrophy occurs as the result of exercise conditioning and is characterized by normal or supranormal left ventricular (LV) contractile function and reversibility of structural alterations. Whether hypertrophy produced by chronic abnormal loading can be termed ‘physiologic' is a matter of debate because in experimental pressure overload hypertrophy normal in vivo ventricular function may be associated with abnormal in vitro function of the papillary muscles. In patients with moderate LV hypertrophy from aortic valve disease (angiographic mass 20 mm Hg and/or cardiac index 2·5 l/mm/m2)interstitial fibrosis (IF) was increased to a similar extent (16 and 18%: normal <5%), whereas muscle fiber diameter (MFD normal ≤ 20 μ) was larger (P <0·05) in the patients with failure (30 μ) than in those with preserved function (27 μ). Moreover patients with depressed postoperative function had a larger (P < 001) preoperative MFD (35 μ) than those with normal postoperative function (30 μ). Seventeen months after successful aortic valve replacement IF increased (P < 0·02) and MFD decreased (P < 0·001) but did not become normal regardless whether postoperative function was normal or depressed. Thus in secondary hypertrophy myocardial structure is pathologic even in the presence of normal LV function and depressed function appears likely to be related to excessive fiber hypertrophy rather than to IF. Massive fiber hypertrophy heralds an unfavorable postoperative LV function and fibrosis is irreversible after surgical correction of the abnormal loa

Limitations and challenges in protein stability prediction upon genome variations: towards future applications in precision medicine

Protein stability predictions are becoming essential in medicine to develop novel immunotherapeutic agents and for drug discovery. Despite the large number of computational approaches for predicting the protein stability upon mutation, there are still critical unsolved problems: 1) the limited number of thermodynamic measurements for proteins provided by current databases; 2) the large intrinsic variability of \u394\u394G values due to different experimental conditions; 3) biases in the development of predictive methods caused by ignoring the anti-symmetry of \u394\u394G values between mutant and native protein forms; 4) over-optimistic prediction performance, due to sequence similarity between proteins used in training and test datasets. Here, we review these issues, highlighting new challenges required to improve current tools and to achieve more reliable predictions. In addition, we provide a perspective of how these methods will be beneficial for designing novel precision medicine approaches for several genetic disorders caused by mutations, such as cancer and neurodegenerative diseases

Left ventricular assist device (LVAD) enables survival during 7 h of sustained ventricular fibrillation

We describe the case of a patient implanted with a DeBakey left ventricular assist device (LVAD) as bridge to transplant who survived 7 h of ventricular fibrillation. He was successfully converted into a stable sinus rhyth

Left ventricular relaxation at rest and during handgrip in aortic valve disease before and after valve replacement

In 14 patients (pts) with aortic valve disease (A VD) left ventricular (LV) relaxation was assessed by the time constant (T) of LV pressure (tipmanometer) fall before and 19 months after successful aortic valve replacement (A VR). 12 control pts (CO) were studied by the same technique. Preoperative LV ejection fraction in AVD (64%) and in CO (69%) did not differ. In AVD T was increased (60 ms) as compared to the CO (38 ms, P< 0.05). During handgrip (HG) there was a similar increase of LV peak systolic pressure (LVSP), heart rate and peak measured contractile element velocity of shortening in A VD and in the CO. L V end-diastolic pressure varied minimally in both groups. T decreased during handgrip in CO (38 to 33 ms, P<0.01) and remained unchanged in A VD. Following AVR T at rest decreased insignificantly to 52 ms, but remained increased (P<0.025) as compared with CO. During postoperative HG however, a decrease to 47ms (P<0.05) was noted. Postoperative angiographic LV muscle mass (105 g/m2) and LVSP at rest (137 mmHg) remained elevated (P<0.02) as compared to CO (72 g/m2; 119 mmHg). It is concluded that (1) in A VD with normal ejection performance L V relaxation at rest is prolonged and the reaction of relaxation to HG is abnormal despite preserved contractile response, (2) following A VR the response of LV relaxation to HG becomes normal and (3) elevated postoperative T at rest appears to be related to residual hypertrophy and probably also to the still increased LVSP rather than to intrinsic disturbances of myocardial relaxatio

Echocardiographic findings late after myectomy in hypertrophic obstructive cardiomyopathy

Postoperative echocardiograms of 50 patients undergoing myectomy for hypertrophic obstructive cardiomyopathy between 1965 and 1982 have been evaluated. In 21 patients a comparison with preoperative echocardiograms showed that postoperatively there was a significant reduction of septal and free wall thickness, an increase of left ventricular end-diastolic as well as outflow tract dimensions and a reduction or disappearance of systolic anterior motion of the mitral leaflet. Postoperative examination at intervals > 3 years revealed a significant increase of left ventricular and left atrial cavity size with unchanged contractile parameters and little reduction of left ventricular hypertrophy. In 4of 12 patients evaluated > 8 years after myectomy, left ventricular dilatation was observed and 3 of these 4 patients developed congestive heart failure. Development of leftventricular dilatation was independent of whether a transventricular and/or transaortic approach was used for myectomy. These data indicate that the late course after myectomy in hypertrophic obstructive cardiomyopathy may be complicated by dilatation of the left ventricular cavit